Blood Pressure Control InType 2 Diabetes

National Evidence Based Guidelines
for the
Management of Type 2 Diabetes Mellitus
Part 4
Blood Pressure Control inType 2 Diabetes
Prepared by
the Australian Centre for Diabetes Strategies
Prince of Wales Hospital, Sydney
for the Diabetes Australia Guideline Development Consortium
APPROVED BY THE NHMRC 18 MARCH 2004

Table of Contents
PART 4
1.0 Blood Pressure Control Expert Working Group .................................................. 3
2.0 Guideline for Blood Pressure Control in Type 2 Diabetes ................................... 5

2.1 Introduction................................................................................................................ 5
2.2 Issues for Blood Pressure Control in Type 2 Diabetes .............................................. 7
2.3 Summary of Recommendations................................................................................. 8
2.4 Overview of Blood Pressure Control in Type 2 Diabetes ....................................... 10
2.5 Recommendations.................................................................................................... 11
Section 1: The target blood pressure in Type 2 diabetes...................................... 11
Section 2: How to measure blood pressure ................................................. 23
Section 3: How often should blood pressure be measured................................... 30
Section 4: Role of ambulatory blood pressure measurement ............................... 34
Section 5: Blood pressure control in Type 2 diabetes .......................................... 40
Section 6: Effect of treatment of blood pressure.................................................. 65
Section 7: Synergy of interventions ..................................................................... 71
Section 8: Influence on metabolic control............................................................ 77
Section 9: Costs/Benefits...................................................................................... 83
References ............................................................................................................. 87
Evidence References ...................................................................................... 87
General References......................................................................................... 95
Other References Identified............................................................................ 98
2.6 Blood Pressure Control Search Strategy and Yield Table ..................................... 106
1.0 Blood Pressure Control Expert Working Group
Chairperson Professor George Jerums
Endocrine Unit
Austin & Repatriation Medical Centre
MELBOURNE VIC
Content Experts Professor Mark Cooper

Department of Medicine
University of Melbourne
MELBOURNE VIC
A/Professor Richard Gilbert

MELBOURNE VIC
Professor Stephen MacMahon

Institute for Intnl Health Research and Development
University of Sydney
SYDNEY NSW
A/Professor Leon Bach

MELBOURNE VIC
Dr Chris O'Callaghan
Clinical Pharmacology Therapeutics Unit
MELBOURNE VIC
Dr Christine Houlihan
MELBOURNE VIC
ADEA Ms Gloria Kilmartin

Department of Diabetes & Endocrinology
Royal Melbourne Hospital
MELBOURNE VIC
Consumer Mr Bruce Wainwright

HAWTHORN VIC
RACGP Dr David Mills

PORT LINCOLN SA
Australian Kidney Foundation Dr Margaret Fraenkel

Australian Kidney Foundation
MELBOURNE VIC
Content and Methods Adviser Professor Stephen Colagiuri

Department of Endocrinology
Prince of Wales Hospital
Research Officers Dr Sianna Panagiotopoulos
3
Austin Hospital Medical Research Foundation
MELBOURNE VIC
Ms Trudy Smith
Endocrine Unit
MELBOURNE VIC
4
2.0 Guideline for Blood Pressure Control in Type 2
Diabetes
2.1 Introduction
Aim of the guideline
This guideline covers issues relating to how an above target blood pressure should be defined,
measured and managed in individuals with Type 2 diabetes. Its aim is to inform all categories
of clinicians, of the problems associated with Type 2 diabetes and elevated blood pressure and
to specifically target GPs with this information.
Quality Assurance
In addition to the methods used to identify and critically appraise the evidence to formulate
the guideline recommendations which are described in detail in Part 1 of the document, the
Project Management Team reviewed and checked each step of the methods process and:
repeated a selection of the searches
double culled the yield from a selection of the database searches
double reviewed all articles used as evidence references
checked all recommendations, evidence statements, evidence tables and search strategy
and yield tables
As a further quality measure the entire final draft was reviewed by the Medical Advisor.
Guideline Format
Issues identified by the EWG and from the literature as critical to the impact of blood pressure
control in Type 2 diabetes are shown in point 4.1.2 (next page).
Each of these issues is addressed in a separate section in a format presenting:

Recommendation(s)
Evidence Statements - supporting the recommendations
Background - to issues for the guideline
Evidence - detailing and interpreting the key findings
Summary - of major evidence found
Evidence tables - summarising the evidence ratings for the articles reviewed
For all issues combined, supporting material appears at the end of the guideline and includes:
Evidence references
General references
Other references identified
Search Strategy and Yield Tables documenting the identification of the evidence sources
5
The prevention of macrovascular disease is a major goal in the
care of the person with Type 2 diabetes.
Multifactorial intervention is the key to the prevention of

macrovascular disease.
This document should be considered in association with the

Macrovascular Disease, Lipid Control and Blood Glucose
Control Guidelines
6
2.2 Issues for Blood Pressure Control in Type 2 Diabetes
What is the target blood pressure in Type 2 diabetes?
How should blood pressure be measured?
How often should blood pressure be measured?
What is the role of ambulatory blood pressure monitoring in blood pressure control?
How should blood pressure be controlled in Type 2 diabetes?
What is the effect of treatment of blood pressure in Type 2 diabetes?
Is there synergy in the effects of simultaneous intervention to control blood pressure,

blood glucose and lipids?
Do blood pressure lowering medications affect metabolic control?
What are the costs/benefits of intensive blood pressure control?
7
2.3 Summary of Recommendations
Recommendations
In Type 2 diabetes, the target blood pressure should be:
below 130/80 mmHg or
below 125/75 mmHg in people with proteinuria exceeding 1 g/day
Measurement of blood pressure should be performed with attention to appropriate rest

period (at least 5 minutes), posture (usually sitting), and cuff size (large size preferred for
all adults)
Systolic blood pressure should be recorded as the first appearance of Korotkoff sounds
and diastolic blood pressure as the disappearance of Korotkoff sounds
A mercury sphygmomanometer is preferred, but a regularly calibrated aneroid

manometer or a validated electronic device can be used
Standing and supine blood pressure measurements are recommended if autonomic

neuropathy is suspected
Blood pressure should be measured at every clinic visit, or at least every 6 months, in
people with Type 2 diabetes
Blood pressure should be measured at least every 3 months in people with Type 2
diabetes taking blood pressure lowering medications
During titration of antihypertensive therapy, blood pressure should be measured more

frequently (every 4 to 8 weeks) until optimal levels are achieved
24 h ambulatory blood pressure monitoring should be considered in people with Type 2

diabetes and suspected office (white coat) hypertension or who are resistant to blood
pressure lowering therapy
8
Modification of factors which contribute to increasing blood pressure (obesity, physical
inactivity, excessive dietary sodium and/or alcohol intake) should be emphasised in all
people with Type 2 diabetes with blood pressure above target
In people with Type 2 diabetes and blood pressure above target, angiotensin converting
enzyme inhibitors, angiotensin receptor blockers, -blockers and diuretics can be used as
initial therapy
Angiotensin receptor blockers and angiotensin converting enzyme inhibitors should be

used to treat people with diabetic nephropathy
Combinations of antihypertensive agents should always be considered when treating

blood pressure in people with Type 2 diabetes
lood pressure in people with Type 2 diabetes should be intensively treated in order to
prevent or attenuate macrovascular and microvascular complications
Concurrent control of blood glucose, blood pressure and lipids is recommended in people
with Type 2 diabetes
Despite the potential for adverse effects on metabolic control, the full range of blood
pressure lowering medications should be considered when selecting treatment for blood
pressure in people with Type 2 diabetes
Intensive control of blood pressure is recommended in people with Type 2 diabetes

because the benefits of therapy outweigh the costs of vascular complications
9
2.4 Overview of Blood Pressure Control in Type 2 Diabetes
Elevated blood pressure is 1.5-2 times more prevalent in people with diabetes than it is in the
general population and most elderly people with Type 2 diabetes require blood pressure
lowering therapy (Drury, 1988). In people with Type 2 diabetes, 35% of men and 46% of
women have an elevated blood pressure (Hypertension in Diabetes Study Group, 1993). An
elevated blood pressure is a well established determinant of stroke, coronary heart disease and
heart failure, and renal disease in the general population (WHO-ISH, 1999). Elevated blood
pressure in people with Type 2 diabetes may indicate evolving diabetic nephropathy, be part
of the metabolic syndrome or represent a chance association. In elderly subjects elevated
blood pressure is often confined to an isolated elevation of systolic blood pressure. If not
associated with diabetic nephropathy, an elevated blood pressure may precede the
development of Type 2 diabetes (Reaven, 1988). In young people, a rise in blood pressure
affects systolic and diastolic blood pressure in parallel. By contrast, in older people the most
common pattern is a rise in systolic and a fall in diastolic blood pressure leading to a rise in
pulse pressure which may itself be involved in the pathogenesis of vascular events (Figure 1,
Section 2) (Franklin et al, 1999).
An elevated blood pressure and hyperglycaemia are independent risk factors for
microvascular and macrovascular complications in Type 2 diabetes. Current evidence
indicates that intensive intervention for blood pressure control achieves a significant reduction
in the United Kingdom Prospective Study (UKPDS) defined endpoints (UKPDS 38, 1998).
This effect may be more than that achieved by intensive blood glucose control (UKPDS 33,
1998), a similar conclusion reached by OConnor et al (1998). However, differences in the
design and treatment aims of the blood glucose and blood pressure arms of the UKPDS, make
direct comparison of outcomes difficult. Nevertheless, blood pressure control is clearly
important in attenuating the complications of Type 2 diabetes.
The recommendations in this Guideline indicate how an elevated blood pressure should be
defined, measured and managed in people with Type 2 diabetes. Emphasis is placed on the
role of ACE inhibitors and angiotensin receptor blockers (ARBs), the importance of multiple
drug therapy in achieving blood pressure targets, and the effects of intensive blood pressure
control on vascular disease.
10
2.5 Recommendations
Section 1: Blood Pressure Control

Issue
What is the target blood pressure in people with Type 2 diabetes?
Recommendation
In people with Type 2 diabetes, the target blood pressure should be:
below 130/80 mmHg or
below 125/75 mmHg in people with proteinuria exceeding 1 g/day
Evidence Statements
There is a strong, graded and continuous relationship between systolic and diastolic blood
pressure and cardiovascular risk
Evidence Level III-2
People with Type 2 diabetes have greater cardiovascular risk at equivalent blood pressure
levels than people without diabetes
Evidence Level II
Cardiovascular outcomes in people with Type 2 diabetes are better with lower blood
pressure levels
Evidence Level II
The target blood pressure should be lower in people with proteinuria exceeding 1 g/day
Evidence Level II
Aggressive lowering of blood pressure has not been shown to be harmful in people with
Type 2 diabetes
Evidence Level II
11
Background - Target blood pressure for Type 2 diabetes
Blood pressure levels are directly and continuously related to risk of cardiovascular and
cerebrovascular disease. Therefore the definition of an elevated blood pressure is arbitrary
(WHO-ISH, 1999). Defining elevated pressure levels is based on epidemiological studies,
which consider associations between blood pressure level and vascular events, and
intervention studies, which examine risk reduction associated with blood pressure lowering.
In 1999, the World Health Organization (WHO) and International Society for Hypertension
(ISH) released Guidelines for the Management of Hypertension (WHO-ISH, 1999). Two
years earlier, the Sixth Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC-VI, 1997) was published and made
evidence based and consensus recommendations on hypertension and its control. More
recently the summary version of the Seventh Report of the Joint National Committee on
Prevention, Evaluation, and Treatment of High Blood Pressure (JNC-7, 2003) and guidelines
for the management of arterial hypertension of the European Society for Hypertension
European Society of Cardiology (2003) have been released.
Each of these reports defines hypertension as a SBP 140 mmHg and/or DBP 90 mmHg in
subjects who are not taking antihypertensive medication.
Target levels for blood pressure are based on:

epidemiological data which indicate that there is a consistent association between lower
blood pressure and lower cardiovascular risk
blood pressure levels achieved in people treated with antihypertensive medications and the
effect on cardiovascular risk
Since elevated blood pressure accelerates the onset and progression of microvascular and
macrovascular complications in people with Type 2 diabetes, interventions which lower blood
pressure should be aggressive and should be commenced early (Sawicki et al, 1995).
12
Evidence - Target blood pressure for Type 2 diabetes
There is a strong, graded and continuous relationship between systolic and diastolic
blood pressure and cardiovascular risk
Studies in the general population and people with diabetes have documented a continuous
relationship between blood pressure levels and risk of cardiovascular disease, including stroke
and coronary heart disease (CHD) (Stamler et al, 1993), heart failure (Levy et al, 1996), risk
of death from coronary heart disease or non-fatal myocardial infarction (MacMahon et al,
1990), and renal disease (Klag et al, 1996).
The MRFIT study included 347,978 men aged 35-57 years at entry to the study of whom
5,163 reported taking medication for diabetes (Stamler et al, 1993). In the diabetes group
there were 1,092 deaths including 603 cardiovascular disease (CVD) deaths during an average
of 12 years of follow-up. Among the 342,815 men not taking medication for diabetes, 20,867
deaths were reported of which 8,965 were from CVD. Systolic blood pressure (SBP) was
positively related to the risk of CVD death with a significant trend in both cohorts (p <0.001).
For men with diabetes, CVD death rate increased from 53.6 deaths/10,000 person years (for
SBP <120 mmHg) to 158.7 deaths/1,000 person years (for SBP 160-179 mmHg), and for men
without diabetes, from 12.2 to 56.5 deaths/1,000 person years respectively (Figure 1). Men
with diabetes also had an increased risk of dying of stroke as compared with men without
diabetes with a relative risk (RR) of 2.8 and a 95% confident interval (CI) of 2.0-3.7.
Among individuals of mostly middle age, a sustained decrease in diastolic blood pressure
(DBP) of 5 mmHg was shown to be associated with a 35-40% lower risk of stroke, with no
lower level identified below which the risk of stroke did not continue to decline (MacMahon
et al, 1990). Among 124,774 participants from eastern Asia who were followed-up for an
average of 7 years, 1,798 strokes were identified. Each decrease in DBP of 5 mmHg was
associated with lower risk of nonhaemorrhagic stroke with an OR of 0.61 (CI 0.57-0.66) and
lower risk of haemorrhagic stroke (OR 0.54 [CI 0.50-0.58]) (Eastern Stroke and Coronary
Heart Disease Collaborative Group, 1998). In the MRFIT Study (Klag et al, 1996), compared
with men with optimal level of blood pressure (SBP <120 mmHg and DBP <80 mmHg), men
with SBP 210 mmHg or DBP 120 mmHg had a significantly increased risk of end-stage
renal disease (RR 22.1 [CI 14.2-34.3], p<0.001).
13
Figure 1. The rate of CVD deaths for men with diabetes compared with non-diabetic
men at varying systolic blood pressure levels
250
Diabetic
Rate of Non-Diabetic
CVD 200
deaths
(per
10,000 150
person-
yr)
100
50
0
<120 120-139 140-159 160-179 180-199 200
Systolic Blood Pressure level (mmHg)
People with Type 2 diabetes have greater cardiovascular risk at equivalent blood
pressure levels than people without diabetes
In the MRFIT study, people with diabetes (type of diabetes was not specified) had more
cardiovascular events compared with people without diabetes at similar blood pressure levels
(Stamler et al, 1993; Flack et al, 1995). Among the 5,163 men with diabetes studied
prospectively for a mean of 12 years, the death rate due to CVD was 85.1/10,000 person
years, 3.5 times higher than in men (n=342,815) without diabetes (22.9/10,000 person years)
(Stamler et al, 1993). For men with diabetes, CVD death rate increased from 53.6
deaths/10,000 person years (for SBP <120 mmHg) to 158.7 (for SBP 160-179 mmHg), and
for men without diabetes, from 12.2 to 56.5 respectively. At every level of SBP, the age
adjusted CVD death rate was greater for diabetic than non-diabetic men. The RR for men with
diabetes compared with non-diabetic men at varying SBP levels ranged from 4.4 (for SBP
<120 mmHg) to 2.8 at higher SBP levels (160-179 mmHg) (Stamler et al, 1993). The RR for
men with diabetes compared with non-diabetic men at varying SBP levels is summarised in
Figure 1 and Table 1.
Table 1: The relative risk for men with diabetes compared with non-diabetic men at
varying systolic blood pressure levels
SBP (mmHg) RR for diabetic v non-diabetic men
<120 4.40
120-139 3.43
140-159 3.16
160-179 2.81
14
Several large intervention studies, which have included diabetic subgroups (type of diabetes
not always specified) and both men and women, have also shown that the co-occurrence of
diabetes and elevated blood pressure increases the risk of cardiovascular and renal disease.
In the placebo-treated subjects in the Systolic Hypertension in the Elderly Program (SHEP)
Study (Curb et al, 1996) and the Syst-Eur Study (Tuomilehto et al, 1999), the incidence of
major cardiovascular events was 1.71 and 1.90 times higher in the presence of diabetes than in
people without diabetes, and the RR for stroke was 1.92 and 2.16 and for all deaths 1.63 and
2.09, respectively. In the Hypertension Optimal Treatment study (HOT) (Hansson et al,
1998), the incidence of major cardiovascular events was 1.71 times higher in diabetic subjects
than in people without diabetes, and the RR for myocardial infarction was 1.52, for stroke
1.65, for cardiovascular mortality 2.13 and for total mortality 1.45.
With regard to renal disease, in the placebo-treated group in the SystEur trial the incidence of
proteinuria was much higher in people with diabetes than in those without diabetes (58.0
versus 15.1 cases per 1000 patient years) (Voyaki et al, 2001). In the MICRO-HOPE substudy
of the HOPE study, the incidence of clinical proteinuria among people with diabetes receiving
placebo was 8.4% during 4.5 years (HOPE Study, 2000a).
In people with Type 2 diabetes, the effect of blood pressure is accentuated by the presence of
associated vascular risk factors. This has been documented in a UKPDS cohort of 3,055
people with newly diagnosed Type 2 diabetes and without evidence of atheroma who were
followed for 7.9 years of whom 355 people developed coronary artery disease (Turner et al,
1998). After adjusting for age and sex, the hazard ratios (HR) for coronary artery disease
comparing the third with the highest blood pressure with the third with the lowest blood
pressure was 2.26 (CI 1.7-3.0) for LDL-cholesterol, 0.55 (CI 0.41-0.73) for HDL-cholesterol,
1.52 (CI 1.15-2.01) for HbA1c and 1.41 (CI 1.06-1.88) for smokers. Similar associations were
seen for fatal or non-fatal myocardial infarction.
Cardiovascular outcomes in people with Type 2 diabetes are better with lower blood
pressure levels
Table 2 illustrates the blood pressure levels and outcomes achieved in intervention studies
with antihypertensive therapies including studies with a placebo group or in which the study
investigated different blood pressure targets.
The HOT study recruited 18,790 people (1,501 with diabetes) and initial DBP 100-115 mmHg
who were randomly assigned to a target DBP of 90 mmHg, 85 mmHg or 80 mmHg using
calcium channel blocker based therapy (felodipine). The actual mean DBP levels achieved in
the 3 groups were 85 mmHg, 83 mmHg, and 81 mmHg respectively. In the total cohort,
outcomes were similar in the 3 groups except for a small reduction in myocardial infarction in
the groups randomised to a target DBP 90 and 85 mmHg (p<0.05). However in the diabetic
subgroup, those randomised to a DBP target 80 mmHg had significant reductions in major
cardiovascular events and cardiovascular and all cause mortality but no difference in stroke
compared with a DBP target of 90 mmHg (Hansson et al, 1998).
The mean SBP at entry in the HOT study was 170 mmHg in all 3 groups and at the end to the
study was 144 mmHg, 141 mmHg and 140 mmHg respectively. For the entire cohort the
lowest point of risk for a major cardiovascular event was a mean SBP of 138.5 mmHg and
DBP of 82.6 mmHg. The corresponding values for cardiovascular mortality were 138.8 and
86.5 mmHg and for stroke 142.2 and 80 mmHg. The authors concluded that the blood
15
pressure values which provided the maximum benefit in terms of risk reduction were a SBP
between 130 and 140 mmHg and a DBP between 80 and 85 mmHg (Hansson et al, 1998).
These findings are consistent with evidence from the UKPDS 38 (1998) which assessed the
effects of blood pressure control in people with Type 2 diabetes. Intensive blood pressure
control achieving a blood pressure of 144/82 mmHg significantly reduced the risk of any
diabetes related end point by 24%, diabetes related death by 32%, stroke by 44% and
microvascular endpoints by 37% compared with the less intensively treated group achieving a
blood pressure of 154/87 mmHg (UKPDS 38, 1998).
The blood pressure levels achieved in other studies which showed significant reductions in
cardiovascular events were 148/68 mmHg in the SHEP study (Curb et al, 1996), 153/78
mmHg in SystEur Study (Tuomilehto et al, 1999), 143/81 mmHg in the HOT study (Hansson
et al, 1998) and 140/77 mmHg in HOPE/MICROHOPE study (HOPE Study, 2000a).
Therefore, DBP values between 77 and 82 mmHg were achieved in studies in people with
elevated SBP and DBP and 68-78 in people with isolated systolic hypertension.
Studies which have compared intensive and less intensive treatments have achieved SBP
levels ranging from 128 to 144 mmHg. Improved outcomes were achieved in people with
diabetes in the HOT study with a SBP of 140 mmHg (Hansson et al, 1998) and in the UKPDS
with a SBP of 144 mmHg (UKPDS 38, 1998). In the two ABCD studies total mortality was
reduced with a SBP of 132 mmHg in ABCD-HT study (Estaccio et al, 1998) and stroke was
reduced with a SBP of 128 mmHg in ABCD-NT study (Schrier et al, 2002).
In placebo controlled studies, stroke and major cardiovascular events were deceased with a
SBP of 148 mmHg in the SHEP study (Curb, 1996), with a SBP of 140 mmHg in the
HOPE/MICROHOPE study (HOPE Study, 2000a) and with a SBP of 133 mmHg in the
PROGRESS study (PROGRESS, 2001). Renal outcomes were improved in the IDNT study
with a SBP of 140 mmHg (Lewis et al, 2001), IRMA II with a SBP of 141 mmHg (Parving et
al, 2001) and in the RENAAL study with a SBP of 143 mmHg (Brenner et al, 2001) and with
a SBP of 140 mmHg in the HOPE/MICROHOPE study (HOPE Study, 2000a).
In placebo controlled studies of people with systolic hypertension, improved outcomes were
achieved with a SBP of 148 mmHg in the SHEP study (Curb et al, 1996) and 153 mmHg in
the Syst-Eur study (Tuomilehto et al, 1999).
These results of these studies support a target blood pressure in people with diabetes of
<130/80.
16
Table 2: Summary of blood pressure levels achieved in studies assessing blood pressure lowering therapy
Study Baseline blood pressure Blood Pressure at end of study Main results
Fatal & non-fatal MI
ABCD - HT Nisoldipine: 155/98 mmHg Intensive treatment - 132/78 Nisoldipine > enalapril RR 4.2
(Estacio, 1998) Enalapril: 156/98 mmHg Moderate treatment 140/84 Total mortality moderate > intensive
ABCD - NT Intensive treatment - 136/85 mmHg Intensive treatment - 128/75 Less CVA - moderate > intensive
(Schrier, 2002) Moderate treatment - 137/84 mmHg Moderate treatment 137/78 OR 3.3
In people with diabetes:

ALLHAT* Chlorthalidone: 146/84 mmHg Chlorthalidone: 134/75 mmHg No difference between groups for fatal CHD or nonfatal MI, all
(2002a) Amlodipine: 146/84 mmHg Amlodipine: 135/75 mmHg cause mortality, stroke, or combined CHD, or combined CVD.
Lisinopril: 146/84 mmHg Lisinopril; 136/75 mmHg Less heart failure with chlorthalidone v amlodipine and lisinopril.
CAPPP Captopril: 164/97 mmHg Captopril: 156/89 mmHg Captopril v conventional:
(Niskanen, 2001) Conventional: Conventional: fatal and non fatal stroke, MI and CVD death by 41%
Diuretic/ blocker: 163/97 mmHg Diuretic/ blocker: 154/88 mmHg AMI by 66%
all CV events by 33%
FACET Fosinopril: 170/95 mmHg Fosinopril: 157/88 mmHg CV events with fosinopril
(Tatti, 1998) Amlodipine: 171/94 mmHg Amlodipine: 153/86 mmHg (14/189 v 27/191)
Ramipril lowered risk of

HOPE and Ramipril: 142/80 mmHg Ramipril: 140/77 mmHg CV death by 37%
MICROHOPE Placebo: 142/79 mmHg Placebo: 142/77 mmHg total mortality by 24%
(Heart Outcomes stroke by 33%
Prevention Evaluation overt nephropathy by 24%
study Investigators, 2000a) After adjustment for SBP and DBP, ramipril reduced the combined
primary endpoint by 25%
People with diabetes: DBP 80 v 90 mmHg
HOT * 170/105 mmHg in all 3 groups DBP 80 mmHg target: 140/81 mmHg total mortality 55%
(Hansson, 1998) DBP 85 mmHg target: 141/83 mmHg CV mortality 67%
DBP 90 mmHg target: 144/85 mmHg CV events 51%??
Primary composite endpoint: Irbesartan 20% reduction v placebo
IDNT Irbesartan: 160/87 mmHg Irbesartan: 140/77 mmHg & 23% reduction v amlodipine.
(Lewis, 2001) Amlodipine: 159/87 mmHg Amlodipine: 141/77 mmHg Risk of doubling of creatinine:
Placebo: 158/87 mmHg Placebo: 144/80 mmHg Irbesartan 29% less v placebo & 39% less v amlodipine
Creatinine increased 24% slower in irbesartan v placebo and 21%
slower v amlodipine
* BP results for whole study population, not just people with diabetes
17
Primary endpoint (the onset of diabetic nephropathy, AER >200
IRMA II Irbesartin 300 mg gp: 153/91mmHg Irbesartin 300 mg gp: 141/83 mmHg ug/min & at least 30% higher than the baseline level:
(Parving, 2001) Irbesartin 150 mg gp: 153/90 mmHg Irbesartin 150 mg gp: 143/83 mmHg 5.7% in 300 mg gp, 9.7% in 150 mg gp and 14.9% in placebo gp
Placebo gp: 153/90 mmHg placebo gp: 144/83 mmHg HR 0.30 for 300 mg gp
HR 0.61 for 150 mg gp
Losartan v Atenolol
LIFE Losartan: 176/97 mmHg Losartan: 146/79 mmHg Primary Endpoint: RR 0.76
(Lindholm, 2002) Atenolol: 177/96 mmHg Atenolol: 148/79 mmHg CVD death: RR 0.63
All cause mortality: RR 0.61
Diabetes cohort:
NORDIL * Diltiazem: 174/106 mmHg Diltiazem: 152/88 mmHg No difference between treatments.
(Hansson, 2000) Diuretic & blocker:173/106 mmHg Diuretic & blocker:150/87 mmHg Primary endpoint: RR 1.01
All MI: RR 0.99
Fatal MI: RR 2.45
All Stroke: RR 0.80
Fatal stroke:RR 0.71
Total mortality: RR 1.07
All cardiac events: RR 1.04
PROGRESS * Active gp:147/86 mmHg Active gp:133/80 mmHg Active treatment v. placebo:
(2001) Placebo gp: 147/86 mmHg Placebo gp: 142/84 mmHg RRR of 28% for total stroke
Active group received Perindopril 4 mg [estmated from publication] RRR of 26% for total major vascular events
indapamide 2.5 mg daily The average difference between the groups Similar reductions in RR of stroke in hypertensive and
at the end of the study was 9.0/ 4.0 mm/Hg nonhypertensive subgroups
in both people with and without diabetes.
Losartan v placebo:
RENAAL Losaratin: 152/82 mmHg Losaratin: 143/77 mmHg 16% risk reduction in the primary composite endpoint
(Brenner, 2001) Placebo: 153/82 mmHg Placebo: 144/77 mmHg 25% risk reduction in doubling serum creatinine concentration
28% risk reduction in developing ESRD

SHEP Diuretic: 170/77 mmHg Diuretic: 148/68 mmHg major CVD events 34%
(Curb, 1996) Placebo: 170/75 mmHg Placebo: 160/70 mmHg nonfatal & fatal MI 54%
all-cause mortality 26%
STOP Hypertension-2 * 194/98mmHg in all gps ACE inhibitor: 159/81 mmHg Old and new medications similar in prevention of CVD mortality
(Hansson, 1999b) Ca antagonist: 159/80 mmHg or major events.
-blockers and/ or diuretics: 158/81 ACE inhibitors significantly less MI and congestive heart failure v
mmHg Ca antagonists.
18
Syst-Eur Nitrendipine: 175/86 mmHg, Nitrendipine: 153/79 mmHg, Benefit of treatment:
(Tuomilehto, 1999) Placebo: 175/86 mmHg Placebo: 161/83 mmHg CVD mortality reduced by 70% (CI 19-89)
All CVD events reduced by 62% (CI 19-80)
Stroke reduced by 69% (CI 14-89)
Captopril and atenolol similar
UKPDS Tight control: 159/94 Tight control:144/82 Tight v less tight control:
(UKPDS 38, 1998, Less tight control: 160/94 mmHg Less tight control: 154/87 mmHg diabetes related event 24%
UKPDS 39, 1998) Captopril: 159/94 mmHg Captopril: 144/83 mmHg diabetes related death 32%
Atenolol: 159/93 mmHg Atenolol: 143/81 mmHg MI 21% (NS)
19
The target blood pressure should be lower in people with proteinuria exceeding 1
g/day
The Modified Diet in Renal Disease Study consisted of 2 randomised trials of 840
people (Peterson et al, 1995). Study A included 585 people with baseline creatinine
clearance between 25-55 ml/min and Study B included 225 people with baseline
creatinine clearance between 13-24 ml/min. Overall there were 26 people with non-
insulin treated diabetes. Participants in both studies were randomised to a usual blood
pressure goal group (target mean BP 107 mmHg for people 60 years and 113
mmHg for people > 60 years) or to a low blood pressure goal group (target mean BP
92 mmHg for people 60 years and 98 mmHg for people > 60 years). Both non-
pharmacological and pharmacological therapies were used to lower blood pressure.
Greater baseline proteinuria was associated with greater decline of glomerular
filtration rate (p<0.02 in Study A and p<0.01 in Study B). Mean BP increased in both
usual and low blood pressure target groups in people with baseline proteinuria 1
g/day while mean BP decreased in people with proteinuria <1g/day. In Study A the
low BP group had a greater beneficial effect on decline of glomerular filtration rate in
people with proteinuria >0.25 g/day while in Study B the benefit was seen only in
people with proteinuria >1.0 g/day. The authors concluded that in people with
proteinuria >1 g/day the target blood pressure should be 125/75 mmHg.
Aggressive lowering of blood pressure has not been shown to be harmful in

The J-curve hypothesis predicts that excessive lowering of blood pressure may
increase the risk of coronary events by lowering perfusion pressure in the coronary
circulation. While a J-curve effect has been detected in older non-diabetic people with
elevated blood pressure, so far clinical trials in people with diabetes have not
demonstrated the existence of a J-curve effect for blood pressure reduction.
No evidence of a J-curve was found with aggressive lowering of blood pressure in the
HOT study (Hansson et al, 1998) or the ABCD-NT study (Schrier et al, 2002). In the
HOT study, although no additional benefit was noted with blood pressure lowering
below certain levels, there was also no increase in major cardiovascular events,
myocardial infarction, stroke and cardiovascular mortality with SBP down to 120
mmHg and DBP down to 70 mmHg (Hansson et al, 1998). In the ABCD-NT study,
intensive blood pressure lowering in normotensive diabetic subjects did not increase
cardiovascular events (Schrier et al, 2002).
20
Summary - Target blood pressure for Type 2 diabetes
There is a strong positive relationship between systolic and diastolic blood
pressure and cardiovascular mortality, coronary heart disease, heart failure, stroke
and renal disease
People with diabetes have greater cardiovascular risk at equivalent blood pressure
levels than people without diabetes
Interventions which lower blood pressure should be used aggressively in people

with Type 2 diabetes and blood pressure above target
The target blood pressure for people with Type 2 diabetes is <130/80
The target blood pressure for people with Type 2 diabetes who have proteinuria of
> 1 g/day is <125/75 mmHg
The frequent occurrence of isolated systolic hypertension in elderly people may

make it difficult to achieve the systolic blood pressure target of <130 mmHg and a
more realistic target may be a systolic blood pressure of <140 mmHg
21
Evidence Table: Section 1
What is the target blood pressure for Type 2 diabetes?
Author Evidence
Level of Evidence Quality Magnitude Relevance
Level Study Type Rating Rating Rating
ALLHAT (2002a)
II RCT High High+ Low
(Adults US; Canada)
Brenner BM (2001)
II RCT High High+ High
(Adults multicentres)
Curb JD (1996)
(Older adults US)
Systematic
ESCHDC Group (1998)
III-2 review of cohort High High+ Low
(Adults China; Japan)
studies
Estacio RO (1998)
(Adults US)
Flack JM (1995) +
III-2 Cohort High High Low
(Adult men US)
Hansson L (1998)
(Adults Europe; North & II RCT Medium High+ Low
South America; Asia)
Hansson L (1999b)
(Elderly Sweden)
Hansson L (2000)
(Adults Norway; Sweden)
HOPE (2000a) +
II RCT High High High
(Adults Canada)
Klag MJ (1996)
III-2 Cohort High High+ Low
(Adult men US)
Levy D (1996) +
III-2 Cohort High High High
(Adults US)
Lewis EJ (2001)
(Adults multicentres)
Lindholm LH (2002) +
(Adults Sweden)
MacMahon S (1990)
(Adult men US; Puerto III-2 Cohort High High+ Low
Rico; UK)
Niskanen L (2001)
(Adults Finland)
Parving HH (2001)
(Adults UK; Canada; II RCT High High+ High
Europe)
Peterson JC (1995)
(Adults US)
PROGRESS (2001)
(Adults Asia; II RCT High High+ Low
Australasia; Europe)
Schrier RW (2002)
(Adults US)
Stamler J (1993) +
III-2 Cohort High High High
(Adult men US)
Tatti P (1998)
II RCT Medium High+ High
(Adults Italy)
Tuomilehto J (1999) +
(Elderly Europe)
Turner RC (1998)
III-2 Cohort High High+ High
(Adults UK)
UKPDS 38 (1998)
(Adults UK)
UKPDS 39 (1998)
(Adults UK)
Voyaki SM (2001) +
(Elderly Europe)
Magnitude rating: The direction of the effect is by + for a positive effect and - for a negative effect. High = clinically
important & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically
significant effect
*RCT but only the epidemiological data from this study were used for the relevant evidence statement
22
Issue
Recommendation
Measurement of blood pressure should be performed with attention to appropriate rest
period (at least 5 minutes), posture (usually sitting), and cuff size (large size preferred
for all adults).
Systolic blood pressure should be recorded as the first appearance of Korotkoff

sounds and diastolic blood pressure as the disappearance of Korotkoff sounds.
A mercury sphygmomanometer is preferred, but a regularly calibrated aneroid

manometer or a validated electronic device can be used.
Standing and supine blood pressure measurements are recommended if autonomic

neuropathy is suspected.
Evidence Statements
Blood pressure varies according to body position
Large cuff size (34 cm 15 cm) is recommended for all adults, although small
cuff size may be used for people with a small arm circumference
The mercury sphygmomanometer is the preferred device for measuring blood

pressure in routine clinical practice
Standing and supine measurements are recommended if autonomic neuropathy is

suspected
23
Background How to measure blood pressure
In the clinic setting, the procedure for the indirect measurement of arterial blood
pressure using a sphygmomanometer is well established, and consensus
recommendations have been produced in the interest of standardisation (Perloff et al,
1993; JNC-VI, 1997; WHO-ISH, 1999).
Blood pressure measurement should be taken preferably with a mercury

sphygmomanometer, otherwise a recently calibrated aneroid manometer or a validated
electronic device can be used. Ideally the person should refrain from smoking or
ingesting caffeine for 30 minutes preceding the measurement which should begin after
at least 5 minutes of rest. For blood pressure measurement, the person should be
seated in a chair with their back supported and their arm bared and supported at the
level of the right atrium defined as the midpoint of the sternum. Both SBP and DBP
should be recorded. The first appearance of Korotkoff sounds (phase 1) is used to
define SBP. The disappearance of Korotkoff sounds (phase 5) is used to define DBP.
The blood pressure reading should be based on an average of at least 2 sitting readings
on 2 or more occasions (JNC-7, 2003). If the 2 readings differ by more than 5 mmHg,
additional readings should be obtained and averaged. Clinicians should explain the
meaning of blood pressure readings and advise regular measurement to provide a
cumulative record of progress. Blood pressure should be measured in both arms at the
first visit, especially if there is evidence of peripheral vascular disease. Blood pressure
should be measured in the lying and standing position if autonomic neuropathy is
suspected or during titration of antihypertensive therapy (Perloff et al, 1993; JNC-VI,
1997; WHO-ISH, 1999).
It is important that blood pressure is measured accurately. Table 3 lists some of the
common pitfalls when measuring a persons blood pressure (modified from Perloff et
al, 1993).
Table 3: Common pitfalls in measuring blood pressure, which may result in

inaccurate readings.
Equipment Distorted stethoscope sounds
Due to damaged stethoscope or poorly fitting ear pieces
Inaccurate reading due to:
Mercury manometer meniscus not at 0 at rest or mercury column not vertical
Aneroid manometer needle not at 0 at rest
Leaky tubing or bulb
Incorrect cuff size
Subject Insufficient rest period (< 5 min)
Arm positioned above or below the heart level
Incorrect posture of subject, legs unsupported
Fist clenched
Technique Cuff wrapped too loosely or applied over clothing
Manometer read above or below eye level
Stethoscope head incorrectly positioned
Inflation pressure too high or too low
Deflation rate too fast or too slow
In clinical practice blood pressure is routinely measured as systolic and diastolic

pressures but other measures of blood pressure may more accurately reflect
cardiovascular risk. The recommendation target blood pressure in people with
diabetes of <130/80 mmHg is equivalent to a mean arterial pressure (MAP) of
approximately 100 mmHg. MAP is defined as DBP + 1/3 (SBP - DBP).
24
Recent studies suggest that pulse pressure (pulse pressure (PP) = SBP - DBP) may be
more important in contributing to cardiovascular risk (Benetos et al, 1998). In a large
French population (7,128 men and 5,503 women, followed for 19.5 years), high PP
was an independent predictor of cardiovascular mortality (especially coronary
mortality). In men, an elevation in PP of 10 mmHg significantly increased the RR of
cardiovascular mortality by 20% (CI 1.01-1.44) in normotensive subjects, defined as
SBP <140 mmHg and DBP <90 mmHg, and not receiving antihypertensive treatment.
The RR of cardiovascular mortality was also increased by 9% (CI 1.03-1.14) in
hypertensive male subjects (defined as SBP 160 mmHg or DBP 96 mmHg).
However, no association between cardiovascular mortality and PP was observed in
either normotensive or hypertensive women (OR 0.85, CI 1.01-1.44 and OR 1.0, CI
0.91-1.11) respectively (Benetos et al, 1998).
More recently, PP was examined in a sub-group analysis 1,924 people enrolled and
followed for 14.3 years in the Framingham study, who did not have a history or
clinical evidence of CHD and who were not receiving antihypertensive treatment. All
blood pressure components (SBP, DBP and PP) were higher in both males and
females who experienced new CHD events than in those without CHD events. The
HRs associated with a 10 mmHg increment in blood pressure were PP 1.23 (p
<0.001), SBP 1.16 (p <0.001) and DBP 1.14 (p <0.05) respectively after adjustment
for other risk factors. Furthermore, there was no significant difference in predicting
CHD risk for men compared with women (p=0.29 for PP, p=0.23 for SBP and p=0.81
for DBP) (Franklin et al, 1999).
Further intervention trials are awaited in order to assess the relative importance of PP
and MAP. This has special relevance to elderly diabetic people with isolated systolic
hypertension. In these people, as shown in the SHEP Study (Curb, 1996) and the Syst-
Eur Study (Tuomilehto et al, 1999), major benefits were achieved with reductions of
systolic blood pressure even though diastolic blood pressure was normal or
subnormal. These concepts are illustrated in Figure 2.
Figure 2. The effect of hypertension on mean arterial pressure and pulse

pressure in young and elderly people
Young (<40years) Elderly (>65years)
Onset of
Onset of
hypertension
hypertension
SBP SBP
MAP PP Blood 140

Blood 130
DBP pressure
PP
pressure (mmHg)
(mmHg) 85 MAP
80
DBP
25
Evidence - How to measure blood pressure
Blood pressure varies according to body position
A recent study by Netea et al (2002) has highlighted the important influence of body
position on blood pressure measurement. 142 people with diabetes had blood pressure
measured in 5 positions:
sitting with the arm supported at level of the right atrium
sitting with the arm supported on the arm support of the chair
lying on a bed
standing with the arm supported at the level of the right atrium
standing with the arm hanging by the side
Significant differences in BP were noted depending on the body position as shown in

the Table 4.
Table 4: Differences in blood pressure depending on body position

Arm at chair Arm on chair Standing arm Standing arm
Lying
level support at atrial level by side
Systolic BP 124.818.8 131.018.7 131.819.4 120.519.3 130.218.0
Diastolic BP 70.89.9 78.810.0 77.910.5 71.510.3 81.810.8
Both SBP and DBP were significantly lower with the arm at the level of the atrium
while sitting and standing and compared with lying. The differences were of the order
of 6-8 mmHg for both SBP and DBP. This study demonstrates the importance of
standardising body position in measuring and comparing blood pressure and
highlights the emphasis placed on body position in the international recommendations
for the routine measurement of blood pressure sitting with the arm at the level of the
right atrium.
Large cuff size (34 cm 15 cm) is recommended for all adults, although small
cuff size may be used for people with a small arm circumference
The size of the cuff influences blood pressure measurement. An appropriate sized cuff
in which the cuff bladder encircles at least 80% of the arm should be used when
measuring blood pressure. The cuff should be placed at heart level, whatever the
position of the patient. Wittenberg et al (1994) compared blood pressure readings
taken with a standard cuff (2312 cm) and a large cuff (3415 cm) in 50 people with
elevated blood pressure and found that the use of the standard cuff resulted in an
overestimation of blood pressure in people with an arm circumference 30 cm (blood
pressure reading: 15322/9916 mmHg with the standard cuff v 14419/9316
mmHg with the large cuff, p<0.005). Subsequent continuous ambulatory blood
pressure monitoring readings were very similar to the readings obtained with the large
cuff.
In another study, arm circumference and blood pressure were measured in 85 subjects
with small (3212 cm) and large (3415 cm) cuffs. Table 5 shows that the small cuff
significantly overestimated blood pressure compared with the large cuff in each
group. There was less difference between both cuffs for DBP in the small arm
circumference group although it was still significantly different (Iyriboz et al, 1994).
These data were used to propose that the large cuff (3415 cm) be used for routine
blood pressure measurement in all adults.
26
Table 5: Comparison of mean blood pressure values obtained using large or
small cuffs (Iyriboz et al, 1994)
Blood pressure Cuff size Large arm circumference Small arm circumference
(mmHg) (>29cm) (29 cm)
Systolic BP Large 119.9 13.2* 119.1 20.0*
Small 125.3 13.1 123.2 21.3
Diastolic BP Large 73.5 9.0* 69.3 9.1*
Small 77.7 9.2 71.2 9.2
Values expressed as mean standard deviation. * significant differences between each cuff
The mercury sphygmomanometer is the preferred device for measuring blood

pressure in routine clinical practice
Eight electronic blood pressure measuring devices (including one finger-cuff device)
and a mercury sphygmomanometer were simultaneously compared in 16-18 subjects.
Six of the eight electronic devices significantly under read SBP (p<0.01) and only one
machine satisfied the criteria of the British Hypertension Society (Mann et al, 1992).
In another recent study the semi-automated blood pressure measuring device,

Dinamap, overestimated SBP below 118 mmHg (p<0.0001), and underestimated
SBP above 152 mmHg (p<0.0001) compared to readings taken with a random zero
sphygmomanometer (Raptis et al, 1997).
Sturrock et al (1997) reached a different conclusion in their study which compared 3

methods of blood pressure measurement (n=40) - the Hawksley random zero
sphygmomanometer, the semiautomated Dinamap monitor and the 24 h ambulatory
blood pressure monitoring using the Spacelabs 90207. They found good agreement
between the 2 instruments and daytime ambulatory blood pressure monitoring and
concluded that semi-automated methods eg Dinamap may have a place in the clinic.
Because of these variable results, it is currently recommended that semi-automated

blood pressure measuring devices and mercury sphygmomanometers should not be
used interchangeably in clinical practice.
Standing and supine blood pressure measurements are recommended if

autonomic neuropathy is suspected
Although blood pressure measurements are generally performed in the sitting

position, significant postural effects on blood pressure may occur in people with
diabetes, especially those with autonomic neuropathy. In a study of 702 people with
Type 1 or Type 2 diabetes, orthostatic hypotension, defined as a fall in SBP >30
mmHg on standing, was observed in 12% of men and 13% of women (Krolewski et
al, 1985). Postural hypotension was the initial clinical feature of diabetic autonomic
neuropathy in 35% (25/73) of people with symptoms suggestive of diabetic autonomic
neuropathy in a 5 year prospective study (Ewing et al, 1980). In this clinical context,
blood pressure should be measured in both lying and standing positions.
27
Summary - How to measure blood pressure
Blood pressure measurement should be taken preferably with a mercury
sphygmomanometer
A recently calibrated aneroid manometer or a validated electronic device may be

used
A large cuff (3415 cm) should be routinely used for the measurement of blood
pressure in adults and use of the large cuff is essential in overweight people.
Routine measurement of blood pressure should be performed in the sitting position

after at least 5 minutes rest with the arm at the level of right atrium
Systolic blood pressure should be recorded as the first appearance of Korotkoff

sounds and diastolic blood pressure as the disappearance of Korotkoff sounds
Blood pressure should be measured in both lying and standing positions in people
with autonomic neuropathy
28
Author Evidence
Ewing JD (1980)
III-2 Cohort Medium High+ High
(Adults UK: Scotland)
Franklin SS (1999)
III-2 Cohort Medium Medium+ Low
(Adults US)
Iyriboz Y (1994)
III-2 Cross-sectional Medium High+ Low
(Adults US)
Krolewski AS (1985)
III-2 Cross-sectional Medium High+ High
(Adults US)
Mann S (1992)
(Adults New Zealand)
Netea RT (2002)
(Adults The III-2 Cross-sectional Medium High+ High
Netherlands)
Raptis AE (1997)
III-2 Cross-sectional Medium High+ High
(Adults UK)
Sturrock NDC (1997) +
III-2 Cross-sectional Medium High High
(Adults UK)
Wittenberg C (1994)
(Adults Israel)
Magnitude rating: The direction of the effect is by + for a positive effect and - for a negative effect. High = clinically important
& statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically significant effect
29
Issue
Recommendations
Blood pressure should be measured at every clinic visit, or at least every 6 months, in
people with Type 2 diabetes.
Blood pressure should be measured at least every 3 months in people with Type 2
diabetes taking blood pressure lowering medications.
During titration of antihypertensive therapy, blood pressure should be measured more

frequently (every 4 to 8 weeks) until optimal levels are achieved.
Evidence Statements
Regular blood pressure measurement is required in people with diabetes
More frequent measurement of blood pressure is required during titration of

antihypertensive therapy
30
Background - How often should blood pressure be measured
Elevated blood pressure is a common finding in people with Type 2 diabetes, with a
prevalence increasing from 10-20% in people under 45 years of age to over 50% in
people over 65 years (Tarnow et al, 1994). Increasing blood pressure is also a major
risk factor for both large and small blood vessel disease, and interacts with
hyperglycaemia and elevated lipids to increase aggregate vascular risk. Therefore
blood pressure measurement should be regarded as an integral part of every clinical
visit in a person with diabetes.
Evidence - How often should blood pressure be measured

Regular blood pressure measurement is required in people with diabetes
Blood pressure measurement is required in order to establish the presence of an

elevated blood pressure. By consensus the diagnosis of an elevated blood pressure is
based on repeat blood pressure measurements because a number of situations may
cause short-term variability in blood pressure.
Age is an important modulator of blood pressure (Figure 2, Section 2). The third
National Health and Nutrition Examination Survey (Burt et al, 1995) showed that the
prevalence of elevated blood pressure in the non-Hispanic white population increased
with increasing age and was 12% in the 18 to 49 year age group, 35% in the 50 to 69
year age group and 50% in the 70 year age group in men. The corresponding rates
for women were 5%, 22%, and 55%, respectively. The overall age-adjusted
prevalence of elevated blood pressure was 23.3% in the United States.
The optimum frequency of blood pressure measurement in people with Type 2

diabetes has not been studied. Therefore recommendations on frequency of blood
pressure measurement are based on consensus which attempt to take into
consideration the variability of blood pressure measurements and the rate of increase
of blood pressure in people with diabetes with increasing age.
Consensus statements suggest that blood pressure should be measured at every clinic
visit in people with Type 2 diabetes (ADA, 2004). The recommended frequency of
clinical visits for routine care of people with Type 2 diabetes is every 6 months
increasing to every 3 months for people with above target blood pressure.
More frequent measurement of blood pressure is required during titration of

antihypertensive therapy
In the 6 week Perindopril Therapeutic Safety Study (Stumpe et al, 1993), the effect of
ACE inhibitor treatment on the reduction of SBP and DBP was assessed at 3 time
points (1, 3 and 6 weeks). Two hundred and sixty nine people with elevated blood
pressure (52 of who had Type 2 diabetes) were randomised to receive either
perindopril (4 mg/day) or placebo. The mean baseline SBP/DBP was 159/99 mmHg
and 158/99 mmHg for the perindopril and placebo groups, respectively. Although
there was a significant reduction in SBP and DBP at week 1 (p<0.001), there was a
further reduction at week 3 (p<0.001) and week 6 (p<0.001) in the perindopril treated
group (Stumpe et al, 1993). Some agents may take up to 6 weeks to achieve their
maximum blood pressure lowering effect after a dose change, therefore blood
31
pressure should be measured every 4-8 weeks while titrating antihypertensive drug
therapy.
Summary - How often should blood pressure be measured

There have been no randomised controlled trials to assess the optimum frequency
of blood pressure measurement in people with Type 2 diabetes
Recommendations on the frequency of blood pressure measurement are based on

the variability of blood pressure measurements, and the rate of increase of blood
pressure with increasing age
Consensus statements suggest that blood pressure should be measured at every

clinic visit in people with Type 2 diabetes
Repeated measurements of blood pressure are required to confirm a diagnosis of

above target blood pressure to take into account day-to-day and diurnal variation
Antihypertensive agents may take up to 6 weeks to achieve their maximum blood

pressure lowering effect after a dose change, therefore blood pressure should be
measured every 4-8 weeks while titrating antihypertensive therapy
32
Author Evidence
Burt VL (1995)
III-2 Cohort High Medium+ Low
(Adults US)
Stumpe KO (1993)
III-2* RCT High High+ Low
(Adults Germany)
significant effect
*RCT but only the epidemiological data from this study were used for the relevant evidence statement
33
Issue
What is the role of ambulatory blood pressure monitoring in blood pressure control?
Recommendations
24 h ambulatory blood pressure monitoring should be considered in people with Type
2 diabetes and suspected office (white coat) hypertension or who are resistant to
blood pressure lowering therapy.
Evidence Statements
Ambulatory blood pressure monitoring is useful for ruling out office (white
coat) hypertension, which has implications for both diagnosis and management
of above target blood pressure
Ambulatory blood pressure monitoring correlates more closely than clinic blood
pressure with cardiovascular risk
Ambulatory blood pressure monitoring identifies people with Type 2 diabetes

who lack the normal nocturnal fall in blood pressure (non-dippers) and who are
at increased risk of micro- and macrovascular complications and death, but the
implications for management are uncertain
34
Background - Role of ambulatory blood pressure monitoring
Ambulatory blood pressure monitoring (ABPM) provides additional information to
clinic blood pressure readings, which may help in both diagnosis of above target
blood pressure and in assessing the effectiveness of treatment. However, there is
insufficient information to recommend its routine use in all people with elevated
blood pressure (JNC-VI, 1997).
Potential benefits of ABPM are a more accurate classification of blood pressure,

assessment of orthostatic hypotension, better prediction of cardiovascular risk and
improved ability to monitor blood pressure response to treatment (JNC-VI, 1997,
WHO-ISH, 1999).
In addition, ABPM may be useful in people with unusual variability of blood pressure
over the same or different visits, in people with symptoms suggestive of hypotensive
episodes and in people resistant to drug treatment (WHO-ISH, 1999).
Blood pressure values taken by ABPM are generally lower than clinic readings by
about 10 mmHg for SBP and 5 mmHg for DBP, and provide measures of overall SBP
and DBP load (Appel & Stason, 1993). Blood pressure taken by ambulatory
measurements are lower than clinic readings while people are awake (usually <135/85
mmHg) and even lower while people are asleep (usually <120/75 mmHg) (JNC-VI,
1997).
Evidence - Role of ambulatory blood pressure monitoring

Ambulatory blood pressure monitoring is useful for ruling out office (white
coat) hypertension, which has implications for both diagnosis and management
of above target blood pressure
Office (white coat) hypertension refers to the situation where raised clinic blood
pressure readings are not replicated with ABPM. The systematic review by Appel &
Stason (1993), analysed the results of 8 studies in non-diabetic people (total n=295)
which compared office, self-measured and ambulatory (24 h or daytime) blood
pressure measurement. Office blood pressure was found to be greater than self-
measured pressure which, was in turn, greater than ambulatory blood pressure
readings. The difference between office blood pressure and daytime ambulatory blood
pressure ranged from -1 to 34 mmHg for SBP and -1 to 8 mmHg for DBP. This
difference was even greater between office blood pressure and 24 h ambulatory blood
pressure with a range from 5 to 40.7 mmHg for SBP and 1.5 to 12.2 mmHg for DBP
due to the nocturnal decline in blood pressure of 10% to 20%, which occurs in the
majority of individuals.
In a subsequent large Italian study of non-diabetic people (n=2,400), Mancia et al

(1995) reported that clinic blood pressure readings were significantly higher than 24 h
mean ambulatory blood pressure for both SBP (128.216.5 v 117.911.0 mmHg,
p<0.001) and DBP (81.99.9 v 73.97.4 mmHg, p<0.001).
Pickering et al (1988) studied 371 non-diabetic people of whom 292 had a clinic DBP
between 90 and 104 mmHg, and 42 had a clinic DBP above 105 mmHg (Pickering et
al, 1988). 21% of the 292 people with untreated borderline clinic hypertension (DBP
90-104 mmHg) had normal ambulatory daytime measures and were defined as having
white coat hypertension and reclassified as normotensive. Furthermore, 2 people with
35
established hypertension (DBP >105 mmHg) also had normal ambulatory daytime
readings.
Blood pressure responses to antihypertensive medications have traditionally been

assessed by office blood pressure measurement. In people with inadequately
controlled office blood pressure, ambulatory blood pressure may better identify the
response to changes in medical therapy, by ruling out those with office (white coat)
hypertension (Appel & Stason, 1993).
Ambulatory blood pressure monitoring correlates more closely than clinic blood
pressure with cardiovascular risk
In people with an elevated blood pressure, ABPM correlates more closely than clinic
blood pressure with a variety of measures of cardiovascular risk. Left ventricular
hypertrophy (measured by echocardiography criteria) and heart size (on radiograph)
were more strongly correlated with mean daytime systolic (r=0.57) and diastolic
(r=0.54) ambulatory blood pressure than with corresponding office measurements
(r=0.52 and 0.43) (Appel & Stason, 1993). Echocardiographic measurements of left
ventricular structure have shown that left ventricular mass is more closely correlated
with systolic than with diastolic blood pressure and with daytime or 24 h ambulatory
blood pressure than with office blood pressure (Appel & Stason, 1993). In the
Framingham Heart Study, left ventricular mass was strongly predictive of both fatal
and non-fatal cardiovascular events (Levy et al, 1996). A recent prospective study
(Mancia et al, 1997) reported that after antihypertensive treatment, the reduction in
left ventricular hypertrophy (15832 v 13326 g/m2) was related to the changes in 24
h ambulatory blood pressure (14916/9511 v 13112/8310 mmHg) (r=0.42 in men,
r=0.38 in women, p<0.01) but not with the change in clinic blood pressure
(16515/1055 v 13912/877 mmHg) among 206 non-diabetic people with essential
hypertension.
Ambulatory blood pressure monitoring identifies people with Type 2 diabetes

who lack the normal nocturnal fall in blood pressure (non-dippers) and who
are at increased risk of micro- and macrovascular complications and death, but
the implications for management are uncertain.
Nocturnal blood pressure has consistently been found to be higher in people with
Type 2 diabetes and elevated blood pressure than in people without diabetes and the
nocturnal dip in blood pressure is often absent (Fogari et al, 1993). Impaired or
reversed circadian rhythm is seen in 30% of normotensive and 31% of hypertensive
people with Type 2 diabetes compared with 6% of normotensive and 6.4% of
hypertensive non-diabetic controls (Fogari et al, 1993). In a study of people with Type
1 (n=11) and Type 2 (n=29) diabetes and elevated blood pressure, 55% were non-
dippers (Sturrock et al, 1997) i.e. their nocturnal blood pressure decreased by less than
10% when compared with daytime blood pressure levels.
People with Type 2 diabetes and an elevated albumin excretion rate (AER) have a
higher percentage of non-dippers than normoalbuminuric people or non-diabetic
controls (Equiluz-Bruck et al, 1996). A correlation between nocturnal blood pressure
and AER was found in 72 people with Type 2 diabetes compared with 41 people
without diabetes and with essential hypertension (systolic: r=0.32, p<0.007 and
diastolic: r=0.24, p<0.04). Non-dipping was observed in 80% of the
macroalbuminuric, 74% of the microalbuminuric, 43% of the normoalbuminuric
people with diabetes, but only in 37% of the controls (p<0.04) (Equiluz-Bruck et al,
36
1996). Of 76 normotensive people with Type 2 diabetes, Nakano et al (1991) found
54 had a circadian mean blood pressure rhythm similar to that of 34 age-matched
nondiabetic controls, while 22 had a reversed mean blood pressure rhythm, with a
peak value during the night. The prevalence of hypotension and reduced variation of
R-R intervals were also greater in this group (64 v 6%, and 64 v 24%, respectively,
p<0.01). A correlation between the reversed circadian mean blood pressure rhythm
and overt nephropathy (p<0.05), and postural hypotension (p<0.001) was observed in
these 22 people.
Knudsen et al (2002) examined the association of 24 h ambulatory blood pressure and

complications in 80 people with Type 2 diabetes. People with retinopathy,
nephropathy and macrovascular complications had higher systolic night/day ratios
compared with those without complications (p<0.05 for retinopathy, p<0.02 for
nephropathy, p<0.05 for macrovascular complications).
Non-dipping is associated with increased mortality. Sturrock et al (2000)

retrospectively analysed data on 75 people with diabetes (31 with Type 1 diabetes and
44 with Type 2 diabetes) and observed 8% deaths over 4 years in dippers compared
with 26% deaths in non-dippers (p<0.04). Mortality was particularly increased in
those whose creatinine unequivocally rose (10% in dippers v 42% in non-dippers,
p<0.03).
Non-dipping is also associated with increased cardiovascular risk (Liniger et al,

1991). Of 24 people with diabetes, there were three fatal and five nonfatal
cardiovascular events which occurred in 4 out of 6 people whose blood pressure rose
at night during follow-up, compared with only one event in those (n=7) with a small
fall in blood pressure of 5 mmHg and no serious events in those (n=11) with a
markedly fall (p=0.02).
Although non-dipping indicates an increase in overall blood pressure load is

associated with evolving diabetic nephropathy and with an increase in cardiovascular
risk, there are as yet no specific data to support more aggressive intervention in this
subgroup.
37
Summary - Role of ambulatory blood pressure monitoring
While ambulatory blood pressure monitoring is not a substitute for routine office
blood pressure measurement, it may provide useful additional clinical information
and has a place in the evaluation and management of some people with elevated
blood pressure
Blood pressure values taken by ambulatory blood pressure measurement are about
10 mmHg for systolic blood pressure and 5 mmHg for diastolic blood pressure
lower than clinic readings
Ambulatory blood pressure measurement can be used to exclude office (white

coat) hypertension and monitor response to treatment
Nocturnal blood pressure is higher in people with Type 2 diabetes and elevated
blood pressure than in non-diabetic people and the nocturnal dip in blood pressure
is often absent (non-dippers)
People with Type 2 diabetes with elevated albumin excretion rate have a higher
percentage of non-dippers than normoalbuminuric people or non-diabetic
controls
38
What is the role of ambulatory blood pressure monitoring in blood pressure

control?
Author Evidence
Systematic review
Appel LJ (1993) III-2 of cross-sectional Medium Medium+ Low
studies
Equiluz-Bruck S (1996)
III-2 Case-control Medium High+ High
(Adults Austria)
Fogari R (1993)
III-2 Case-control Medium High+ High
(Adults Italy)
Knudsen ST (2002)
III-2 Cross-sectional Medium Medium High
(Adults Denmark)
Levy D (1996)
III-2 Cohort High High+ Low
(Adults US)
Liniger C (1991) +
III-2 Case-control Medium High High
(Adults Switzerland)
Mancia G (1995)
III-2 Cross-sectional High High+ Low
(Adults Italy)
Mancia G (1997) +
III-2 Cohort High High Low
(Adults Italy)
Nakano S (1991)
III-2 Case-control Medium Medium- Low
(Adults Japan)
Pickering TG (1988) +
III-2 Cross- sectional Medium High Low
(Adults US)
Sturrock NDC (1997)
III-2 Cross- sectional Medium Medium+ High
(Adults UK)
Sturrock NDC (2000)
III-2 Cross- sectional Medium Medium+ High
(Adults UK)
significant effect
39
Issue
Recommendations
Modification of factors which contribute to increasing blood pressure (obesity,
physical inactivity, excessive dietary sodium and/or alcohol intake) should be
emphasised in all people with Type 2 diabetes with blood pressure above target
In people with Type 2 diabetes and blood pressure above target, angiotensin
converting enzyme inhibitors, angiotensin receptor blockers, -blockers and diuretics
can be used as initial therapy.
Angiotensin receptor blockers or angiotensin converting enzyme inhibitors should be

used to treat people with diabetic nephropathy.
Combinations of antihypertensive agents should always be considered when treating

blood pressure in people with Type 2 diabetes.
Evidence Statements
Lifestyle modifications including weight reduction, increase in physical activity,
reduction of excessive sodium intake and alcohol intake have been shown to
reduce blood pressure
Evidence Level I
Blood pressure reduction improves outcomes in people with Type 2 diabetes

Evidence Level I
A variety of antihypertensive agents are efficacious in the treatment of people

Evidence Level II
40
Evidence Statements continued
The role of non blood pressure lowering effects of antihypertensive medications
remains uncertain
Evidence Level I
Angiotensin receptor blockers and angiotensin converting enzyme inhibitors are

specifically indicated in people with increased albuminuria
Evidence Level I
Angiotensin converting enzyme inhibitors and/or -blockers are specifically

indicated in people with Type 2 diabetes after myocardial infarction
Evidence Level I
A number of blood pressure lowering medications are useful as initial therapy in

elderly people with isolated systolic hypertension
Evidence Level I
In order to achieve target blood pressure levels in people with Type 2 diabetes, it
is usually necessary to combine blood pressure lowering medications
41
Background - Blood pressure control in Type 2 diabetes
The aim of management of an above target blood pressure in people with Type 2
diabetes is to prevent or reduce morbidity and premature mortality from
cardiovascular and renal disease. In addition to control of the blood pressure, this
requires treatment of the diabetes and other modifiable risk factors such as lipids and
smoking.
It is widely accepted that blood pressure lowering therapy should be used (unless
contraindicated) in the management of all people with Type 2 diabetes:
who have had a previous cardiac or cerebrovascular event
who have nephropathy.
The main issue considered in this Section is the use of blood pressure lowering
medications in people with diabetes who have not had a previous cardiovascular event
or who do not have nephropathy. Previously published guidelines have used the
following approaches to blood pressure lowering in people with diabetes:
intervention based on blood pressure reading alone (ADA 2004, JNC 7 2003,
NHF 2004)
intervention based on blood pressure reading and assessment of overall
cardiovascular risk (WHO-ISH 1999, UK NICE guidelines 2002, European
Society of Hypertension and European Society of Cardiology 2003, International
Diabetes Federation, 2003). However it should be noted that both WHO-ISH and
the European Society of Hypertension and European Society of Cardiology
classify all people with diabetes with blood pressure above target as being at high
risk and requiring blood pressure lowering.
Absolute risk assessment and the prediction of future vascular events

The concept of risk factors for vascular disease is universally accepted based on
epidemiological studies showing an association of particular risk factors and
cardiovascular events and intervention studies demonstrating that reducing risk factors
results in a reduction in cardiovascular events.
In recent years there has been an increasing focus on using a combination of risk
factors rather than single risk factors to predict the likelihood of a future vascular
event. The concept of using absolute risk assessment to inform clinical decision
making in the primary prevention of vascular disease is widely accepted (Jackson,
2000). Absolute risk assessment allows identification of individuals in whom the
largest number of vascular events will occur.
Most methods for calculating absolute risk are based on data derived from the
Framingham study (Anderson et al, 1991). However the applicability of the
Framingham equations to predict CHD in people with diabetes has been questioned
because of the low prevalence of diabetes in the Framingham study. Yeo and Yeo
(2001) compared mean values for age, sex, systolic blood pressure, smoking habit,
diabetes status, total cholesterol and HDL cholesterol to estimate predicted CHD
events and mortality using the Framingham equations for subjects participating in the
UKPDS (UKPDS 33) with actual event rates observed during the study. The
Framingham estimate for annual CHD events was 1.6% and 0.2% for mortality
compared with UKPDS observed event rates of 2.7% and 1.0% respectively, a 40%
42
and 80% respectively underestimate by the Framingham equations. By comparison
the Framingham estimates correlated closely with observed event rates in the non-
diabetic WOSCOPS population (Shepherd et al, 1995). Recently a specific risk
assessment tool has been developed based on the UKPDS which may more accurately
define risk in people with diabetes (Stevens et al, 2001).
There is no universal agreement on the level of risk for intervening, a decision which
is not only influenced by the risk level but also by available resources (British Cardiac
Society, British Hyperlipidaemia Association, British Hypertension Society, British
Diabetic Association, 2000).
In Australia, the National Vascular Disease Prevention Alliance (an alliance of the
National Heart Foundation, Diabetes Australia, National Stroke Foundation and the
Australian Kidney Foundation) is working with the Department of Health and Ageing
to develop a policy and tool for Absolute Risk assessment for Australia on which to
base interventions to reduce CVD risk factors.
The position adopted in this Guideline is that until the above work is completed
people with Type 2 diabetes with blood pressure levels above target should be
considered at high absolute risk of a future event and that blood pressure lowering
interventions should be implemented.
Approach to Lowering Blood Pressure

Modifiable lifestyle factors should always be addressed. Initiation of pharmacological
therapy in people with Type 2 diabetes presents a question of choice among many
therapeutic agents.
The ideal medication for blood pressure control in a person with Type 2 diabetes
should:
lower blood pressure effectively
not impair glucose tolerance or impair the action of hypoglycaemic agents
be lipid neutral
not cause postural hypotension
not worsen diabetic complications
prevent or ameliorate microvascular and macrovascular complications
The many antihypertensive agents available can be subdivided into 5 major classes
(Table 6).
43
Table 6: Classes of antihypertensive agents
1. Inhibitors of the renin angiotensin system
Angiotensin converting enzyme (ACE) inhibitors
Angiotensin receptor blockers (ARB)
2. Calcium channel blockers (CCB)
Dihydropyridines (eg nifedipine, amlodipine and felodipine)
Non-dihydropyridines (non-DHP)
- Benzothiazepines (eg diltiazem)
- Phenylalkylamines (eg verapamil)
3. Diuretics
Thiazide
Loop
Indapamide
4. -blockers
5. -blockers
Non cardioselective
Cardioselective
The choice of blood pressure lowering medication should take into account the overall
clinical context including consideration of target organ damage, the side effect profile
of the medication and the persons history of side effects with previous blood pressure
lowering medications (Figure 3).
44
Figure 3. The choice of antihypertensive agents according to clinical syndrome in
diabetic patients with above target blood pressure (Jerums & Chattington, 1999)
Clinical Agent
Indications Comments
LVH cardiac failure

+
Avoid with K , renal artery stenosis
Microalbuminuria
Less effective in African Americans
Diabetic retinopathy ACE ARBs have similar indications to ACEi with a
Diet controlled Type 2 inhibitor or
diabetes dyslipidaemia
much lower incidence of cough
ARB Avoid coadministration of K sparing diuretic
Post MI
Avoid with asthma, intermittant claudication

Beta May cause impotence
blocker
Angina Non-DHP
Avoid diltiazem+ blocker
combination
Calcium
channel
blocker DHP Less effects on albuminuria
Diet controlled Type 2 diabetes
l
Safer in combination with ACEi
dyslipidaemia
Alpha Especially in prostatomegaly

blocker
K, Renin, Aldo
Thiazide Avoid thiazide+ blocker combination if
Indapamide diet controlled Type 2 diabetes
ISH in elderly
dyslipidaemia
May cause impotence
Renal impairment, fluid Large doses may be needed in

overload Frusemide overt nephropathy
Since approximately one half of people treated for elevated blood pressure do not
achieve recommended blood pressure targets (Burt et al, 1995) it is important to
assess reasons for failure of blood pressure to improve with antihypertensive therapy.
Most surveys show that one third of people do not comply with antihypertensive
therapy (Vaur et al, 1999). One reason for this is the side effects of antihypertensive
medications. Reasons for failure to respond include co-administration of non-steroidal
anti-inflammatory drugs (NSAID) and a high dietary sodium intake. Recreational
drugs such as caffeine, nicotine and alcohol can raise blood pressure (Goodman &
Gilman, 2001). Non-recreational drugs such as NSAIDs may reduce the effectiveness
of thiazide diuretics, and tricyclic antidepressants may induce postural hypotension.
Alpha-adrenergic nasal decongestants such as ephedrine or pseudoephedrine may
increase blood pressure.
In this context it is important to note that CVD is more prevalent in people of lower
socio-economic class than in other people. For instance, in a United Kingdom study of
45
18,403 men aged 40-60 years, men in the lowest grade of employment had three times
the mortality rate from CHD and from all causes combined compared with those in
the highest grade of employment (Marmot et al, 1984). In a study of health outcomes
in the 50 states of the USA, there was a significant correlation (r=0.62, p<0.001)
between the percentage of total household income received by the 50% less well off
households in each state and all cause mortality (Kaplan et al, 1996). Differences in
compliance may be a factor however no studies have specifically addressed the degree
of compliance with non-pharmacological or pharmacological antihypertensive therapy
in different socio-economic classes.
46
Evidence- Blood pressure control in Type 2 diabetes
Lifestyle modifications including weight reduction, increase in physical activity,
reduction in excessive sodium intake and alcohol intake have been shown to
reduce blood pressure
Lifestyle modifications are an integral part of controlling blood pressure, whether or

not medications are used. Effective non-pharmacological measures may abolish or
reduce the need for blood pressure lowering medications. Therefore, when initiating
treatment for an above target blood pressure in a person with Type 2 diabetes, it is
important to institute lifestyle measures where appropriate even if antihypertensive
therapy is commenced. The effects of lifestyle intervention on blood pressure are
summarised in Table 7.
Table 7: Non-pharmacological treatment on blood pressure

Intervention Magnitude of blood pressure (mmHg) reduction
Systolic BP/Diastolic BP
Weight loss 15/8
Alcohol restriction 5/3
Salt restriction 6/3
Exercise 4/3
Energy restriction and weight loss has been shown to significantly decrease blood
pressure in people with Type 2 diabetes. In a meta-analysis of weight loss studies
involving 1,800 people with Type 2 diabetes, Brown et al (1996) reported a
significant reduction in SBP (effect size 0.790.16, p<0.05) and DBP (effect size
0.720.30, p<0.05) with diet only interventions which achieved a mean weight loss of
9 kg (effect size 0.710.53, p<0.05). Reynolds et al (2002) reported a mean reduction
in SBP of 15 mmHg and in DBP of 8 mmHg following a 9 kg weight loss among 21
people with Type 2 diabetes in a 6-month study.
The effect of alcohol intake on blood pressure has been reviewed in the NHMRC
Australian Alcohol Guidelines (NHMRC, 2001). Blood pressure increases with
increasing alcohol intake. For example in the MRFIT study, alcohol intake (as percent
of daily energy intake) was significantly and positively related to both SBP and DBP
in men in both the special intervention group (coefficient 0.16, Z score 7.33 for SBP
p<0.001; coefficient 0.06, Z score 5.53 for DBP p<0.001) and usual care group
(coefficient 0.17, Z score 5.54 for SBP p<0.001; coefficient 0.07, Z score 4.20 for
DBP p<0.001) (Stamler et al, 1997). Conversely blood pressure decreases with
interventions to decrease alcohol intake. For example, a study in 44 men without
diabetes with essential hypertension showed after 6 weeks of reducing ethanol intake
from 450 ml/week to 64 ml/week, the mean reduction in SBP was 5.01.4 mmHg
supine (p<0.001) and 5.91.6 mmHg standing (p<0.001), the corresponding fall in
DBP was 3.00.9 mmHg supine and 2.91.0 mmHg standing (Puddey et al, 1987).
Reduction of sodium intake may reduce or correct an elevated blood pressure. A

meta-analysis of 32 studies of sodium restriction in hypertensive individuals showed a
mean blood pressure reduction of 5.8/2.5 mmHg per 100 mmol reduction in sodium
intake per day (Cutler et al, 1997). This along with epidemiological observations has
led Australian and international health authorities to recommend that dietary sodium
intake should be reduced to achieve urinary sodium below 100 mmol per day. It
47
should be noted that approximately 75% of dietary salt comes from processed foods,
especially canned food, preserves, bread and take away food. Reduction in sodium
intake can also potentiate the blood pressure lowering effect of antihypertensive
agents.
Short-term human studies have shown that alterations in dietary sodium intake can
affect the blood pressure lowering effect of antihypertensive agents. Sacks et al (2001)
evaluated the effect of reducing sodium intake on blood pressure among 412 people
with an average blood pressure of 120-159/80-95 mmHg who were randomly
assigned to a control diet or the Dietary Approaches to Stop Hypertension (DASH)
diet, which was rich in vegetables, fruits, and low-fat dairy products, over a 30-day
period. Reducing the sodium intake from 150 mmol/day (high level) to 100 mmol/day
(medium level) reduced SBP by 2.1 mmHg during the control diet (p<0.001) and by
1.3 mmHg during the DASH diet (p<0.001), while reducing sodium intake from 100
mmol/day to 50 mmol/day (low level) produced additional reductions in SBP by 4.6
mmHg (p<0.001), and 1.7 mmHg (p<0.01), respectively. A 4-day oral salt-load (NaCl
150 mmol/day) in 6 males with primary hypertension on chronic ACE inhibitor
treatment caused a significant increase in 24 h blood pressure (129/85 [3/2] v 124/82
[2/2] mmHg, p=0.025) (Herlitz, 1998).
Dodson et al (1989) randomised 34 diabetic subjects with mild hypertension (>160/95

mmHg) to a moderate sodium restricted diet (80 mmol/day) or a usual diabetic diet
for 7 weeks. Compared to the usual diet, a sodium restricted diet resulted in a
significant reduction in SBP (supine 19.2 mmHg, erect 21.4 mmHg, p<0.001), but
there was no significant changes in DBP. Houlihan et al (2002) studied the effect of
reducing sodium intake to 50-70 mmol/day compared with >100 mmol/day in
hypertensive people with Type 2 diabetes who were randomised to treatment with
losartan (n=10) or placebo (n=10) over a 2 week period. Both diets were associated
with similar 24 h blood pressure in the placebo treated group but the low sodium diet
potentiated the effect of losartin and reduced SBP by 10 mmHg (p=0.002) and DBP
by 6 mmHg (p=0.002), with a change in mean arterial blood pressure of 7.3 mmHg
(p=0.003).
A meta-analysis of randomised controls on the effects of aerobic exercise on blood

pressure has reported a significant reduction in SBP of approximately 4 mmHg and of
DBP of approximately 3 mmHg in both hypertensive and normotensive people but
details of diabetes status were not included (Whelton et al, 2002).
However, in a systematic review of the effects of exercise in people with Type 2

diabetes, Kelley and Goodpaster (2001) reported that the data are equivocal with some
studies showing a modest blood pressure lowering effect and other studies showing no
change.
48
Table 8: Summary of studies assessing blood pressure lowering therapy in people with diabetes
Study Proportion Description No. of Follow-up Blood Pressure effects Main results
with people
Diabetes with
diabetes
ABCD-HT All Type 2 Type 2 diabetes & DBP 90 mmHg 470 Mean BP at baseline 1 outcome GFR
(Estacio, 1998) diabetes Nisoldipine v enalapril 5 years Nisoldipine: 155/98 mmHg Fatal & non-fatal AMI
Enalapril: 156/98 mmHg Nisoldipine 25 cases
No significant difference in BP reduction between Enalapril 5 cases
the two medications
MAP: Nisoldipine 98, enalapril 98
ABCD-NT All Type 2 Type 2 diabetes & DBP 80-89 mmHg 480 Mean BP at baseline & after 5.3 years Intensive v moderate:
(Schrier, 2002) diabetes Intensive: 5.3 years Intensive treatment - 136/84, 128/75 mmHg Death: OR 1.1 (0.56-2.12)
-Nisoldipine Moderate treatment - 137/84, 137/81 mmHg CVD death: OR 0.66 (0.28-1.58)
-Enalapril MI: OR 0.75 (0.37-1.52)
Moderate: Less CVA: OR 3.29 (1.06-10.25)
-Placebo
-Some on placebo required
antihypertensive during follow-up (SBP
160 &/or DBP 90)
ALLHAT 35% Type 2 Randomly assigned to Mean 3.3 BP at baseline & after 4 years No difference between the group for fatal CHD
(2000) diabetes Doxazosin 2-8 mg 3,182 years Doxazosin: 145/84, 138/78 mmHg or non fatal MI & total mortality.
Chlorthalidone 12.5 25 mg 5,481 Chlorthalidone: 145/83, 136/78 mmHg Doxazosin had a higher risk of:
Similar BP reduction for both drugs Stroke RR 1.19(1.01-1.40, p=0.04)
Combined CVD RR 1.25(.17-1.33, p<0.001)
ALLHAT 36% Type 2 Randomly assigned to Mean 4.9 BP at baseline & at 4 years In people with diabetes:
(2002a) diabetes Chlorthalidone 12.5 25 mg 5,528 years Chlorthalidone: 146/84; 134/77 mmHg No difference between the groups for fatal CHD
Amlodipine 2.5-10mg 3,323 Amlodipine: 146/84; 135/76 or nonfatal MI, all cause mortality or stroke.
Lisinopril 10-40mg 3,212 Lisinopril; 146/84; 136/77 Heart failure less with chlorthalidone compared
with amlodipine and lisinopril.
CAPPP Diabetes Diastolic blood pressure>100 mmHg Median BP at baseline & after 6 years 1 endpoint 40% (fatal and non fatal stroke,
(Niskanen, 2001) subgroup Captopril 309 >6 year Captopril: 164/97, 156/89 mmHg MI and CVD death)
analysis Diuretic/ blocker1 263 Diuretic/ blocker: 163/97, 154/88 mmHg AMI 65%
all CV events 33%
FACET All Type 2 Systolic blood pressure>140 mmHg or 380 Mediasn BP at baseline & after 6 years CV events with fosinopril
(Tatti, 1998) diabetes Diastolic blood pressure>90 mmHg <3 years Fosinopril: 170/95, 157/88 mmHg (14/189 v 27/191)
Open randomised Amlodipine: 171/94, 153/86 mmHg
Amlodipine v fosinopril Amlodipine resulted in a greater reduction in SBP
than fosinopril (-19 [CI -22 to -15] v -13 [-16 to -
10], p<0.05) but same reduction in DBP (-8
mmHg)
MAP: amlodipine 108 v fosinopril 111 mmHg
HOPE and MICROHOPE All diabetes 56% had a history of hypertension 3,577 4.5 years BP at baseline & after treatment Ramipril lowered risk of
(Heart Outcomes Prevention Type of Ramipril 10 mg/d v placebo Ramipril: 142/80, reduced -1.9/-3.3 mmHg cardiovascular death by 37% (CI 21-51)
Evaluation study Investigators, diabetes not Placebo: 142/79, changed +0.55/-2.3 mmHg total mortality by 24% (CI 8-37)
2000a) specified Ramipril v placebo, p=0.0002 for SBP, p=0.008 for stroke by 33% (CI 10-50)
DBP overt nephropathy by 24% (CI 3-40, p=0.027)
After adjustment for SBP and DBP, ramipril
reduced the combined primary endpoint by 25%
(CI 12-36, p=0.0004)
* greater clinical benefit in diabetic cohort with intensive blood pressure lowering. CVA cerebral vascular accident
49
with people
Diabetes with
diabetes
HOT 8% type of DBP 100-115 mmHg 1501 Median BP at baseline & after 3.8 years *Benefit only detected in diabetic cohort
(Hansson, 1998) diabetes not Randomisation into 3 target BP groups: (500 per 3.8 years DBP 80 mmHg target: 170/105, 140/81 mmHg total mortality 55%
specified felodipine based ACE inhibitors/- group) DBP 85 mmHg target: 170/105, 141/83 mmHg CV mortality 67%
blocker/diuretic DBP 90 mmHg target: 170/105, 144/85 mmHg CV events 51%
DBP target 80 mmHg
DBP target 85 mmHg
DBP target 90 mmHg
IDNT All Type 2 Elevated BP (SBP >135 mmHg or DBP 1715 2.6 years BP at baseline & after 2.6 years Irbesartan associated with 20% reduction v
(Lewis, 2001) diabetes >85 mmHg) Irbesartan: 160/87, 140/77 mmHg placebo (p=0.02) & 23% reduction v amlodipine
Type 2 diabetes with nephropathy - Amlodipine: 159/87, 141/77 mmHg (p=0.006) in primary composite endpoint
urinary protein excretion 900mg/24 h Placebo: 158/87, 144/80 mmHg Risk of doubling of creatinine: 29% lower with
RCT MAP was 3.3 mmHg lower in two active-treated irbesartan v placebo (p=0.009) & 39% lower v
Irbesartan 75-300 mg/d gps v placebo (p=0.001) amlodipine (p<0.001)
Amlodipine 2.5-10 mg/d Creatinine increased 24% slower with irbesartan
Placebo v placebo (p=0.008) and 21% slower v
amlodipine (p=0.02)
IRMA II All Type 2 Elevated BP (mean SBP >135 mmHg or 590 2 years BP at baseline & after 2 years 5.7% with 300 mg, 9.7% with 150 mg v 14.9%
(Parving, 2001) diabetes mean DBP >85 mmHg, or both) Type 2 300 mg: 153/91, 141/83 mmHg with placebo reached the primary endpoint
diabetes and microalbuminuria (AER 20- 150 mg: 153/90, 143/83 mmHg (onset of diabetic nephropathy, AER >200
200 ug/min) placebo: 153/90, 144/83 mmHg ug/min & at least 30% higher than the baseline
Double-blind, placebo-controlled combined irbesartan gp v placebo, p=0.004 for level)
irbesartan 150 or 300 mg/d v placebo comparison for SBP HR 0.30 (CI 0.14-0.61, p<0.001) for 300 mg gp
HR 0.61 (CI 0.34-1.08, p=0.08) for 150 mg gp
LIFE Diabetes Double blind randomised 1195 Minimum BP at baseline & after 4 years Losartan: 176/97, Losartan v Atenolol
(Lindholm, 2002) Subgroup Systolic blood pressure 160-200 mmHg 4 years 146/79 mmHg Primary Endpoint: RR 0.76(CI 0.58-0.98),
Losartan v Atenolol Atenolol: 177/96, 148/79 mmHg p=0.031
CVD death: RR 0.63(CI 0.42-0.95), p=0.028
All cause mortality: RR 0.61(CI 0.45-0.84),
p=0.002
NORDIL 6.7 % type of Diastolic BP 100mmHg or more on at 727 4.5 years BP at baseline RRR in people with diabetes not significantly
(Hansson, 2000) diabetes not least two occasions Diltiazem: 174/106 mmHg different between groups
specified Randomised to Diltiazem based regimen Diuretic & blocker:173/106 mmHg Fatal + non-fatal:
or conventional therapy ( blockers, During follow-up, reduction in BP Stroke: RR 0.80 (CI 0.65-0.99), p=0.04
diuretics or both) Diltiazem: 20.3/18.7 mmHg (p<0.001) MI: RR 1.16 (CI 0.94-1.44), p=0.17
Diuretic & blocker: 23.3/18.7 mmHg (p<0.001)
PROGRESS 12.5% type of no BP entry criteria 762 Mean 3.9 BP at baseline Active treatment v. placebo:
(2001) diabetes not randomised, double-blinded, placebo- years Active:147/86 mmHg RRR of 28% (CI 17-38) for total stroke
specified controlled Placebo: 147/86 mmHg (p<0.0001)
perindopril 4 mg daily + indapamide 2.5 BP reduction: RRR of 26% (CI 16-34) for total major vascular
mg daily Average difference between groups at end of the events
perindopril 4 mg daily alone study was 9.0/ 4.0 mm/Hg. Similar reductions in risk of stroke in
hypertensive and nonhypertensive subgroups (all
p<0.01)
Combination of perindopril & indapamide
reduced stroke risk by 43% (CI 30-54)
* greater clinical benefit in diabetic cohort with intensive blood pressure lowering
50
with people
Diabetes with
diabetes
RENAAL All Type 2 All with diabetic nephropathy 1,513 3.4 years BP at baseline: Losartan v placebo:
(Brenner, 2001) diabetes 93.5% received antihypertensives Losartan: 152/82 mmHg RRR of 16% for primary composite endpoints
losartan v placebo Placebo: 153/82 mmHg RRR of 25% for doubling serum creatinine
BP at 3 years: RRR of 28% for ESRD
Losartan: 140/74 mmHg RRR of 20% for ESRD or death
Placebo: 142/74 mmHg
SHEP 12.3% Type 2 Systolic hypertension 583 4.5 years BP at baseline Benefit similar to non-diabetic cohort
(Curb, 1996) diabetes 160-219/<90 mmHg diuretic: 170/77 mmHg CV events 34%
diuretic (chlorthalidone) v placebo Placebo: 170/75 mmHg
After 4.5 years , BP was lower with active therapy,
with a difference between groups of 9.8/2.2 mmHg
MAP: diuretic 95 v placebo 100 mmHg
STOP Hypertension-2 10.9% type of 6614 Randomised to 719 4.5 years BP at baseline: 194/98mmHg in all gps Old and new antihypertensive medications
(Hansson, 1999b) diabetes not ACE inhibitor: BP at 54 months: similar in prevention of cardiovascular mortality
specified Ca antagonist ACE inhibitor: 159/81 mmHg or major events.
-blockers and/ or diuretics Ca antagonist: 159/80 mmHg ACE inhibitors significantly less MI and
-blockers and/ or diuretics: 158/81 mmHg congestive heart failure v Ca antagonists.
Syst-Eur (Tuomilehto, 1999) 10.5% type of Systolic hypertension 492 Median BP at baseline In people with diabetes:
diabetes not 160-219/<95 mmHg 2 years Nitrendipine: 175/86 mmHg, Benefit of treatment:
specified double-blind Placebo: 175/86 mmHg CVD mortality reduced by 70% (CI 19-89)
nitrendipine v placebo BP reduction after 2 years: All CVD events reduced by 62% (CI 19-80)
Nitrendipine: 22.1/6.8 mmHg Stroke reduced by 69% (CI 14-89)
Placebo: 13.5/2.9 mmHg
The difference between groups 8.6/3.9 mmHg
MAP: nitredipine 103 v placebo 109 mmHg
UKPDS All Type 2 Open randomised Median BP at baseline & after treatment No difference Captopril v atenolol
(UKPDS 38, 1998, UKPDS 39, diabetes Less tight blood pressure (<180/105 390 8.4 years Captopril: 159/94, 144/83 mmHg Tight v less tight:
1998) mmHg) v Atenolol: 159/93, 143/81 mmHg diabetes related event 24%
Tight blood pressure (<150/85 mmHg), 758 Less tight control: 160/94, 154/87 mmHg diabetes related death 32%
Randomised to captopril or atenolol Cap 400 MAP: tight control 103 v Less tight control 109 MI 21% (NS)
Aten 358 mmHg
* greater clinical benefit in diabetic cohort with intensive blood pressure lowering
51
Blood pressure reduction improves outcomes in people with Type 2 diabetes
Several meta-analyses of the effects of blood pressure lowering regimens in

nondiabetic hypertensive people have been performed. An earlier meta-analysis
(Collins et al, 1990) of 14 RCTs in 36,908 people with moderate hypertension (DBP
<110 mmHg) showed that treatment with blood pressure lowering medications
(mainly diuretics and blockers) resulted in significant reductions in fatal (p<0.0001),
nonfatal (p<0.0001) and total strokes (p<0.0001) compared with placebo. A reduction
in mean DBP of 5-6 mmHg was associated with about 35-40% less stroke and 20-
25% less CHD. Psaty et al (1997) analysed the data from 18 long-term RCTs with an
average follow-up of 5 years which involved 48,220 people and with an average
follow-up of 5 years and found that blockers and high-dose diuretics were effective
in preventing stroke (RR 0.71 [0.59-0.86]; RR 0.49 [0.39-0.62] respectively) and
congestive heart failure (RR 0.58 [0.40-0.84]; RR 0.17 [0.07-0.41], respectively).
Low-dose diuretics prevented not only stroke (RR 0.66 [0.55-0.78]) and congestive
heart failure (RR 0.58 [0.44-0.76]) but also coronary disease (RR 0.72 [0.61-0.85])
and total mortality (RR 0.90 [0.88-0.99]).
More recent meta-analyses have examined cardiovascular outcomes with blood

pressure lowering medications. The Blood Pressure Lowering Treatment Trialists
Collaboration (2000) showed that treatment with ACE inhibitors resulted in overall
reductions in stroke (30% [15-43%]), coronary heart disease (20% [11-28%]), and
major cardiovascular events (21% [14-27%]) in 4 placebo-controlled trials of 12,124
people with coronary heart disease. Similarly, the two trials of 5,520 people treated
with CCB showed reductions in stroke (39% [15-56%]) and major cardiovascular
events (28% [13-41%]). Another meta-analysis analysed the effects of blood pressure
reduction using different blood pressure lowering medications in 62,605 people with
hypertension (Staessen et al, 2001). Compared with older medications such as
diuretics and -blockers, ACE inhibitors and CCBs provided similar overall
cardiovascular protection but CCBs provided more reduction in risk of stroke and less
reduction in risk of myocardial infarction. Staessen et al concluded that blood pressure
control is important and that all blood pressure lowering medications have similar
efficacy and safety.
A meta-analyses of blood pressure medication studies in people with Type 2 diabetes

was performed by Huang et al (2001) and included the results of 6 studies (data on
7572 people) published until 2000. Blood pressure lowering was associated with a
rate ratio of 0.73 (CI 0.57-0.94) for aggregate cardiac events (coronary heart disease
death and nonfatal myocardial infarction), 0.59 (CI 0.49-0.71) for CVD mortality,
0.78 (CI 0.67-0.92) for myocardial infarction and 0.65 (CI 0.53-0.80) for stroke.
Since this meta-analysis a number of other studies have been published confirming
the beneficial effects of blood pressure lowering in people with diabetes. These are
detailed in Table 8.
A variety of antihypertensive agents are efficacious in lowering blood pressure in

A number of studies have compared the effects of various blood pressure lowering
medications on outcomes in people with diabetes (Table 8)
The UK Prospective Diabetes Study (UKPDS 38, 1998) compared the ACE inhibitor
captopril and the -blocker atenolol (n=358) in people with newly diagnosed Type 2
diabetes. After 9 years follow-up, captopril and atenolol were equally effective in
52
reducing blood pressure and diabetes-related endpoints and mortality. There were no
differences in microvascular and macrovascular complications (p=0.43) or all-cause
mortality (p=0.28).
The Captopril Prevention Project (CAPPP) Study compared cardiovascular morbidity

and mortality with captopril and conventional blood pressure lowering medications
(-blockers/diuretic) and recently the subgroup analysis of the 572 people with
diabetes has been reported (Niskanen et al, 2001). Compared with the conventional
therapy group, captopril therapy resulted in significant reduction in cardiovascular
mortality including fatal stroke and myocardial infarction, sudden death and other
cardiovascular death (RR 0.48, p=0.084). Myocardial infarction was also lower in the
captopril group (RR 0.34, p=0.002). There was no difference in stroke between the
two groups. Total mortality was also lower in people treated with captopril (RR 0.54,
p=0.034).
Several studies have examined the effects of CCBs in lowering blood pressure in
people with diabetes and have given conflicting results. The Appropriate Blood
Pressure Control in Diabetes (ABCD) Trial was primarily established to assess the
progression of diabetic nephropathy when treated with the ACE inhibitor enalapril
compared with the CCB nisoldipine and included 480 normotensive and 470
hypertensive people (Estacio et al, 1998). After 67 months the Data and Safety
Monitoring Committee observed a significant increase in myocardial infarction in the
CCB treated group among the hypertensive cohort and recommended discontinuation
of the CCB therapy. However, the interpretation of the data which lead to this
decision has been questioned on the grounds that it was not a pre specified outcome,
that the study was not powered for this outcome, that more people in the ACE
inhibitor group received diuretics and blockers and more people in the CCB group
stopped treatment (Staessen et al, 2001).
The Fosinopril Amlodipine Cardiovascular Events Trial (FACET) compared the ACE
inhibitor fosinopril and the CCB amlodipine in 380 hypertensive people with Type 2
diabetes (Tatti et al, 1998). Subjects were randomised to receive either medication as
first line therapy but if blood pressure remained elevated the alternate agent was
added. In the intention to treat analysis people treated with the ACE inhibitor had
significantly lower risk of combined endpoints of acute myocardial infarction (10 v 13
events), stroke (4 v 10 events), or hospitalisation for angina (0 v 4 events) total
events 14/189 v 27/191. In total 108 people received combination therapy of ACE
inhibitor and CCB but a separate analysis of this group has not been reported.
A recent meta-analysis has specifically examined the outcomes in the above 4 studies
which included hypertensive people with Type 2 diabetes randomised to treatment
with an ACE inhibitor or an alternate medication and who were followed for 2 or
more years. When the 4 studies were combined the relative risks were significantly in
favour of the ACE inhibitor for myocardial infarction (RR 0.73 [CI 0.54-0.99]) and
cardiovascular events (RR 0.77 [CI 0.61-0.91]) but not for stroke (RR 0.86 [CI 0.59-
1.26] or all-cause mortality (RR 0.85 [CI 0.64-1.12]) (Pahor et al, 2000). There was
heterogeneity in the study results with the UKPDS study providing results different to
that of the other studies. Excluding the results of the UKPDS showed a significant
reduction by the ACE inhibitor in myocardial infarction, cardiovascular events and
all-cause mortality but not stroke. It is not possible to reconcile the difference in
findings of the large UKPDS study with the other studies.
The Swedish Trial in Old Patients with Hypertension-2 (STOP HT-2) study compared
conventional blood pressure lowering medications ( blocker or diuretic) and newer
therapies (ACE inhibitor or CCBs) in people aged 70-84 years with systolic
53
hypertension and 719 (10.9%) of the study cohort has diabetes (Hansson et al, 1999b).
For the overall results the older and newer medications achieved similar prevention of
cardiovascular mortality and major events but ACE inhibitors were associated with
less risk of myocardial infarction and congestive cardiac failure. However in the
subgroup of people with diabetes, there were no significant differences in the primary
endpoints between the treatment groups (conventional medications v ACE inhibitor v
CCB).
The Nordic Diltiazem (NORDIL) study compared diltiazem (a non dihydropyridine

CCB) with conventional therapy ( blocker, diuretic or both) in people with elevated
DBP ( 100 mmHg) (Hansson et al, 2000). Of the 10,881 subjects enrolled, 727 had
diabetes. Overall the study found that new and old treatments were equally effective
in preventing the combined endpoints of stroke, myocardial infarction and other
cardiovascular death although treatment with diltiazem was significantly better in
preventing stroke (RR 0.80, [0.65-0.99], p=0.04) and non significantly worse in
preventing myocardial infarction (RR 1.16, [0.94-1.44], p=0.17). The subgroup
analysis of the people with diabetes showed no difference in any outcomes.
In summary the studies on CCBs in hypertensive people with diabetes have provided
conflicting results. In systolic hypertension dihydropyridine CCB outcomes were
similar to older treatments and in diastolic hypertension non-dihydropyridine CCB
was also as effective as older treatments. However a worse outcome in risk of
myocardial infarction has been reported in one study (ABCD) (Estacio et al, 1998)
and a worse risk of combined cardiovascular outcomes in another study with the use
of dihydropyridine CCBs compared with ACE inhibitors (FACET) (Tatti et al, 1998).
Although controversy continues about these findings, because of these lingering
doubts and the availability of suitable alternate agents, it is considered that CCBs
should not be used as first line therapy in treating people with diabetes and above
target blood pressure, except possibly in those with systolic hypertension. More data
are required to establish whether any possible differences in outcomes apply equally
to the subclasses of CCBs.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

(ALLHAT) compared 4 blood pressure lowering medications diuretic
(chlorthalidone), blocker (doxazosin), CCB (amlodipine) and ACE inhibitor
(lisinopril) on the incidence of CVD in people with hypertension, including 8,663
people with diabetes (ALLHAT Collaborative Research Group, 2000). In January
2000 after an interim analysis, an independent review recommended discontinuing the
doxazosin treatment arm based on an increased risk of stroke and combined
cardiovascular outcomes (coronary death, nonfatal myocardial infarction, stroke,
angina, coronary revascularisation, congestive cardiac failure and peripheral vascular
disease), especially congestive cardiac failure (ALLHAT Collaborative Research
Group, 2000). The RR of these outcomes was similar in people with and without
diabetes.
More recently another report from the ALLHAT study has detailed the comparison of
treatment with chlorthalidone, amlodipine and lisinopril (ALLHAT, 2002a). The total
cohort of 33,357 people aged 55 years and older included 5,528 people with diabetes
treated with chlorthalidone, 3,323 treated with amlodipine and 3,212 treated with
lisinopril. The primary outcome of combined fatal CHD or nonfatal myocardial
infarction occurred in approximately 11% of people and stroke in approximately 6%
over the mean follow up period of 4.9 years. In people with diabetes there were no
differences between the treatment groups for fatal CHD or nonfatal MI, all cause
mortality or stroke. Heart failure occurred significantly less often with chlorthalidone
54
compared with amlodipine and lisinopril.
A number of studies have examined the effects of ARBs and cardiovascular

outcomes. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)
study included 1,195 people with diabetes, hypertension and left ventricular
hypertrophy (Lindholm et al, 2002). Compared with atenolol, losartan was
significantly more effective in reducing primary composite endpoint including
cardiovascular mortality, stroke and myocardial infarction (RR 0.73 [CI 0.57-0.95],
p=0.017), cardiovascular mortality (RR 0.63 [CI 0.42-0.95], p=0.028), as well as
mortality from all causes (RR 0.61 [CI 0.45-0.83], p=0.002).
The Program for Irbesartan Mortality and Morbidity Evaluation (PRIME) is

evaluating combined cardiovascular and renal outcomes in the following 2 studies.
The Irbesartan Diabetic Nephropathy Trial (IDNT) (Lewis et al, 2001) compared the
effects of irbesartan 75-300 mg/d with amlodipine 2.5-10 mg/d and placebo in 1,715
hypertensive people with Type 2 diabetes and nephropathy. Over a mean of 2.6 years
followup, treatment with irbesartan reduced progression of renal disease or death by
20% compared with placebo (p=0.02) and by 23% (p=0.006) compared with
amlodipine. In the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria
Study (IRMA II), 590 hypertensive people with Type 2 diabetes were randomised to
receive irbesartan (150 or 300 mg) or placebo and were followed for 2 years. People
treated with irbesartan 150 mg or 300 mg had a slower progression of renal disease
compared to those treated with placebo (HR 0.61 [CI 0.34-1.08], p=0.08, and HR 0.30
[CI 0.14-0.61], p<0.001, respectively) (Parving et al, 2001). The Reduction of
Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study
which involved 1,513 hypertensive people with Type 2 diabetes compared the effects
of the addition of losartan 50-100 mg daily or placebo, taken in addition to
conventional blood pressure lowering medications, on cardiovascular events. Over a
mean of 3.4 years, treatment with losartan reduced the risk of primary composite
endpoint (end-stage renal disease or death) by 16% (p=0.02), doubling of creatinine
by 25% (p=0.006), end stage renal disease (ESRD) by 28% (p=0.002), but there was
no effect on mortality rate (Brenner et al, 2001).
In summary, for initiation of blood pressure lowering medications in people with

diabetes without a raised AER, a choice can be made between ACE inhibitors, ARBs,
diuretics and -blockers depending on the clinical context.
The role of non-blood-pressure-lowering effects of antihypertensive medications

remains uncertain
The relative importance of blood-pressure-lowering versus non-blood-pressure-

lowering effects of antihypertensive therapy on reducing risk of CVD remains
uncertain in relation to cardiovascular outcomes.
This possibility was first raised by the results of the Heart Outcomes Prevention
Evaluation Study (HOPE, 2000b) which included a total of 9,297 high risk people
aged over 55 years, of whom 3,578 had diabetes (type not specified). People without
diabetes all had evidence of vascular disease, and an additional entry criteria for
people with diabetes was the presence of one other cardiovascular risk factor
(hypertension, hypercholesterolaemia, microalbuminuria or smoking). Participants
were randomly assigned to receive the ACE inhibitor ramipril 10 mg per day or
placebo for a mean of 5 years. The primary outcome was a composite of myocardial
infarction, stroke or death from cardiovascular causes. In people treated with ramipril,
14.0% reached the primary endpoint compared with 17.8% of those treated with
55
placebo (RR 0.78 [CI 0.70-0.86], p<0.001). The beneficial effect of treatment with
ramipril was observed consistently in people with or without diabetes, women and
men, those with or without cardiovascular disease, those younger or older than 65
years, those with or without hypertension at baseline and those with or without
microalbuminuria. When each endpoint was analysed separately, the ramipril group
was associated with a 20% relative risk reduction in myocardial infarction, a 32%
reduction in stroke, and a 16% reduction in death from any cause. In addition, there
was a 16% reduction in complications related to diabetes and a 34% reduction in
newly diagnosed diabetes in the ramipril group. Treatment with an ACE inhibitor was
also associated with a beneficial effect on diabetic nephropathy but the effect on self-
reported retinopathy was not statistically significant. These findings occurred in the
context of no change in HbA1c and a reduction in blood pressure at 4 years of only
2.4/1 mmHg in the diabetic subgroup (HOPE, 2000a).
However these findings have not been confirmed by a recent meta-analysis of

cardiovascular protection in 62,605 people with hypertension (including the HOPE
and UKPDS) which found that CCBs and ACE inhibitors produced similar overall
cardiovascular protection. When compared with diuretics and -blockers, CCBs
reduced the risk of stroke by 13.5% (1.3-24.2%, p=0.03), but increased the risk of
myocardial infarction by 19.2% (3.5-37.3%, p=0.01); whereas ACE inhibitors
resulted in a non significant increase in the risk of stroke (5.8%) and decrease in the
risk of myocardial infarction (1.3%) (Staessen et al, 2001). Staessen et al concluded
that all blood pressure lowering medications have similar long-term efficacy and
safety and did not find that ACE inhibitors affected cardiovascular prognosis beyond
their blood pressure lowering effects.
Angiotensin receptor blockers and angiotensin converting enzyme inhibitors are

specifically indicated in people with increased albuminuria
Two meta-analyses which included more than 20 studies indicate that ACE inhibitors
are the preferred choice in people with Type 2 diabetes and diabetic nephropathy
(Kasiske et al, 1993; Weidmann et al, 1995). In one meta-analysis (Kasiske et al,
1993), 17% of people with diabetes (49% Type 1 and 32% Type 2) had WHO stage 3
diabetic nephropathy (microalbuminuria) and 35% had clinical nephropathy (stage 4
or 5). Compared with other agents, ACE inhibitors had an additional favorable effect
on glomerular filtration rate (GFR) that was independent of blood pressure changes
(3.411.71 ml/min, p=0.05). The other meta-analysis (Weidmann et al, 1995) of 2,152
people with diabetes (39% Type 1 and 40% Type 2) and diabetic nephropathy
(albumin excretion 30 mg/d) showed that ACE inhibitors resulted in significant
reductions in mean blood pressure (-11%, [CI -17 to 5]) and total proteinuria (-37%,
[CI -53 to 22]) compared with conventional therapy (both p<0.001).
Several recent studies have assessed the effects of the ARBs irbesartan or losartan in
hypertensive people with Type 2 diabetes and early (Parving et al, 2001) or late renal
disease (Brenner et al, 2001; Lewis et al, 2001). In The Irbesartan in Patients with
Type 2 Diabetes and Microalbuminuria Study (IRMA II), Parving et al (2001)
compared 2 doses of irbesartan and placebo and has also found that 5.7% of people in
irbesartan 300 mg group, 9.7% in irbesartan 150 mg group and 14.9% in the placebo
group had reached the primary endpoint. A significant reduction in progression of
diabetic nephropathy was observed in people treated with irbesartan 300 mg (hazard
ratio 0.30, CI 0.14-0.61, p<0.001) and with irbesartan 150 mg (HR 0.61, CI 0.34-1.08,
p=0.08). The Irbesartan Diabetic Nephropathy Trial (IDNT) (Lewis et al, 2001)
compared irbesartan with the CCB (amlodipine) and placebo and has been shown to
reduce progression of ESRD or death by 20% compared with placebo (p=0.02) and by
56
23% (p=0.006) compared with amlodipine in 1715 hypertensive diabetic people with
nephropathy (urinary protein excretion 900 mg/24 h). The Reduction of Endpoints in
NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study of 1,513
hypertensive people compared losartan and placebo and reported risk reductions in
doubling of creatinine (25%, p=0.006), ESRD (28%, p=0.002), but had no effect on
the rate of death (Brenner et al, 2001). Lozano et al (2001) studied the effect of
losartan in 422 hypertensive people with Type 2 diabetes and microalbuminuria. Over
a 6 month period losartin was associated with a reduction in albumin excretion from
11585 mg/24 h to 6655 mg/24 h (p<0.0001) and 25% of people normalised their
microalbuminuria.
ACE inhibitors and ARBs seem to be equally effective in reducing microalbuminuria

in hypertensive people with Type 2 diabetes. Lacourciere et al (2000) compared
losartan and enalapril in a 1 year double blind study in 83 people with Type 2
diabetes, hypertension and microalbuminuria. Albumin excretion decreased
significantly with both medications (from 64.1 to 41.5 ug/min for losartan and from
73.9 to 33.5 ug/min for enalapril, both p<0.001) and there were no differences in the
effects in terms of the changes in blood pressure and GFR for the two medications.
The Candesartan and Lisinopril Microalbuminuria (CALM) Study, compared
treatment with candersartin and lisinopril alone or combined in 199 hypertensive
people with Type 2 diabetes and microalbuminuria. After 12 weeks there was a
significant reduction in mean DBP of 9.5 mmHg with candesartan (p<0.001) and of
9.7 mmHg with lisinopril treatment (p<0.001), and reduction in urinary
albumin:creatinine ratio by 30% (p<0.001), and by 46% (p<0.001), respectively. The
combination of both medications showed a greater reduction in mean DBP and
urinary albumin:creatinine ratio (13.6 mmHg, 50%, respectively, both p<0.001) than
observed with candesartan (10.4 mmHg, 24%, both p<0.001) or lisinopril (10.7
mmHg, 39%, both p<0.001) alone at 24 weeks (Mogensen et al, 2000).
ACE inhibitors and ARBs may induce hyperkalaemia, especially in the context of
hyporeninaemic hypoaldosteronism or undiagnosed renal artery stenosis. The long-
term effect of enalapril (ACE inhibitor) or placebo was examined over 5 years in 94
people with Type 2 diabetes (Ravid et al, 1993). The serum potassium level in the
people receiving enalapril was 4.26 0.3 compared with 3.98 0.36 mmol/l for
placebo (p <0.05).
ACE inhibitors and ARBs can be used in combination in people with Type 2 diabetes
and diabetic nephropathy. Rossing et al (2002) studied 18 hypertensive people with
proteinuria (>1g/day) and Type 2 diabetes who were all taking ACE inhibitors. The
addition of candersartin 8mg daily induced a 25% (CI 2-58%, p=0.036) reduction in
albuminuria and a reduction in 24 h SBP of 10 mmHg (CI 2-18, p=0.019).
CCBs are not recommended as first line therapy in diabetic people with renal disease
unless other agents are contraindicated or cannot be tolerated. Studies with CCBs
(both non-DHP) have provided conflicting results with regard to their renoprotective
effect. Bakris et al (1996) reported that treatment with non-DHP-CCB (verapamil and
diltiazem) or ACE inhibitor (lisinopril) resulted in similar reduction in proteinuria
(p>0.99). There was also no difference in the rate of decline of renal function for the
two therapies (p=0.36) in 52 hypertensive diabetic people with nephropathy. In a 3-
year study (Velussi et al, 1996), treatment with either ailazapril or amlodipine lowered
the AER to a similar extent in 44 hypertensive people with Type 2 diabetes with
normoalbuminuria or microalbuminuria. The rate of decline in GFR was significantly
related to the reduction in mean blood pressure (p<0.0001). However, other studies
have shown that ACE inhibitors have a greater antialbuminuric effect than DHP-
57
CCBs (Agardh et al, 1996; De Cesaris et al, 1996; Guasch et al, 1997; Fogari et al,
1999).
Angiotensin converting enzyme inhibitors and/or -blockers are specifically

indicated in people with Type 2 diabetes after myocardial infarction
In hypertensive and non-hypertensive people with Type 2 diabetes, treatment with an

ACE inhibitor has been associated with decreased mortality following myocardial
infarction (Zuanetti et al, 1997). Early treatment with ACE inhibitor (begun within 24
h from the onset of symptoms of MI) compared with treatment with placebo was
associated with a 24.5% reduction in six-week mortality of people with Type 2
diabetes (8.0% v 10.6%, OR 0.73 [CI 0.55-0.97]) and this reduction was greater than
that observed in nondiabetic people (5.6% v 5.9%, OR 0.95 [CI 0.83-1.09], p<0.025).
The beneficial effect was maintained at six months despite withdrawal of the
treatment after six weeks (total mortality 12.9% v 16.1%, OR 0.77, [CI 0.62-0.95]).
The HOPE Study (2000b) of more than 9,000 people, supports the concept that people
with diabetes (type not specified) and at least one other cardiovascular risk factor such
as hypertension, elevated total cholesterol levels, low levels of high density
lipoprotein cholesterol, cigarette smoking or documented microalbuminuria should be
considered for ACE inhibitor therapy after myocardial infarction.
-blockers also reduce mortality following myocardial infarction in people with

diabetes (type not specified), with an absolute and relative beneficial effect in most
cases larger than that observed in people without diabetes (Kendall et al, 1995). The
pooled results of early treatment of myocardial infarction with -blockers indicate a
13% mortality reduction in all people compared with a 37% mortality reduction in
people with diabetes (Kendall et al, 1995). Also there was clear evidence of benefits
of -blockade in people with diabetes (n=340, type not specified) after myocardial
infarction (Kjekshus et al, 1990). Diabetic people who were treated with -blockers
had 1-year cardiac mortality of 10.2% compared to 23.4% in those not on -blocker
(p<0.001). The 1-year mortality was 7% versus 17%, respectively (p<0.04).
With respect to reversal of left ventricular mass index (LVMI), CCBs have been
shown to exert greater (Gerritsen et al, 1998) or similar (Scognamiglio et al, 1997)
effects to ACE inhibitors in people with Type 2 diabetes. Gerritsen et al (1998)
randomised 122 hypertensive people (200/90-115 mmHg) with Type 2 diabetes to
receive nitrendipine, enalapril or placebo. Left ventricular hypertrophy (LVMI 135
g/m2 for men and 111 g/m2 for women) was present in 70%, 73%, and 73% of
people in the three groups, respectively. After 48 weeks treatment, LVMI was
decreased by 5% (-12 g/m2) in the nitredipine group, remained the same (-1 g/m2) in
the enalapril group and increased by 9% (+9 g/m2) in the placebo group (p=0.0002). A
study of 75 Type 2 diabetic people with LVMI 75 g/m2 were treated with captopril
or nifedipine for 36 weeks (Scognamiglio et al, 1997) showed that both drugs were
equally effective in reducing left ventricular mass (captopril: 892 to 852 g/m2;
nifedipine: 872 to 811 g/m2, p=0.0001).
A number of blood pressure lowering medications are useful as initial therapy in

elderly people with isolated systolic hypertension
The Systolic Hypertension in the Elderly Program (SHEP) included 583 people with
diabetes and active treatment based on the diuretic chlorthalidone was compared with
placebo (Curb et al, 1996). Active treatment was associated with significantly better
cardiovascular outcomes (34% reduction) (Table 8).
A post hoc analysis of the Systolic Hypertension in Europe Study (Syst-Eur)
58
compared outcomes of treatment with the CCB nitrendipine in people with and
without diabetes and demonstrated improved outcomes in people with diabetes
compared with the non-diabetic subgroup for total and cardiovascular mortality and
all cardiovascular endpoints (Tuomilehto et al 1999) (Table 8).
The Swedish Trial in Old Patients with Hypertension-2 (STOP HT-2) study compared
conventional blood pressure lowering medications ( blocker or diuretic) and newer
therapies (ACE inhibitor or CCBs) in people aged 70-84 years with systolic
hypertension and 719 (10.9%) of the study cohort has diabetes (Hansson et al, 1999b).
In the subgroup of people with diabetes, there were no significant differences in the
primary endpoints between the treatment groups (conventional medications v ACE
inhibitor v CCB) (Table 8).
In order to achieve target blood pressure levels in people with Type 2 diabetes, it
is usually necessary to combine blood pressure lowering medications
Observational studies in people with hypertension have shown that at least half do not
achieve recommended therapeutic blood pressure targets. An Australian study found
that of 2,331 people with Type 2 diabetes at annual complications assessment, 31%
were normotensive (SBP <140 mmHg or DBP <90 mmHg). Only 31% of treated
hypertensive people were adequately controlled. The remainder were either untreated
(28%) or inadequately treated (29%) (Donnelly et al, 1997).
Assessment of compliance requires careful monitoring of blood pressure levels

achieved after dose adjustment and surveillance of side effects such as erectile
dysfunction, which may decrease adherence to therapy. True resistance to blood
pressure lowering therapy is more frequent in association with overt nephropathy. In
these people and in others where there is a documented failure to respond,
combination therapy should be instigated (Bakris et al, 1998). This recommendation is
based on the knowledge that low doses of drugs used together can maximise
hypotensive effect, minimise side effects, improve quality of life and therefore
increase treatment compliance.
Although single drug treatment with most blood pressure lowering medications
produces sustained reductions of only 5-10%, therapy with multiple agents increases
by at least half, the magnitude of the blood pressure reduction achieved. In
hypertensive people with Type 2 diabetes, the UKPDS 38 (1998) showed that
intensive lowering of blood pressure with either an ACE inhibitor or a -blocker
provided greater protection against death from cardiovascular causes and major non-
fatal events than did less aggressive therapy with the same agents. At 9 years the
percentage of people requiring 3 or more blood pressure lowering medications was
29% compared with 11% for the intensive and less tight control groups respectively.
A similar benefit was observed in the HOT study among hypertensive people with
Type 2 diabetes who were randomly assigned to intensive therapy with the
dihydropyridine calcium antagonist felodipine (Hansson et al, 1998). Additional
therapy and dose increments were prescribed to reach target blood pressure. At the
end of the study, the percentage of subjects requiring the addition of ACE inhibitors
or -blocker was 41% and 28% respectively. In the HOT Study (Hansson et al, 1998),
aggressive combination therapy reduced DBP to below 90 mmHg in over 90% of
people.
Achieving blood pressure targets can be difficult even with multiple therapy.
Tomlinson et al (2003) prospectively studied 49 people with diabetes (36 with Type
2) and diabetic nephropathy (proteinuria 500 mg/24 h) who were treated with a
59
stepped blood pressure lowering regimen aiming at the target blood pressure of
<130/80 mmHg. After 18 months of treatment, mean blood pressure was
146/7622/14 mmHg in people with Type 2 diabetes and the target blood pressure
was achieved in 10 out of 36 with Type 2 diabetes. SBP was difficult to control to
target despite the use of multiple combination therapy.
Mixed combination ACE inhibitor + diuretic or ARB + diuretic are now available and
would be especially suitable in people on multiple medications but here have not been
any studies which have specifically reported the use of combination therapy. An
algorithm for blood pressure lowering in people with Type 2 diabetes can be seen in
Figure 4.
60
Figure 4. Algorithm for the treatment of above target blood pressure in
SBP 130 or DBP 80 mmHg
Initiate lifestyle modifications

not at target BP
Concomitant problem?
No Yes
Initial Therapy
Initial Therapy
ACEi Raised AER
ACEi/ARB
ARB
Heart failure ACEi or diuretic
CCB or blocker
blocker Myocardial ACEi or blocker
diuretic infarction
Isolated systolic thiazide diuretic or

hypertension CCB
Angina blocker
not at target BP
Intermittent
avoid blocker
claudication
Renal
loop diuretic
impairment
not at target BP
Proceed to
combination
therapy
AER = Albumin excretion rate
CCB = Calcium channel blocker
SBP = Systolic blood pressure
DBP = Diastolic blood pressure
ACEi = Angiotensin converting enzyme inhibitor
ARB = Angiotensin receptor blocker
61
Summary Blood pressure control in Type 2 diabetes
Weight reduction, increasing physical activity, reducing excessive dietary sodium
and/or alcohol intake) contribute to lowering blood pressure
There are some differences in the effectiveness of different blood pressure

lowering medications in the treatment of above target blood pressure in people
The absolute effects of aggressive lowering of blood pressure on cardiovascular

events is greater in people with diabetes compared with people without diabetes
The choice of blood pressure lowering medication is influenced by concurrent

medical conditions
ARBs and ACE inhibitors are preferred in the treatment of above target blood
pressure in people with Type 2 diabetes with diabetic nephropathy
Blood pressure control in people with diabetes is often resistant to monotherapy

and two or more classes of agent may be required
Figure 4 illustrates an algorithm for the treatment of above target blood pressure
in people with Type 2 diabetes
62
Author Evidence
Agardh C-D (1996)
(Adults Sweden; Norway;
France; Netherlands; UK;
Ireland; Belgium; Germany)
ALLHAT Study (2000) II RCT High High+ Low
(Adults US; Canada)
ALLHAT Study (2002a) II RCT High High +
Low
(Adults US; Canada)
Bakris GL (1996) II RCT High High +
High
(Adults US)
Bakris GL (1998) II RCT High High +
High
(Adults US)
Blood Pressure Lowering Systematic
I High High+ Low
Treatment Triallists (2000) review
Brenner BM (2001)
(Adults Asia; Nth & Sth II RCT High High + High
America; UK; Europe; NZ)
Systematic
Brown SA (1996) I High High+ High
review
Systematic
Collins R (1990) I High High+ Low
review
Curb JD (1996) II RCT High High+ High
(Older adults US)
Systematic +
Cutler JA (1997) I High High Low
review
De Cesaris R (1996) II RCT High High +
High
(Adults Italy)
Dodson PM (1989) II RCT Medium High+ High
(Adults UK)
Donnelly R (1997) III-2 Cohort Medium High +
High
(Adults Australia)
Estacio RO (1998) II RCT High High +
High
(Adults US)
Fogari R (1999) II RCT High High +
High
(Adult men Italy)
Gerritsen TA (1998) II RCT High High+ High
(Adults The Netherlands)
Guasch A (1997)
(Adults US: African II RCT Medium High+ Low
American)
Hansson L (1998)
(Adults Europe; North & II RCT Medium High+ Low
South America; Asia)
Hansson L (1999b) II RCT High High+ Low
(Elderly Sweden)
Hansson L (2000) II RCT High High+ Low
(Adults Norway; Sweden)
Herlitz H (1998) II RCT Medium High +
Low
(Adults men Sweden)
HOPE (2000a) II RCT High High +
High
(Adults Canada)
HOPE (2000b) II RCT High High+ Low
(Adults Canada)
Houlihan CA (2002) II RCT High High +
High
(Adults Australia)
Systematic +
Huang ES (2001) I High High High
review
Kasiske BL (1993) Systematic +
I High High High
(Adults & adolescents) review
Systematic
Kendall MJ (1995) I Medium High+ High
review
Systematic +
Kelley DE (2001) I High Medium High
review
Kjekshous j (1990) III-2 Cohort Medium High+ High
(Adults US; Canada)
significant effect
63
Author Evidence
Lacourciere Y (2000) II RCT High High+ High
(Adults Canada)
Lewis EJ (2001)
(Adults North & South
II RCT High High + High
America; Europe; UK;
Australia; NZ; Asia)
Lindholm LH (2002)
(Adults Sweden; US; II RCT High High+ High
Denmark; UK; Norway)
Lozano JV (2001) II RCT High High+ High
(Adults Spain)
Mogensen CE (2000)
(Adults Australia, II RCT High High+ High
Sweden, Denmark)
Systematic
NHMRC (2001) I High High+ Low
review
Niskanen L (2001) II RCT High High+ High
(Adults Finland)
Parving HH (2001)
(Adults Europe; Canada; II RCT High High + High
Australia; UK; Sth Africa)
Systematic
Pahor M (2000) I High High+ High
review
Systematic
Psaty BM (1997) I High High+ Low
review
Puddey IB (1987) II RCT Medium High+ Low
(Adults Australia)
Ravid M (1993) II RCT High High +
Medium
(Adults Israel)
Reynolds LR (2002) II RCT High High +
High
(Adults US)
Rossing K (2002) II RCT High High+ High
(Adults Denmark)
Sacks FM (2001) II RCT High High+ Low
(Adults US)
Scognamiglio R (1997) II RCT High High +
High
(Adults Italy)
Stamler J (1997) III-2 Cohort Medium High +
Low
(Adult men US)
Systematic
Staessen JA (2001) I High High+ Low
review
Tatti P (1998) +
II RCT Medium High High
(Adults Italy)
Tomlinson JW (2003) III-2 Cohort Medium High +
High
(Adults UK)
Tuomilehto J (1999)
(Older adults Europe) II RCT High High+ High
UKPDS 38 (1998) II RCT High High+ High
(Adults UK)
Velussi M (1996) II RCT High High +
High
(Adults Italy)
Systematic +
Weidmann P (1995) I High High High
review
Systematic
Whelton SP (2002) I High High+ Low
review
Zuanetti G (1997) II RCT High High+ High
(Adults Italy)
significant effect
64
Issue
What is the effect of treatment of blood pressure in Type 2 diabetes?
Recommendation
Blood pressure in people with Type 2 diabetes should be intensively treated in order
to prevent or attenuate macrovascular and microvascular complications.
Evidence Statements
Treatment of blood pressure in people with Type 2 diabetes reduces
macrovascular complications, including stroke, myocardial infarction and heart
failure
Evidence Level I
There is no evidence of increased cardiovascular risk with intensified blood

pressure lowering in people with Type 2 diabetes
Evidence Level II

microvascular complications, including nephropathy and retinopathy
Evidence Level I
65
Background The effects of treatment of blood pressure
Understanding of the effects of blood pressure lowering medications in people with
Type 2 diabetes has changed considerably in recent years with the publication of
several long-term prospective controlled trials. The two main concepts, which have
emerged, are, firstly, that blood pressure reduction has significant and possibly greater
preventive effects on macrovascular disease than blood glucose lowering (UKPDS 38,
1998). Secondly, that intensive blood pressure control to produces cardiovascular
protective effects which are at least as great or greater in people with diabetes than in
people without diabetes (Hansson et al, 1998).
Coronary heart disease and stroke are main causes of death and morbidity in people
with Type 2 diabetes, with a prevalence of 2-3 times higher than in the non-diabetic
population. Prevention of CHD is therefore a major target of blood pressure lowering
medications in Type 2 diabetes. A review of observational and interventional studies
in hypertension has shown that antihypertensive therapy is more efficient in
preventing stroke than CHD (MacMahon et al, 1990).
Some aspects of the effects on blood pressure lowering and microvascular

complications in older people with Type 2 diabetes compared with younger people
with Type 1 diabetes remain unclear. Recent studies suggest that the renoprotective
effects of blood pressure lowering also apply to Type 2 diabetes. However in people
with Type 1 diabetes, one study has suggested that the development of diabetic
retinopathy can be attenuated by ACE inhibitors (Chaturvedi et al, 1998). Whether
this applies to people with Type 2 diabetes will not be known until the completion of
further randomised controlled trials.
66
Evidence The effects of treatment of blood pressure
macrovascular complications, including stroke, myocardial infarction and heart
failure
A meta-analysis of 15 studies on blood pressure lowering medications in people with

diabetes (Type 1 and Type 2) has shown that blood pressure reduction has a treatment
benefit for cardiovascular mortality with an OR of 0.64 (CI 0-0.80). The OR for CVD
events was 0.68 (CI 0.43 1.05) (Fuller et al, 1999).
A more recent meta-analyses of blood pressure lowering medications studies in

people with Type 2 diabetes was performed by Huang et al (2001) and included the
results of 6 studies (data on 7,572 people) published until 2000. Blood pressure
lowering was associated with a rate ratio of 0.73 (CI 0.57-0.94) for aggregate cardiac
events (CHD death and nonfatal myocardial infarction), 0.59 (CI 0.49-0.71) for CVD
mortality, 0.78 (CI 0.67-0.92) for myocardial infarction and 0.65 (CI 0.53-0.80) for
stroke.
Several studies have been reported since the above meta-analyses and have been
detailed in Section 5 Table 6. These have uniformly shown a beneficial effect on
mortality, CVD events and stroke.
In people with Type 2 diabetes, blood pressure lowering medications may also have
favourable effects on left ventricular hypertrophy (Hansson et al, 1999a), and heart
failure (Tuomilehto et al, 1999).
There is no evidence of increased cardiovascular risk with intensified blood

pressure lowering in people with Type 2 diabetes
Subgroup analyses of intensive blood pressure lowering in large intervention trials

have shown that reduction of cardiovascular events in people with Type 2 diabetes is
at least as great as that observed in non-diabetic people (Curb et al, 1996).
The HOT study showed a greater benefit of intensive blood pressure reduction to near
normal levels in people with Type 2 diabetes than in the general population for total
and CVD mortality and CVD events (Hansson et al, 1998).
Treatment of blood pressure in people with Type 2 diabetes reduces the

microvascular complications of nephropathy and retinopathy
Meta-analyses have shown that blood pressure lowering medications leads to a

reduction in albuminuria in people with micro- or macroalbuminuria (overt diabetic
nephropathy) (Kasiske et al, 1993; Weidmann et al, 1995) in people with Type 1 or
Type 2 diabetes (reviewed in Section 5). The RENAAL study (Brenner et al, 2001)
has demonstrated a reduction in the incidence of end-stage renal failure associated
with blood pressure lowering medications in people with Type 2 diabetes.
Elevate blood pressure is a well recognised risk factor for retinopathy (NHMRC
Retinopathy Guideline, 1997). The UKPDS reported a reduction in microvascular
disease in the tight blood pressure control group compared with the less tight blood
pressure control (p<0.01) (UKPDS 38, 1998). In the tight blood pressure control
group there was a 37% decrease in microvascular endpoints (CI 11-56%),
67
predominantly due to a reduced risk of retinal photocoagulation, a 34% decrease in
the risk of two step progression of existing diabetic retinopathy, and a 47% decrease
in risk of deterioration of visual acuity by three lines using the Early Treatment of
Diabetic Retinopathy Study chart (UKPDS 38, 1998).
It is not known whether certain blood pressure lowering medications have specific
retinoprotective effect independent of blood pressure lowering in people with Type 2
diabetes. A recent study in people with Type 1 diabetes has shown that treatment with
an ACE inhibitor decreases the incidence of diabetic retinopathy by approximately
one third over 2 years (Chaturvedi et al, 1998).
However data from other studies suggest that there is little difference between blood
pressure lowering medications with regard to microvascular outcomes. In the UKPDS
atenolol or captopril were equally effective (UKPDS 39, 1998). The ABCD study
included 470 hypertensive people with Type 2 diabetes randomised to intensive
(achieved blood pressure132/78 mmHg) or moderate (achieved blood pressure 138/86
mmHg) treatment with nisoldipine or enalapril (Estacio et al, 1998). After 5.3 years of
treatment there were no differences in microvascular endpoints between the 2
medications (Estacio et al, 2000).
68
Summary - The effects of treatment of blood pressure
Treatment of blood pressure in people with diabetes reduces mortality,
myocardial infarction, heart failure and stroke
Blood pressure lowering in people with diabetes may be associated with a greater
reduction in macrovascular events than that observed with blood glucose control
alone
Blood pressure reduction in people with Type 2 diabetes, decreases the

development of microvascular disease including microalbuminuria and
retinopathy
Some studies have shown that blood pressure reduction in people with Type 2
diabetes has a greater benefit than in the non diabetic population
There is no evidence that intensified blood pressure lowering therapy leads to an

increase in cardiovascular risk in people with Type 2 diabetes
69
The effects of treatment of blood pressure

Author Evidence
Brenner BM (2001)
(Adults Asia; Nth &
Sth America; UK;
Europe; NZ)
Chaturvedi N (1998)
(Adults Europe)
Curb JD (1996)
(Adults US)
Estacio RO (1998)
(Adults US)
Estacio RO (2000)
(Adults US)
Fuller J (1999) I Systematic review High High+ High
Hansson L (1998)
(Adults Asia; North & II RCT High High+ Low
South America; Europe)
Hansson L (1999a)
(Adults Sweden; II RCT High High+ Low
Finland)
Huang ES (2001) I Systematic review High High+ High
Kasiske BL (1993)
I Systematic review High High+ High
(Adults & adolescents)
NHMRC (1997) I Systematic review High High+ High
Tuomilehto J (1999)
(Older adults Europe)
UKPDS 38 (1998) +
(Adults UK)
UKPDS 39 (1998)
(Adults UK)
Weidmann P (1995) I Systematic review High High+ High
significant effect
70
Issue
Is there synergy in the effects of simultaneous intervention to control blood pressure,
blood glucose and lipids?
Recommendation
Concurrent control of blood glucose, blood pressure and lipids is recommended in
people with Type 2 diabetes.
Evidence Statements
Multifactorial intervention emphasising intensive control of blood pressure, lipids
and blood glucose reduces complications in Type 2 diabetes
Evidence Level II
71
Background - Synergy of interventions
Type 2 diabetes is often associated with elevated blood pressure and lipid levels.
However, few studies have explored the effects of concurrent treatment of 2 or all
three of these metabolic risk factors on the development or progression of
microvascular and macrovascular disease.
Observational population-based studies of large cohorts of subjects for over 10 years

indicate that the risk of death from CHD is related to the presence of multiple risk
factors in a synergistic or additive fashion (Table 9) (Stamler et al, 1993; Flack et al,
1995; Levy et al, 1996).
Table 9: Age-adjusted CVD mortality in men with or without diabetes at initial

screening for MRFIT (Stamler et al, 1993)
Number of Age-adjusted death rate (per 10,000 person years) RR for
risk factors Diabetes Nondiabetes diabetes/nondiabetes
0 30.68 6.02 5.10
1 58.82 12.21 4.82
2 90.87 22.41 4.05

Risk factors defined as systolic blood pressure 120mmHg, total serum cholesterol 5.2 mM, smoker.
Although macrovascular events cause most deaths in people with Type 2 diabetes,
there is also a great demand on health resources to manage the microvascular
complications. Many people develop retinopathy and neuropathy, and Type 2 diabetes
is a principal cause of end-stage renal disease in Australia (ANZDATA Registry
Report, 1998). Some of the risk factors for microvascular complications are
modifiable and this has provided the rationale for a multifactorial approach to
treatment (Gaede et al, 1999).
72
Evidence - Synergy of interventions
Multifactorial intervention emphasising intensive control of blood pressure,
lipids and blood glucose reduces complications in Type 2 diabetes
The Steno Type 2 study was a randomised open parallel trial in which people with
Type 2 diabetes and microalbuminuria were randomly assigned either standard
treatment by their general practitioner or intensive multifactorial intervention with
behavioural modification and stepwise introduction of pharmacological therapy
(Gaede et al, 1999). Eighty people were allocated to standard treatment and another
80 people to intensive treatment. Intensive treatment comprised a stepwise
implementation of behaviour modification and pharmacological therapy targeting
blood glucose, blood pressure, lipids and microalbuminuria. The primary endpoint
was the development of nephropathy (median AER >300mg/24 h). Secondary
endpoints were the incidence or progression of diabetic retinopathy and neuropathy.
After a mean follow up of 3.8 years, people in the intensive group had significantly
lower rates of progression to nephropathy [OR 0.27 (CI 0.10-0.75)], progression of
retinopathy [OR 0.45 (CI 0.21-0.95)] and progression of autonomic neuropathy [OR
0.32 (CI 0.12-0.78)] than those in the standard group. It was concluded that intensified
multifactorial intervention in people with Type 2 diabetes and microalbuminuria
slows progression to nephropathy, and progression of retinopathy and autonomic
neuropathy.
Gaede et al (2003) have recently reported further results of the above study after a 7.8
year follow up. Multifactorial intervention therapy produced greater reductions in
HbA1c values (p<0.001), SBP and DBP (p<0.001, p=0.006, respectively), serum
cholesterol (p<0.001) and triglycerides levels (p=0.015) and AER (p=0.007) than the
conventional therapy over the 7.8 years of follow-up. People receiving multifactorial
therapy had a lower risk of cardiovascular disease (HR 0.47 [CI 0.24-0.75]),
nephropathy (HR 0.39 [CI 0.17-0.87]), retinopathy (HR 0.42 [CI 0.21-0.86]), and
autonomic neuropathy (HR 0.37 [CI 0.18-0.79]).
In the UKPDS (UKPDS 37,1999; UKPDS 38, 1998), a 2 2 multifactorial design

was used to assess the effects of blood glucose and blood pressure lowering. The
UKPDS showed that lowering of HbA1c from 7.9% to 7.0% reduced aggregate
microvascular endpoints by 25%. By contrast, lowering of MAP from 109 to 103
mmHg with captopril or atenolol based therapy, decreased aggregate microvascular
endpoint by 33%. An analysis of possible synergistic effects of both therapies has not
yet been published but has been presented in international forums and indicates that
the combined effects of blood glucose and blood pressure lowering have a synergistic
effect on both microvascular and macrovascular endpoints.
A non-randomised observational study over 7 years on a group of 100 people with

Type 2 diabetes also supports multifactorial intervention based on intensive blood
pressure lowering treatment in reducing cardiovascular complications and mortality in
people with Type 2 diabetes when compared with conventional therapy (Sawicki et al,
1995).
Two other large studies have recently reported results of statin therapy in people also
treated with blood pressure lowering medications.
The ALLHAT study was primarily designed to compare of the effectiveness of
73
different blood pressure lowering medications - chlorthalidone, amlodipine, lisinopril
and doxazoain in people aged 55 years and older with hypertension and at least one
additional CHD risk factor. ALLHAT-LLT was a substudy of ALLHAT which
included 10355 people or whom 3638 had Type 2 diabetes. People in ALLHAT-LLT
were randomised to open-label treatment with pravastatin 40mg if fasting LDL was
3.1-4.9 mmol/L in those without CHD and 2.6-3.3 mmol/L in those with CHD and
fasting triglycerides was lower than 3.9 mmol/L and they were not receiving lipid
lowering medication at the beginning of the study. Over a mean 4.8 year follow-up,
the study failed to show a difference in all-cause mortality or CHD events between
pravastatin and controls, a result which was observed for the total cohort and for the
diabetic population (ALLHAT-LLT, 2002b). Possible explanations for this lack of
difference include the modest differential reduction in LDL cholesterol
(approximately 17%), the open-label study design, or the decreased benefit of lipid
lowering therapy in people with well controlled hypertension.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a randomised CHD

primary prevention study comparing conventional (-blocker diuretic) and more
contemporary (CCB ACEI) blood pressure lowering therary in 10,305 adults aged
40-79 years with hypertension. The study included a 22 factorial design comparing
additional treatment with atorvastatin 10 mg/day in people with a total cholesterol of
6.5 mmol/L. The study population included 2,532 people with diabetes (24.3% in
the atorvastatin treament group and 24.8% in the placebo group) (Sever et al, 2003).
The lipid lowering part of the study was discontinued after 3.3 years follow-up
because cardiovascular outcomes were significantly higher in the placebo group
although the blood pressure was 138/80 mg/Hg for both groups. The hazard ratios
were 0.73 (0.56-0.96, p=0.02) for fatal and non-fatal stroke, 0.79 (0.69-0.90,
p=0.0005) for CVD and 0.71 (0.59-0.86, p=0.0005) for coronary events. However
analysis of the diabetic subgroup did not show a significant difference in the primary
endpoint of non-fatal MI plus fatal CHD. The authors speculate that this might be the
result of the low number of absolute events among people with diabetes resulting in
inadequate power to demonstarte a difference and the increased usage of statins in the
diabetes placebo group (14%) compared with the non-diabetic placebo group (8%).
However the possibility remains that lipid lowering therapy is not as effective in
people with diabetes who have well controlled blood pressure.
The Heart Protection Study (HPS) was a primary and secondary prevention study of
treatment with simvastatin 40mg daily (Heart Protection Study Collaborative Group,
2002a). HPS included 20,536 people aged 40-80 years with total cholesterol >3.5
mmol/L and a substantial 5 year risk of death because of a past history of coronary
disease or occlusive arterial disease of non-coronary arteries, or diabetes or treated
hypertension (Heart Protection Study Collaborative Group, 2002a). In the 10,269
people assigned to treatment with simvastatin 40 mg daily, the risk of a major
vascular event (CHD, stroke or revascularisation) was 19.8% compared with 25.2% in
the 10,267 people on placebo (24% relative risk reduction, P<0.00001). The incidence
of a first major vascular event was reduced by 22% in people with diabetes treated
with simvastatin compared with placebo (p < 0.0001).Of the 5,963 people with
diabetes, 1981 had had a prior MI or other CHD event at baseline. Overall there was a
highly significant 13% reduction in all cause mortality (14.9% v 12.9%, p< 0.0003)
due to an 18% reduction in coronary death (p<0.0005). Simvastatin therapy reduced
the incidence of the first major vascular event by 11% (325/972 v 381/1009)
compared with placebo (OR of 0.89 [CI 0.75-1.05]), however this was not significant
(HPS Collaborative Group, 2002a). In the 2912 people with diabetes and no
74
diagnosed vascular disease at baseline, there was a 33% reduction in first major
vascular event (p=0.0003) (HPS Collaborative Group, 2003). The subgroup analysis
performed according to whether or not participants had treated hypertension, showed
that the benefits of simvastatin in reducing first major vascular events applied equally
to people with or without hypertension, although the absolute rate of events remained
higher in those with diabetes and treated hypertension compared to those with
diabetes and no treated hypertension.
Summary Synergy of interventions

Multifactorial intervention to improve blood glucose, blood pressure and lipids is
associated with improved macrovascular and microvascular outcomes
Two recent studies of lipid lowering therapy in people with diabetes and well
controlled hypertension have not shown beneficial CVD outcomes
75
Is there synergy in the effects of simultaneous intervention for blood

pressure, blood glucose and lipids?
Author Evidence
ALLHAT Collaborative
Research Group (2002b)
II RCT High Low Low
(Adults US; Canada; Puerto
Rico)
Gaede P (1999)
(Adults Denmark)
Gaede P (2003)
(Adults Denmark)
Heart Protection Study
(2002a) II RCT High High+ High
(Adults UK)
Heart Protection Study
(2003) II RCT High High+ High
(Adults UK)
Sawicki PT (1995)
III-2 Cohort Medium Medium+ High
(Adults Germany)
Sever PS (2003)
II RCT High High Low
(Adults Europe)
UKPDS 37 (1999)
(Adults UK)
UKPDS 38 (1998) +
(Adults UK)
significant effect
76
Issue
Recommendation
Despite the potential for adverse effects on metabolic control, the full range of blood
pressure lowering medications should be considered when selecting treatment for
blood pressure in people with Type 2 diabetes.
Evidence Statements
Some blood pressure lowering medications adversely affect glucose and lipid
metabolism in people with Type 2 diabetes
Evidence Level II
Despite potentially adverse metabolic effects of some blood pressure lowering

medications, no randomised controlled trials have shown them to increase
cardiovascular mortality in people with Type 2 diabetes
Evidence Level II
Some blood pressure lowering medications may affect the rate of development of
Type 2 diabetes
Evidence Level II
77
Background - Influence on metabolic control
Although the blood pressure reduction is a major determinant of outcome in people
treated for elevated blood pressure, other clinical factors should be considered in
selecting the appropriate blood pressure lowering medication (Figure 3, Section 5). In
Type 2 diabetes, elevated blood pressure is frequently associated with one or more of
the components of the metabolic syndrome including central obesity, insulin
resistance, hyperuricaemia, hypertriglyceridaemia, reduced high density lipoprotein
(HDL) levels, and microalbuminuria. Because hypertriglyceridaemia and low HDL
are associated with high plasminogen activator inhibitor (PAI-1) and fibrinogen
levels, they represent an increase in cardiovascular risk (Byberg et al, 1998).
Therefore the choice of blood pressure lowering medications needs to take into
account the potential effect on metabolic parameters as well as the overall clinical
context, with special indications existing for people with associated cardiac failure,
angina, hyperkalaemia, renal impairment, fluid overload and isolated systolic
hypertension in the elderly.
Three lines of evidence have suggested a possible link between specific blood
pressure lowering medications and metabolic control. Firstly long term studies of
blood pressure lowering medications which have monitored metabolic effects;
secondly experimental studies of the short-term effects of individual blood pressure
lowering medications using the glucose clamp technique; and finally the observed
association between insulin resistance and elevated blood pressure and the suggestion
that insulin resistance may be a causative factor for hypertension (Reaven, 1988).
Based on these data, it has been suggested that medications which are metabolically
neutral should be favoured in people with Type 2 diabetes and above target blood
pressure in order to avoid an increase in insulin resistance and possible exacerbation
of the metabolic syndrome which is characterised by impaired glucose tolerance,
raised blood pressure, central obesity, hypertriglyceridaemia and low HDL cholesterol
levels (Reaven et al, 1996; Groop et al, 1993). However, these considerations should
be balanced by the results of long term intervention studies, which have reported the
clinical outcomes of people treated with various blood pressure lowering medications.
In this Section, metabolic control refers not only to glucose and insulin metabolism
but also to lipid, electrolyte and uric acid metabolism. Glycaemic control
encompasses glucose tolerance, and insulin secretion and action (insulin sensitivity
and resistance).
Evidence Influence on metabolic control

Some blood pressure lowering medications adversely affect glucose and lipid
metabolism in people with Type 2 diabetes
Blood pressure lowering medications have a variable effect on insulin sensitivity.

Lind et al (1994) showed that ACE inhibitors significantly improved insulin
sensitivity (p<0.05) over a 3 year period. Pollare et al (1989) also showed that ACE
inhibitors improved while hydrochlorothiazide decreased insulin action. Diuretics and
-blockers have also been shown to impair insulin sensitivity (Lind et al, 1994). A 20-
week study in people with Type 2 diabetes found that CCBs caused no adverse effects
on glucose tolerance, insulin secretion or platelet aggregation (Klauser et al, 1990).
Also one study reported an association between current use of ACE inhibitors and an
78
increased risk of hospital admission for hypoglycaemia in 94 people with Type 2
diabetes (OR 2.8, CI 1.4-5.7) (Herings et al, 1995).
In the Treatment of Mild Hypertension Study (TOMHS) (Neaton et al 1993; Grimm et

al 1996), a total of 902 people with diastolic hypertension (DBP <100 mmHg) were
recruited from 11,914 community screened people. Participants were randomised to 1
of 6 treatment groups: (1) placebo, (2) -blocker (acebutolol), (3) calcium antagonist
(amlodipine), (4) diuretic (chlorthalidone), (5) alpha 1 antagonist (doxazosin), and (6)
ACE inhibitor (enalapril) and studied for 4.4 years. The alpha 1 antagonist
(doxazosin) group had the greatest decrease in plasma total cholesterol, LDL
cholesterol and triglycerides (all p <0.01 v placebo). Increases in HDL cholesterol
were greatest with enalapril and doxazosin (p <0.01) (Neaton et al, 1993; Grimm et al,
1996).
In an 8 month trial, 30 hypertensive people (15 with diabetes, mainly Type 2) and 15
patients with essential hypertension) were treated with amlodipine. Amlodipine did
not modify serum lipid levels, and in the diabetic group, the insulin and glucose
responses to an oral glucose tolerance test were unchanged (Zanetti-Elshater et al,
1994).
-blockers and thiazides may influence the lipid profile and glycaemic status in
people with Type 2 diabetes. High-dose thiazide and loop diuretics may produce
short-term increases in cholesterol levels (total cholesterol: +0.290.59 mmol/l,
p<0.001 v baseline; LDL cholesterol: +0.250.70 mmol/l, p<0.01 v baseline), and -
blockers, without intrinsic sympathetic activity, may elevate triglyceride levels
transiently (+0.501.0 mmol/l, p<0.001 v baseline) and reduce levels of HDL-
cholesterol (-0.130.20 mmol/l, p<0.001 v baseline) (Lind et al, 1994). Harper et al
(1995) did not find an increase in serum lipids after 3 months of treatment with
bendrofluazide in hypertensive people with Type 2 diabetes. However, the
combination of diuretic (hydrochlorothiazide) and -blocker (propanolol) decreased
HDL-cholesterol (p<0.05) and increased triglycerides (p<0.05).
Short-term use of diuretics including thiazides and loop diuretics such as ethacrynic
acid, frusemide and bumetanide has been shown to marginally increase glucose levels
in association with decreases in serum potassium, sodium and magnesium levels (Fuh
et al, 1990; Harper et al, 1995). This effect may be dose dependent. Low-dose thiazide
treatment (bendrofluazide 1.25 mg) compared to conventional dose (bendrofluazide 5
mg) had a similar blood pressure lowering effect but significantly less effect on serum
potassium (p<0.01) and fasting glucose concentration (p<0.05) (Harper et al, 1995).
After 3 months of combined diuretic and -blocker treatment, fasting serum glucose
levels increased from 7.30.6 to 8.50.6 mmol/l (p<0.001) in 20 hypertensive people
with Type 2 diabetes (Fuh et al, 1990). In contrast, fasting plasma insulin
concentration was similar before (13.51.6 uU/ml) and after (14.41.7 uU/ml)
treatment. In addition, significant increases in fasting plasma total triglyceride
(p<0.05), VLDL-triglyceride (p<0.05) and VLDL-cholesterol (p<0.05), whereas
reduction in fasting HDL-cholesterol (p<0.05) were observed after treatment.
Despite potentially adverse metabolic effects of some blood pressure lowering

medications, no randomised controlled trials have shown them to increase
cardiovascular mortality in people with Type 2 diabetes
The above data on potential adverse metabolic effects of some blood pressure
lowering medications must be balanced with the results of outcome studies.
79
The numerous outcomes studies have been reviewed in Section 7 and detailed in
Table 8, Section 5. All studies have shown improved outcomes with blood pressure
lowering except for the ALLHAT study in which doxazosin was associated with an
increase in cardiovascular mortality (ALLHAT Collaborative Research Group, 2000).
In particular -blockers (UKPDS 38, 1998) and thiazides (Curb et al, 1996) improve
cardiovascular outcomes in people with diabetes.
Some blood pressure lowering medications may affect the rate of development of
Type 2 diabetes
The Heart Outcomes Prevention Evaluation Study (HOPE, 2000b) included 5,769
high risk non diabetic people aged over 55 years. In addition to improved clinical
outcomes in the ramipril group, a 34% reduction in newly diagnosed Type 2 diabetes
compared with the control group (3.6% v 5.4%, RR 0.66 [CI 0.51-0.85], p<0.001) was
observed in the ramipril group.
Also in the CAPPP study, hypertensive people assigned to captopril based therapy had
a lower risk of developing diabetes than people assigned to diuretic or -blocker
based therapy (Hansson et al, 1999a). The RR of developing diabetes mellitus in the
captopril group compared with the conventional therapy was 0.70 (CI 0.67-0.94),
p<0.007).
In a prospective study of 6 years in 12,550 people aged 45 to 64 years who did not
have diabetes at entry, Gress et al (2000) demonstrated that people treated with
thiazides were not at greater risk for the development of diabetes than people not
treated with thiazides (relative hazard 0.91, [CI 0.73-1.13]). In contrast, people treated
with -blockers had a 28% higher risk for subsequent diabetes (RR 1.28, CI 1.04-
1.57).
80
Summary - Influence on metabolic control
ACE inhibitors, calcium channel blockers, alpha-antagonists and indapamide do
not adversely affect insulin action and plasma glucose and lipid levels
Thiazides and -blockers may impair glucose tolerance, especially if used in

combination
-blockers and thiazides may adversely affect lipid levels
Despite potentially adverse metabolic effects of thiazides and -blockers, no

randomised controlled trials have shown them to adversely affect outcomes in
ACE inhibitors may reduce the rate of development of diabetes in elderly people
with elevated blood pressure
81
Author Evidence
ALLHAT Study (2000)
(Adults US; Canada)
Curb JD (1996)
(Older adults US)
Fuh MM-T (1990)
III-2 Cohort Low High Medium
(Adults Taiwan)
Gress TW (2000)
(Adults US)
Grimm RH (1996)
(Adults US)
Hansson L (1999a)
(Adults Sweden; II RCT Medium High+ Low
Finland)
Harper R (1995)
(Adults UK)
Herings RMC (1995) +
III-2 Case-control Medium High High
(Adults The Netherlands)
HOPE (2000b)
(Adults Canada)
Klauser R (1990) +
II RCT Medium High High
(Adults Austria)
Lind L (1994)
III-2 Cohort Medium High Low
(Adults Sweden)
Neaton JD (1993) +
II RCT High High Low
(Adults US)
Pollare T (1989)
(Adults Sweden)
UKPDS 38 (1998) +
(Adults UK)
Zanetti-Elshater F (1994)
(Adults Switzerland)
significant effect
82
Issue
Recommendation
Intensive control of blood pressure is recommended in people with Type 2 diabetes
because the benefits of therapy outweigh the costs of vascular complications.
Evidence Statement
Controlling blood pressure in people with Type 2 diabetes is cost-effective
Evidence Level II
83
Background - Costs/benefits
Several studies have documented the clinical benefits of blood pressure lowering
medications in people with Type 2 diabetes. Three studies have shown that people
with diabetes respond to blood pressure lowering with a greater reduction in
cardiovascular events than observed in people without diabetes (Hansson et al, 1998;
Hansson et al, 1999a; Tuomilehto et al, 1999).
The effectiveness of blood pressure lowering medications does not wane with time
(UKPDS 38, 1998), in contrast to blood glucose lowering therapy, which requires
progressive intensification of treatment in order to maintain its effects (UKPDS 39,
1999).
As emphasized by the JNC-VI (1997), a valid cost analysis should include all of the
costs of treatment and not just the cost of the medication. Factors such as the
individual's tolerance and compliance, side effects, adverse effects on other
cardiovascular risk factors, number of visits to the doctor and number of laboratory
tests associated with the blood pressure lowering medications are important
considerations. In addition indirect and intangible costs should also be considered.
Evidence - Costs/benefits
Controlling blood pressure in people with Type 2 diabetes is cost-effective
The UKPDS compared the effectiveness of tight blood pressure control (n=758, MAP
achieved 103 mmHg) with captopril or atenolol, with less tight control (n=340, MAP
achieved 109 mmHg) in hypertensive people with Type 2 diabetes over 10 years
(UKPDS 38, 1998). This study showed that blood pressure lowering medications
based on captopril or atenolol achieved significant benefits on the incidence of
microvascular and macrovascular events. The costs and benefits of blood pressure
reduction in hypertensive people with Type 2 diabetes was also examined (UKPDS
40, 1998). The two main measures of effectiveness were time free from diabetes
related endpoints and life years gained. The increased costs of blood pressure
lowering medications in the group under tight control of blood pressure were offset by
lower costs of microvascular and macrovascular complications. In total, tight blood
pressure control was associated with a reduction in the cost of complications of 949
(AUD $2375) per person. Based on use of resources in standard clinical practice, the
incremental cost per extra year free from endpoints in the tight control group
amounted to 1,049 (AUD $2,625) (costs and effects discounted at 6% per year) or
434 (AUD $1,085) (costs discounted at 6% per year and effects not discounted). The
incremental cost per life year gained was 720 (AUD $1,800) (costs and effects
discounted at 6% per year) or 291 (AUD $730) (costs discounted at 6% per year and
effects not discounted) (UKPDS 40, 1998).
The UKPDS (UKPDS 40, 1998) concluded that tight control of blood pressure in
hypertensive people with Type 2 diabetes substantially reduced the cost of
complications. It increased the interval without complications and survival, and had
an effectiveness ratio that compared favourably with other accepted health care
programs such as cholesterol lowering (3,200 ($AUD8,000) per life year gained) and
lifestyle advice (9,500 ($AUD 23,750) per life year gained). It was calculated that
there was an 83% probability that tight blood pressure control for hypertensive people
84
with Type 2 diabetes is more cost effective than secondary prevention of
hypercholesterolaemia and a 92% probability that it is more cost effective than
lifestyle advice to lower cardiovascular risk (UKPDS 40, 1998).
Herman et al (2003) recently conducted an economic cost analysis of the RENAAL

study and reported that treatment with losartan and conventional blood pressure
lowering medications reduced the number of days with ESRD by 33.6 per person (CI
10.9-56.3) compared with treatment with placebo over 3.5 years (p=0.004). This
reduction in ESRD days resulted in a reduction associated with ESRD of US$5,144
(US$1,701-8,587) per person (p=0.003). After adjusting for the cost of losartan, the
reduction in ESRD days resulted in a net savings of US$3,522 (US$143-6,900) per
person (p=0.04).
Modelling has also been used to assess the cost-effectiveness of intensified

hypertension control in Type 2 diabetes (The CDC Diabetes Cost-effectiveness
Group, 2002). Intensive blood pressure control as used in the UKPDS was found to be
cost saving and saved $US 776 over the persons lifetime. The cost effectiveness ratio
was negative ($US -1,959/QALY) since costs were lower and QALYs increased, and
this effect was not affected by the age of the person. These results compared with a
cost effectiveness ratio of $US 9,614/QALY for intensive blood glucose in people
aged 25-34 years and $US 51,889/QALY for cholesterol lowering.
Summary Costs/benefits
Achieving good blood pressure control in people with Type 2 diabetes is cost-
effective
Early and intensive blood pressure lowering medications decreases the incidence
and delays the progression of both micro- and macrovascular complications in
85
Author Evidence
Herman WH (2003)
(Adults US)
The CDC Diabetes Cost-
effectiveness Group II RCT High High+ High
(2002)
UKPDS 38 (1998)
(Adults UK)
UKPDS 40 (1998) +
(Adults UK)
significant & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically
significant effect
86
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105
2.6 Blood Pressure Control Guideline Search Strategy And Yield
Electronic Databases Searched:
Medline
Embase
CINAHL
Cochrane
Terms used to search the databases:

Detailed within the table below
Search Inclusion Criteria:

Where possible the searches were limited by the English Language and Human Research. The databases were searched for the following years of publication:
Medline 1990 - 2003; Embase 1988 - 2003; CINAHL 1990 - 2003; Cochrane 1993 - 2003.
Other searching:
Reference lists at the end of review articles of particular relevance were hand searched.
Relevant articles were solicited from expert colleagues and organisations.
Local and international clinical practice guidelines were reviewed for relevant references.
Abbreviations:
The database searched has been indicated next to each set of keywords using the following abbreviations. M= Medline, EM= Embase, CO= Cochrane and CI=
CINAHL. All Embase and Medline searches were done using English Language En.La and human as a limit. The symbol / after a word indicates that it is a MeSH
term and any article found by this method has been allocated to this subject heading used in the database; .mp indicates that that word was searched as a keyword in
the database; *indicates that the search was more directly focused Other abbreviations used were NIDDM = diabetes mellitus, non-insulin dependent/ or .mp, or
niddm.mp or type 2 diabetes.mp (human and English Language); ACR = albumin-to creatinine.mp or ACR.mp or albumin creatinine ratio.mp; Antihypertensives =
antihypertensive agents/ or antihypertensive.mp, or blood pressure lowering.mp; Complications = diabetic angiopathies/, diabetic nephropathies/, diabetic
neuropathies/, diabetic retinopathy/; dh = diet therapy; dt = drug therapy; th = therapy; cl = classification; di = diagnosis; pc = prevention and control;
Identified = number of articles which matched the mesh terms listed or contained the text terms in each particular database
Relevant = those articles considered relevant to the questions being asked after viewing titles or abstracts
Articles identified by other strategies = articles identified by hand searching, other searches for other questions, or from colleagues
Total for Review = Those articles which were relevant to the question, contained original data or were systematic reviews of original articles and met the following
criteria.
106
Criteria used to determine the suitability of articles for review
In assessing the evidence the following criteria were used to determine the suitability of studies:
1. Papers or editorials that present original data.
2. Appropriate population for question being addressed.
3. Article in the English language.
4. Study conducted in humans.
5. Articles were obtained from journals able to be accessed within our Library or ordered through an interlibrary loan.
107
QUESTIONS KEY WORDS NO. NO ARTICLES TOTAL LEVEL LEVEL LEVEL LEVEL TOTAL NO HIGHEST
ARTICLES RELEVANT IDENTIFIED FOR I II III IV REVIEWED LEVEL OF
IDENTIFIE ARTICLES BY OTHER REVIEW & GRADED EVIDENC
D STRATEGIES E
108
D STRATEGIES E
1. What is the target blood Total for Question 755 18 49 43 2 38 3 0 38 II
pressure in Type 2
diabetes? Hypertension/ cl, di AND 23 M
NIDDM M, CI, EM, CO 3 CI
0 Co
NIDDM AND definition.mp 392 EM
AND (hypertension.mp/) M,
CI, EM, CO
Hypertension/cl, di AND
NIDDM M, EM, CI 99-03 32 M
62 EM
8 CI
NIDDM AND definition.mp
AND hypertension.mp/ M, 14M
EM, CI 99-03 13 EM
0 CI
NIDDM.mp AND
hypertension.mp CO 99-03
(Issue 2, 2003) 32
NIDDM.mp AND
hypertension.mp AND
definition.mp CO 99-03 (Issue 5
2, 2003)
NIDDM AND
hypertension.mp/ AND
target.mp M, CI, EM, CO 26 M
3 CI
0 CO
NIDDM.mp AND 48 EM
hypertension.mp AND
target.mp Co 99-03 (Issue 2, 2
2003)
NIDDM AND
hypertension.mp/ AND
target.mp M, EM, CI 99-03 42 M
52 EM
8 CI
109
D STRATEGIES E
2. How should blood Total For Question 465 14 6 9 0 2 5 0 6 II
pressure be
NIDDM AND blood 105 M
measured? pressure.mp/ AND 13 CI
measurement.mp M, CI, CO 3 CO
197 EM
NIDDM AND (blood
pressure determination/ OR
.mp) EM, M
NIDDM.mp AND blood 12

pressure.mp/ AND
measurement.mp CO 99-
03 (Issue 2, 2003)
NIDDM AND blood 51 M

pressure.mp/ AND 8 CI
measurement.mp M, CI 99-
03
NIDDM AND blood 67

pressure.mp/ AND
measurement.mp M, CI 99-
03
NIDDM AND blood
pressure.mp/ AND
(measurement/ OR blood 9
pressure measurement/)
EM 99-03
NIDDM AND blood

pressure determination.mp/
M 99-03
110
D STRATEGIES E
3. How often should Total For Question 267 8 5 7 0 3 2 0 4 II
blood pressure be
Blood pressure 84M
measured? determination.mp/ AND 0CI
frequency.mp M, CI, EM, 0CO
CO 190 EM
NIDDM AND Blood

AND frequency.mp M
Blood pressure 5
determination.mp/ AND
frequency.mp CO 99-03
(Issue 2, 2003)
Blood pressure 41
determination.mp/ AND
frequency.mp M 99-03
(blood pressure 42
measurement.mp OR blood
pressure determination.mp/)
AND frequency.mp CI 99-
03
NIDDM AND (Blood 4

pressure measurement/ OR
measurement/) AND
frequency.mp EM 99-03
NIDDM AND Blood 1

AND frequency.mp M 99-
03
111
D STRATEGIES E
4. What is the role of Total For Question 202 13 10 14 1 4 9 0 12 I
ambulatory blood
NIDDM AND (blood pressure 37 M
pressure monitoring monitoring, ambulatory/ OR 1 Ci
in blood pressure blood pressure monitoring.mp 3 Co
OR dipper.mp) M, CI, EM,
control? 48 EM
CO
NIDDM.mp AND
(ambulatory blood pressure 0
monitoring.mp OR blood
pressure monitoring.mp OR
dipper.mp) CO 99-03 (Issue
2, 2003)
NIDDM AND (blood

pressure monitoring, 23 M
ambulatory/ OR blood 1 CI
pressure monitoring.mp OR
dipper.mp) M, CI 99-03
NIDDM AND (blood

pressure monitoring.mp/ 89
OR ambulatory monitoring/
OR dipper.mp) EM 99-03
112
D STRATEGIES E
5. How should blood Total For Question 416 38 40 65 11 49 4 0 48 I
pressure be
NIDDM AND 41 M
controlled in Type 2 hypertension/ th, pc M, CI, 11 CI
diabetes? EM, CO 3 CO
78 EM
Hypertension.mp AND 54 CO
NIDDM AND (Exercise th
OR dt OR antihypertensives
OR dh) CO
NIDDM.mp AND 32
(Issue 2, 2003)
NIDDM.mp AND 18
hypertension.mp AND
(exercise.mp OR
antihypertensives.mp OR
antihypertensive agents.mp
OR antihypertensive.mp)
CO 99-03 (Issue 2, 2003)
NIDDM AND 76 M
hypertension/ th, pc M, 68 EM
EM, CI 99-03 35 CI
113
D STRATEGIES E
6. What is the effect of Total For Question 776 61 18 34 6 21 1 0 26 I
treatment of blood
NIDDM AND 190 M
pressure in Type 2 antihypertensives AND 13 CI
diabetes? (complications OR 123 EM
complications.mp) M, CI, EM,
11 Co
NIDDM AND
antihypertensives AND
(disease progression/ OR
.mp) M, CI, EM,
NIDDM AND lifestyle.mp/

AND hypertension.mp/ M,
CI, EM
NIDDM AND hypertension

AND treatment
outcome.mp CO
NIDDM.mp AND
hypertension.mp AND
4
treatment outcome.mp CO
99-03 (Issue 2, 2003)
NIDDM AND
137 M
(complications OR
17 CI
complications .mp) M, CI
99-03
NIDDM AND
145 EM
(complications OR
complications .mp/) EM
99-03
NIDDM AND
15 M
(disease progression.mp/ )
7 CI
M, CI 99-03
114
D STRATEGIES E
6. What is the effect of NIDDM AND 47
treatment of blood (disease course/ OR disease
pressure in Type 2 progression.mp) EM 99-03
diabetes?
NIDDM AND lifestyle.mp/ 67 M
AND hypertension.mp/ M, 11 CI
CI 99-03
NIDDM AND lifestyle.mp/ 19

AND antihypertensives EM
99-03
NIDDM AND 20 M
antihypertensives AND 0 CI
(diabetic retinopathy.mp/) 6 CO
M, CI, EM, CO 51 EM
NIDDM.mp AND 3
(antihypertensives.mp OR
AND diabetic
retinopathy.mp CO 99-03
(Issue 2, 2003)
NIDDM AND 4M
antihypertensives AND 15 EM
(diabetic retinopathy.mp/) 2 CI
M, EM, CI 99-03
115
D STRATEGIES E
7. Is there synergy in the Total For Question 976 3 20 23 3 13 2 0 17 I
effects of
NIDDM AND 17 M
simultaneous hyperglycemia/pc, dh, dt, th 2 Ci
intervention to control AND hyperlipidemia/pc, dh, dt, 5 Co
th AND hypertension/pc, dh,
blood pressure, blood dt, th M, CI, CO
752 EM
glucose and lipids?
116
D STRATEGIES E
7. Is there synergy in the Antihypertensives AND
NIDDM AND (antilipemic
effects of agents.mp/ OR
simultaneous hypoglycemic agents.mp/)
intervention to control M
blood pressure, blood NIDDM AND (drug
glucose and lipids? synergism.mp/) EM,
NIDDM.mp AND 3
(hyperglycaemia.mp OR
hyperglycemia.mp) AND
(hyperlipidaemia.mp OR
hyperlipidemia.mp) AND
(Issue 2, 2003)
NIDDM AND 7M
hyperglycemia/pc, dh, dt, th 1 EM
AND hyperlipidemia/pc, 0 CI
dh, dt, th AND
hypertension/pc, dh, dt, th
M, EM, CI 99-03
NIDDM AND 44 M
(antilipemic agents.mp/ OR 3 CI
hypoglycemic agents.mp/)
M, EM, CI 99-03
NIDDM AND (drug 20 M

synergism/ OR drug 0 CI
synergy.mp) M 99-03
NIDDM AND (drug 41

potentiation/ OR drug
synergism.mp) EM 99-03
NIDDM AND drug 0

synergism.mp/ CI 99-03
117
D STRATEGIES E
8. Do blood pressure Total For Question 933 13 12 21 1 13 4 2 20 I
lowering medications
Antihypertensives AND 62 M
affect metabolic NIDDM AND blood 4 CI
control? glucose.mp/ M, CI, CO 19 CO
369 EM
NIDDM.mp AND 7
AND (blood glucose.mp
OR glycaemic control.mp
OR glycemic controlmp)
CO 99-03 (Issue 2, 2003)
NIDDM AND (glycemic

control.mp OR glycaemic
control.mp) M, EM
NIDDM AND (glycaemic

control/ OR glycemic
control/) EM
NIDDM AND 42 M
antihypertensives AND 4 CI
blood glucose.mp/ M, CI
99-03
NIDDM AND 24 M
(glycaemic control.mp OR
glycemic control.mp) M,
EM 99-03
NIDDM AND (glycemic 378

control.mp/ OR glycaemic
control.mp) CI 99-03
118
D STRATEGIES E
9. What are the Total For Question 26 4 12 12 0 5 2 0 5 II
costs/benefits of
NIDDM AND 2M
intensive blood antihypertensives AND 1 CI
pressure control? cost-benefit analysis.mp/ 1 CO
M, CI, EM, CO 11 EM
NIDDM.mp AND 1
AND (cost-benefit
analysis.mp OR cost benefit
analysis.mp) CO 99-03
(Issue 2, 2003)
NIDDM AND 3M
cost-benefit analysis.mp/ 1 CI
M, EM, CI 99-03
119

Blood Pressure Control InType 2 Diabetes

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Blood Pressure Control InType 2 Diabetes

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National Evidence Based Guidelines

Blood Pressure Control inType 2 Diabetes

APPROVED BY THE NHMRC 18 MARCH 2004

1.0 Blood Pressure Control Expert Working Group .................................................. 3

2.0 Guideline for Blood Pressure Control in Type 2 Diabetes ................................... 5

Content Experts Professor Mark Cooper

A/Professor Richard Gilbert

Professor Stephen MacMahon

A/Professor Leon Bach

ADEA Ms Gloria Kilmartin

Consumer Mr Bruce Wainwright

RACGP Dr David Mills

Australian Kidney Foundation Dr Margaret Fraenkel

Content and Methods Adviser Professor Stephen Colagiuri

Research Officers Dr Sianna Panagiotopoulos

Each of these issues is addressed in a separate section in a format presenting:

Multifactorial intervention is the key to the prevention of

This document should be considered in association with the

What is the target blood pressure in Type 2 diabetes?

How should blood pressure be measured?

How often should blood pressure be measured?

How should blood pressure be controlled in Type 2 diabetes?

What is the effect of treatment of blood pressure in Type 2 diabetes?

Is there synergy in the effects of simultaneous intervention to control blood pressure,

Do blood pressure lowering medications affect metabolic control?

What are the costs/benefits of intensive blood pressure control?

Measurement of blood pressure should be performed with attention to appropriate rest

A mercury sphygmomanometer is preferred, but a regularly calibrated aneroid

Standing and supine blood pressure measurements are recommended if autonomic

During titration of antihypertensive therapy, blood pressure should be measured more

24 h ambulatory blood pressure monitoring should be considered in people with Type 2

Angiotensin receptor blockers and angiotensin converting enzyme inhibitors should be

Combinations of antihypertensive agents should always be considered when treating

Intensive control of blood pressure is recommended in people with Type 2 diabetes

Section 1: Blood Pressure Control

Target levels for blood pressure are based on:

In people with diabetes:

Ramipril lowered risk of

In people with diabetes:

Aggressive lowering of blood pressure has not been shown to be harmful in

Interventions which lower blood pressure should be used aggressively in people

The frequent occurrence of isolated systolic hypertension in elderly people may

What is the target blood pressure for Type 2 diabetes?

Systolic blood pressure should be recorded as the first appearance of Korotkoff

A mercury sphygmomanometer is preferred, but a regularly calibrated aneroid

Standing and supine blood pressure measurements are recommended if autonomic

The mercury sphygmomanometer is the preferred device for measuring blood

Standing and supine measurements are recommended if autonomic neuropathy is

Blood pressure measurement should be taken preferably with a mercury

Table 3: Common pitfalls in measuring blood pressure, which may result in

In clinical practice blood pressure is routinely measured as systolic and diastolic

Figure 2. The effect of hypertension on mean arterial pressure and pulse

MAP PP Blood 140

Significant differences in BP were noted depending on the body position as shown in

Table 4: Differences in blood pressure depending on body position

The mercury sphygmomanometer is the preferred device for measuring blood

In another recent study the semi-automated blood pressure measuring device,

Sturrock et al (1997) reached a different conclusion in their study which compared 3

Because of these variable results, it is currently recommended that semi-automated

Standing and supine blood pressure measurements are recommended if

Although blood pressure measurements are generally performed in the sitting

A recently calibrated aneroid manometer or a validated electronic device may be

Routine measurement of blood pressure should be performed in the sitting position

Systolic blood pressure should be recorded as the first appearance of Korotkoff