139

CHAPTER 13
GLYCEMIC VARIABILITY IN
TYPE 2 DIABETES MELLITUS:
Oxidative Stress and Macrovascular Complications
Eric L. Johnson
Department of Family and Community Medicine, University of North Dakota, Grand Forks, North Dakota, USA
Email: eric.l.johnson@med.und.edu
Abstract: Diabetes mellitus is a worldwide health issue with potential for signifcant negative
health outcomes, including microvascular and macrovascular complications. The
relationship of hemoglobin HbA1
C
and other glycosylation end products (AGEs) to
these complications, particularly microvascular disease, is well understood. More
recent evidence suggests that glycemic variability may be associated with diabetes
macrovascular complications. As HbA1
C
is better representative of average glucose
levels and does not account as well for glycemic variability, hence new methods to
assess and treat this variability is needed to reduce incidence of complications. In
this chapter, the relationship of glycemic control to diabetes complications will be
explored with focus on the mechanisms of tissue damage from this variability along
with the oxidative stress. Additionally, treatment strategies to optimize HbA1
C
and
glycemic variability with the goal of reducing risk of complications in persons with
diabetes are reviewed.
INTRODUCTION
The global burden of diabetes is currently estimated at 285 million people (6.4% of
the population) and expected to grow to 438 million people (7.8% of the population) by
2030.
1
Diabetes is associated with signifcant morbidity due to associated macrovascular
and microvascular complications,
1,2
and is a leading non-infectious cause of death
worldwide.
1
A critical goal of diabetes management is effective glycemic control for
the prevention of micro and macrovascular complications. Glycosylated hemoglobin
Diabetes: An Old Disease, a New Insight, edited by Shamim I. Ahmad.
2012 Landes Bioscience and Springer Science+Business Media.

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140 DIABETES
(HbA1
C
) is a glycosylation end product and has been the traditional measure of
overall glycemic control, but evidence exists to suggest that glycemic variability,
postprandial blood glucose excursions, and hypoglycemia are independent risk
factors for cardiovascular disease, perhaps showing greater association than HbA1
C

in some populations.
3-12
Persons with diabetes are 2 to 4times more likely to develop
cardiovascular complications compared to those without diabetes.
13-16
Limiting glycemic
variability may be important step towards achieving glucose homeostasis in persons
with diabetes to reduce overall risk of complications. However, this requires continuous
glucose monitoring or frequent selfmonitored blood glucose (SMBG) measurements
to determine the true 24 hour blood glucose pattern. By doing so, glucose excursions
over the entire day, rather than just fasting plasma glucose (FPG) can be monitored.
2-hour postprandial glucose (PPG), as well as hypoglycemic episodes, can also be
avoided, assessed and treated. Detecting when glucose excursions occur and treating
them appropriately using the most effective agents should be the focus of proposed
therapeutic regimens. Although many currently available diabetes medications do not
have specifc evidence of cardiovascular beneft, many new agents have better postprandial
coverage and lower rates of hypoglycemia. Insulin may be the most effective therapy
for achieving glycemic goals with studies suggesting that early initiation of insulin
in patients with Type 2 diabetes mellitus (T2DM) may provide signifcant benefts to
the patient, but other classes of agents may offer beneft depending on the individual
patients diabetes history and medical comorbidities. In this chapter the mechanisms
and consequences of glycemic variability will be discussed, and different diabetes
medications used for achieving appropriate glycemic goals will be reviewed.
Goals for Glycemic Control
When treating patients with T2DM the following treatment goals should be
considered: (1) lowering HbA1
C
; (2) lowering fasting blood glucose; (3) minimizing
glycemic variability, including postprandial glucose excursions. The purpose behind these
treatment goals is to reduce the risk factors for developing complications of diabetes.
Table 1 contains the most recent glycemic control goals from the American Diabetes
Association (ADA) and the American Association of Clinical Endocrinologists (AACE).
HbA1
C
has been considered the gold standard for monitoring glycemic control
in patients with Type 1 diabetes mellitus (T1DM) and T2DM. HbA1
C
is an average of
glucose control over the preceding 2 to 3 months and represents a composite of blood
glucose values over the entire 24hour interval, including FPG and 2hour PPG. HbA1
C

Table 1. Comparison of currently recommended treatment goals
ADA (17) ACE (82)
Fasting blood glucose (mg/dL) 90-130 <110
Postprandial plasma glucose (mg/dL) <180 <140
HbA1
C
(%) <7* 6.5
*Recommended as in general but guideline indicates for the individual patient HbA1
C
should be
as close to normal (<6%) as possible without hypoglycemia.
ADA, American Diabetes Association; AACE, American Association of Clinical Endocrinologists;
HbA1
C
, glycosylated hemoglobin.

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141 GLYCAEMIC VARIABILITY IN TYPE 2 DIABETES MELLITUS
refects overall glucose average, but accounts for glycemic variability to a lesser degree.
The classic Diabetes Complications and Control Trial (DCCT) (T1DM) and United
Kingdom Prospective Diabetes Study (UKPDS) (T2DM) have linked lowering HbA1
C

to reducing the risk and progression of microvascular complications associated with
diabetes;
17,18
however, data in these studies was less compelling for macrovascular
complication risk reduction. Interestingly, extended DCCT data showed that patients
randomized to intensive treatment following conventional insulin treatment did not
exhibit a reduction in the risk of progression of microvascular retinopathy despite having
comparable HbA1
C
values. One hypothesized explanation of this fnding is that there
was a greater frequency of glucose excursions (glycemic variability) occurring in the
conventionally treated group who received fewer daily insulin injections.
19,20
Other
data have linked HbA1
C
to cardiovascular disease risk. Longer term data from both
DCCT (EDIC) and UKPDS showed improvement in cardiovascular risk with overall
lower HbA1
C
.
21-24
Long term follow-up data in both of these studies did note reduced
risk of cardiovascular disease markers with overall lower HbA1
C
.
Intensive glucose control may have some beneft for macrovascular risk reduction but
this appears to be the case for patients earlier in the course of their diabetes.
25
A recent
metaanalysis of 102 studies found a relative risk of cardiovascular disease of 1.18 for
each 1% increase in HbA1
C
. As well, elevated HbA1
C
may have more association with
poorer cardiovascular outcomes for T1DM patients compared to those with T2DM.
25
A
long term observational study from Finland showed an increase of cardiovascular disease
mortality in T1DM patients of 52% for every 1% elevation in HbA1
C
, compared to 7.5%
in those with T2DM.
26
HbA1
C
association with cardiovascular risk has been questioned in recent years
in patients with T2DM. The landmark ACCORD (Action to Control Cardiovascular
Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax
and Diamicron Modifed Release Controlled Evaluation), and VADT (Veteran
Administration Diabetes Trial)
27-29
did not show a signifcant association of tighter
blood glucose control, as measured by HbA1
C
, with improved cardiovascular disease
outcomes in T2DM. Respectively, the primary cardiovascular disease endpoint in the
intensive arms was reduced by 10%, 6% and 13%, none of which achieved signifcance.
The ACCORD study was halted at 3.5 years due to signifcant rises in overall (22%)
and cardiovascular (35%) mortality. Smaller, nonsignifcant trends were noted in the
ADVANCE and VADT. Several explanations have been offered for the lack of positive
cardiovascular effect, including weight gain, hypoglycemia, diffcult to achieve HbA1
C
goal, and drug interactions. Subsequent subgroup analysis from ACCORD, ADVANCE,
and VADT, along with an Italian observational study have suggested that younger
patients with lower comorbidities may have a protective effect from more intensive
intervention earlier in their disease.
27-32
Further evidence of linking hypoglycemia to
an increased risk of cardiovascular events in T2DM has also recently been published.
33

As a result, those with longterm poor glycemic control in T2DM may not beneft
from intensive reduction of HbA1
C
in terms of cardiovascular complications. In
relationship to cardiovascular complications, limiting glycemic variability is likely an
important part of overall glycemic control and may be more associated with reduction
of cardiovascular risk.
33-35
In 2009, The American Diabetes Association, the American
College of Cardiology Foundation, and the American Heart Association have issued
a joint statement regarding management of glycemia in diabetes in the context of
cardiovascular disease.
25

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142 DIABETES
IMPLICATIONS OF GLYCEMIC VARIABILITY
Normal physiologic insulin secretion, in addition to other mechanisms, prevents
glucose fuctuations in healthy adults. In patients with diabetes, abnormalities in insulin
secretion are a key pathophysiologic process. Recently, additional mechanisms have
been suggested as components of glycemic control deterioration in T2DM. In addition
to peripheral insulin resistance and b-cell decline, accelerated lipolysis, incretin
defciency in the gastrointestinal tract, alphacell hyperglucagonemia, increased glucose
reabsorption at the kidney, and changes in the brain, all contribute to pathophysiology
of hyperglycemia and glycemic variability in T2DM.
36
These abnormalities disrupt
normal physiologic response, and result in chronic sustained hyperglycemia and short
term fuctuations in glucose levels. These glycemic disorders appear to be associated
with a state of increased oxidative stress and likely subsequent development of
cardiovascular complications.
Cellular Response to Hyperglycemia
The imbalance between the production of reactive oxygen species (ROS) and the
ability to eliminate them is the defnition of oxidative stress, and has been described
to be central in the pathogenesis of cardiovascular complications related to diabetes.
Figure 1 depicts the pathophysiologic role of oxidative stress in the development of
cardiovascular complications. Both insulin resistance and hyperglycemia are implicated
in the pathogenesis of these complications.
37,38
Hyperglycemia has been hypothesized
to induce vascular injury via at least four different biochemical pathways: (1) enhanced
polyol activity leading to sorbitol and fructose accumulation; (2) increased formation of
advanced glycation end products; (3) activation of protein kinase C and nuclear factor
kappaB; and (4) increased hexosamine pathway fux.
39
Brownlee
38
has described the
unifying link between these four mechanisms which is the overproduction of superoxide
(O
2
-.
) by the mitochondrial electrontransport chain resulting in a general state of oxidative
stress. O
2
-.
can react with nitric oxide to generate peroxynitrite and nitrotyrosine,
which can lead to endothelial damage and further vascular damage.
38-40
Endothelial
dysfunction is characterized by impaired endotheliumdependent vasodilation due
to the unavailability of vasodilators such as nitric oxide. Endothelium activation is
a proinfammatory, proliferative, and procoagulatory setting, ultimately leading to
arterial narrowing and susceptibility to atheroma deposition. Clinical studies have
shown that endotheliumdependent vasodilation is abnormal in patients with diabetes.
41

Hyperglycemia can also induce alterations in the co-agulation system resulting in
increased thrombosis.
42
Association of Glycemic Variability with Oxidative Stress
Oxidative stress has been implicated as a major pathophysiologic process in the
development of macrovascular complications, particularly cardiovascular disease, which
in turn, contributes signifcantly to the increased morbidity and mortality reported in
patients with diabetes. The impact of variable glucose concentrations versus chronic
hyperglycemia on markers of oxidative stress (nitrotyrosine/8hydroxydeoxyguanosine)

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143 GLYCAEMIC VARIABILITY IN TYPE 2 DIABETES MELLITUS
and apoptosis has been evaluated in a model using human umbilical cord vein
endothelial cells. Both acute glucose fuctuations and chronic hyperglycemia stimulated
overproduction of ROS and increased cellular apoptosis; however the effects were more
pronounced in cells with intermittent high glucose levels. This study surmised that
acute glucose fuctuations are involved in the development of vascular complications.
43

Other data have further established that variability in glycemic control resulted in more
endothelial cell damage than chronic sustained hyperglycemia.
44
Other cell culture
suggests that normal protective mechanisms of oxidative stress are impaired by chronic
hyperglycemia. When subsequently exposed to intermittent glycemic variability there
was more pronounced toxicity.
45
Figure 1. The role of oxidative stress in the development of vascular complications.

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144 DIABETES
Cardiovascular Toxicity and Glycemic Variability
Concordant with experimental data, clinical data have emerged over the last
several years establishing glycemic variability as an independent predictor of these
complications. Monnier et al
4
provided data in patients with T2DM to support the
concept of acute glucose fuctuations as a more important trigger of oxidative stress than
chronic hyperglycemia. In this study, a linear correlation was demonstrated between
increased free radical production and the magnitude of glucose fuctuation. Reducing
glucose fuctuations has been shown to reduce both oxidative and nitrosative stress.
40
Several studies have shown that postprandial hyperglycemia is an independent
risk factor for development of vascular complications in patients with T2DM.
3-12

In the DECODE study more than 25,000 patients were followed for over 7 years.
Increased mortality was more closely associated with increased 2hour postprandial
glucose (PPG) levels than with FPG.
12
Elevated glucose 2 hours after an oral challenge
increased the relative risk for cardiovascular disease by up to 40% independent of
fasting hyperglycemia in nondiabetic patients in the Framingham Offspring Study.
14,15

Glycemic variability as measured by continuous blood glucose monitoring system
(CGMS) has also been associated with cardiovascular risk
46
and severity of coronary
artery disease in patients with T2DM.
47
Oxidative stress from glycemic variability
may have a stronger association with atherosclerosis and subsequent cardiovascular
disease than FPG or HbA1
C
.
CHALLENGES FOR ACHIEVING GLYCEMIC CONTROL
Evidence suggests that achieving the recommended glycemic control goals can
reduce long-term complications; current treatment standards recommend a more
aggressive approach to managing patients with T2DM.
48-50
Historically, as many
as 60% of patients with T2DM did not achieve the recommended glycemic control
targets, and many of the currently available treatment options do not sustain these
goals over time as the disease progresses as a result of a variety of mechanisms.
36,51,52

Brown et al
53
found that patients receiving monotherapy with either a sulfonylurea
or metformin had HbA1
C
levels greater than 8% for a mean of 20 months and 14
months, respectively, before a treatment change was implemented. Current guidelines
suggest treatment changes should be implemented within 2 to 3 months of initiation or
change of therapy.
48-50
Medications that improve postprandial glucose levels include
sulfonylureas, metiglinides, amylin analogs, GLP1 agents and DPPIV inhibitors. In
addition, multiple daily injection (MDI) insulin programs that include long acting and
rapid acting insulin can improve postprandial glucose and may also reduce glycemic
variability (Package Inserts, Tables 3 and 4).
Better methods, such as CGMS, for identifying glycemic average, glycemic
variability, hyperglycemia, and hypoglycemia may lead to more responsive adjustments
in treatment regimens and to improvement in the quality of care compared to traditional
self-monitored blood glucose strategies. The use of continuous subcutaneous insulin
infusion (CSII) (pumps), particularly when combined with CGMS is an effective
modality to improve glycemic variability in those with T1DM,
54-56
and may be of beneft

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145 GLYCAEMIC VARIABILITY IN TYPE 2 DIABETES MELLITUS
in T2DM patients as well.
57,58
A recent study demonstrated a relationship between
glucose excursions and oxidative stress in patients with T2DM using continuous
glucose monitoring data.
57
DIABETES MEDICATIONS AND GLYCEMIC CONTROL
IN CLINICAL SETTINGS
The Role of Insulin in Glycemic Control and Oxidative Stress
Insulin appears to have many benefcial effects. Insulin exerts an antiinfammatory
effect by reducing the increase in Creactive protein and serum amyloid A.
59
Other
benefcial effects of insulin, that have been previously described, include partial
restoration of insulin-stimulated endothelial function,
60
improved vasodilation
by increased nitric oxide production,
61
and improved fbrinolytic profles.
62
Early
initiation of insulin therapy can increase peripheral insulin sensitivity and preserve
b-cell function.
63-65
In patients who have failed oral agents the use of insulin can
signifcantly improve b-cell function
63,66,67
and even short periods of insulin therapy
in newly diagnosed patients with T2DM may set the foundation for better longterm
control.
68
The DIGAMI study evaluated the effect of insulin (insulin infusion followed
by subcutaneous insulin for 3 months) in patients with diabetes who present with
acute myocardial infarction.
69
Overall, the use of insulin infusion in these patients
reduced morbidity and mortality compared to those patients who received standard
injection therapy. The largest mortality reductions were seen in insulinnave patients
with the lowest cardiovascular risk profle (3month mortality rate 6.5% in the infusion
group vs 13.5% in the control group [relative reduction 52%, P = 0.046]). The authors
suggested that the benefcial effects of insulin may not only be related its ability to
control blood glucose levels but via other mechanisms such as restoration of platelet
function although this study did not specifcally evaluate other mechanisms.
69
Differences in Insulin Preparations
The frst use of insulin dates back to 1922 and represented a signifcant medical
breakthrough.
70
Since this frst report of insulin use, the product has evolved from insulin
extracted from bovine or porcine pancreas to human insulin to the newest recombinant
insulin products, insulin analogs. Ideally, insulin therapy should mimic physiologic
insulin secretion. However, the pharmacodynamic profles of conventional human
insulin products are suboptimal and fail to mimic normal physiology. With the help of
recombinant DNA technology, those limitations of conventional human insulin have
been overcome by molecular modifcations of the human insulin molecule.
Older strategies tended to reserve insulin until patients with T2DM failed combination
therapy with oral agents, possibly resulting in years of suboptimal glycemic control.
Newer strategies that have been recommended entail earlier initiation of insulin, perhaps
as soon as a frst or secondline agents.
48,49
The development of insulin analogs has
changed insulin management to potentially achieve better glycemic control and outcomes
for patients with T2DM.

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146 DIABETES
Rapid-Acting Insulins
Pharmacological Differences
Rapidacting insulin analogs improve glycemic control compared to regular human
insulin when used at mealtimes, but due to their ultra-short action basal insulin is usually
administered in combination multiple daily injection regimens. The frst rapidacting
insulin analog to be introduced was insulin lispro in 1996. This agent is different from
human insulin by the inversion of the amino acid residues in positions 28 and 29 of the
insulin bchain using recombinant DNA techniques. This inversion prevents the formation
of hexamers and dimers that tend to diffuse more slowly, thereby allowing for its rapid
uptake into blood and tissues.
71,72
The second agent of this rapid-acting analog class,
marketed in 2000, was insulin aspart, in which proline at position 28 is substituted by
aspartic acid of the bchain of human insulin. After injection, insulin aspart dissociates
rapidly.
73
The most recent rapid-acting analog is insulin glulisine, which is designed
with amino acid substitutions lysine for asparagine near the N-terminus of the b-chain
and glutamic acid for lysine near the C-terminus of human insulin.
Overall, these molecular changes result in the analogs quickly dissociating into
monomers that are absorbed rapidly and achieve faster peak levels compared to regular
human insulin which occurs as dimers and hexamers that require considerably more
time to become absorbed.
74
The changes to the insulin molecule do not result in any
signifcant differences in binding of the insulin analogs to the insulin receptor compared
to regular human insulin.
75,76
The absorption of human insulin is not suffciently rapid around mealtimes to
control prandial glucose.
77
Therefore, if used, it is essential to administer regular insulin
30 minutes before meals. As well, regular human insulin is associated with large day-to-day
variations in insulin absorption.
78
The insulin analogs improve on these pharmacokinetic
and pharmacodynamic defciencies, allowing these agents to produce plasma profles that
more closely simulate normal, physiologic meal-stimulated insulin release.
79
The three
rapidacting agents (lispro, aspart, glulisine) have very similar onset and duration of
action with the peak effect occurring close to injection time (Table 2).
80,81
Other clinical
Table 2. Pharmacokinetic properties of human insulin and insulin analogs
Insulin Preparation Onset of Action Peak Action Duration of Action
Short-Acting
Regular 30-60 minutes 2-3 hours 8-10 hours
Aspart 5-15 minutes 30-90 minutes 4-6 hours
Lispro 5-15 minutes 30-90 minutes 4-6 hours
Glulisine 20 minutes 90 minutes 5.3 hours
Long-Acting
NPH 2-4 hours 4-10 hours 12-18 hours
Glargine 2-4 hours Relatively fat Up to 24 hours
Detemir 1-2 hours Relatively fat Up to 24 hours
NPH, neutral protamine Hagedorn.

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147 GLYCAEMIC VARIABILITY IN TYPE 2 DIABETES MELLITUS
advantages to rapid acting analog insulins are the ability to administer closer to meal
times, which may give patients more fexibility, and tighter prandial glucose control with
consequential reductions in glycemic excursions, and the ability to better match insulin
dose to anticipated carbohydrate intake (i.e., insulin to carb ratio). As a result, this can
result in better postprandial control, with fewer and less severe hypoglycemic events.
80,82-84
Long-Acting Insulins
Pharmacological Differences
Basal or longacting insulins are important for maintaining normoglycemia over
24 hours. Neutral protamine Hagedorn (NPH) insulin has peak effects which are reached 4
to 10 hours after injection, and the duration of effect lasts 12 to 18 hours. NPH is therefore
often dosed twicedaily. Furthermore, NPH also exhibits variability in the absorption in
the subcutaneous tissue. The variability in absorption may account for as much as 80%
of the daytoday blood glucose fuctuations,
85
and as a result, this agent does not closely
resemble normal physiologic basal insulin secretion. Basal insulin analogs are designed
to mimic more normal physiologic basal insulin secretion. There are currently two
long-acting or basal insulin analogs; insulin detemir and insulin glargine. Glargine contains
a glycine for asparagine substitution in the alpha-chain, two arginine residues added at
the Cterminus, and the addition of zinc to enhance the aggregation and slow release at
a neutral pH. Insulin glargine precipitates in the subcutaneous tissue, which slows down
its absorption and results in a relatively fat insulin plasma profle.
86-89
Insulin detemir, is
a combination of the original insulin molecule with a saturated fatty acid (myristic acid).
Insulin detemir is designed to bind albumin (98% albuminbound in circulation) through
this fatty acid chain in the plasma after injection. Insulin detemir also has an extended
plasma profle thought to be due in part to this mechanism.
91-96
Unlike insulin glargine
and NPH, which form crystalline depots, detemir is soluble and the subcutaneous depot
remains in a liquid state resulting in less absorption variability (Table 2).
80
Longacting insulin analogs have advantages over conventional human insulin such as
NPH, primarily due to their prolonged duration of action (up to 24 hours) and absence of
a pronounced peak, permitting oncedaily dosing in many patients.
80,85-96
The signifcance
of these pharmacokinetic and pharmacodynamic differences, compared to NPH insulin,
is related to a lower incidence of nocturnal and overall hypoglycemia, which has been
observed in several clinical trials comparing the longacting insulin analogs to NPH
insulin.
86-96
Both of the basal analogs have shown lower measurements of withinsubject
variability in blood or plasma glucose when compared to NPH.
94-96
Low variability in glucoselowering effect may be an advantage of the longacting
and rapid acting insulin analogs versus older human preparations not only in terms of
a lower incidence of hypoglycemia but by potentially minimizing glycemic excursions
and the development of oxidative stress and subsequent vascular disease; however, this
is needed to be further confrmed in clinical trials.
Other Diabetes Medications and Glycemic Variability
Oral diabetes medication have positive effects in lowering HbA1
C
and plasma glucose
levels (Table 3). However, there is a relative paucity of data regarding their effect on
glycemic variability. A recent study of acarbose showed improvement in postprandial blood

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148 DIABETES
glucose when combined with premix insulin.
97
Older medications such as sulfonylureas
and metiglinides can also lower postprandial glucose, but may not be durable over time
due to a variety of mechanisms, most notably b-cell decline.
36
Several newer medications have been introduced for T2DM over the last decade, and
some of these target postprandial blood glucose levels with minimal risk of hypoglycemia,
potentially reducing oxidative stress. These agents include the GLP1 mimetic exenatide,
GLP-1 analog liraglutide,
98,99
DPPIV inhibitors (gliptins) sitagliptin and saxagliptin,
100,101

and amylin analogs (pramlintide)
101
(Table 4).
102
In addition, weight loss and improvement
in other cardiovascular risk markers may be associated with some of these agents.
98-105
Cardiovascular safety studies are underway for several newer diabetes medications, but
their future roles in reducing cardiovascular disease risk is yet undetermined. Metfomin,
an older oral diabetes medication, has been associated with improved cardiovascular
outcomes.
106
In contrast, the thiazolidinedione rosiglitazone has been called into question
for cardiovascular risk.
107
Other therapeutic categories of noninsulin diabetes medications
are also in development.
108,109
Challenges in the Hospital Setting
In the hospital setting management of glycemic control is benefcial. However,
several studies have suggested that treatment of hyperglycemia and limiting glycemic
variability in the hospitalized patient may have a signifcant impact on hospital morbidity
and mortality.
69,110-118
Glycemic control in the hospital may promote white blood cell
function, reduce wound infections and reduce length of stay.
119
Hyperglycemia in the
Table 4. Injectable diabetes medications
Treatment FPG Reduction HbA1
C
Reductions
Exenatide (Byetta) Targets ppd 1-1.5%
Liraglutide (Victoza) Targets ppd 1-1.5%
Pramlintide (Symlin) Targets ppd 1-2%
Insulin Limited only by hypoglycemia 1.5-3.5+%
*Based on package insert data as monotherapy.
Table 3. Oral antidiabetic agents
Treatment FPG Reduction HbA1
C
Reduction
Sulfonylureas 5060 mg/dL 1-2%
Metformin 5060 mg/dL 1-2%
a-Glucosidase inhibitors (Precose) 1530 mg/dL 0.5-1%
Repaglinade (Prandin) 60 mg/dL 1.7%
Thiazolidinediones 4060 mg/dL 1-2%
Gliptins (Januvia, Onglyza) Targets ppd 0.5-0.8%
*Based on package insert data as monotherapy.

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149 GLYCAEMIC VARIABILITY IN TYPE 2 DIABETES MELLITUS
hospital may be a result of stress, decompensation of underlying diabetes, infection,
iatrogenic or a variety of other mechanisms.
118
Treatment standards recommend against the use of sliding scale insulin regimens
since this approach is not a proactive regimen for managing glucose excursions.
Therefore scheduled and corrective doses of insulin should be utilized instead.
48,49,118,120

The use of continuous glucose monitoring devices could allow for a better description
of glycemic variability in hospitalized patients. Improved glycemic control not only has
implications on long-term complications, but also results in decreased lengths of hospital
stay, decreased inpatient costs of complications, a reduction in hospital readmission rates
of 50%, and improved quality of life.
121
More recently, the American College of Physicians
has released an updated management guideline for inpatient diabetes management.
122
CONCLUSION
Glycemic control is essential in the management of patients with T2DM for prevention
of cardiovascular disease and related complications. In addition to fasting glucose and
HbA1
C
, there is evidence to suggest that glycemic variability is an independent risk factor
for cardiovascular complications. Hyperglycemic excursions cause oxidative stress,
which is a likely mechanism for macrovascular complications. Improving technologies
and management strategies with self monitored blood glucose, and continuous glucose
monitoring, in addition to better medications used in the clinical setting appear to improve
detection and treatment of glycemic variability. Insulin, particularly analogs, along with
other newer agents, including GLP1 analogs and mimetics, amylin analogs, and DPPIV
inhibitors may play a role in improving glycemic variability, including postprandial
control, while minimizing hypoglycemia. Additional clinical data is needed to establish
overall cardiovascular safety and risk reduction in persons with diabetes. Interventions
targeting other macrovascular risk factor targets such as hypertension and dyslipidemia
are also part of an overall diabetes management program.
48,49,123
Treatment strategies
for T2DM involve aggressive interventions for management of risk factors to achieve
the above goals in addition to glycemic parameters.
ACKNOWLEDGEMENT
Some of the materials in this chapter were adapted from the article: Johnson EL.
Glycemic variability: too often overlooked in Type 2 diabetes? J Fam Prac 2010;
59(8):E1E8, with the kind permission from the Journal of Family Practice.
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119. Furnary AP, Zerr KJ, Grunkemeier GL et al. Continuous intravenous insulin infusion reduces the incidence
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120. Garber AJ, Moghissi ES, Bransome ED et al. American College of Endocrinology position statement on
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