Medical Management of Hyperglycemia

in Type 2 Diabetes

Dharma Lindarto
Div. Endokrin-Metabolik Departemen Ilmu Penyakit Dalam FK USU /
RSUP H Adam Malik Medan
Rationale for glycemic goals
Glycemic goals of therapy are based on:
Clinical studies
Type 1: DCCT, Stockholm Diabetes Intervention
Study
Type 2: UKPDS, Kumamoto
Epidemiological data
Goals of therapy in DCCT and UKPDS
Neither study was able to maintain HbA1c level
in the nondiabetic range

3
 Risk of complications
Benefits of lowering hemoglobin HbA1c

16
of complications

12
Relative Risk

0
6 7 8 9 10 11 12
Hemoglobin HbA1c (%)

Average Glucose
120 150 180 210 240 270 300
mg/dl

Adapted from UKPDS 33: Lancet 1998;352:837-853. 4

Adapted from DCCT Study Group. N Engl J Med
1993;329:977.
 Diagnostic Criteria Associated
with Glucose Abnormalities

FPG 2-Hour PG on OGTT

Diabetes Mellitus Diabetes Mellitus

126 mg/dL 7.0 mmol/L 200 mg/dL 11.1 mmol/L
Prediabetes Impaired Glucose
Tolerance
100 mg/dL 5.6 mmol/L 140 mg/dL 7.8 mmol/L

Normal Normal

Adapted from The Expert Committee on the Diagnosis and Classification of

Diabetes Mellitus.
Diabetes Care. 2001;24(Suppl 1):S5-S20.
 NHANES reveals the under-management
of diabetes

NHANES 1999 2000 population with diabetes

Mean HbA1c value was 7.8%

37% had an HbA1c value <7.0%
26% had an HbA1c value of 7.08.0%
37% had an HbA1c value >8.0%

27% were receiving insulin therapy with or

without Oral Glucose Lowering Drugs

6
Saydah S, et al. JAMA 2004;291:33542.
 Is glycemic control improving over
time?
%
40 1999-2000
35 2001-2002

30 2003-2004

25

20

15

10

0
<6.0% 6.0 6.9%
7.0 7.9%
8.0 8.9%
9.0 9.9%10.0%

HbA1c levels
7
US data in adults
NHANES Diabetes Care 2008;31:8186.
 Benefits of intensive vs conventional
glycemic management

10
DCCT conventional
9
HbA1c (%)

8 UKPDS conventional
UKPDS intensive

7
DCCT intensive

5
0 1 2 3 4 5 6 7 8 9
Time (y)

8
Turner R, et al. Ann Intern Med.
1996;124:136-145.
 No HbA1c threshold in Type 2 Diabetes
Adjusted incidence per
1000 person years (%) Epidemiolog
80 ic data from
Myocardial infarction the UKPDS
Microvascular endpoints
60

ADA goal
40
?

20

0
5 6 7 8 9 10 11
Updated mean HbA1C (%) 9
Stratton IM, et al. BMJ.
2000;321:405-412.
 Fasting blood glucose is an important determinant
of CVD burden

Total
Total stroke ischemic CV death
4.0
Heart disease
Hazard ratio (95% CI)

2.0

1.0

Risk Risk Risk

21% (CI 18-24) rise 23% (CI 19-27) rise 19% (CI 15-22) rise
0.5 per per per
1 mmol/L rise in 1 mmol/L rise in 1 mmol/L rise in
glucose glucose glucose
4.5 5.0 5.5 6.0 6.5 7.0 7.5 4.5 5.0 5.5 6.0 6.5 7.0 7.5 4.5 5.0 5.5 6.0 6.5 7.0 7.5

Usual fasting glucose (mmol/L)

CVD: cardiovascular disease 10
Asia Pacific Cohort Studies Collaboration. Diabetes Care 2004;27:2836-
2842.
 Why not aiming for lower
HbA1c?
Normal HbA1c levels are difficult to
achieve with present therapies

Intensive therapy increases the risk of

weight gain and hypoglycemia

The absolute risks and benefits of

lower HbA1c are largely unknown
11
American Diabetes Association. Diabetes Care 2008;31(Suppl 1):S12-S54.
 HbA1c- How low is low enough?
Benefit of intensive glycemic control on
CVD outcomes not proven

HbA1c level of 7% should serve as a

call to action to initiate or change
therapy

Goal: HbA1c <7%

But need for an individualised target
12
Nathan DM, et al. Diabetes Care 2009;32 193-203.
 T2DM guidelines focus on glycaemic control
and CVD risk factors

HbA1c levels correlate with the development of diabetic

complications
Multiple CVD risk factors cluster in T2DM
Dyslipidaemia
Hypertension
Obesity
Hypercoagulability
Insulin resistance
Thus, control of hyperglycaemia and CVD risk factors
is the focus of T2DM treatment

IDF Clinical Guidelines Task Force. Brussels, 2005. 13

ADA. Diabetes Care 2008;31(Suppl. 1):S1254.
Ryden L, et al. Eur Heart J 2007;28:88136.
 Principles in selecting antihyperglycemic
interventions

Effectiveness in lowering blood glucose

When high HbA1c (8.5%)
Classes with greater and more rapid glucose-
lowering effectiveness are recommended
Potentially earlier initiation of combination therapy
Extraglycemic effects that may reduce long-term
complications
Hypertension, dyslipidemia, BMI, insulin resistance,
insulin secretory capacity
Safety profiles
Tolerability
Ease of use
Cost 14
Nathan DM, et al. Diabetes Care 2009;32 193-203.
 ADA/EASD consensus algorithm
Overarching principles

Early intervention
Patients empowerment
Education, SMBG, treatment adjustment
Shorten delays in treatment changes
Achieve and maintain normal glycemic goals
Add medications, transition to new regimens quickly
Whenever HbA1c levels are 7%

STEP 1: Lifestyle intervention + metformin

STEP 2: Add another agent basal insulin or SU
STEP 3: Intensify therapy
Timely basal insulin therapy for patients not meeting targets
15
SMBG: self-monitoring blood glucose
Nathan DM, et al. Diabetes Care 2009;32:193-203.
 Expected HbA1c reduction according
to intervention

Intervention Expected in HbA1c (%)

Lifestyle interventions 1 to 2%
Metformin 1 to 2%
Sulfonylureas 1 to 2%
Insulin 1.5 to 3.5%
Glinides 1 to 1.5%1
Thiazolidinediones 0.5 to 1.4%
-Glucosidase inhibitors 0.5 to 0.8%
GLP-1 agonist 0.5 to 1.0%
Pramlintide 0.5 to 1.0%
DPP-IV inhibitors 0.5 to 0.8%

1. Repaglinide is more effective than nateglinide 16

Adapted from Nathan DM, et al. Diabetes Care
2009;32:193-203.
 ADA/EASD consensus algorithm
Tier 1: Call to action if HbA1c is 7%
well-validated therapies
Lifestyle + Lifestyle +
Metformin Metformin
+ Basal insulin + Intensive insulin
At diagnosis:
Lifestyle +
Metformin Lifestyle +
Metformin
+ Sulfonylurea

STEP 1 STEP 2 STEP 3

Tier 2: Lifestyle +
Less well Metformin Lifestyle +
validated + Pioglitazone Metformin
therapies No hypoglycaemia + Pioglitazone
Oedema/CHF + Sulfonylurea
Bone loss
Lifestyle +
metformin Lifestyle +
+ GLP-1 agonist metformin
No hypoglycaemia + Basal insulin
Weight loss 17
Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.
 ADA/EASD consensus algorithm
Tier 1: Well-validated therapies

STEP 1 STEP 2 STEP 3

Lifestyle + Lifestyle +
Metformin Metformin
At diagnosis: + Basal insulin + Intensive insulin
Lifestyle +
Metformin Lifestyle +
Metformin
+ Sulfonylurea

When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effectiveness,
or potentially earlier initiation of combination therapy, are recommended
18
Nathan DM, et al. Diabetes Care 2009;32 193-203.
 ADA/EASD consensus
algorithm: step 1
At diagnosis

STEP 1

Lifestyle
+
Metformin

19
Nathan DM, et al. Diabetes Care 2009;32 193-203.
 Exercise significantly reduces
HbA1c
Pooled meta-analysis of 14 exercise
trials %
0.2
0.08%
0.1
Exercise
from baseline to post-intervention

0.0
Non-exercise control
-0.1
(weighted mean difference)

-0.2
-0.3
p<0.001
Change in HbA1c

-0.4
-0.5 Effect was
weight-
-0.6 independent
-0.7 -0.66%
20
Boul NG, et al. JAMA 2001;286:1218-27.
 Why should metformin be initiated concurrently
with lifestyle intervention at diagnosis?

For most individuals with Type 2 Diabetes,

lifestyle interventions fail to achieve or maintain
the metabolic goals either because of:

Failure to lose weight

Weight regain

Progressive disease

A combination of factors

21
Adapted from Nathan DM, et al. Diabetes Care
2009;32:193-203.
 Attributes of metformin
Decreases hepatic glucose output
How it works
Lowers fasting glycemia
Expected HbA1c
1 to 2% (monotherapy)
reduction
GI side effects
Adverse events
Lactic acidosis (extremely rare)

Weight effects Weight stability or modest weight loss

Demonstrated beneficial effect in UKPDS which needs
CV effects
to be confirmed

22
Adapted from Nathan DM, et al. Diabetes Care
2009;32:193-203.
All About Metformin After
50 Years........
5600
publikasi

12800
penulis

23
 Vascular Effects of Metformin

Anti-atherogenic actions
cholesterol deposition
lipid peroxidation
endothelial function
oxidative stress

Antithrombotic actions
platelet activation
blood flow
PAI-1 and fibrin breakdown
Metformin: Intrinsic Vascular Protective Properties
24
Diabetes Technology and Therapeutics 2000; 2:259272
 MET with 51 Metabolic-Cardiovascular-Cancer (MCC) Risk Reducing Effects 18
(Illustrated : Tjokroprawiro 1994 2010)

VASPIN 47 INSULIN RESISTANCE 2 Glucose Absorption

AMPK 46 1 3 FBS
-Endorphin 45 4 2h PP
ADMA 44 5 Glycogenesis
Apn 43 6 Ins. Receptor Binding
SMC Fibroblast 42 7 GUT : GLUT-5 Exp.
Oxidative Stress 41 8 Post-Receptor Effect
Plaque Regression 40 9 Gluco- & Lipo-toxicity
NO ( HSP-90, eNOS) Tot-Chol, LDL-Chol
Capillary Perm.
39
METFORMIN 10
38 11 DPP-4 GLP-1
MMP-9 37 with 12 AGE
Periph. A Blood Flow 36 MCC 13 Fibrinogen
PTEN 35 EFFECTS 14 Factor-VII
HT-29 34 15 PAI-1
LNCaP 33 16 Factor-XVIIIa
PC-3 32 17 VAT
DU 145 31 18 TSH
cyclin D1 30 19 Respiratory Complex I
TSC2 29 20 TG
TSC1 28 21 HDL-Chol
mTORC1 27 22 Erythrocyte Deform.
LBK1 26 48 49 50 51 23 Platelet Aggregation
p53 25 Cytosolic Ca++ NFB LCN2 HCy 24 Hyperinsulinemia
ASK-DNC
 The Pharmaceutical
Development of Metformin

The potential to improve

patient tolerability & compliance
26
 Solutions to Overcoming
Limitations of Standard Metformin

Providing the same great benefits

minus the adverse effects

Tablet that

has better GI tolerability

offers once-a-day dosing

Smooth, Sustain,
Simple 27
The Technology Unique Only To Glucophage
XR

The GelShield Diffusion System

Dual
hydrophilic Metformin hydrochloride
polymer
system that
permits once-
daily dosing 1,2 Outer solid continuous
phase

Inner solid particulate

28
phase
1. Timmins P, et al. Clin Pharmacokinet 2005;44:721-729 2. Fujioka K, et al. Clin Ther 2003;25:515-529.
The GelShield Diffusion System
Optimises Metformin Delivery

Before
ingestion Hours after
ingestion
29
Sustained Metformin Release from the XR
Tablet
Plasma Conc. (mg/mL)

2000 2 x 500 mg metformin

2 tab 500 mg Glucophage XR
1600

1200

800

400

0
0 4 8 12 16 20 24
Time (h)
Absorption
Slower and longer Equivalent Systemic Exposure
30
Timmins P. Clin Pharmacokinet 2005; 44:
721-729
 ADA-EASD
Audit of Anti-Diabetic Agents
Titration of Metformin
Start low 500 mg/day
Increment slowly 2000 mg/day
Reduce dose if GI side effects develop
Maximum dose is 3000 mg/day given
b.i.d or t.i.d
Consider once-a-day longer acting
formulation if standard metformin is not
suitable

31
Nathan. Diabetes Care 2006; 29:19631972
Conclusions: Glucophage XR

Novel drug delivery system optimises smooth &

sustain drug delivery
Superior gastrointestinal tolerability vs.
immediate-release metformin
Convenient, once-daily dosing supports good
compliance with therapy
Simple, convenient & straightforward initiation of
therapy
All the proven glycaemic and cardiovascular
benefits of Metformin
32
 ADA/EASD consensus
algorithm: step 2
STEP 1 STEP 2

Lifestyle
+ Metformin
+ Basal insulin
At diagnosis:
Lifestyle HbA1c 7%
+
Metformin
Lifestyle
+ Metformin
+ Sulfonylurea

When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effe
or potentially earlier initiation of combination therapy, are recommended
33
Adapted from Nathan DM, et al. Diabetes Care
2009;32:193-203.
 ADA/EASD consensus
algorithm: step 2
If step 1 fails to achieve or sustain HbA1c <7%,
another medication should be added within 2-3
months

The HbA1c level will determine (in part) which

agent is selected next:
Most of newly diagnosed Type 2 Diabetic
patients will usually respond to sulfonylurea*
Basal insulin if HbA1c >8.5% or symptoms of
hyperglycemia

* Sulfonylureas other than glybenclamide (glyburide) or 34

chlorpropamide
Nathan DM, et al. Diabetes Care 2009;32:193-203.
 ADA/EASD consensus algorithm: step 2
Addition of sulfonylurea

STEP 1 STEP 2

At diagnosis:
Lifestyle
+
Metformin
HbA1c 7%
Lifestyle
+ Metformin
+ Sulfonylurea*

* Sulfonylureas other than glybenclamide (glyburide) or 35

chlorpropamide
Nathan DM, et al. Diabetes Care 2009;32:193-203.
 Attributes of sulfonylureas

How they work Enhance insulin secretion

Expected HbA1c
1 to 2%
reduction

Adverse events Hypoglycemia* (but severe episodes are infrequent)

Weight effects ~ 2 kg weight gain common when therapy initiated

CV effects None substantiated by UKPDS or ADVANCE study

* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide)

than other 36
second- generation sulfonylureas (gliclazide, glimepiride, glipizide)
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
 Adding sulfonylurea to metformin is
particularly effective in lowering HbA1c

Drug 1 more beneficial Drug 1 less beneficial

Drug 1
Glyb vs. other
SU
TZD vs. SU
TZD vs. Met
Repag vs. SU
SU vs. Met
SU vs.
Acarbose
Met + TZD vs. Met
SU + TZD vs. SU
Met + SU vs. Met
Met + SU vs. SU
Glyb: glyburide
TZD: thiazolidinedione -1.5 -1.0 -0.5 0 0.5
Repag: repaglinide
SU: sulfonylurea Weighted mean difference
Met: metformin in HbA1c Value, % 37
Bolen S, et al. Ann Intern Med 2007;147:386-
399.
Introducing

Greater A1c
Control
38
 Introducing Glucovance

A fixed-dose combination of two of the most established OADs worldwide

METFORMIN GLIBENCLAMIDE
Foundation treatment for T2D 2nd-generation sulfonylurea

Shown to improve Shown to improve

CV outcomes (1) microvascular outcomes (2)

39

(1) UKPDS 34, The Lancet 1998; 352: 854-65 (2) UKPDS 33, The Lancet 1998; 352: 837-53
What is specific about

40
Fixed vs Free Tablet Combinations
Reduce number of tablets

Clinical Equivalence
Fixed Dose tablet Free tablet
Combination Combination

FDC Same profile Met + Rosiglitazone

FDC Same profile Met + Pioglitazone

FDC Same profile Met + Sitagliptin

FDC Same profile Metformin + Glimepiride

FDC Same profile Met + Vidagliptin

Glucovance Improved
41 profile Met + Glibenclamide
Superior A1c Reduction
Patients on Glucovance experienced superior A1c
reductions compared to those on free combinations of
metformin and glibenclamide after 2.5 to 6 months of
treatment.(1)

Cohort of 1421 US patients, with a mean

follow up of 128 days for Glucovance and
135 days for free combination.

A1c at baseline:
9.2% (Glucovance)
A1c Reduction (%)

9.1% (free combination)

42

(1) Blonde L et al., Diabetes, Obesity and Metabolism 2003; 5: 424-31

 More Patients Reach A1c Goal

This improved efficacy helps more patients reach A1c goal (<7.0%)

Cohort of 1421 US patients, with a

mean follow up of 128 days for
Glucovance and 135 days for free
combination.

A1c at baseline:
9.2% (Glucovance)
9.1% (free combination)

43

(1) Blonde L et al., Diabetes, Obesity and Metabolism 2003; 5: 424-31

 Advanced Tablet Technology

Each tablet of Glucovance is comprised of a precise range of

glibenclamide microparticles embedded in a soluble matrix of
metformin:(1)

Soluble Metformin matrix

Glibenclamide particle spectrum

%: dia25meter 6 m
25%: 7 m < diameter < 10 m
25%: 11 m < diameter < 20 m
25%: diameter 21 m

This design influences the absorption rate of Glibenclamide into

the blood: smaller particles dissolve quicker, allowing RAPID
44
RELEASE.(1)
(1) Howlett H et al., Current Medical Research and Opinion 2003; 19(3): 218-25
Glucovance tablet technology:
engineered to optimise drug delivery

6m 7- 11- >
m 10mm 20mm 20mm
25% 50% 75%
Metformin Glibenclamide
soluble matrix particle range
45

Howlett H et al. Curr Med Res Opin 2003;19:218-25

 Faster Glibenclamide
Absorption Rate
Glibenclamide absorption is faster with Glucovance
than Free Combination(1)
Glibenclamide concentration: Glucovance vs. Free Combination

46

(1) Howlett H et al., Current Medical Research and Opinion 2003; 19(3): 218-25
 Faster Glibenclamide Concentration-
Timely action

The need for glycaemic control is at it highest immediately after a meal.(1)

The glibenclamide plasma concentrations are higher during this time period with
Glucovance than with free combination.

Simulated 24-h plasma

concentrations of glibenclamide
following administration of
Glucovance tablets or co-
administered metformin and
glibenclamide.

Drugs were administered twice

daily at 8:00 and 18:00.

47

(1) Howlett H et al., Current Medical Research and Opinion 2003; 19(3): 218-25
Greater Efficacy On Post Prandial
Glycaemia

48
Low Risk of Hypoglycaemia

Patients on Glucovance have a low risk of hypoglycaemia comparable to

those on free combinations of metformin and sulfonylureas:(1)(2)(3)

Study 1(1) Study 2:(2) Study 3:(3)

Marre et al, 2002 DeFronzo et al, 1995 Charpentier et al, 2001

Most episodes of hypoglycaemia associated with Glucovance were mild-to-

moderate and required no medical intervention.
49
(1) Marre M et al., Diabetic Medicine 2002, 19: 67380. (2) DeFronzo RA et al., N Engl J Med 1995 31;333(9):541-9.
(3) Charpentier G et al., Diabet Med 2001;18(10):828-34.
Conclusions

Glucovance: Advanced Tablet Technology

Glucovance: Greater A1c Control
Glucovance: Established Safety Profile
Glucovance: Better Adherence

Glucovance not only offers the promise of better

compliance through the fixed dose concept but
delivers the evidence through various studies

50
Glucovance is Unique

The ADA/EASD recommend that glibenclamide

should not be used in preference to the
sulfonylureas -----------Hypoglycaemia

but the argument rests in the fact that

does not contain standard glibenclamide

51
 Conclusions
A new sense of urgency

Early intervention

Patients empowerment
Education, SMBG, treatment adjustment

Shorten delays in treatment changes

Achieve and maintain normal glycemic goals

Add medications, transition to new regimens

quickly
Whenever HbA1c levels are 7% 52
Nathan DM, et al. Diabetes Care 2009;32 193-203.
 Case 1
Mr. B is a 49-year-old man with Type 2
diabetes since 1997.
He has a history of CHD and underwent
CABG in 2004.
He has a history of hypertension and
dyslipidaemia
Diabetes is poorly controlled due to poor
adherence to anti-diabetic therapy
Physical examination

Height: 172.7 cm (5 8)
Weight: 113.9 kg (251 lb)
BMI 38.1kg/m2
Neurological examination results are also
unremarkable
Laboratory values
Fasting plasma glucose: 8.0 mmol/l (144
mg/dl)
Total cholesterol: 4.1 mmol/l (158 mg/dl)
LDL cholesterol: 2.6 Mmol /l (99 mg/dl)
HDL cholesterol: 0.9 mmol/l (35 mg/dl)
HbA1C: 9.1%
 He is taking
1. Metformin 500 mg bd.
2. Clopidogrel
3. Simvastatin
4. Enalapril,
5. Hydrochlorothiazide,
6. Low-dose aspirin
What is Problem / Diagnosis?:
Prediabetes/diabetes uncontrol
Dislipidemia
hypertension
CHD
obesity
More metformin?
How much more reduction in HbA1c is
possible by increasing metformin to 2000
mg/day?
A. 0.5%
B. 1.0%
C. 2.0%
How dose Metformin ?
 Glucophage XR 500 mg tablet
Minimum dose Maximum dose
Initial dose 500mg OD 2000 mg OD

Additional information
Should not be used if SCr>150 mol/l or CrCl<30 mL/min),
liver cirrhosis, CCF, recent MI, chronic respiratory disease,
vascular disease and severe infections or any conditions
that can cause lactic acid accumulation.

Patient counseling points

Take with evening meals
Swallow whole and do not crush or chew

Unit Cost
RM 0.23 / tab
You increase his metfomin after 3 months
HBA1c is 8%. Would you consider
combination anti-diabetic therapy for Mr. B?

A. Yes
B. No
What would you do in your practice?

A. metformin plus Insulin glargine

B. metformin plus sitagliptin
C. metformin plus SU
D. Metfomin plus TZD
E. Metformin plus Exenatide
 Fixed Dose Combinations

1. Metformin + Glibenclamide (Glucovance )

2. Metformin + Glipizide (Metaglip )

3. Metformin + Rosiglitazone (Avandamet )

4. Metformin + Pioglitazone (Competact)

5. Metformin + Sitagliptin (Janumet)

6. Metformin + Vildagliptin (Eucreas)

 UKPDS
1977 - 1997

UKPDS Post Trial Monitoring

1997 - 2007

Follow up
Maximum 30 years Median 17.7 years
Overweight group

Oxford