The Role of Sulfonylurea in Management T2DM:

Now and Then

 Topics

 Management of T2DM in Indonesia: inadequate

glycemic target
 Natural History of T2DM: Beta Cell Failure and
Insulin Resistance
 Choosing Pharmacology Agents in Diabetes
 Role of Sulphonylurea in T2DM: The new
generation of SU
 Take Home Message
 Topics

 Management of T2DM in Indonesia: inadequate

glycemic target
 Natural History of T2DM: Beta Cell Failure and
Insulin Resistance
 Choosing Pharmacology Agents in Diabetes
 Role of Sulphonylurea in T2DM: The new
generation of SU
 Take Home Message
Incidence of complication in DM2 (UKPDS 35)

Stratton IM. BMJ 2000

 Association of glycemia with macrovascular and
microvascular complication of DM2 (UKPDS 35):prospective
observational study

Stratton IM. BMJ 2000

Majority of patients with type 2 diabetes remain far above
glycaemic goals

10.1% have HbA1c > 10%2

10.0

20.2% have HbA1c > 9%1

9.0

37.2% have HbA1c > 8%1

8.0
63.0% of patients
with type 2 diabetes 7.0 ADA target (< 7%)3
have HbA1c > 7.0%1* AACE/ACE target (≤ 6.5%)4
6.0

HbA1c

AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ADA = American Diabetes Association
* Adapted from Saydah SH, et al. JAMA. 2004;291:335-342.
1. Saydah SH, et al. JAMA. 2004;291:335–342; 2. Oluwatowoju I, et al. Diabet Med. 2010;27:354–359; 3. ADA. Diabetes Care. 2003;26:S33–S50;
4. AACE/ACE. Endocr Pract. 2009;15:540–559.
Most Patients do not Reach
Treatment Goals

ADA EUDPG APDPG

ADA American Diabetes Association

EUDPG European Diabetes Policy Group
APDPG Asian Pasific Type 2 Diabetes Policy Group

Barnett AH. European Journal of Endocrinology 2004

 Current Practice in the Management of T2DM
in Indonesia: IDMPS Study
The HbAlc average was 8.27% and only 37.4% had reached the HbAIc target of <7%.

IDMPS study: The International Diabetes Management Practices Study

Soewondo P. J Indon Med Assoc. 2011
 Topics

 Management of T2DM in Indonesia: inadequate

glycemic target
 Natural History of T2DM: Beta Cell Failure and
Insulin Resistance
 Choosing Pharmacology Agents in Diabetes
 Role of Sulphonylurea in T2DM: The new
generation of SU
 Take Home Message
 Natural History of Type 2 Diabetes
Years from -10 -5 0 5 10 15
diagnosis
Onset Diagnosis

Insulin resistance
Insulin secretion

Impaired Fasting “Metabolic Syndrome”

Glucose

Post-Meal glucose
Microvascular complications
Fasting glucose
Cardiovascular Complications
Pre-diabetes Type 2 diabetes

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Nathan DM. N Engl J Med. 2002;347:1342-1349
 Relative Risk of Progression of Diabetic
Complications

15
13
11 Retinop

9
RELATIVE RISK

Neph
7
5 Neurop

3
1
6 7 8 9 10 11 12
Mean A1C

DCCT Research Group, N Engl J Med 1993, 329:977-986.

 Beta Cell Deficit in DM2
-cell mass (%)

150
~65%

100

50

0
Lean Obese T2DM
(non-diabetic) (non-diabetic)
Modified from Butler AE, et al. Diabetes 2003;52:102–10.
 Factors for progressive loss of B- cell function & mass
Glucotoxicity plays important pathways in the deterioration of beta cell function
Lowering hyperglycemia remains the main target for both
 slowing beta cell dysfunction and
 decrease the risk of chronic complications

Glucotoxicity Lipotoxicity

Inflamatory Amyloid deposition

Cytokines& ROS

Insulin
Apoptosis
Secretion
Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.
 • Experimental study
• The expression of
insulin gene
transcriptions were
depressed by high
glucose level
• Chronic exposure of
RIPE-3b1
activator
STF-1 cells to high glucose
After 4-h incubations concentration results
in diminished insulin
Line 1 & 4: under 11.1 mM glucose
Line 2 & 5: under 0.8 mM glucose secretion
Line 3 & 6: under 11.1 mN switched to 0.8 mM glucose
Moran A et al. J Clin Invest 1997
 Glucotoxicity must be cut
at any point of the disease progression
• Glucotoxicity phenomenon is partially reversible by
switching glucose in the culture media from a high to a
low concentration after insulin gene expression has
been lost.

• Glucotoxicity events are not due simply to beta cell

exhaustion because inclusion of somatostatinto prevent
glucose stimulation insulin secretion during chronic
culture with supraphysiologic glucose concentrations
did not prevent loss of insulin gene expression

• Glucotoxicity instead of beta cell exhaustion, has its

own role in beta cell dysfunction

Moran A et al. J Clin Invest 1997

The fundamental target
Reduce glucotoxicity
Reduce lipotoxicity
Preserve β cell’s function
Improve insulin reistance
Reduce complications

Delay the progression

 UKPDS: Observational data for a
1% decreases in HbA1c
Any Diabetes- All Peripheral
diab-related related cause Myocardial vascular Microvascular Cataract
endpoint death mortality infarction Stroke disease* disease extraction
0
–5
21% 21% 14% 14% 12% 43% 37% 19%
Percentage reduction in relative risk
corresponding to a 1% fall in HbA1c

–10
–15
–20
†
† ‡
–25 †
†
–30 †

–35
–40
†
–45
*Lower extremity amputation or fatal PVD
–50 †P < 0.0001; ‡P = 0.035

–55 Error bars = 95% CIs †

Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000;321:405–412.
 Ultimate Goals Of
Diabetes Treatment

Sustained No Long Term

Normal Blood Diabetes
Glucose Control Complications

Lowest Incidence No Acute

of Hypoglycemia Diabetes
Complications

Best Quality of Life

with a Chronic Disease
 Glycaemic Goals
Continue to Become More Aggressive

ADA ACE/AAC
Parameter
Goals1 E Goals2
Fasting plasma glucose (mg/dL) 70-130 <110
Postprandial plasma glucose
<180* <140**
(mg/dL)
A1c (%) <7*** ≤6.5
ADA, American Diabetes Association; ACE, American College of Endocrinology;
AACE, American Association of Clinical Endocrinologists.

*1-2 hours post-meal

**2 hours post-meal
***as close to normal (<6%) as possible without undue risk of hypoglycaemia

1ADA Position Statement. Diab Care 2008; 31 (Suppl 1): S12-S54.

2ACE/AACE Diabetes Road Map Task Force. Endocrine Practice 2007; 13: 260-268.
20
 Topics

 Management of T2DM in Indonesia:

inadequate glycemic target
 Natural History of T2DM: Beta Cell Failure
and Insulin Resistance
 Choosing Pharmacology Agents in Diabetes
 Role of Sulphonylurea in T2DM: The new
generation of SU
 Take Home Message
 Antihyperglycemic Therapy in
Type 2 Diabetes

• Today there are more therapy options for managing type 2

diabetes than ever before
• Those options serve a wide range intervention.
• Each drug has its own profile both advantage and side effects
• Therapeutics decision making has become increasingly
challenging

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S27. Figure 2;

adapted with permission from Inzucchi SE, et al. Diabetes Care 2012;35:1364–1369
 Efficacy
 Beta cells apoptosis and de-differentiation
 Weight gain
 Hypoglycemia
 Cardiovascular safety
 (Cost)
Principles in Selecting
Antihyperglycemic Interventions

Efficacy in lowering glucose

Extraglycemic effect
Safety profiles
Tolerability
Ease of use
Expense

Nathan Diabetes Care 2009

Changes in A1c Observe with Oral
Antihyperglycemia Therapy in
subject with DM2

Among oral anti diabetics agents,

new generation of SU (glimepiride)
has the most potent hypoglycemic effect
Kabadi UM et al. Manage Care 2013
 Comparison of the Effects of Major OADs
on Glycaemic Control

Glitazones
(PPAR  SUs Glinides
Acarbose agonists) Metformin

↓ HbA1c
0.5-1.0 0.3-1.0 1.4 1.0-2.0 1.1
(%)
↓ FPG 43-74
20-30 20-55 53 31-49
(mg/dL)
↓ PPG No No
49-61 63-94 22-99
(mg/dL) effect effect
Abbreviations: OADs – oral antidiabetic drugs: PPAR-γ – peroxisome proliferator-activated receptor- γ ; SUs – sulfonylureas;
HbA1c – glycosylated haemoglobin:FPG – fasting plasma glucose; PPG – postprandial plasma glucose

Fonseca V. Current Medical Res Opin 2003; 19: 635–641

 Topics

 Management of T2DM in Indonesia:

inadequate glycemic target
 Natural History of T2DM: Beta Cell Failure
and Insulin Resistance
 Choosing Pharmacology Agents in Diabetes
 Role of Sulphonylurea in T2DM: The new
generation of SU
 Take Home Message
 Beta cells de-differentiation
– Account for reduced B-cell mass and insulin secretion
– Glimepiride enhanced B-cell secretory capacity
 Weight gain
– Glimepiride: ≈netral; Glibenclamide: increased body
weight
 Hypoglycemia
– Glimepiride < Glibenclamide
 Cardiovascular safety
– Modern SUs (Glimepiride) < risk of all cause CV-
related mortality compared to conventional SUs

Adopted from Kalra S et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia:
A consensus Statement. Indian J Endocrinol Metab 2015; 20: 577-596
Avoiding use of SUs as a class of medication as an add-on to metformin is not
appropriate as there are many patients whose glycemic control would improve
with use of these drugs with minimal risk of adverse events

Starting SU at a low dose and escalating the dose to submaximal doses that are as
effective as maximal doses in those who warrant such escalations could help more
people achieve therapeutic goals more rapidly, especially early after diagnosis, and
thus reduce the longterm consequences of this disorder
 Second-line after Metformin
 First-line: metformin intolerance or MODY
 Modern SU (Glimepiride) initiated early in the course
T2DM, to achieve maximum glycemic benefits and obtain
the benefit of metabolic memory
 Modern SU should be preffered over conventional SUs in
patients with:
– overweight/obese
– increased risk of CVD or with CVD
– Elderly
– Ramadan
Kalra S et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus
Statement. Indian J Endocrinol Metab 2015; 20: 577-596
 Diabetes Care 2015

Suggested that
“the ideal antihyperglycemic agent would be:
- easy to administer
- unlikely to cause symptomatic side effects that pose
barriers to adherence
- inexpensive,
- reliably efficacious, and safe

By such standards, it can be argued that the remaining

modern SUs do well
(although they do leave some clinical needs unmet)
An early and intensive approach to T2DM
diabetes management is needed !

WHY ?
At diagnosis of type 2 diabetes:
• 50% of patients already have complications1
• ~ 50% of -cell function has already been lost2
• 2/3 of patients do not achieve target HbA1c3,4

HOW ?
Current management:
• The majority of patients require polypharmacy to meet
glycaemic goals across time5

1. UKPDS Group. Diabetologia. 1991;34:877–890; 2. Holman RR. Diabetes Res Clin Prac. 1998;40:S21–S25;
3. Saydah SH, et al. JAMA. 2004;291:335–342; 4. Liebl A, et al. Diabetologia. 2002;45:S23–S28;
5. Turner RC, et al. JAMA. 1999;281:2005–2012.
Potential advantages of early combination
therapy

 Earlier achievement of therapeutic goals

 Potential to delay disease progression
 Potential reduction in risk of side effects if you combine
drugs at lower doses versus up-titration of single dose

Opportunity to combine oral antidiabetic

drugs with complementary modes of
action
 Proactive management of glycemia:
step-wise approach
Diet and
OAD*
exercise
monotherapy OAD
combinations
OAD
up-titration
10 OAD + basal insulin

OAD + multiple daily insulin

9 injections
HbA1c (%)

8
ACTION POINT:

7 HbA1c = 7%
HbA1c = 6.5%
6
*OAD = oral antidiabetic
Duration of diabetes
 Efficacy as a combination therapy

Regimen HbA1c FPG

Metformin+SU ~1.7% ~65mg/dl
Metformin+Rosi ~1.2% ~50mg/dl
Metformin+Pio ~0.7% ~40mg/dl
SU + Rosi ~1.4% ~60mg/dl
SU + Pio ~1.2% ~50mg/dl

Diabetes 1999:48(Supple 1): A100-117, NEJM 1995; 333; 541-9

Are All Sulfonylureas
The Same ?
We continue to generalize about
Sulfonylureas.
But, they are all different
 Glimepiride / Amaryl® :
Unique Interaction at receptor site
Glimepiride dissociated from its binding protein
8 - 9 times more rapidly than glibenclamide
3H sulphonylurea bound (%)
100

80

60

40

20

0 10 20 30 40 50 60 70 80 90 minutes
glimepiride glibenclamide

Fig. Dissociation kinetics of 3H sulphonylurea binding to -cells (RINm5F-

cells)

Biochimica et Biophysica Acta (1994):1191: 267-277

 Glimepiride / Amaryl® :
Unique Interaction at receptor site
Glimepiride associated 2.5 - 3 times faster to the
receptor than glibenclamide
3H sulphonylurea bound (% of max.)

100

80

60

40

20

0 5 10 15 20 25 30 35 40 45 minutes
glimepiride glibenclamide

Fig. Association kinetics of 3H sulphonylurea binding to cells

(RINm5F-cells)

Biochimica et Biophysica Acta (1994):1191: 267-277

 Insulin Secretion
Glimepiride / Amaryl® : The ONLY sulfonylurea to treat
fasting AND postprandial hyperglycemia

First and second phase insulin secretion

before and after treatment with Amaryl®
p=0.02

100 Euglycemic and

hyperglycemic clamp
Incremental plasma insulin

studies in 11 obese
patients with T2DM
with good glycemic control
(pmol/L)

p=0.04 before and after 4 months

50 treatment with
Amaryl® to assess effect of
Amaryl® on insulin secretion

0
First Phase Second Phase
Insulin secretion

Before treatment After treatment

41

Korytkowski M et al. Diabetes Care 2002; 25(9):1607-11.

Insulin and Glucose Plasma Profiles Throughout the Day
with Once-Daily Glimepiride
In su lin (m cU /m L )

40

20

0
Glucose (m g/dL)

250

150

50
8am 12 noon 6pm 10pm 2 am 24 Hrs

Amaryl
Placebo 6 mg Glimepiride once-a-day

Patients with type 2 diabetes Sonnenberg et al. Ann Pharmacother 1997;31:671.

Glimepiride can control 24 hour blood glucose
with once or twice daily administrations.
Glimepiride – once or twice dosing

Blood glucose mg/dl

350

300

250

200

150

0 2 4 6 8 10 12 14 16 18 20 22 24 hours

12.00 18.00 Placebo

08.00 breakfast
Lunch Dinner 3 mg glimepiride twice-a day (BID)
6 mg glimepiride once-a-day (QD)

Sonnenberg G.E. et al.: Short term comparision of once- versus twice-daily administration of glimepiride in patients with non-insulin-dependent
diabetes mellitus. Ann Pharmacother. 1997;31:671-6
 Unique Dual Mode of Action

Glimepiride / Amaryl®
the first and only
anti-diabetic drug
with a dual mode of action

Insulin secretion  Insulin resistance

Sonnenberg G.E. et al. Ann Pharmacother. 1997;31:671-6

Weitgasser R et al. Diabetes Res Clin Pract. 2003; 61: 13-19
 Unique Dual Mode of Action
Action on insulin Action on insulin
secretion resistance

Glimepiride / Amaryl® + +
Conventional
Sulfonylureas + -

Glinides + -

Biguanides - +

Glitazones - +
-Glucosidase
Inhibitors - +

Henry. Endocrinol Metab Clin. 1997;26:553-573; Gitlin, et al. Ann Intern Med. 1998;129:36-38
Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41; Goldberg, et al. Diabetes Care 21:1897-1903
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139
Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176; Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537
De Fronzo, et al. N Engl J Med. 1995;333:541-549; Bailey & Turner. N Engl J Med. 1996;334:574-579
 Comparison of Extrapancreatic Action of
Glimepiride and Other Sulfonylureas
Glimepiride has greatest extrapancreatic activity among sulfonylureas
PI : Mean increase in plasma insulin (PI)
BG : Mean % decrease in blood glucose
( over 6 hours after single dose )

PI/BG ratio
Glimepiride® 0.03 (n=16)
Sulfonylurea

Glibenclamide 0.16 (n=16)

Gliclazide 0.07 (n=14)

Glipizide 0.11 (n=13)

0 5 10 15 20
Mean plasma insulin increase (µU/ml) PI
Mean blood glucose decrease (%) BG

Müller G et al. Diabetes Res Clin Pract 1995;28 (suppl):S115-S137

 Extra Pancreatic Effects of Glimepiride

increasing adiponectin reducing insulin resistance

Plasma Adiponectin (mcg/ml) HOMA-IR

Baseline
8 weeks
Plasma Adiponectin (mcg/ml)

HOMA-IR

Glimepiride Control Baseline 4 weeks 8 weeks 12 weeks

Adiponectin : reduce glucose level, anti

atherogenic anti hypertension Taku Tsunekawa et al. 2005
 Effect of Glimepiride on
Adiponectin levels
20
P<0.05

16

12 NS NS
Adiponectin 0 weeks
(ug/ml) 28 weeks
8

0
Glibenclamide Glimepiride Insulin

Koshiba J Med Invest 2006

 Glimepiride or glibenclamide?
HbA1c evolution and cumulative incidence of hypoglycaemic events
during 1-year treatment with glimepiride or glibenclamide

HbA1c (%) Cumulative incidence of hypoglycaemic

events (%)
9
27
Glimepiride (n=261) Glimepiride (n=289)
24
Glibenclamide (n=259) 21 Glibenclamide (n=288)
18

8 15
12
9
6
3
7 0
2 4 6 8 10 12 14 16 20 26 36 44 52
0 8 16 6 8 10 12
Weeks
Weeks Months

Dills and Schneider. Horm Metab Res 1996; 28:426

 Safety: Hypoglycemia
Significantly lower incidence of severe hypoglycemic events with
Glimepiride vs. glibenclamide (0.86 vs. 5.6/1000 person-years)

Prospective,
population-based,
6
4-year study to
# Episodes/1000 person-years

compare
frequency of
4
severe
hypoglycemia in
5.6 patients with
T2DM treated
2 with Glimepiride®
(estimated
n=1768)
0.86 versus
0 glibenclamide
Glimepiride® Glibenclamide
(estimated
n=1721)
Incidence of severe* hypoglycemic events
according to treatment
*Defined as requiring IV glucose or glucagon
Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73
 Safety: Weight
Treatment with Glimepiride has a stable weight neutral or even weight
reducing effect in most patients with Type 2 diabetes

Open,
uncontrolled,
Months of treatment observational
study.
4 12 18 1770 T2DM
0 patients were
Mean weight change (kg)

enrolled and 284

-1 were followed-up
for 1.5 years.
Patients received
-2 0.5 to > 4 mg
-1.9 kg
(p<0.0001*) glimepiride once
-3 daily.
-2.9 kg -3.0 kg
(p<0.05*) (p<0.005*)

Mean intra-individual weight change

relative to baseline
*vs. baseline

Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19

 Initial treatment of type 2 diabetes with Glimepiride is
associated with a signficantly greater weight decrease than
with Glibenclamide

Weight BMI
0

-0,5
- 0, 20

- 0, 58 - 0,71
Weight -1

change
-1,5
*
(kg)

-2

- 2, 04 glibenclamide
-2,5
glimépiride
*
* P < 0,001
HbA1c : -1.23 vs -1.26 % ( ns )
Martin S et al. Diabetologia 2003; 46: 1611
 Safety: Cardiovascular
Unlike glibenclamide, Glimepiride does not block the beneficial
cardioprotective effect of ischemic preconditioning

p = 0.049 p = 0.01 p = NS
% change in mean ST shift

100 Double-blind,
randomized, placebo-
controlled trial in 45
patients with stable
coronary artery disease.
Mean ST segment shift
50 (mV) after repetitive
balloon dilatation was
measured to compare
the effects of
Glimepiride®,
glibenclamide and
placebo on ischemic
0
preconditioning.
Placebo Glimepiride® Glibenclamide
(n=15) (n=15) (n=15)

Baseline After drug administration

Mean ST segment depression during

balloon occlusion according to treatment
Klepzig et al. Eur Heart J 1999;20:439-446
 Non adherence* to treatment
leads to poor glycaemic control and outcome
* Nonadherence defined as medication possession ratio (MPR) < 80%.

Prevalence of nonadherence* to oral glucose

28.9%
lowering medication1

HbA1c decrease for every 10% increase in

0.16%
treatment adherence2

2.5 x increase in risk of hospitalisation associated with

treatment non adherence1

increase in risk of all-cause mortality associated

1.6 x
with treatment non adherence3

1. Lau D, et al. Diabetes Care. 2004;27:2149–2153; 2. Schectman J, et al. Diabetes Care. 2002;25:1015–1021.
3. Currie C, et al. Diabetes Care. 2012; doi: 10.2337/dc11-127.
 Compliance with OAD Treatment:
Once or Three Times per Day?
OBADE: 201 patients with type 2 diabetes randomized to
glimepiride qd or glibenclamide tid; 10 weeks titration followed
by 14 weeks maintenance

Glimepiride Glibenclamide p

Average compliance (%) 87 ± 16 80 ± 17 <0.0001

Days with appropriate

90 ± 13 76 ± 19 <0.0001
compliance (%)

Patients with compliance >

72 56 0.02
80% (%)

HbA1c (%) 6.9 ± 1.2 7.1 ± 1.2 NS

Evolution of Compliance with OAD once or
three time per day

Charpentier G Diabetes Metab 2005; 31: 189

 Summary of Glimepiride Efficacy

 Glimepiride is the first and only OAD that reduces hyperglycaemia by

increasing insulin secretion and improving insulin resistance
 In in vitro studies, glimepiride’s extrapancreatic effect is evident from
increased peripheral glucose uptake.
 Lower incidence of hypoglycaemia compared with other sulfonylureas
 Glimepiride has shown the stable or bodyweight decrease compared to
other sulfonylurea drugs
 The ability to augment the first-phase of insulin secretion makes
Glimepiride unique among second-generation sulfonylureas
 Glimepiride does not block the beneficial cardioprotective effect of
ischemic preconditioning
 Glimepiride-Metformin Combination
Insulin -cell
Combination resistance deficit
a. Metformin+ insulin
secretagogue (glimepiride)  

b. Metformin + TZD  X

c. Metformin + AGI  X

d. TZD + Sulfonylurea  

e. Sulfonylurea + AGI X 

f. TZDs + AGI  X

 = appropriate, a and d are rational combination.

 Modes of Action of
Glimepiride-Metformin Combination

 Sulfonylureas and biguanides act complementary to each other.1

 Both compounds have an additive antihyperglycaemic effect

without increasing the adverse effects of either pharmacological
class.2

 Glimepiride acts via stimulating beta cells of pancreas to release

insulin and also increases peripheral sensitivity of insulin.3

 Metformin decreases hepatic glucose production, decreases

intestinal absorption of glucose and improves insulin sensitivity by
increasing peripheral glucose uptake and utilization.4
1. Charpentier G. Diabetes Metab Res Rev 2002; 18 (Suppl 3): S70-S76.
2. Riddle M. Am J Med 2000; 108 (Suppl 6a): 15S-22S
3. Raptis SA and Dimitriadis GD. Exp Clin Endocrinol Diabetes 2001; 109 (Suppl 2): S265-S287
4. Hundal RS and Inzucchi SE. Drugs 2003; 63 (18): 1879-1894
 Efficacy of Glimepiride+Metformin
Combination on FBG
Superior glycemic control with metformin+Glimepiride
than with Metformin or Glimepiride alone

225
Mean FBG (mg/dL)

200 Prospective, multicenter,

randomized, double-blind,
double-dummy parallel
175 group study of 372 T2DM
patients inadequately
controlled by metformin
150 850 mg tid. Patients
received metformin,
Glimepiride or both for 20
125 weeks.
0 3 6 9 12 15 18 20
Titration Maintenance
Treatment Duration (wk)
Glimepiride Metformin Metformin + Glimepiride

Evolution in FBG over time according to treatment

Charpentier G, et al. Diabet Med 2001; 18: 828-834.

 Efficacy of Glimepiride+Metformin
Combination on PBG
Combination therapy was more efficient in reducing
postprandial blood glucose than Metformin or Glimepiride alone
Baseline PBG
15.2 mmol/L 14.9 mmol/L 14.8 mmol/L * p < 0.001 vs. Metformin
1.5
# p < 0.001 vs. Glimepiride
1.0 +0.3** **p = 0.029 vs. Metformin
+1.1
Δ in PBG (mmol/L)

0.5 ±0.5
±0.8
Prospective, multicenter,
0 randomized, double-blind,
-0.5 double-dummy parallel
-2.6*# group study of 372 T2DM
-1.0
±0.3 patients inadequately
-1.5 controlled by metformin
850 mg tid. Patients
-2.0
received metformin,
-2.5 Glimepiride or both for 20
-3.0 weeks.
Metformin Glimepiride Metformin + Glimepiride
n = 75 n = 150 n = 147

Mean (+SEM) change in PBG at week 20 according to treatment

Charpentier G, et al. Diabet Med 2001; 18: 828-834.

Relative cost of combination therapy with oral agents in their
maximum daily dose

Kabadi UM. Managed care 2004

 Take home message

 Glimepiride is the third generation of SUs that

exhibit lower risk of hypoglycemia and weight gain
than that of among older generation SUs

 Despite the emergence of new OADs, SUs still

represent the save, inexpensive and effective drug,
with consideration of several factors related
hypoglycemia and weight gain

 Fixed combination of metformin and glimepiride

increase the patient obedience and the
effectiveness of blood glucose lowering effect
THANK YOU