Glimepiride is an oral anti-hyperglycemic medication from the sulfonylurea class. It works by stimulating the pancreas to secrete more insulin and by increasing insulin sensitivity in muscle and fat cells. Glimepiride has been shown to effectively lower blood glucose levels with a lower risk of hypoglycemia compared to other sulfonylureas like glibenclamide. Studies also indicate Glimepiride may provide cardiovascular benefits such as reducing inflammatory markers and not blocking the protective effects of ischemic preconditioning like glibenclamide. When used in combination with metformin, Glimepiride is associated with lower mortality than other sulfonylureas.

1. Translating evidence into patients’ benefits
By: Abbas Oraby

3. Drugs in this class
Sulfonylureas were the first widely used oral anti-hyperglycaemic
medications. Many types of these pills have been marketed but not all
remain available.
• Acetohexamide • Glipizide
• Chlorpropamide • Gliclazide
• Glibenclamide (glyburide)
• Tolbutamide
• Gliquidone
• Tolazamide
• Glyclopyramide

4. MECHANISMS OF ACTION OF SUs

5. Insulin release
•
It involves 3 main steps :
1. Translocation of insulin granules.
2. Docking of insulin granules.
3. Fusion of insulin granules.
8

6. Microtubules form a network radiating from the
perinuclear region outwords
.
The framework provides
the mechanical pathway
along which secretory
granules move toward the
exocytic sites close to the
plasma membrane.
It gives the way but not the force
10

7. Ca+ is essential for almost all steps
involved in insulin release, thus factors
increasing intracellular Ca+ will augment
insulin release.Mechanisms involved in
increasing intra-cytoplasmic Ca+ :
 Ca-influx from outside.
 Inhibition of Ca-reuptake by Ca++ Store
intracellulas stores. x
 Increased Ca-sensitivity.
12

8. Increased intracellular Ca+ is essential for
granules translocation and fusion hence release of
insulin.
ATP-sensitive Voltage-gate Ca
Glucose
K+ channel channel
6
GLUT2 X
Fusion
K retention 4
Glucose 3
Depolarization Ca+
2
Glucokinase 1 5
G-6-P ATP Translocation
Each B-cell contains up to 500 Ca channels
13

9. Mechanisms of action cont.
• The rise in intracellular calcium leads to
increased fusion of insulin granules with the
cell membrane, and therefore increased
secretion of (pro)insulin.
• There is some evidence that sulfonylureas
also sensitize β-cells to glucose, that they
limit glucose production in the liver, that they
decrease lipolysis and decrease clearance of
insulin by the liver.

10. Insulin Secretion (Glimepiride)
Glimepiride binds to the 65 kDa subunit of the sulfonylurea
receptor; glibenclamide binds to the 140 kDa subunit

11. Therapeutic actions
Pancreas
Sulfonylurea +
Impaired glimepiride
Insulin secretion
Insulin
– resistance
Increased Decreased
glucose glucose
production Hyperglycaemia uptake
Liver Muscle
Metformin
16

12. 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
second- generation sulfonylureas (gliclazide, glimepiride, glipizide) 17
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

13. IDF Global Guideline for Type 2 Diabetes
Diagnosis
Lifestyle intervention then metformin
HbA1c 6.5 %
Add sulfonylurea
HbA1c 6.5 % HbA1c 6.5 %
*Alternatively, start Add thiazolidinedione* Add insulin
thiazolidinedione before
sulfonylurea,
and sulfonylurea later. HbA1c 7.5 % HbA1c 7.0 %
Start insulin intensify insulin
Meal-time + basal insulin + metformin ± thiazolidinedione
IDF. Global Guideline for Type 2 Diabetes. 2005

16. ADA and EASD algorithm for the management
of type 2 diabetes
Tier 1: Well validated therapies
Lifestyle and
At Lifestyle and met + intensive
diagnosis: met + basal insulin
Lifestyle insulin
+
metformin Lifestyle and
met + SUa
Step 1 Step 2 Step 3
Tier 2: Less well validated therapies
Lifestyle and
met + pio Lifestyle and met
No hypoglycaemia
Oedema/CHF
+ pio + SUa
Bone loss
Lifestyle and met
+ GLP-1 agonistb Lifestyle and
No hypoglycaemia
Weight loss
met + basal insulin
Nausea/vomiting
Reinforce lifestyle interventions every visit and check HbA1C every
3 months until HbA1C is <7% and then at least every 6 months.
The interventions should be changed if HbA1C is ≥7%
aSUs other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.
Met=metformin; Pio=pioglitazone; SU=sulfonylurea
Nathan et al., Diabetes Care 2008 [Epub]

18. Unique Dual Mode of Action
Action on insulin Action on insulin
secretion resistance
1
Glimepiride ► ►
Conventional
Sulfonylureas1 ► -
Glinides1,2 ► -
Biguanides1,3-5 - ►
Glitazones1,6 - ►
1MedicalManagement of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139; 2Goldberg 1998, et al. Diabetes Care
21:1897-1903; 3Bell & Hadden. Endocrinol Metab Clin 1997;26:523-37; 4De Fronzo, et al. N Engl J Med 1995;333:541-9; 5Bailey & Turner. N Engl J Med
1996;334:574-9; 6Henry. Endocrinol Metab Clin 1997;26:553-73

19. 2nd Action: Extra-Pancreatic
The extrapancreatic effect of Glimepiride
Rate limiting step for glucose
utilization is glucose uptake via GLUT4
transporter
Glimepride↑ translocation of GLUT4
transporters from low-density
microsomes to plasma membrane
of insulin-resistant fat and muscle
cells
Glimepiride appears to ↑ peripheral
glucose uptake and to mimic the
action of insulin
27 Müller & Wied. Diabetes. 1993;42: 1852-1867

20. Glimepiride Controls Glycemia with Less Insulin Secretion
• For an equivalent glycemic effect, Glimepiride induces a lower
secretion of insulin
Mean variation of insulin and Mean ratio between increased level of
glycemia over a 36-h period insulin and reduced glycemia
Sulfonylureas tested in
fasted male beagle dogs
3 to determine ratios of
Insulinemia
2
Ratio mean plasma insulin
release/ blood glucose
(U/mL)
1 decrease
0.20
n=16
0
Glimepiride Glibenclamide Gliclazide Glipizide 0.15
0 n=13
0.10
5 n=14
variation (%)
10 0.05 n=16
Glycemic
15
0.00
20 Glibenclamide Glipizide Gliclazide Glimepiride
28 Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37

21. Glimepiride Beneficial Effect on Adiponectin Levels
• Glimepiride increases plasma adiponectin levels
whilst achieving control of glycemia
Evolution of adiponectin and HbA1c levels during 12 weeks of
Glimepiride treatment
11 9
concentration (g/mL)
10
10.2
Plasma adiponectin
9 8
HbA1c (%)
A study in 17 elderly
patients with type 2
8 diabetes who were
8.2 treated with Glimepiride
for 12 weeks.
7 7
7.5
6.6 6.9
6 6.5
5 6
Baseline 4 weeks 8 weeks 12 weeks
Plasma adiponectin HbA1c (%)
29 Tsunekawa T, et al. Diabetes Care 2003; 26(2); 285-289

22. GLIMEPIRIDE IS MORE THAN AN
INSULIN SECRETAGUGE !!!

23. Glimepiride : Efficacy Proven in Monotherapy
Tight glycemic control (HbA1c<7.2%) Glimepride : decreased FPG by 46
was achieved in 69% of Glimepiride patients mg/dL more and 2-hour PPG by 72 mg/dL
and 32% of placebo patients more than placebo (p<0.001)
Change from baseline to week 22 Change from baseline to week 22 in
in median HbA1c median FPG and 2-hour PPG
Prospective,
Baseline HbA1c randomized, double-
blind, placebo- FPG PPG
9.1% 8.9% controlled, dose-
0 titration study. T2DM n=117 n=118 n=108 n=101
Δ in glucose concentration (mg/dL)
0
patients received
-1% Glimepiride (n=123) or
Δ in median HbA1c (%)
-1 placebo (n=126) for a -20 -13
-2.4%# 10-week dose-titration
period and then the -40 -31
-2 optimal dose (1 to 8
7.9% mg) for 12 weeks. -60
54% of patients on -59*
-3 active treatment -80
received <4 mg/day
Glimepiride
-4 6.7% -100
HbA1c at Endpoint -120
-117*
*p<0.001 vs placebo -140
Glimepiride Placebo
Schade DS et al. J Clin Pharmacol 1998;38:636-51
31

24. SAFETY ?!!!

25. Safety: Hypoglycemia vs Glibenclamide
Significantly lower incidence of severe hypoglycemic events
with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)
Incidence of severe* hypoglycemic events
according to treatment
6
# Episodes/1000 person-years
Prospective, population-
based, 4-year study to
6.5x compare frequency of
4 severe hypoglycemia in
less patients with T2DM
risk of 5.6 treated with
Glimepiride (estimated
hypo n=1768)
versus glibenclamide
2 (estimated n=1721)
0.86
0
Glimepiride Glibenclamide
*Defined as requiring IV glucose or glucagon
Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73

26. CARDIAC SAFETY ?!!!

29. Glimepiride Beneficial Effect on Cardiovascular Risk Factors
Glimepiride significantly reduces cardiovascular risk markers
Reductions metabolic parameters after 12 months of
treatment with Glimepiride
Lp(a) PAI-1 Hcy
mg/dL (ng/mL) (mol/L)
0
Randomized, double-
Change from baseline
-5 blind study in which
patients with type 2
-10 diabetes were treated
-15 -21.4† with Glimepiride
(n=62)or repaglinide
-20 ng/mL (n=62) for 12 months.
-25
-30
-39.7* -40.1*
-35
mg/dL mol/L
-40
-45 Lp(a) = Lipoprotein A
PAI-1 = plasminogen activator inhibitor-1
*p<0.01; †p<0.05 vs baseline Hcy = homocysteine
De Rosa, et al. Clin Ther 2003; 25(2); 472-484

30. Cardiovascular Safety: Ischemic Preconditioning
Unlike glibenclamide, Glimepiride does not block the beneficial
cardioprotective effect of ischemic preconditioning
Mean ST segment depression during
balloon occlusion according to treatment
p = 0.049 p = 0.01 p = NS
100
% change in mean ST shift
Double-blind,
randomized,
placebo-controlled
trial in 45 patients
with stable coronary
artery disease.
50 Mean ST segment
shift (mV) after
repetitive balloon
dilatation was
measured to
compare the effects
of Glimepiride
0
glibenclamide and
Placebo Glimepiride(n=15) Glibenclamide placebo on ischemic
(n=15) (n=15) preconditioning.
Baseline After drug administration
Klepzig et al. Eur Heart J 1999;20:439-446

31. Safety: All-Cause Mortality
In combination with metformin, Glimepiride is associated with lower all-cause
mortality than other sulfonylureas with less selectivity for β-cell receptors
Kaplan-Meier survival analysis
1.0
Glimepiride or gliclazide
Retrospective,
observational cohort
Repaglinide study in T2D
0.9
Cumulative survival
outpatients. A total of
696 patients received
insulin secretagogues
in combination with
0.8 biguanides. A Kaplan-
Glibenclamide Meier survival analysis
was conducted in
patients treated with
Yearly mortality metformin in
0.7 Glimepiride 0.4% combination with
Gliclazide 2.1%* glibenclamide,
gliclazide, repaglinide
Repaglinide 3.1%*
or Glimepiride .
Glibenclamide 8.7%**
0.6
Time
* P < 0.05 vs Glimepiride 0 10.0 20.0 30.0 40.0 (months)
**P <0.01 vs all comparators
Monami M, et al. Diabetes Metab Res Rev 2006; 22(6): 477-482

33. GLIMEPIRIDE IN 2010
A NON-STOPPING WEALTH OF EVIDENCE

34. 2010
2010
Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75

35. Research Design and methods
2010
• Objective:
– To investigate the effects of Glimepiride on blood glucose
in patients with newly diagnosed type 2 diabetes mellitus
(T2DM) in connection with plasma lipoproteins and
plasminogen activity.
• Methods
– A total of 565 T2DM patients received Glimepiride (n =
333) or Glibenclamide (n = 232) for 12 weeks. The level of
blood glucose (BG), glycated hemoglobin (HbA1C), the
insulin resistance (IR) state, plasma lipoproteins, tissue-
type plasminogen activator (t-PA) and plasminogen
activator inhibitor type I (PAI-1) were observed before
and after a 12 weeks of treatment.
Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75

36. Results Cont. 2010
Conclusion: Glimepiride can rapidly and
stably improve glycemic control and
lipoprotein metabolism, significantly
alleviate insulin resistance and enhance
fibrinolytic activity.
Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75

37. 2010
2010
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29

38. Research Design and methods
2010
• Objective: The purpose of this study is to assess the
relationship of individual sulfonylureas and the risk of overall
mortality in a large cohort of patients with type 2 diabetes.
• Methods: A retrospective cohort study , 11,141 patients with
type 2 diabetes (4,279 initiators of monotherapy with
glyburide, 4,325 initiators of monotherapy with glipizide, and
2,537 initiators of monotherapy with glimepiride), ≥ 18 years
of age, with and without a history of coronary artery disease
(CAD), and not on insulin or a non-insulin injectable at
baseline. The patients were followed for mortality
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29

39. Results 2010
• No statistically significant difference in the risk of
overall mortality was observed among these agents
in the entire cohort,
But
• evidence of a trend towards an increased overall
mortality risk with glyburide vs. glimepiride (HR
1.36; CI 0.96-1.91) and glipizide vs. glimepiride (HR
1.39; 95% CI 0.99-1.96), in those with documented
CAD was found.
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29

40. Mortality Risk with Sulfonylurea Monotherapy
2010
Conclusion: The results did not identify an
increased mortality risk among the
individual sulfonylureas but did suggest that
glimepiride may be the preferred
sulfonylurea in those with underlying CAD.
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29

41. Conclusion
Glimepiride the 3rd generation SU:
– Unique dual mode of action
– Fast and sustained blood glucose lowering effect
– Ideal for combination with insulin and/or other oral
antidiabetic agents
– Benefits beyond blood glucose-lowering
– Clinically proven safety profile
– Glimepiride and Metformine in fixed dose combination
presentation offer a synergistic combination serving the efficacy
and safety objectives needed in the management of T2DM and
Described in ADA/EASD Guidelines.
61