By: Abbas Oraby

Translating evidence into patients’ benefits

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.

MECHANISMS OF ACTION OF SUs

Insulin release •

8

It involves 3 main steps :

1. Translocation of insulin granules.

2. Docking of insulin granules.

3. Fusion of insulin granules.

Microtubules form a network radiating from the perinuclear region outwords

10

.

It gives the way but not the force

The framework provides the mechanical pathway along which secretory granules move toward the exocytic sites close to the plasma membrane.

12

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

intracellulas stores. Increased Ca-sensitivity.

xCa++ Store

13

Increased intracellular Ca+ is essential for granules translocation and fusion hence release of insulin.

Each B-cell contains up to 500 Ca channels

Glucose ATP-sensitive K+ channel

K retention3

Depolarization

4

Glucokinase

TranslocationATP

Voltage-gate Ca channel

Fusion

Ca+

5

6

Glucose

1

G-6-P

2

GLUT2 X

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.

Glimepiride binds to the 65 kDa subunit of the sulfonylurea receptor; glibenclamide binds to the 140 kDa subunit

Insulin Secretion (Glimepiride)

Therapeutic actions

16

Hyperglycaemia

Pancreas

Liver Muscle

ImpairedInsulin secretion

Metformin

Increasedglucoseproduction

Decreasedglucoseuptake

Insulin resistance

Sulfonylurea +

glimepiride

–

17

Attributes of sulfonylureas

* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide) than other second- generation sulfonylureas (gliclazide, glimepiride, glipizide)Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

How they work Enhance insulin secretion

Expected HbA1c reduction 1 to 2%

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

IDF Global Guideline for Type 2 Diabetes

Diagnosis

Lifestyle intervention then metformin

HbA1c 6.5 %

Add sulfonylurea

Meal-time + basal insulin + metformin ± thiazolidinedione

Add insulin

Start insulin

Add thiazolidinedione*

HbA1c 6.5 %

HbA1c 7.5 % HbA1c 7.0 %

HbA1c 6.5 %

IDF. Global Guideline for Type 2 Diabetes. 2005

*Alternatively, start thiazolidinedione before sulfonylurea,and sulfonylurea later.

intensify insulin

ADA and EASD algorithm for the management of type 2 diabetes

Nathan et al., Diabetes Care 2008 [Epub]

aSUs other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.Met=metformin; Pio=pioglitazone; SU=sulfonylurea

No hypoglycaemiaWeight lossNausea/vomiting

Lifestyle and met + intensive insulin

Atdiagnosis:

Lifestyle+

metformin

Step 1 Step 2 Step 3

Lifestyle and met + pio

No hypoglycaemiaOedema/CHFBone loss

Lifestyle and met + GLP-1 agonistb

Lifestyle and met + pio + SUa

Lifestyle andmet + basal insulin

Tier 2: Less well validated therapies

Lifestyle and met + SUa

Lifestyle andmet + basal insulin

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%

Tier 1: Well validated therapies

Action on insulinresistance

Action on insulinsecretion

►Glimepiride ►

►-Glitazones1,6

►-Biguanides1,3-5

-Glinides1,2

-►ConventionalSulfonylureas1

►

Unique Dual Mode of Action

1Medical Management 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

1

27 Müller & Wied. Diabetes. 1993;42: 1852-1867

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

2nd Action: Extra-Pancreatic

28

Glimepiride Controls Glycemia with Less Insulin Secretion

• For an equivalent glycemic effect, Glimepiride induces a lower secretion of insulin

Mean variation of insulin and glycemia over a 36-h period

Mean ratio between increased level of insulin and reduced glycemia

5

10

15

0

1

2

3

Glimepiride Glibenclamide Gliclazide Glipizide

20

0

Gly

cem

ic

varia

tion

(%)

Insu

linem

ia

(U

/mL)

Glimepiride Glibenclamide Glipizide Gliclazide

0.00

0.05

0.10

0.15

0.20n=16

n=13

n=14

n=16

Ratio

Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37

Sulfonylureas tested in fasted male beagle dogs to determine ratios of mean plasma insulin release/ blood glucose decrease

29

Glimepiride Beneficial Effect on Adiponectin Levels

• Glimepiride increases plasma adiponectin levelswhilst achieving control of glycemia

Tsunekawa T, et al. Diabetes Care 2003; 26(2); 285-289

11

10

9

8

7

6

5

9

8

7

6Baseline 4 weeks 8 weeks 12 weeks

Plasma adiponectin HbA1c (%)

Plas

ma

adip

onec

tin

conc

entr

atio

n (

g/m

L)

HbA

1c (%

)

8.2

6.57.5

6.96.6

10.2

Evolution of adiponectin and HbA1c levels during 12 weeks of Glimepiride treatment

A study in 17 elderly patients with type 2 diabetes who were treated with Glimepiride for 12 weeks.

GLIMEPIRIDE IS MORE THAN AN INSULIN SECRETAGUGE !!!

31

Glimepiride : Efficacy Proven in Monotherapy

Schade DS et al. J Clin Pharmacol 1998;38:636-51

Δ in

med

ian

HbA

1c (%

)

6.7%

Change from baseline to week 22in median HbA1c

9.1%

Tight glycemic control (HbA1c<7.2%) was achieved in 69% of Glimepiride patients and 32% of placebo patients

7.9%

-1%8.9%

Baseline HbA1c

-4

-3

-2

-1

0

HbA1c at Endpoint

-2.4%#

Glimepride : decreased FPG by 46 mg/dL more and 2-hour PPG by 72 mg/dL more than placebo (p<0.001)

Change from baseline to week 22 in median FPG and 2-hour PPG

n=117 n=118 n=108 n=101

Δ in

glu

cose

con

cent

ratio

n (m

g/dL

)

FPG PPG

-59*

-117*

-13-31

-140

-120

-100

-80

-60

-40

-20

0

Glimepiride Placebo

*p<0.001 vs placebo

Prospective, randomized, double-blind, placebo-controlled, dose-titration study. T2DM patients received Glimepiride (n=123) or placebo (n=126) for a 10-week dose-titration period and then the optimal dose (1 to 8 mg) for 12 weeks. 54% of patients on active treatment received <4 mg/day Glimepiride

SAFETY ?!!!

Incidence of severe* hypoglycemic events according to treatment

*Defined as requiring IV glucose or glucagon

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

Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73

0.86

5.6

GlibenclamideGlimepiride

# Ep

isod

es/1

000

pers

on-y

ears

0

2

4

6

Prospective, population-based, 4-year study to compare frequency of severe hypoglycemia in patients with T2DM treated with Glimepiride (estimated n=1768)versus glibenclamide (estimated n=1721)

Safety: Hypoglycemia vs Glibenclamide

6.5x less risk of hypo

CARDIAC SAFETY ?!!!

Reductions metabolic parameters after 12 months of treatment with Glimepiride

Glimepiride Beneficial Effect on Cardiovascular Risk Factors

De Rosa, et al. Clin Ther 2003; 25(2); 472-484

Glimepiride significantly reduces cardiovascular risk markers

-45-40-35-30-25-20-15-10-50

Lp(a)mg/dL

PAI-1(ng/mL)

Hcy(mol/L)

Chan

ge fr

om b

asel

ine

-39.7*mg/dL

-21.4†

ng/mL

-40.1*mol/L

*p<0.01; †p<0.05 vs baseline

Lp(a) = Lipoprotein APAI-1 = plasminogen activator inhibitor-1Hcy = homocysteine

Randomized, double-blind study in which patients with type 2 diabetes were treated with Glimepiride (n=62)or repaglinide (n=62) for 12 months.

% c

hang

e in

mea

n ST

sh

ift

Baseline After drug administration

Mean ST segment depression duringballoon occlusion according to treatment

Klepzig et al. Eur Heart J 1999;20:439-446

Unlike glibenclamide, Glimepiride does not block the beneficial cardioprotective effect of ischemic

preconditioning

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

50

100

Placebo(n=15)

Glimepiride(n=15) Glibenclamide (n=15)

p = 0.01 p = NSp = 0.049

0

Cardiovascular Safety: Ischemic Preconditioning

Safety: All-Cause Mortality

Retrospective, observational cohort study in T2D outpatients. A total of 696 patients received insulin secretagogues in combination with biguanides. A Kaplan-Meier survival analysis was conducted in patients treated with metformin in combination with glibenclamide, gliclazide, repaglinide or Glimepiride .

Monami M, et al. Diabetes Metab Res Rev 2006; 22(6): 477-482

Kaplan-Meier survival analysis

In combination with metformin, Glimepiride is associated with lower all-cause mortality than other sulfonylureas with less selectivity for β-cell receptors

Glimepiride or gliclazide

Repaglinide

Glibenclamide

Time (months)

Cum

ulat

ive

surv

ival

1.0

0.9

0.8

0.7

0.6

0 10.0 20.0 30.0 40.0

Glimepiride GliclazideRepaglinideGlibenclamide

Yearly mortality0.4%2.1%*3.1%*8.7%**

* P < 0.05 vs Glimepiride**P <0.01 vs all comparators

GLIMEPIRIDE IN 2010A NON-STOPPING WEALTH OF EVIDENCE

2010

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

2010

Research Design and methods

• 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

2010

Results Cont.

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

2010

2010

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

2010

Research Design and methods

• 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

2010

Results • 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

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.

Mortality Risk with Sulfonylurea Monotherapy

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

2010

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

Conclusion