Abbas orabi.translating evidence

By: Abbas Oraby

Translating evidence into patients’ benefits

Drugs in this class

• Acetohexamide

• Chlorpropamide

• Tolbutamide

• Tolazamide

• Glipizide

• Gliclazide

• Glibenclamide (glyburide)

• Gliquidone

• Glyclopyramide

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.

x Ca++ 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 retention

3

Depolarization

4

Glucokinase

Translocation ATP

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

Impaired

Insulin secretion

Metformin

Increased glucose production

Decreased glucose uptake

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 hypoglycaemia Weight loss Nausea/vomiting

Lifestyle and

met + intensive

insulin

At diagnosis: Lifestyle

+

metformin

Step 1 Step 2 Step 3

Lifestyle and

met + pio No hypoglycaemia Oedema/CHF Bone loss

Lifestyle and met

+ GLP-1 agonistb

Lifestyle and met

+ pio + SUa

Lifestyle and

met + basal insulin

Tier 2: Less well validated therapies

Lifestyle and

met + SUa

Lifestyle and

met + 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 insulin

resistance

Action on insulin

secretion

► Glimepiride ►

► - Glitazones1,6

► - Biguanides1,3-5

- Glinides1,2

- ► Conventional Sulfonylureas1

►

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

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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

ce

mic

va

ria

tio

n (

%)

Ins

ulin

em

ia

(U

/mL

)

Glimepiride Glibenclamide Glipizide Gliclazide

0.00

0.05

0.10

0.15

0.20 n=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 levels whilst 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

6 Baseline 4 weeks 8 weeks 12 weeks

Plasma adiponectin HbA1c (%)

Pla

sm

a a

dip

on

ec

tin

co

nc

en

tra

tio

n (

g/m

L)

Hb

A1c (

%)

8.2

6.5

7.5 6.9 6.6

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 !!!

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Glimepiride : Efficacy Proven in Monotherapy

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

Δ i

n m

ed

ian

Hb

A1c (

%)

6.7%

Change from baseline to week 22

in 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 i

n g

luc

ose

co

nce

ntr

ati

on

(m

g/d

L)

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

Glibenclamide Glimepiride

# E

pis

od

es

/10

00 p

ers

on

-ye

ars

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

-5

0

Lp(a) mg/dL

PAI-1 (ng/mL)

Hcy (mol/L)

Ch

an

ge

fro

m b

ase

lin

e

-39.7* mg/dL

-21.4†

ng/mL

-40.1* mol/L

*p<0.01; †p<0.05 vs baseline

Lp(a) = Lipoprotein A PAI-1 = plasminogen activator inhibitor-1

Hcy = 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.

%

ch

an

ge

in

me

an

ST

shift

Baseline After drug administration

Mean ST segment depression during

balloon 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 = NS p = 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)

Cu

mu

lati

ve

su

rviv

al

1.0

0.9

0.8

0.7

0.6

0 10.0 20.0 30.0 40.0

Glimepiride Gliclazide

Repaglinide

Glibenclamide

Yearly mortality

0.4%

2.1%*

3.1%*

8.7%**

* P < 0.05 vs Glimepiride

**P <0.01 vs all comparators

GLIMEPIRIDE IN 2010 A 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.


2010

Results Cont.

Conclusion: Glimepiride can rapidly and stably improve glycemic control and lipoprotein metabolism, significantly alleviate insulin resistance and enhance fibrinolytic activity.


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


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.


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


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.

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Conclusion

Abbas orabi.translating evidence

Health & Medicine

Transcript of Abbas orabi.translating evidence