GLIMEPIRIDE JOURNEY IN MANAGEMENT OF

TYPE 2 DM

Estimated Global Prevalence Of Diabetes

2000 2014 2035

151 million 387 million 592 million

International Diabetes Federation. IDF Diabetes Atlas, 2014

Chan JCN, et al. Diabetes Care 2009;32:227-233.

3.6%

49.0%

64.4%

33.2%

19.2%

36.4%

Triglycerides <150 mg/dL

HDL cholesterol >40 mg/dL

LDL cholesterol <100 mg/dL

Blood Pressure <130/80 mmHg

HbA1c <7%

0% 20% 40% 60%

% Patients (with available data)

Reached HbA1c, blood pressure, and

LDL cholesterol recommended

targets

Only 36% of T2D patients were at glycemic target

(HbA1c <7%) across regions

Importance of tight glycemic control

Hb

A1

C(%

)UKPDS: Long-term follow-up

Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247.

Holman RR, et al. N Engl J Med 2008; 359:1577–1589.

Differences in mean glycated

hemoglobin levels between the

intensive therapy group and the

conventional-therapy group

were lost by 1 year, with similar

glycated hemoglobin

improvements thereafter in all

groups (p= not significant)

P=0.71

Glucose similar

BUT CV

events now

better

Metformin group 21% 33% 27%

A new paradigm

Del Prato S. Diabetologia 2009; 52:1219–1226.Del Prato S. Diabetologia 2009; 52:1219–1226.

Glycemic Goals

Parameter NormalADA

Goals

ACE/AACE

Goals

Fasting plasma glucose

(mg/dL)< 100 90-130 < 110

Postprandial plasma glucose

(mg/dL)< 120 < 180* < 140**

A1C (%) 4-6 < 7*** ≤ 6.5

*1-2 hours post-meal

**2 hours post-meal

***as close to normal as possible without undue risk of hypoglycemia

Sulfonylurea & Guidelines

LIFESTYLE MEASURESThen at each step, if not to target (generally HbA1c <7.0%)

IDF Treatment algorithm for people with type 2 diabetes

or

oror

MetforminSulfonylurea or

α-Glucosidase inhibitor

Sulfonylureaα-Glucosidase inhibitor

or DPP-4 inhibitoror Thiazolidinedione

Basal insulin orPre-mix insulin

GLP-1 agonist

Basal + meal-time insulin

Metformin(if not first line)

α-Glucosidase inhibitoror DPP-4 inhibitor

or Thiazolidinedione

Basal insulin orPre-mix insulin

(later basal + meal-time)

Alternative approachUsual approach

Considerfirst line

Considersecond line

Considerthird line

Considerfourth line

Management of Hyperglycemia in

Type 2 Diabetes, 2015:

A Patient-Centered Approach

Update to a Position Statement of the American Diabetes Association (ADA)

and the European Association for the Study of Diabetes (EASD)

Diabetes Care 2015;38:140–149

Diabetologia 2015;58:429–442

ANTI-HYPERGLYCEMIC THERAPY

• Glycemic targets

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)

- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key:

Tighter targets (6.0 - 6.5%) - younger, healthier

Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc.

- Avoidance of hypoglycemia

PG = plasma glucose

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015

Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

more stringent

less stringent

Patient attitude and expected treatment efforts highly motivated, adherent,

excellent self-care capacities

less motivated, non-adherent,

poor self-care capacities

Risks potentially associated with hypoglycemia and other drug adverse effects

low high

Disease duration newly diagnosed long-standing

Life expectancy long short

Important comorbidities absent severe few / mild

Established vascular complications absent severe few / mild

Readily available limited

Usually not modifiable

Potentially modifiable

HbA1c7%

PATIENT / DISEASE FEATURES

Approach to the management of hyperglycemia

Resources and support system

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

HbA1c ≥9%

Metformin intolerance or

contraindication

Uncontrolled hyperglycemia

(catabolic features, BG ≥300-350 mg/dl,

HbA1c ≥10-12%)

OralClass Mechanism Advantages Disadvantages Cost

Biguanides • Ac vatesAMP-kinase(?other)• ̄ Hepa cglucoseproduc on

• Extensiveexperience• Nohypoglycemia• Weightneutral• ?̄ CVD

• Gastrointes nal• Lac cacidosis(rare)• B-12defici e ncy• Contraindica ons

Low

Sulfonylureas

• ClosesKATPchannels• ­Insulinsecre on

• Extensiveexperience• ̄ Microvascularrisk

• Hypoglycemia• ­Weight• Lowdurability• ?Bluntsischemicprecondi oning

Low

Megli nides

• ClosesKATPchannels• ­Insulinsecre on

• ̄ Postprandialglucose• Dosingflexibility

• Hypoglycemia• ­Weight• ?Bluntsischemicprecondi oning• Dosingfrequency

Mod.

TZDs • PPAR-gac vator• ­Insulinsensi vity

• Nohypoglycemia• Durability• ̄ TGs(pio)• ­HDL-C• ?̄ CVDevents(pio)

• ­Weight• Edema/heartfailure• Bonefractures• ­LDL-C(rosi)• ?­MI(rosi)

Low

Table1.Proper esofan -hyperglycemicagentsDiabetes Care 2015;38:140-149;

Diabetologia 2015;10.1077/s00125-014-3460-0

Extensive experience and efficacy for supporting SU vs. new comers class

DPP-IV inhibitors and the debate of increase the HF ?!

Death from CV causes, non-fatal MI or non-fatal stroke Death from CV causes, MI or ischemic stroke

Comparison :

Glimepiride vs DPP4 Inhibitors

*from Baseline in Premarketing trials

†2-6 mg Glimepiride vs Maximum DPP4 Inhibitors

‡Severe, Rare with both

#MI in UKPDS, ADOPT, ADVANCE,BARI trials[Diabetes Care,2015;38(1):166]

¶ Increased CHF [Clin Ther,2014;36(12):20729,CurrTreatOptionsCardiovascMed,2014;16(12):353]

Glimepiride DPP4 Inhibitors

Efficacy:∆A1c(minus) 25-30%* 8-12%*

Efficacy:∆A1c(minus) More or equal† Less or equal†

Cost Less More

Cost Efficacy More Less

Hypoglycemia ++++ ++

CVD Decreased# No Change¶

Injectable

Class

Mechanism Advantages Disadvantages Cost

Amylinmimetics

• Activates amylinreceptor• glucagon• gastric emptying• satiety

• Weight• Postprandial glucose

• Gastrointestinal• Modest A1c• Injectable• Hypo if insulin dose not reduced• Dosing frequency• Trainingrequirements

High

GLP-1 receptor agonists

• Activates GLP-1 R• Insulin, glucagon• gastric emptying• satiety

• Weight• No hypoglycemia• Postprandial glucose• Some CV risk factors

• Gastrointestinal• ? Pancreatitis• Heart rate• Medullary ca(rodents)• Injectable• Training requirements

High

Insulin • Activates insulin receptor• Myriad

• Universally effective• Unlimited efficacy• Microvascular risk

• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable

Variable

Table 1. Properties of anti-hyperglycemic agentsDiabetes Care 2015;38:140-149;

Diabetologia 2015;58:429-442

SU management in T2DM

Mechanism of action

Bind to the sulfonylurea receptor on the surface of the

β-cell

Closes KATP channels → Inhibit potassium efflux

(depolarizing the β-cells)

↑ Insulin secretion

GLIMEPIRIDE

K+

K+GlimepirideGlibenclamide

Solubilisation

Glibenclamide Glimepiride

65 kDa

140 kDa

65 kDa

140 kDa

cell membrane

Sulfonylurea

receptorPotassium channels

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

Kramer W et al., Biochim Biophys Acta 1994;1191: 278-290

Hypothetical Model of Sulfonylurea Receptor in -cells

0 10 20 30 40 50 60 70 80 90 minutes

3H

su

lph

on

ylu

rea

bo

un

d (

%)

Glimepiride dissociates from its binding protein

8-9 times faster than glibenclamide

Glimepiride Glibenclamide

Müller G et al., Biochim Biophys Acta 1994;1191: 267-277.

80

60

40

20

1001.5x106 RINm5F cells

were incubated (4°C for 45 mins)

with 2 nM [3H]

Glimepiride or [3H]

glibenclamide. At

time zero,

dissociation was

induced by addition

of unlabeled

sulfonylurea (final

conc 2µM). Specific

binding is given as a

percentage of

specific binding at

time zero (100%).

Sulfonylurea Receptor Binding Affinity

Dissociation kinetics of 3H sulfonylurea binding to RINm5F cells

Acting on Both Phases of Insulin Secretion

Glimepiride: The only sulfonylurea to treat

fasting and postprandial hyperglycemia

First Phase Second Phase

Insulin secretion

Before treatment After Glimepiride treatment

Inc

rem

en

tal p

lasm

a in

sulin

(pm

ol/

L)

0

50

100

p=0.04

First and second phase insulin secretion

before and after treatment with Glimepiride

p=0.02

+Glimepiride

+Glimepiride

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

Euglycemic and

hyperglycemic

clamp studies in 11

obese patients with

T2DM with good

glycemic control

before and after 4

months treatment

with Glimepiride to

assess effect of

Glimepiride on insulin

secretion

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 (

%)

Insu

lin

em

ia

(U

/mL)

Glimepi

ride

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

Glimepiride reduces Insulin Resistance

Inukai K, et al. Diabetes Res Clin Pract 2005; 68: 250-257

0

1

2

3

4

5

HOMA-IR

6

6.5

7

7.5

8

HbA1c (%)

Baseline 6 months

Gliclazide or

glibenclamide

(n=52)

all patients BMI ≥ 25 BMI < 25

Glimepiride

(n=120)

all patients BMI ≥ 25 BMI < 25

Glimepiride

(n=120)

*

* *

Mean homeostasis model of insulin resistance (HOMA-IR) and

HbA1c (%) levels at baseline and after 6 months of treatment

*p< 0.05 vs baseline

Glimepiride maintains glycemic control and improves insulin sensitivity in

patients switching from gliclazide or glibenclamide

Gliclazide or

glibenclamide

(n=52)

Multicentre study in 172

Japanese patients in

whom glycemia was

inadequately controlled

(HbA1c ≥7%) by

gliclazide or

glibenclamide. Patients

were randomly assigned

to continue their usual

sulfonylurea or switch to

Glimepiride and were

followed for 6 months.

Baseline HbA1c: 7.5%

gliclazide/glibenclamide

; 7.6% Glimepiride

EFFICACY

Effectiveness of Antidiabetic Agent

DPP-4 = dipeptidyl peptidase 4; TZD = thiazolidinedione.

Nathan DM. N Engl J Med. 2007;356(5):437-440.

1.5 1.5 1.0-1.5 0.5-0.9 0.8-1.0

≥2.5

SUs

Biguanides

(metformin) Glinides

DPP-4

inhibitors TZDs Insulin

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Hb

A1

cR

ed

uc

tio

n (

%)

Efficacy as

monother

apy

Antidiab

etic

agents

Glimepiride Efficacy Proven in Monotherapy

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

and 32% of placebo patients

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

Δ in

me

dia

n H

bA

1c

(%)

6.7%

Change from baseline to week 22

in median HbA1c

9.1%

7.9%

-1%

8.9%

Baseline HbA1c

-4

-3

-2

-1

0

HbA1c at Endpoint

-2.4%#

Glimepiride 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

co

se c

on

ce

ntr

atio

n (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

Modest efficacy of gliptins in meta-analyses1-3

1Amori et al. JAMA 2007;298:194-206.2Richter et al. Cochrane Database Syst Rev 2008;Apr 16;(2):CD006739.3Richter et al. Vasc Health Risk Manag 2008;4:753-68.

28994Gliptins vs. active control

419016Gliptins vs. placebo

30959Duration 12-24 wk vs. placebo

10957Duration 12 wk vs. placebo

17869Vildagliptin vs. placebo

24047Sitagliptin vs. placebo

No. of

patients

No. of

studies

-1.0 0 1.0

Favors gliptins Favors control

Weighted mean

difference, % (95% CI)

-0.74 (-0.85 to -0.62)

-0.70 (-0.83 to -0.58)

-0.78 (-1.00 to -0.56)

-0.73 (-0.94 to -0.52)

-0.74 (-0.84 to -0.63)

0.21 (0.02 to 0.39)

0.5-0.5-1.5

Weighted mean difference in change in HbA1C (%)

for gliptins vs. control in adults with type-2 diabetes1

A multicenter, 52-week, randomized, double-blind study in patients with type-2

diabetes inadequately controlled on metformin therapy

Vildagliptin, less effective than glimepiride?

1Ferranini et al. Diabetes Obes Metab 2009;11:157-66.2Haute Autorité de Santé. 10 December 2008. http://www.has-sante.fr/portail/upload/docs/application/pdf/2010-11/galvus_ct_5731.pdf.

100

0

36.5%

43.4%

Pa

tie

nts

(%

)

Target HbA1C ≤6.5%

at Week 522

50

Glimepiride

(n=1014)

Vildagliptin

(n=1043)

p=0.001

A multicenter, 30-week, randomized, double-blind study in patients with type-2

diabetes inadequately controlled on metformin therapy

Sitagliptin, less effective than glimepiride?

Goldstein et al. EASD 2010.

100

0

21.2%

27.5%

Pa

tie

nts

(%

)

Target HbA1C ≤6.5%

at Week 30

50

Glimepiride

(n=436)

Sitagliptin

(n=443)

Odds ratio (95% CI):

0.67 (0.47 to 0.95)

Additional Benefits for the Patient

Beyond Blood Glucose Control

Reductions metabolic parameters after 12 months of

treatment with Glimepiride

Glimepiride Beneficial Effect on Cardiovascular Risk Factors

Glimepiride significantly reduces cardiovascular risk markers

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

-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.

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

6Baseline 4 weeks 8 weeks 12 weeks

Plasma adiponectin HbA1c (%)

Pla

sma

ad

ipo

ne

ctin

co

nc

en

tra

tio

n (

g/m

L)

Hb

A1c

(%)

8.48.2

6.5

7.56.96.6

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.

Change from baseline in lipid and lipoprotein

concentrations

Glimepiride Beneficial Effects on Lipid and

Lipoprotein Parameters

Glimepiride significantly improves lipid and lipoprotein parameters in

patients with metabolic syndrome vs rosiglitazone

Derosa G, et al. Diabetes Obes Metab 2006; 8: 197-205

TC LDL-C HDL-C TG Apo-AI Apo B

-60

-40

-20

0

20

* * *

*p<0.05 vs rosiglitazone + metformin

Glimepiride + metformin Rosiglitazone + metformin

Co

nc

en

tra

tio

n (

mg

/dL) Double-blind study

in which 95 patients

with metabolic

syndrome (T2DM,

triglycerides ≥150

mg/dL, BP ≥130/85

mmHg) were

randomized to

Glimepiride +

metformin or

rosiglitazone +

metformin for 12

months

Safety Profile of Glimepiride

Hypoglycemic Events

Impact on Weight

Cardiovascular Effects

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

# E

pis

od

es/

10

00

pe

rso

n-y

ea

rs

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

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

Mean intra-individual changes from baseline in body

weight and HbA1c

Months of treatment

Reduction in glycemia with Glimepiride is accompanied by significant and stable weight loss

Ch

an

ge

fro

m b

ase

lin

e

*p<0.0001; †p<0.05; ‡p<0.005 vs baseline

4 12

- 1

- 2

- 3

180

Safety: Weight

-1.9*

-2.9†-3.0‡

-1.4* -1.5*-1.7*

Body weight (kg) HbA1c (%)

Open, uncontrolled,

observational study.

1770 T2DM patients

were enrolled and

284 were followed-up

for 1.5 years. Patients

received 0.5 to > 4

mg Glimepiride once

daily. Baseline HbA1c:

8.4%; body weight:

79.8kg

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

lativ

e s

urv

iva

l

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

Take Home Message

Take Home Message

• DM is a complex disease with multiple etiologies.

• Glycemic control in important to reduce the risk of

microvascular complications of DM & glucose

control in the early years of DM may reduce the risk

of macrovascular disease.

• Various guidelines insists on the importance of

lifestyle modification & metformin as initial treatment

of T2DM.

• ADA-EASD 2015 position statement introduce the

concept of individualization of target & treatment of

DM.

• SU is a cornerstone in management of T2DM..

Glimepiride : Take Home Message

Unique dual mode of action

• Improves 1st and 2nd phases of insulin secretion

• Improves peripheral insulin resistance (extrapancreatic effects)

Fast and sustained blood glucose lowering effect in monotherapy

Suitable for combination with insulin and/or other oral antidiabetic

agents

Benefits beyond blood glucose-lowering

Suitable for use in all type 2 diabetes patients

Clinically proven safety profile

• Low incidence of hypoglycemic events

• No weight gain

• Lower risk of cardiovascular complications

Convenient, once-daily dosing resulting in excellent compliance

THANK YOU