Dr. Nizar ALBACHE

Aleppo University- Diabetes Research Unit

President of Syrian Endocrine Society

Vice President of Mediterranean Group for Study of Diabetes

PIOGLIT-METThe advantages from combining two

insulin sensitizers

Diabetes Mellitus in Syria 2006 (>25 year)

Epidemiology of Type 2 diabetes mellitus in Aleppo, SyriaN. ALBACHE, R. ALI, S. RASTAM, F. M. FOUAD, F. MZAYEK,. W. MAZIAK; Journal of Diabetes 2 (2009) 1–7

Firstsulphonylureas

Metformin

Glitazones

Acarbose

Gliptins

?

1920 1940 1960 1980 2000

Major progress in the oral treatment of diabetes

LenteInsulins

NPHInsulin

Insulindiscovered Insulin pump

HumanInsulin

GLP-1

Insulinanalogues

Glinides

.....But the good glycemic control of the type 2 diabetic patient remains a challenge

Metformin

Derived from the plant known as Goat's Rue, French Lilac, Italian Fitch or Professor-weed (Galega officinalis)

-In USA since 1992

-In Europe since 1957

craze

First disappointments

Discussion of a possible

withdrawal

Final withdrawal

progressive disaffection

New success

New“steady – state”

Remarkable story of metformin

Undisputed first choice!

Commer-cialization

Fatal lactic acidosis!

1957 1998 2011

metformin

UKPDS

FDA

Phenformin Buformin

1980 1992

Oral Antihyperglycemic MonotherapyMaximum Therapeutic Effect on A1C

-0.50 -1.0 -1.5 -2.0

Nateglinide

Reduction in A1C (%)

Glipizide GITS

Glimepiride

Repaglinide

Pioglitazone

Acarbose

Metformin

Rosiglitazone

Diabetes Care. 2000;23:202-207; Precose (acarbose) package insert; Drugs. 1995;50:263-288; J Clin Endocrinol Metab. 2001;86:280-288; Diabetes Care. 2000;23:1605-1611; Diabetes Care. 1996;19:849-856; Diabetes Care. 1997;20:597-606; Am J Med. 1997;102:491-497

UKPDS: Global Clinical OutcomesOverweight patients

Met v Sus or Insulinp=0.0034

Met v Diet p=0.0023

0

20

40

60

0 3 6 9 12 16

Pro

port

ion

of p

atie

nts

with

eve

nts

Time from randomisation (years)

Insulin orSulphonylureas

Metformin

Conventional DietAny diabetes-related endpoint

32%Reduction

Lancet 1998;352:854-65

UKPDS: Risk reduction with metformin in overweight patientsN = 4075 with type 2 diabetes

UKPDS Group. Lancet. 1998;352:854-65.

Favors metforminor intensive

Favors conventionalAll-cause mortality

MetforminIntensive

Myocardial infarctionMetforminIntensive

StrokeMetforminIntensive

0.021

0.021

0.021

Aggregate endpoints P*

0.1 1 10

*metformin vs intensive therapy

Relative risk reduction(95% CI)

Metformin associated with lower mortality

Masoudi FA et al. Circulation. 2005;111:583-90.

N = 16,417 with diabetes and HF

Metformin (n = 1861)

No insulin sensitizer (n = 12,069)

Time (days)

1.0

0.9

0.8

0.7

0.6

0.50 50 150 200 250 300 350100

13% Relativerisk reduction

Proportionof patientssurviving

-10

-5

0

5

Total-C LDL-C Triglycerides HDL-C

Mea

n c

han

ge

fro

m b

asel

ine

(%)

Metformin (n=143)

Placebo (n=146)

Metformin and lipid profiles

DeFronzo RA & Goodman AM. NEJM 1995;333:541-9

p=0.001

p=0.019

Kurukulasuriya R et al. Diabetes 1999;48:A315

Data are Means. Duration of Treatment: 6 Months.

Weight (kg)

Body Mass Index (Kg/m2)

Total Body Fat (L)

Total Subcutaneous Fat (L)

Abdominal Subcutaneous Fat (L)

Viscera Fat (L)

Lean Body Mass

Change from

baseline

-3.3 -1.2 -2.8 -2.1 -1.2 -0.6 0

%Decrease

from baseline

4% 4% 9% 7%

11%15%

No change

p

value

0.006 0.006 0.014 0.025 0.013

0.01NS

Selective loss of visceral fat

Metformin and body fat composition

Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50 . *P = 0.0027 vs placebo

Before treatment After treatment

400

300

250

200

150

50

0

350

Metformin 1000 mg (3 months)

3

Increase in forearm blood

flow)%(

Acetylcholine (g/min)

100

*

Placebo

10 30 3 10 30

*

*

Metformin improves endothelial function

Myocardial Infarction

Heart Attacks

0

5

10

15

20

Inci

de

nce

pe

r 1

00

0 p

atie

nt

yea

rs

Coronary Deaths

0

2

4

6

8

10

Conventional Diet

Insulin or

Sulphonylureas

Metformin

p=0.02

50%Reduction

Conventional Diet

Metformin

p=0.01

39%Reduction

NS

Inci

de

nce

pe

r 1

00

0 p

atie

nt

y ea

r s

Stroke

0

2

4

6

8

Eve

nts

per

100

0 p

atie

nt

year

s

-60

-40

-20

0

20

40

60

% R

isk

Red

uct

ion

41%

14%

P=0.13(NS) P=0.032

MetforminConventional Diet

Insulin or Sulphonyl

Metformin Insulin or Sulphonylureas

Survival in Overweight Group

Diabetes Related Deaths

0

3

6

9

12

15

Inci

denc

e (D

eath

s pe

r 10

00 P

atie

nt Y

ears

)

All Cause Mortality

5

10

15

20

25

Inci

denc

e (D

eath

s pe

r 10

00 P

atie

nt Y

ears

)

Conventional Diet

Insulin or

Sulphonylureas

Metformin

p=0.017

42%Reduction

p=0.011

36%Reduction

Conventional Diet

Insulin or

Sulphonylureas

Metformin

p=0.021

NS

NS

Mechanisms of vascular protection

1. Reduce insulin resistance

2. Improved lipid profiles

3. Adiposity

4. Improved hemostasis

5. Inhibition of glycoxidation

6. Inhibition of inflammation

Metformin ;effect on cancer risk and mortality

Diabetes Prevention Program (DPP)

0

20

40

60

DIET +EXERCISE

METFORMIN TROGLITAZONE

%de

crea

seIG

T

T2D

M

58%

31%23%

DPP, NEJM 2002; 346:393-403

Early metformin therapy to delay menarche and augment height in girls with precocious pubarche

• Early metformin therapy to delay menarche and augment height in girls with precocious pubarche Lourdes Ibáñez M.D., Ph.D.a, , , Abel Lopez-Bermejo M.D, Abstract – selected,Fertility and Sterility,Article in Press

Conclusion(Early metformin therapy (age 8–12 years) suffices Delay menarche Augment postmenarcheal height Reduce total, visceral, and hepatic adiposity Curb the endocrine-metabolic course of LBW-PP girls away from adolescent PCOS.

Contraindications for metformin treatment

• Decrease renal function• Congestive heart failure• Patients > 80 years of age• Liver disease• Chronic alcohol disease• Sepsis or other acute illnesses with decreased

tissue perfusion• During intavenous radiographic contrast

administration(+-)

• Oral Antihyperglycemic MonotherapyMaximum Therapeutic Effect on A1C

• Metformin associated with lower mortality• Metformin and lipid profiles• Decrease Visceral Fat• Metformin improves endothelial function• Decrease Myocardial Infarction• Decrease Stroke• Decrease risk of Cancers• Decrease the risk of Developing Diabetes(DPP)

63% of Patients With Diabetes are Not At ADA A1C Goal <7%

0

20

40

60

80

100

>10%

>9%

>8%

7-8%

<7%

37.2%>8%

63%7%

7.8%

25.8%

37.0%

17.0%

12.4%

%of

Sub

ject

sn

= 40

4A1C

National Health and Nutrition Examination Survey (NHANES), 1999-2000.

Only 7% of adults attained :A1c <7%, BP 130/80, and

Total Cholesterol <200mg/dL

1 in 5Have A1c

>9%

Need for an early and intensive approach to type 2 diabetes management

30% of MD2 undiagnosed

At Diagnosis of type 2 diabetes:

50% of patients already have complications1

up to 50% of -cell function has

already been lost2

Current management:

two-thirds of patients do not

achieve target HbA1c3,4

majority require polypharmacy

to meet glycaemic goals over time5

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

Stepwise approach: delays control and leaves patients at risk of complications

1Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345–1355. 2Stratton IM et al. BMJ 2000; 321:405–412.

Duration of diabetes

Hb

A1c

(%

)1

7

6

9

8

10

Diet andexercise

OADmonotherapy

OAD combination

OAD +basal insulin

OAD monotherapy

uptitration

OAD + multiple daily

insulin injections

Mean

Complications2

Early, intensive intervention: reach glycaemic goals and reduce the risk of complications

1Adapted from Del Prato S et al. Int J Clin Pract 2005; 59:1345–1355. 2Stratton IM et al. BMJ 2000; 321:405–412.

Duration of diabetes

Hb

A1c

(%

)1

7

6

9

8

10

Complications2

OAD monotherapy

OAD combination

OAD uptitration

OAD + basal insulin

OAD + multipledaily insulin

injections

Mean

OAD uptitration

Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity

Metformin

Blood glucose

↑Glucose uptake in muscle and fat by increasing insulin sensitivity5

1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 2. Setter SM et al. Clin Ther. 2003;25:2991–3026.3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626.5. Bailey CJ et al. N Engl J Med. 1996;334:574–579.

MuscleAdipose

tissue

Liver

↓Gluconeogenesis ↓Glycogenolysis

↑Glycogen synthesis

↓Glucose production reduced by1–4:

Liver

Hepatic glucose

output

Insulin resistance

Glucose uptake in muscle and fat

Glucagon)alpha cell(

Insulin)beta cell(

Hyperglycemia

Islet-cell dysfunction

Major Pathophysiologic Defects in Type 2 DM

Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

Pancreas

Liver Adipose tissue

Liver

Muscle

Complementary Mechanisms of Action

Combining Pioglitazone and Metformin

Glucose absorption

Hepatic glucoseoverproduction

Beta-celldysfunction

Insulinresistance

Major Targeted Sites of Oral Drug Classes

DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.DeFronzo RA. Ann Intern Med. 1999;131:281–303 .Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.

Pancreas

↓Glucose level

Muscle and fatLiver

Biguanides

TZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

Alpha-glucosidase inhibitors

Gut

DPP-4 inhibitorsGLP-1

DPP-4 inhibitors

Biguanides

No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

Alpha-Glucosidase Inhibitors1,2

Meglitinides3 SUs4,5 TZDs6,7 Metformin8

DPP-4 Inhibitors

Insulin deficiency

Insulin resistance

Excess hepatic glucose output

Maj

or P

atho

phys

iolo

gies

1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.

8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004 .

Intestinal glucose absorption

52%

4%

4%

40%

Oral MonotherapyOral Combination TherapyInsulin/Oral Combination TherapyInsulin Only Therapy

40%

29%

12%

19%

1995 2000

Trends in Antidiabetic Therapy

Effects of Pioglitazone and Metformin on FBG and HbA1c

Egan J et al. Diabetes. 1999;47(suppl 1):A117. Abstract.

-0.8

0.2

-0.8

-0.6

-0.4

-0.2

0.0

0.2

Placebo + metformin Pioglitazone 30 mg + metformin

-5

-38

-55

-45

-35

-25

-15

-5

5

*P0.05 for comparison with placebo

*

*

C

FBG(mg/dL)

changefrom

baseline

HbA1c

(%)change

frombaseline

35%

23%

0

10

20

30

40

50

60

MET 2 g/day RSG 8 mg/day + MET 1 g/day

% o

f P

ati

en

ts R

es

po

nd

ed

*ADA A1c goal <7%, AACE A1C goal 6.5%. †P<0.05.‡Patients received Avandia® 8 mg/day plus metformin 1 g/day (n=322; baseline A1c 8.05%) versus maximum dose metformin (n=313; baseline

A1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study.

Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin: More Patients Reach A1c Goal* vs. MET Monotherapy (2 g)

45%

55%

Goal‡

<6.5%

Goal‡ <7%

†

Insulin sensitizers vs other glucose-lowering agents following AMI8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication

Metformin TZD Both

Mortality 0.92(0.81–1.06)

0.92(0.80–1.05)

0.52(0.34–0.82)

Myocardial infarction readmission

1.02(0.86–1.20)

0.92(0.77–1.10)

0.88(0.56–1.37)

Heart failurereadmission

1.06(0.95–1.18)

1.17(1.05–1.30)

1.24(0.94–1.63)

All-cause readmission

1.04(0.96–1.13)

1.09(1.00–1.20)

1.06(0.87–1.30)

Neutral effect of PPAR activationand metformin on hospital readmission

All-cause HF

TZD 1.04 (0.99–1.10) 1.06 (1.00–1.12)

Metformin 0.94 (0.89–1.01) 0.92 (0.86–0.99)

N = 16,417 with diabetes and HF

Hospital readmission

TZD = thiazolidinedione

Mortality benefit with combined insulin-sensitizing therapy

8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication

No insulin sensitizer (n = 6641)Thiazolidinediones (n = 1273)

Metformin (n = 819)TZD + MET (n = 139)

48% Relativerisk reduction

Days from discharge

1.00

0.95

0.90

0.85

0.800 50 200 250 300 350100

Proportionof patientssurviving

150

Fixed-dose combination tablets may help to increase patient compliance and improve efficacy

Patient compliance can be a difficult obstacle to overcome

Among newly DM2=53.8% adhered to their treatment regimen

Compliance problems result in higher A1C levels

10% increase in drug adherence decreased A1C 0.16%

optimal compliance vs the group with the worst compliance = 1.4% difference in A1C

Patient compliance is influenced by the frequency of doses taken

Patient compliance is dependent on two behavioral aspects:Dose taking :

QD dosing is 98.7%BID dosing is 83.1%TID dosing is 65.8%

Dose timing:QD dosing is 79.1%BID dosing is 65.6%TID dosing is 38.1% QD dosing regimens are associated with higher rates of adherence than BID or TID regimens.

Advantages of combination therapy

The side effects and toxicities;

not altered by combinationdose related in individual patientslower doses in combination better tolerated

Patient compliance increases as complexity decreases

Dosing flexibility may be key to tight control

ADA/EASD Revised Consensus Statement(2009)

David Nathan

Diabetes Care 2009; 32:193-203

Tier 1 : Well-validated core therapies

At diagnosis:

Lifestyle+

Metformin

Step 1

Lifestyle + Metformin+

Intensive Insulin

Step 3

Lifestyle + Metformin+

PioglitazoneNo hypglycemia

Oedema/CHFBone loss

Lifestyle + Metformin+

GLP-1 agonistb

No hypglycemiaWeight loss

Nausea/Vomitting

Lifestyle + Metformin+

Pioglitazone+

Sulphonylureas

Lifestyle + Metformin+

Basal insulin

Tier 2 : Less well-validated core therapies

Lifestyle + Metformin+

Basal Insulin

Lifestyle + Metformin+

Sulphonlyureasa

Step 2

Evidence vs. opinion based guidelines for the management of type 2 diabetic patients

. 2010 ; 53)7(: 1258–1269Diabetologia July

Debate on The ADA and EASD algorithm(Nathan) Deficiencies in the algorithm

• Not evidence based approach • Not offer the best quality of treatment

– on the basis of our understanding of the multifactorial pathophysiology of type 2 diabetes or the need for individualised therapy

• Based more on an outdated expert opinion• Priorities for treatment

– on the benefits of all available classes of glucose-lowering agents– In favouring initial use of metformin monotherapy followed by sulfonylurea, an

approach known to fail• Does not offer appropriate selection

– of options to individualise and optimise care

. 2010 ; 53)7(: 1258–1269Diabetologia July

A1C 6.5 – 7.5%**

Monotherapy

MET +

GLP-1 or DPP4 1

TZD 2

Glinide or SU 5

TZD + GLP-1 or DPP4 1

MET + Colesevelam

AGI 3

2 - 3 Mos.***

2 - 3 Mos.***

2 - 3 Mos.***

Dual Therapy

MET +GLP-1 or DPP4 1

+

TZD 2

Glinide or SU 4,7

A1C < 9.0%

No Symptoms

Drug Naive Under Treatment

INSULIN

± Other

Agent(s) 6

Symptoms

INSULIN

± Other

Agent(s) 6

INSULIN

± Other

Agent(s) 6

Triple Therapy

AACE/ACE Algorithm for Glycemic Control Committee

Cochairpersons:Helena W. Rodbard, MD, FACP, MACEPaul S. Jellinger, MD, MACE

Zachary T. Bloomgarden, MD, FACEJaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACEJames R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACEEdward S. Horton, MD, FACEHarold Lebovitz, MD, FACEPhilip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACEStanley S. Schwartz, MD, FACE

*May not be appropriate for all patients **For patients with diabetes and A1C < 6.5%,

pharmacologic Rx may be considered ***If A1C goal not achieved safely

†Preferred initial agent

1DPP4 if PPG and FPG or GLP-1 if PPG

2TZD if metabolic syndrome and/or

nonalcoholic fatty liver disease (NAFLD)

3AGI if PPG

4Glinide if PPG or SU if FPG

5Low-dose secretagogue recommended

6a)Discontinue insulin secretagoguewith multidose insulin

b)Can use pramlintide with prandial insulin

7Decrease secretagogue by 50% when added to GLP-1 or DPP-4

8If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution

9If A1C < 8.5%, in patients on Dual Therapy,insulin should be considered

MET +

GLP-1

or DPP4 1 ± SU 7

TZD 2

GLP-1

or DPP4 1 ± TZD 2

A1C 7.6 – 9.0%

Dual Therapy 8

2 - 3 Mos.***

2 - 3 Mos.***

Triple Therapy 9

INSULIN

± Other

Agent(s) 6

MET +

GLP-1 or DPP4 1

or TZD 2

SU or Glinide 4,5

MET +

GLP-1

or DPP4 1+ TZD 2

GLP-1

or DPP4 1 + SU 7

TZD 2

MET † DPP4 1 GLP-1 TZD 2 AGI 3

Available at www.aace.com/pub© AACE December 2009 Update. May not be reproduced in any form without express written permission from AACE

Take home messages

• Guidelines changing now, we expect the new one to be release soon

• We have many choices to initiate oral TT• Combination of 2 Sensitizers looks a good one• With adding Piogl. To Metf. You add the benefits:

Increase patients adherence

More redaction on A1c

Improve Lipid profile

Increase cardiac protection

Decrease the cancer risk

nizar-albache.com