P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N

TZD’s in the management of diabetes & CV disease: All about benefits and safety

Prof. John Betteridge, MDUniversity College LondonLondon, United Kingdom

Cardio Diabetes Master ClassAsian chapterJanuary 28-30 2011, Shanghai

Slide lecture prepared and held by:

Presentation topic

Diabetes and Cardiovascular Disease: Time To Act!“With the rising tide of diabetes around the globe, the double jeopardy of

diabetes and cardiovascular disease is set to result in an explosion of these and other complications- unless preventive action is taken.”

Prof Sir George Alberti, IDF President. International Diabetes Federation

Glucose Toxicity

Nephropathy

-celldamage

Retinopathy

Neuropathy

Cardiovasculardisease

Hepatic and skeletal muscleinsulin resistance

H

OH

H

H H

H

OH

OH

OH

CH2OH

O

UKPDS:Microvascular Complications, MI, and HbA1c

• Incidence rates by updated HbA1c

• Adjusted for age, sex, and ethnic group

• Expressed for white men, 50–54 years old at diagnosis; mean diabetes duration 10 years

Adapted from Stratton IM et al BMJ 2000;321:405-412.

0

40

60

80

Adj

uste

d in

cide

nce

per

1000

pat

ient

yea

rs (%

)

Updated mean HbA1c concentration (%)

20

5 116 7 8 109

MIMicrovascular endpoints

UKPDS:Endpoints by Glucose Treatment Group

Intensive Conventional rate/1000 rate/1000 % risk

Cause patient-years patient-years P reduction

Any diabetes-related* 40.9 46.0 0.029 12MI 14.717.4 0.052 16Stroke 5.6 5.0 0.52 –PVD† 1.1 1.60 0.15 –Microvascular 8.6 11.4 0.0099 25

*Combined microvascular and macrovascular events. †Amputation or death from PVD.

.UKPDS Group. Lancet 1998;352:837-53

Haemoglobin A1c: Cardiovascular Disease and Mortality -The EPIC Study

• Design: Prospective population study. 4662 men and 5570 women aged 45-79yrs, Norfolk England

• Analysis: HbA1c and CVD risk factors assessed 1995-1997. CVD events and mortality assessed during follow-up period to 2003

• Events: 806 CVD, 521 deaths

012345678

5-5.4%

5.5-5.9%

6-6.4%

6.5-6.9

>7% KnownDM

Age Adjusted RR by HbA1c CHD CVD Death

Khaw et al Ann Intern Med 2004; 141: 413

MENRR

Skyler et al Diabetes Care 2009, 33: 187

Conclusions:RCTs of intensive versus standard glycaemic therapy have not shown a significant reduction in CVD outcomes during the randomized period of the trials. NB Long-term follow-up of DCCT and UKPDS suggests that HbA1c around 7% in years soon after diagnosis is associated with long-term risk reduction.Less stringent HbA1c goals may be appropriate for patients with history of severe hypoglycaemia, advanced CVD complications or extensive co-morbid conditions or those with long-standing diabetes in whom the general goal is difficult to maintain.Evidence-based recommendations should be followed for blood pressure management, statins smoking cessation, aspirin and healthy lifestyles

Hyperglycemia

Decreased glucose uptake

Increased HGP

Increased lipolysis

Decreased insulin secretion β and -cell dysfunction

• GLP1-agonists

• DPP4-inhibitors

Decreased incretin effect

• TZDs• Metformi

n

• TZDs• Metformi

n

• GLP1-agonists

• DPP4-inhibitors

• Sulfonylureas

• GLP1-agonists

• DPP4-inhibitors

Increased glucagon secretion

• TZDs

Patho-physiology of Type 2 diabetes Site of Action of Available Drugs

Muscle

Liver

Hyperglycaemia,Hyperinsulinaemia,IGT and Diabetes

Lipolysis

FFA mobilization

FFA oxidation FFA oxidation

Glucose utilization Gluconeogenesis

Free Fatty Acids:Insulin Resistance, IGT and Type 2 NIDDM

Insulin

Adiponectin

Pioglitazone 30-45 mg/d Reduces Plasma Glucose,Insulin and FFA and Increase Adiponectin in Diabetes

NAGASHIMA K et al. J Clin Invest 115:1323, 2005

Glu

cose

(mg/

dL )

200150100

500

P=0.035

P=0.035

FAs

( mE

q/L)

0.60.50.40.30.20.10.0

Adi

pone

ctin

( µg

/mL

)

P=0.000425201510

50

P=0.08

Insu

lin( µ

U/m

L )

40302010

0

N at Risk: 5238 5018 4786 4619 4433 4268 693 (228)

HR 95% CI p value

pioglitazone vs placebo 0.904 0.802, 1.018 0.0951

Time from randomisation (months)

0 6 12 18 24 30 36

Time to Primary Composite Endpoint*

Kaplan-Meier event rate

0.0

0.05

0.10

0.15

0.20

0.25

pioglitazone

placeboN events:

514 / 2605

572 / 26333-year estimate:

21.0%

23.5%

*Death, non-fatal myocardial infarction (including silent MI), stroke, major leg amputation, acute coronary syndrome, coronary or leg revascularisation

Risk reduction : 10 %

PROactive Total Events

DeathNon-fatal MI ACSStrokePCI/CABGMajor leg amputationLeg revascularisation

Pioglitazone Placebo 177 186 131 157 65 78 92 119 195 240 28 28 115 92 803 900

N at Risk: 5238 5102 4991 4877 4752 4651 786 (256)

Time from randomisation (months)

0 6 12 18 24 30 36

0.0

0.05

0.10

0.15

pioglitazone

placeboN events:

301 / 2605

358 / 26333-year estimate:

12.3%

14.4%

HR 95% CI p value

pioglitazone vs placebo 0.841 0.722, 0.981 0.0273

Risk reduction : 16 %

Time to : Death, MI ( excluding silent ) or Stroke

Secondary composite endpoint

In high-risk patients with type 2 diabetes and previous MI, pioglitazone significantly reduced the occurrence of recurrent fatal and nonfatal MI and ACS

Time to Fatal/Non-fatal MI

0.02

0.04

0.06

0.08

0.10

0 6 12 18 24 30 36

Kaplan-Meier event rate

Time from Randomization (months)

N at Risk: 2445 2387 2337 2293 2245 2199 399 (139)

pioglitazone (65 / 1230)placebo (88 / 1215)

0.0

HR 95% CI p valuepioglitazone vs placebo

0.72 0.52, 0.99

0.045

Patients with previous MI n=2445

Risk reduction : 28 %

Stroke, 2007;38:865-873

In high-risk patients with type 2 diabetes and previous stroke, pioglitazone significantly reduced the occurrence of recurrent fatal and nonfatal stroke.

Time to Fatal or Non-Fatal Stroke in Patients with Previous Stroke

N at Risk:

Time from Randomization (months)

984 952 926 903 877 849 132

Kaplan-Meier event rate

0.04

0.06

0.08

0.10

0.00

0.12

0 6 12 18 24 30 36

pioglitazone (27 / 486)

placebo (51 / 498)

0.02

0.0080.34, 0.850.53pioglitazone vs placebo

p value95% CIHR

Risk reduction : 47 %

Patients with previous Stroke n=984

1Nissen SE and Wolski K. NEJM 2007; 356:2457-2471; 2Krall RL. Lancet 2007; 369:1995-1996; 3FDA-Homepage www.fda.gov; FDA-Hearing 30.07.2007;4 SPC Avandia®; 5Bracken MB N Engl J Med. 2007; 357:937; 6Singh S et al. JAMA 2007;298:1189-1195; 7Diamond G et al. Ann Int Med 2007; in press; 7Dormandy JA et al. Lancet 2005; 366:1279-1289; 8Erdmann E et al. JACC 2007; 49:1772-1780; 9Lincoff AM et al. JAMA 2007;298;1180–1188.

10 2

ç Glitazones better Glitazones worse

Hazard Ratio/Odds Ratio

RosiglitazoneMetaanalysis Nissen et al.1 Myocardial Infarction (OR)Metaanalysis Nissen et al.1 Cardiovascular Death (OR)Metaanalysis Krall2 Myocardial Infarction (OR)Metaanalysis FDA3 Myocardial Ischemia (OR)Metaanalysis GSK4 Myocardial Ischemia (HR)Data from Nissen + RECORD5 Myocardial Infarction (OR)

Cardiovascular Death´(OR)Metaanalysis Singh6 Myocardial Infarction (HR) 1.42

1.43

1.64

1.31

1.4

1.24

1.07

Hazard Ratios for CardiovascularEvents with Glitazones

PioglitazonePROactive7 Primary Endpoint (HR)PROactive7 MI, Stroke and Death (HR) PROactive MI-Subgroup8 Myocardial Infarction (HR)Metaanalysis Lincoff et al9 MI, Stroke and Death (HR) 0.82

0.84

0.90

0.72

CHICAGO: Glycaemic Control Change in HbA1c

Mazzone T et al. JAMA. 2006.*P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference)

Glimepiride Pioglitazone

724824Baseline-0.6

-0.4

-0.2

0

0.2

A1C change

from baseline

(least square means,

%)

60403216Week

* †

‡

CHICAGO: Treatment effect on posterior wall mean CIMT

Mazzone T et al. JAMA. 2006.

P = 0.02

Week 72Week 48Week 24Baseline-0.012

-0.008

-0.004

0

0.004

0.008

0.012

0.016

Mean change

from baseline

(least squares,

mm)

Glimepiride Pioglitazone

CIMT = carotid intima-media thickness

Objective: Will pioglitazone stabilize carotid artery vulnerable plaque in patients with acute coronary syndromes (ACS) and type 2 diabetes.

Population:61 patients with type 2 diabetes, age 63yrs, approx 70% male and echo lucent carotid plaques within 5 days of ACS. Random allocation to pioglitazone 15-30mg/day or matching placebo.

Methods:Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated back scatter (IBS)An increase in IBS reflects an increase in plaque echogenicity.Echolucent plaques with low IBS represent identify lipid and macrophage-rich lesions, unstable plaques

PROactiveMetabolic Effects of Pioglitazone

HbA1c - 0.5%

HDL-cholesterol + 8.9%

LDL-cholesterol + 2.3%Triglycerides - 13.2Systolic BP - 3 mmHgWeight + 4 kg

Change in LDL cholesterol, Particle size,Apoprotein B and Particle Concentration

Changefrom baselineat week 24 (%)

15.7*

23.3

2.4** 1.7

-7.8*

12.0

1.5*

11.5

n=363

n=356

n=333

n=325

n=333

n=346

n=334

*p<0.001 and **p=0.005between treatment groups

n=325

Goldberg et al. Diabetes Care 2005; 28: 1547-1554Goldberg et al. Circulation 2005; 111: 1727–1728

-10-505

10152025

LDL-

C

LDL

part

icle

size

LDL

part

icle

conc

entr

atio

n

Apo

B

Pioglitazone Rosiglitazone

CHF

CHFDeath

Lancet, 2007; 370: 1129-1136

More pioglitazone (5.7%) than placebo patients (4.1%) had episode of serious heart failure,(requiring hospitalization or life threatening) but there was no difference in mortality p=0.639

Erdmann et al Diabetes Care 30:2773–2778, 2007

P=0.007

Kaplan Meier estimates of time from serious heart failure to all-cause mortality

The Development of Heart failure on Pioglitazone in PROactive did not affect subsequent prognosis

Pioglitazone

Erdmann et al Diabetes Care 30:2773–2778, 2007

Placebo

Whole body glucose disposal and Myocardial glucose utilization during hyperinsulinaemic clamp FDG uptake using Positron Emission Tomography

Whole body glucose disposal

Myocardial glucose utilization

p<0.05 between treatment differences

JACC, 2007; 50: 2051

Hyperaemic Myocardial Blood FlowBefore and After Pioglitazone

JACC, 2007; 50: 2051

p<0.05 between treatment differences

• Setting:• UK general practice research dta

Objective:To investigate risk of incident MI, congestive heart failure and all cause mortality associated with prescription of oral anti diabetes drugs

Design:Retrospective cohort studySetting:UK general practice research data base 1990-2005

Participants:91521 people with diabetesMethods:Person time intervals for drug treatment were categorised by drug class excluding non-drug intervals and intervals for insulin 3588 MIs, 6900 CCF, 18548 deaths