The Rosiglitazone storm Nabil Isseh, MD Damascus medical school.

The Rosiglitazone storm

Nabil Isseh, MDDamascus medical school

What is the Most Common Cause of What is the Most Common Cause of Death in People with Diabetes?Death in People with Diabetes?

0

10

20

30

40

50

Ischemicheart

disease

% o

f D

eath

s%

of

Death

s

Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.

Mortality in People with DiabetesCauses of Death

Otherheart

disease

DiabetesCancer Stroke Infection Other

Why new recommendations ? Why new recommendations ? 2006 consensus 2006 consensus

EASD ADAEASD ADA

IDFIDF

MoneyMedicinePolitics

The Story of Rosiglitazone

The Origin of the RSG storm

Glitazone in Diabetes Therapy

1. May preserve B-cell function

2. Protective CVD Effects

3. The Impact on Clinical CVD endpoints!!

Can any of the available

treatments change the

course of the disease?

(i.e. preserve β cell function)

Can the Can the Glitazones Glitazones

Reduce Reduce CVD in CVD in

diabetes?diabetes?

The insulin resistance syndrome and its components

Insulin resistance syndrome

Microalbuminuria

HypertensionCentral/abdominal obesity

Coronary heart

disease

Dyslipidemia

Type 2 diabetes

Hyperinsulinemia

Groop et al. Front Horm Res 1997; 22:131–156.

Glitazones: potential Impact on CVD Risk

TZDIR

Hyperglycemia

HDL and sdLDLBP

PAI-1 Microalbuminuria

Vascular reactivityCRP

Atherosclerosis, CVD?

WHEN ALL HELL BROKE LOOSE!

N Engl J Med

23/5/2007

Effect Of Rosiglitazone on the risk

Of MyocardialInfraction and Death

From Cardiovascular Causes

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A correction has been published: N Engl J Med 2007;357(1):100.

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Steven E. Nissen, M.D., and Kathy Wolski, M.P.H

Volume 356:2457-2471      June 14, 2007      Number 24

Nissen Meta-Analysis

• 42 Studies

• Increased odds ratio of 1.43 for Acute MI risk

• And 1.64 for the risk of cardiac death

NEJM May 21, 2007

Nissen Analysis Weakness

1. No access of original source data:

unable to perform time – to – end analysis.

2. The trials were not designed to explore CVD outcomes.

3. The number of adverse events were small.

4. Confidence intervals were very wide.

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes

Conclusions• Rosiglitazone was associated with a

significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance

Nissen, S.E. and Wolski, K., N Engl J Med 2007;356.

…AND HELL BROKE LOOSE!

Heart Attack Risk Seen in Drug for Diabetes

May 22 2007

Money Aspect of RSG Storm

World wide sales $ 3.2 billion

RSG prescriptin down 42%

sales down 22%

share price down

Deutsche Bank June 26, 2007

The USA Congress

Consistent concern about the possibility of increased CVD risk with RSG

ADA Panel debate

Rosiglitazone: The scientific and regulatory issues underlying the current controversy

Steven Nissen, MD

Rosiglitazone Panel

John Buse, MD, PhD; Barry Goldstein, MD; Philip Home, MD; Richard Kahn, PhD; David Nathan, MD; Steven Nissen, MD

Rosiglitazone and CV disease: does the RECORD study help?

Philip Home, MD

Perspectives - Rosiglitazone and CVD Science and Public Health

Rosiglitazon

The scientific and regulatory issues underlying the current controversy

Steve E. Nissen MD

ADA June Meeting 2007

Rosiglitazon Registratione (May 1999)

• Major concerns had emerged about hepatic toxicity of troglitazone.

• FDA was eager to approve a “safer” alternative and rosiglitazone and pioglitazone appeared free of this life-threatening side effect.

• The registration “package” for rosiglitazone consisted of 5 trials (2902 patients), mostly short-term (24 weeks) glycemic control studies.

• The drug was presented to an FDA Advisory Panel on May 22, 1999.

ADA June Meeting 2007

Rosiglitazone Advisory Panel: CV EventsIschemic Heart Disease Events

Rosiglitazone Comparators Relative Risk

36/2902 (1.24%) 10/1452 (0.69%) 1.80

FED Reviewer “A post-marketing study to evaluate long”Term safety RSG should be required for approval.

ADA June Meeting 2007

Rosiglitazone Approval Issues

• In the initial studies submitted for approval, rosiglitazone increased LDL-cholesterol by 18.6% obviously a major concern in diabetic patients.

• The numerical excess of cardiovascular ischemic events and increase in atherogenic lipoproteins received little attention after initial approval.

• However, one individual, incoming ADA President John Buse, expressed concern at scientific meeting and wrote to the company and FDA.

ADA June Meeting 2007

Post-Registration Studies

• No major cardiovascular outcome trial, but many small, generally short-term, efficacy studies conducted.

• Three larger, longer term studies. Dream: A three year 5000 patient, placebo-controlled,

“diabetes prevention” trial (Lancent September 2006). ADOPT: A four year, 4400 patient metforin and glyburide

controlled study of glycemic durability, but no adjudication of cardiovascular events (NEJM December 2006).

RECORD: An open label, six year, 4400 patient, European regulatory cardiovascular outcome study (comparison with metformin/sulfonylurea) due in 2009.

ADA June Meeting 2007

DREAM: Major Cardiovascular OutcomesRSG

n=2635

Placebo

N=2634HR (95% CI)

P

value

MI 15 9 1.66(0.73-3.80) 0.2

Stroke 7 5 1.39(0.44-4.40) 0.6

CV Death 12 10 1.20(0.52-2.77) 0.7

Adj CHF 14 2 7.03(1.6-30.9) 0.01

New Angine 24 20 1.2(0.66-2.17) 0.5

Revasc 35 27 1.29(0.78-2.14) 0.3

Composite 75 55 1.37(0.97-1.94) 0.08

ADA June Meeting 2007

ADOPT : Major Cardiovascular Outcomes

Myocardial Infarction

Rosiglitazone Comparators Odds Ratio P value

27/1456

(1.85%)

41/2895

(1.42%)

1.33

(0.80-2.21)0.27

ADA June Meeting 2007

Rosiglitazone Staus: December 2006

• Pooled “registration” trials showed a 1.8 fold higher rate of ischemic CV events with rosiglitazone compared with placebo or other agents.

• The DREAM Trial showed a 1.66 fold higher rate of MI with rosigltazone compared with placebo.

• The ADOPT Trial showed a 1.33 fold higher rate of MI with rosiglitazone compared with other agents.

• Although none of the individual studies reached statistical significance, the consistent pattern of excess myocardial infractions was very worrisome.

ADA June Meeting 2007

Meta-analysis NEJM-May 2007

• With published data showing trends towards cardiovascular harm, further analysis warranted.

• Since available trials were too small to provide adequate power to answer this scientific question, a meta-analysis was the next logical step.

• Fortunately, as a result of a lawsuit by NY Attorney General Elliott Spitzer, GSK was required to publicly disclose all clinical trial results.

• This disclosure include 42 randomized studies (mostly unpublished) comparing rosiglitazone with other agents or placebo (> 24 weeks duration)>

ADA June Meeting 2007

Meta - analysis :Myocardial Infarction

RSGControl Group

Odds Ratio P value

Small Trials

44/10285 22/61061.45

(0.88-2.39)0.15

DREAM 15/2635 9/26341.65

(0.74-3.68)0.22

ADOPT 27/1456 41/28951.33

(0.80-2.21)0.27

Overall1.43

(1.03-1.98)0.03

ADA June Meeting 2007

Meta - analysis : Cardiovascular Death

RSGControl Group

Odds Ratio P value

Small Trials

25/6845 7/39802.40

(1.17-4.91)0.15

DREAM 12/2635 10/26341.20

(0.52-2.78)0.67

ADOPT 2/1456 5/28950.80

(0.17-3.86)0.78

Overall1.64

(0.98-2.74)0.06

ADA June Meeting 2007

Glaxo Smith Kline and FDA Analysis

• Near completion of our meta-analysis, we learned that GSK had performed a similar study (never published), initially in September 2005, updates in October 2006.

• Not including DERAM and ADOPT, the company’s own analysis showed a statistically significant 31 percent greater rate of “myocardial ischemic events”.

• The GSK analysis used the more powerful patient-level data not available in our meta-analysis.

• Recently, FDA announced that they had conducted their own independent meta-analysis, which showed “approximately 40%” greater rate of ischemic events.

ADA June Meeting 2007

Risk of MI with RSG

• Nissen analysis 43%

• FDA 40%

• Glaxo 31%

• RECORD 11%

ADA June Meeting 2007

Some final thoughtsNissen

• With the limitations of RECORD, in the year 2009, 10 years after the launch of rosiglitazone, We may still not know whether this agent benefits or harms patients with Type 2 diabetes.

• Accordingly, the three meta-analysis (GSK, FDA and NEJM) of all 42 rosiglitazone trials is the best data we are likely to have for the foreseeable future.

• Therefore, each physician must decide for themselves how to integrate these findings into their treatment decisions for individual patients.

ADA June Meeting 2007

Professor Philip Home

New Castle University, UK

ADA June Meeting 2007

Rosiglitazone and CVDScience and Public Policy

Rosiglitazone and CV disease Does the RECORD study help?

Professor philip HomeNewcastle Diabetes CentreNewcastle University UK

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Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis

Philip D. Home, D.M., D.Phil., Stuart J. Pocock, Ph.D., Henning Beck-Nielsen, D.M.S.C., Ramón Gomis, M.D., Ph.D., Markolf Hanefeld, M.D., Ph.D., Nigel P. Jones, M.A., Michel Komajda, M.D., John J.V. McMurray, M.D., for the RECORD Study Group

Volume 357:28-38      July 5, 2007      Number 1

Nissen and Wolski ResultsOR rosiglitazone vs placebo or active comparator• MI 1.43 (95% CI 1.03 to 1.98) P:0.03• CV death 1.64 (95% CI, 0.98 to 2.74), P:0.06

Problems:• 42 studies – some excluded• Many studies only zero or 1 report• Events not endpoints, just investigator reports• No time- to – events analysis• Hypothesis generating not testing

ADA June Meeting 2007

The RECOCRD Study Interim Analysis Why??

• Not normally appropriate• However:

Safety analysis prepared for the regulators were leaking into the press

Acute reaction to the Nissen/Wolski study began to lead to withdrawals

• 23 May – Steering Committee decision that publication of interim analysis lesser of the evils

• 05 June – Publication on line of revised paper after 8 reviewer report

ADA June Meeting 2007

The RECORD Study

• Primarily a cardiovascular safety study• People with Type 2 diabetes in 2001 – 2003 • Primarily endpoints

A composite of cardiac and vascular outcomes Active comparator study Assessed for non-inferiority of rosiglitazone

• Add-on oral agents – combination therapy study• Planned 6 years follow-up

ADA June Meeting 2007

The RECORD Study interim analysisAdjudicated endpoints

Rosi

(n)

Metf/SU

(n)HR(95%CI) P

Primary endpoint Death 217 202 1.08(0.89-1.31) NS

Cardiovascular causes 29 35 0.83(0.51-1.36) NS

Any cause 74 80 0.93(0.67-1.27) NS

CV death/MI/stroke 93 96 0.97(0.73-1.29) NS

Acute myocardial infarction

43 37 1.16(0.75-1.81) NS

Congestive heart failure 38 17 2.24(1.27-3.97) 0.006

ADA June Meeting 2007

RECORDE Study and Interim Analysis: Some Conclusions

• By comparison with other medications believed to improve cardiovascular outcome, rosiglitazone appears to behave similarly for CV-death, all cause death, and CV composite

• This suggests that rosiglitazone should still have a role in the glucose-lowering armoury

• A clinically significant increase in MI not causing death cannot be ruled out from the RECORD data

• The known problem of CHF is again confirmed

• RECORD should continue to its planned end

ADA June Meeting 2007

CVD adverse events following percuteneous coronary revescularization

Rosiglitazone Placebo

n 102 98

Death/MI/stroke or

recurrent ischaemia 30.4 31.4

Death/MI/stroke 6.4 11.9

Death 1.2 2.3

MI 5.2 8.4

Stroke 1.2 2.3

PPAR Study

Bhatt et al Am Heart J 2007

Ischaemic events over 12 months (% patients)

ADA June Meeting 2007

Rosiglitazone and Cardiotoxicity — Weighing the Evidence

David M. Nathan, M.D

Volume 357:64-66      July 5, 2007      Number 1 Next Previous

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NEJM, June 5, 2007

The JuryDavid Nathan

The Jury may still be out with regard to the cardio toxicity of rosiglitazone. But when it comes to patients safety, first do no harm, should outweigh any presumption of innocent.

NEJM June 5, 2007

The Jury-David Nathan

It is reasonable to ask whether physician should feel comfortable using a drug that might have an excess risk of CVD when other choices available, including Pioglitazone which has limited clinical trial data suggesting a Proactive CVD….

NEJM June 5, 2007

A Special FDA Advisory Panel Meeting July 31, 2007

A Special FDA Advisory Panel Meeting July 31, 2007

1. RSG increases the Cardiac Ischemic risk in Type II diabetes

2. The drug should stay on the market

More Risk – Subset Analysis

1. CHF

2. CHD

3. Taking Insulin

4. Taking Nitrate

5. Taking ACE – I

6. Taking Metformin

And RSG

• CHD

• CHF

• Insulin

• Nitrate

• CHD

• CHF

• Insulin

• Nitrate

What about Pioglitazone?

Rosiglitazone vs PioglitazoneClass effect ??

1. Lipids

2. PROactive

3. CHICAGO

4. FDA data

Coke VS Pepsi

Risk of MI in Pioglitazone

1. FDA: unpublished data

2. Pioglitazone reduced MI risk by 22%

FDA Advisory panel meeting July 31, 2007

Have Glitazones lost the throne?

Where I stand?

My Stand

1. RSG has proven glucose – lowering abilliteis

2. Long – established risks for CHF

3. It poses a small but significant risk of MI

4. Still useful but in very selective cases

A correction has been published: N Engl J Med 2007;356(13):1387.

Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy

Steven E. Kahn, M.B., Ch.B., Steven M. Haffner, M.D., Mark A. Heise, Ph.D., William H. Herman, M.D., M.P.H., Rury R. Holman, F.R.C.P., Nigel P. Jones, M.A., Barbara G.

Kravitz, M.S., John M. Lachin, Sc.D., M. Colleen O'Neill, B.Sc., Bernard Zinman, M.D., F.R.C.P.C., Giancarlo Viberti, M.D., F.R.C.P., for the ADOPT Study Group

Volume 355:2427-2443      December 7, 2006      Number 23

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Wonder drug Wonder drug Approved Approved

prematurely prematurely Caused Caused

undue harm to undue harm to patientspatients

Rosen CRosen C

N EJM – Aug, 2007N EJM – Aug, 2007

Conclusion Conclusion RSG storyRSG story

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