Transcript The Rosiglitazone Storm

The Rosiglitazone storm
Nabil Isseh, MD
Damascus medical school
What is the Most Common Cause of
Death in People with Diabetes?
Mortality in People with Diabetes
Causes of Death
% of Deaths
50
40
30
20
10
0
Ischemic Other Diabetes Cancer Stroke Infection
heart heart
disease disease
Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.
Other
Why new recommendations ?
2006 consensus
IDF
EASD ADA
The Story of Rosiglitazone
Money
Medicine
Politics
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
Glitazones
Reduce
CVD in
diabetes?
The insulin resistance syndrome
and its components
Central/abdominal
obesity
Hypertension
Coronary
heart
disease
Dyslipidemia
Insulin
resistance
syndrome
Type 2 diabetes
Hyperinsulinemia
Microalbuminuria
Groop et al. Front Horm Res 1997; 22:131–156.
Glitazones: potential Impact on CVD Risk
Hyperglycemia
BP
HDL and sdLDL
PAI-1
TZD
IR
CRP
Microalbuminuria
Vascular reactivity
Atherosclerosis, CVD?
WHEN ALL HELL BROKE LOOSE!
N Engl J Med
Effect Of Rosiglitazone
on the risk
Of Myocardial
Infraction and Death
From
Cardiovascular Causes
23/5/2007
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A correction
has been published: N Engl J Med 2007;357(1):100.
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Volume 356:2457-2471
June 14, 2007
Number 24
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
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!
May 22 2007
Heart Attack Risk Seen in Drug for
Diabetes
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
Perspectives - Rosiglitazone and CVD
Science and Public Health
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
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 Events
Ischemic 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 Outcomes
RSG
n=2635
Placebo
N=2634
HR (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%)
ADA June Meeting 2007
1.33
(0.80-2.21)
0.27
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
RSG
Small
Trials
Control
Group
44/10285 22/6106
DREAM
15/2635
9/2634
ADOPT
27/1456
41/2895
Overall
ADA June Meeting 2007
Odds Ratio
1.45
(0.88-2.39)
1.65
(0.74-3.68)
1.33
(0.80-2.21)
1.43
(1.03-1.98)
P value
0.15
0.22
0.27
0.03
Meta - analysis : Cardiovascular Death
RSG
Control
Group
Small
Trials
25/6845
7/3980
DREAM
12/2635
10/2634
ADOPT
2/1456
5/2895
Overall
ADA June Meeting 2007
Odds Ratio
2.40
(1.17-4.91)
1.20
(0.52-2.78)
0.80
(0.17-3.86)
1.64
(0.98-2.74)
P value
0.15
0.67
0.78
0.06
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
FDA
Glaxo
RECORD
ADA June Meeting 2007
43%
40%
31%
11%
Some final thoughts
Nissen
• 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 CVD
Science and Public Policy
Rosiglitazone and CV disease
Does the RECORD study help?
Professor philip Home
Newcastle Diabetes Centre
Newcastle University UK
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Volume 357:28-38
July 5, 2007
Number 1
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
Nissen and Wolski Results
OR 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 analysis
Adjudicated 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
Ischaemic events over 12 months (% patients)
Rosiglitazone
n
Death/MI/stroke or
recurrent ischaemia
Death/MI/stroke
Death
MI
Stroke
Placebo
102
98
30.4
6.4
1.2
5.2
1.2
31.4
11.9
2.3
8.4
2.3
PPAR Study
Bhatt et al Am Heart J 2007
ADA June Meeting 2007
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Volume 357:64-66
July 5, 2007
Number 1
Next
Rosiglitazone and Cardiotoxicity — Weighing the Evidence
David M. Nathan, M.D
NEJM, June 5, 2007
The Jury
David 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.
2.
3.
4.
5.
6.
CHF
CHD
Taking Insulin
Taking Nitrate
Taking ACE – I
Taking Metformin
And RSG
• CHD
• CHF
• Insulin
• Nitrate
• CHD
• CHF
• Insulin
• Nitrate
What about
Pioglitazone?
Rosiglitazone vs Pioglitazone
Class effect ??
1.
2.
3.
4.
Lipids
PROactive
CHICAGO
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
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A correction has been published: N Engl J Med 2007;356(13):1387.
Volume 355:2427-2443
December 7, 2006
Number 23
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
Conclusion
RSG story
Wonder drug
Approved
prematurely
Caused undue
harm to patients
Rosen C
N EJM – Aug, 2007