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

On May 22, 7:12 am, MarilynMann <m...@xxxxxxxxxxx> wrote:
Editorial
Published atwww.nejm.orgMay 21, 2007 (10.1056/NEJMe078099)

Rosiglitazone and Cardiovascular Risk

Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D.

In this issue of the Journal, Nissen and Wolski1 report the results of
a meta-analysis of treatment trials of rosiglitazone, as compared
either with other therapies for type 2 diabetes or with placebo.
Eligible studies included randomized trials that lasted for at least
24 weeks. The prespecified primary end points of interest were
myocardial infarction and death from cardiovascular causes. The
authors identified 42 eligible studies, many of which were small or
short-term trials, that included a total of 158 myocardial infarctions
and 61 deaths from cardiovascular causes. They used the Peto method to
combine data from the trials. In this meta-analysis, rosiglitazone was
associated with a significant increase in the risk of myocardial
infarction (odds ratio, 1.43; 95% confidence interval [CI], 1.03 to
1.98; P=0.03) and a borderline-significant finding for death from
cardiovascular causes (odds ratio, 1.64; 95% CI, 0.98 to 2.74;
P=0.06).
The meta-analysis has a number of strengths. Among these were the
effort to include unpublished studies, the prespecified analysis plan,
the use of major cardiovascular events as the primary outcome, and an
analysis in which rosiglitazone was compared with placebo. In the
latter analysis, the odds ratio for myocardial infarction was 1.80
(95% CI, 0.95 to 3.39; P=0.07), and the odds ratio for death from
cardiovascular causes was 1.22 (0.64 to 2.34; P=0.55).

The study also has a number of weaknesses. Only summary trial-level
data (rather than patient-level data) were available, so it was not
possible to conduct time-to-event analyses or to evaluate the time
course of risks. Data were not adequate to conduct dose-response
analyses. The eligible trials included both placebo and active-
treatment control groups. Across the trials, there was no standard
method for identifying or validating outcomes; events in eligible or
ineligible trials may have been missed or misclassified. The total
number of events was relatively small, with the result that there was
little or no power to detect potential differences among the trials if
they were present. Although, in general, these limitations are likely
to move estimated odds ratios toward the null, the weaknesses, which
are largely related to the quality of the available data, are
nonetheless substantial. A few events either way might have changed
the findings for myocardial infarction or for death from
cardiovascular causes. In this setting, the possibility that the
findings were due to chance cannot be excluded. In their discussion,
the authors properly emphasize the fragility of their findings.

Rosiglitazone, a thiazolidinedione, is an agonist of peroxisome-
proliferator-activated receptors (PPARs), primarily receptors, in the
cell nucleus.2 These ligand-activated nuclear transcription factors
activate the transcription of genes that affect glucose and lipid
metabolism.3 Rosiglitazone increases hepatic and peripheral insulin
sensitivity4 and reverses insulin resistance, a prominent feature of
type 2 diabetes.2 Approved in 1999 for the treatment of hyperglycemia
in type 2 diabetes, rosiglitazone has been shown in small, short-term
trials to reduce levels of fasting glucose and glycated hemoglobin.2
At usual doses, the thiazolidinediones decrease glycated hemoglobin
levels by an average of about 1 percentage point or less, but they are
also associated with increases in body weight, adverse effects on
lipids, fluid retention, and anemia.2 The product label for
rosiglitazone, which summarizes the results of randomized trials
lasting 26 weeks, lists many of these adverse effects in the section
on warnings.

The thiazolidinediones represent an interesting and potentially
important class of drugs. The current epidemic of obesity in the
United States has spawned an epidemic of type 2 diabetes, with 1.5
million new cases per year.5 The complications of diabetes, both
microvascular and macrovascular disease, are directly related to
levels of fasting glucose and glycated hemoglobin. Even in older
adults, elevated levels of fasting glucose are directly and strongly
associated with major cardiovascular events, and the attributable risk
of an elevated glucose level is second only to elevated systolic blood
pressure in this population.6 In patients with type 1 diabetes,
intensive insulin treatment is associated with a reduced risk of
cardiovascular events.7 A treatment that simultaneously reduces
insulin resistance, improves glycemic control, and decreases the risk
of cardiovascular events would be a major therapeutic advance for type
2 diabetes.

On the basis of this meta-analysis, however, the possibility of
cardiovascular benefit associated with the use of rosiglitazone seems
remote. We are not aware of data showing that rosiglitazone prevents
microvascular disease. In view of the potential cardiovascular risks
and in the absence of evidence of other health advantages, except for
laboratory measures of glycemic control, the rationale for prescribing
rosiglitazone at this time is unclear. Unless new data provide a
different picture of the risk-benefit profile, regulatory action by
the Food and Drug Administration (FDA) is now warranted. If patients
using rosiglitazone are concerned about the findings of this meta-
analysis, they should discuss them with their physicians and not
unilaterally stop taking the medication. Ongoing trials using
rosiglitazone may provide important new data, but for a drug approved
in 1999, the delay in obtaining information about health outcomes has
already been considerable.

During the market life of rosiglitazone, tens of millions of
prescriptions for the drug have been written for patients with type 2
diabetes. Insofar as the findings of Nissen and Wolski represent a
valid estimate of the risk of cardiovascular events, rosiglitazone
represents a major failure of the drug-use and drug-approval processes
in the United States.

Physicians who chose to prescribe rosiglitazone perhaps focused on the
single dimension of glycemic control. The underlying assumption
represents a kind of linear "physiological" argument: high levels of
glycated hemoglobin increase risk, so a reduction in glycated
hemoglobin will automatically translate into improved health outcomes
for patients. This perspective ignores the many actions of the genes
activated by PPAR- agonists, only some of which are currently known.
Many physicians did not require proof of health benefits as a
criterion for selecting rosiglitazone as a therapy for type 2
diabetes.

Had practicing physicians required this higher standard, they would
have been at a loss for evidence from large, long-term trials.
Rosiglitazone was approved on the basis of short-term studies of the
surrogate end point of glycemic control. The use of surrogate end
points in the drug-approval process has been problematic.8
Muraglitazar, another PPAR agonist,9 and torcetrapib, a cholesteryl
ester transfer protein inhibitor that raises levels of high-density
lipoprotein cholesterol,10 are two recent examples. Indeed, at the
time of approval of rosiglitazone, the evidence from 26-week studies
of expected health benefits was at best mixed. For a lifelong
condition such as diabetes, how do the risks of weight gain, edema,
and adverse changes in lipids play out against the benefits of
improved glycemic control? For a drug that activates a large set of
genes, what is the overall balance of risks and benefits? Rofecoxib,
whose biologic actions early on suggested the possibility of both
gastrointestinal benefit and cardiovascular harm,11 represented a
similar regulatory failure to insist on large trials of public health
importance in a timely fashion.12

The current approach to drug approval involves an intensive, high-
quality evaluation in the preapproval setting. For many sponsors,
approval marks the transition from research to marketing.13 The FDA's
Adverse Event Reporting System is not capable of discerning the risk
of events as common as coronary disease. The FDA frequently requires
phase 4 trials to address some of the unanswered efficacy or safety
questions at the time of approval. But sponsors propose the designs,
which sometimes compare their products with inferior treatments or
doses.14 During the period from 1998 through 2003, only about a
quarter of the required phase 4 trials were completed,15 and as of
September 30, 2006, a total of 899 phase 4 studies remain pending.16
This desultory approach to postmarketing studies necessarily leads to
an incomplete evaluation in the postapproval setting. If the FDA
approves a drug on the basis of surrogate end points for the long-term
treatment of conditions such as diabetes, large, long-term, randomized
clinical trials, completed as soon as possible after approval, are
essential to identify the health benefits and risks associated with
treatment. In the long run, this approach is likely to be in the
interests of sponsors, the FDA, and the health of the public.

On May 10, 2007, the Senate passed the Food and Drug Administration
Revitalization Act.17 Although the Senate bill has many strengths,
including the allocation of new authority to the FDA, none of its
provisions would necessarily have identified the cardiovascular risks
of rofecoxib or rosiglitazone in a timely fashion. One section of the
bill (title II, subtitle A) focuses largely on the mitigation of known
risks at the time of approval. In contrast, a true life-cycle
approach, as advocated by the Institute of Medicine,18 would continue
the evaluation of both efficacy and safety after approval, convert
surrogate end points into clinically meaningful outcomes,19 integrate
new information about health benefits and risks, and communicate those
findings effectively to patients and physicians. The health of the
public would benefit ...

read more »

This article again shows that when drugs are aimed at surrogate
targets they may well have dire results. Recently several "proven
therapy's " have been shown to actually increase mortality. Think of
it you go to the Doctor who follows proper protocols and his treatment
increases your chance of dying or having some other serious event.
Something is radically wrong with that system. I recommend people read
and reread thatNEJM editorial. From Medpage today
article....."Meta-Analysis Links Rosiglitazone (Avandia) to Risk of
Myocardial Infarction" May 21'2007 ...CLEVELAND, May 21 --" A
meta-analysis of data from 42 clinical trials found a 43% increase in
relative risk of myocardial infarction among type 2 diabetics treated
with rosiglitazone (Avandia)." while several including the manufatuer
question the conclusions of the study Dr. Nissen of the Cleaveland
clinic from the article.... " Dr. Nissen said the was confident that
the conclusions would stand up to close scrutiny, especially because
he said that an analysis based on published data is more likely to
underestimate event risk." he discussed the use of surrogates by the
FDA..........".The FDA uses sustained reduction in blood glucose as a
marker of efficacy, but Dr. Nissen said a better test of drugs for
diabetes would be "a drug's abilities to reduce the complications of
diabetes-such as cardiovascular death."


Reducing serum glucose, he said, may address microvascular damage seen
with diabetes "but it doesn't affect macrovascular damage, which, of
course, is the case with MI."


He noted that in 2005 he reported that an investigational drug in the
same class as rosiglitazone -- muraglitazar (Pargluva) -- doubled the
risk of death, heart attack, and stroke. That report came just weeks
after an FDA advisory panel had overwhelmingly recommended that the
drug be approved.
full story.......http://www.medpagetoday.com/Endocrinology/Diabetes/tb/
5701
Thanks Vince
..

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