Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
MarilynMann
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.
ABSTRACT
Background Rosiglitazone is widely used to treat patients with type 2
diabetes mellitus, but its effect on cardiovascular morbidity and
mortality has not been determined.
Methods We conducted searches of the published literature, the Web
site of the Food and Drug Administration, and a clinical-trials
registry maintained by the drug manufacturer (GlaxoSmithKline).
Criteria for inclusion in our meta-analysis included a study duration
of more than 24 weeks, the use of a randomized control group not
receiving rosiglitazone, and the availability of outcome data for
myocardial infarction and death from cardiovascular causes. Of 116
potentially relevant studies, 42 trials met the inclusion criteria. We
tabulated all occurrences of myocardial infarction and death from
cardiovascular causes.
Results Data were combined by means of a fixed-effects model. In the
42 trials, the mean age of the subjects was approximately 56 years,
and the mean baseline glycated hemoglobin level was approximately
8.2%. In the rosiglitazone group, as compared with the control group,
the odds ratio for myocardial infarction was 1.43 (95% confidence
interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death
from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06).
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.
Our study was limited by a lack of access to original source data,
which would have enabled time-to-event analysis. Despite these
limitations, patients and providers should consider the potential for
serious adverse cardiovascular effects of treatment with rosiglitazone
for type 2 diabetes.
* * *
Just posting this in case anyone is on this medication.
Marilyn
MarilynMann
Published at www.nejm.org May 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 from additional revisions to the drug-safety
legislation as it moves through the House of Representatives.
No potential conflict of interest relevant to this article was
reported.
* * *
This editorial is worth reading for its discussion of the use of
surrogate endpoints in the drug approval process, something that is
often discussed in this forum (see, e.g., Vytorin thread).
Marilyn
Andrew B. Chung, MD/PhD
amount to lose the VAT rather than take medications for this purpose.
Here is what is keeping folks from easily doing this:
http://groups.google.com/group/sci.med.cardiology/msg/891fbe3b18290e4f?
May GOD bless you.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets."
http://HeartMDPhD.com/Love/TheTruth
Andrew B. Chung, MD/PhD
amount to lose the VAT rather than take medications for this purpose.
Here is what is keeping folks from easily doing this:
http://groups.google.com/group/sci.med.cardiology/msg/891fbe3b18290e4f?
May GOD bless you.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets."
http://HeartMDPhD.com/Love/TheTruth
bigvince
> Editorial
> Published atwww.nejm.orgMay 21, 2007 (10.1056/NEJMe078099)
>
> 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
.
MarilynMann
entertaining Wall Street Journal article discussing how Dr. Nissen
found "a trove of study data" with a Google search and how
GlaxoSmithKline executives got wind of the impending publication of
his study and rushed to Cleveland to try to talk him out of it. What
is also interesting is that he asked Glaxo for the raw data but they
refused to provide it, although they offered to collaborate with him
if they could crunch the data themselves. Those terms were
understandably not acceptable to him. One has to wonder why Glaxo was
so nervous about giving him the data.
Rep. Henry Waxman plans to hold a hearing in early June and summon FDA
Commissioner Eschenbach, Glaxo CEO Jean-Pierre Garnier and Dr. Nissen.
If anyone wants to read the full WSJ article, give me your e-mail
address and I will e-mail it to you.
Marilyn
Andrew B. Chung, MD/PhD
<snip>
> 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."
This comment would also apply to the ASD philosophy of "test, test,
test..."
> 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."
This comment would apply to metformin, sulfonylureas, Byetta, and even
insulin...
... it remains wiser to lose the VAT, which is the main source of
inflammatory cytokines causing the vascular damage in all blood
vessels in type-2 diabetics.
May GOD bless you.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
tr...@is-better.com
> 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."
"This comment would also apply to the ASD philosophy of "test, test,
test...""
Proof if you please.
> 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."
"This comment would apply to metformin, sulfonylureas, Byetta, and even
insulin..."
Proof if you please.
"... it remains wiser to lose the VAT, which is the main source
ofinflammatory cytokines causing the vascular damage in all blood
vessels in type-2 diabetics."
Proof if you please.
Because in past you have completely lost creadibility in this area you
must provide research based support for your opinions. Recitation of
that opinion is no longer sufficient in the absence of proof.
Off hand I can think of several lines of research and logic which show
you are wrong on most of the above points of opinion..
God bless.
Andrew B. Chung, MD/PhD
sulfonylureas, Byetta, and even insulin will result in similar
conclusions.
It remains wiser to lose the VAT to cure the metabolic syndrome (MetS)
that is behind the vascular inflammation leading to increased CV risk:
http://HeartMDPhD.com/HolySpirit/overweight.asp
May GOD bless you.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
http://HeartMDPhD.com/Love/TheTruth
MarilynMann
hcrenewal.blogspot.com, quoting extensively from the WSJ article.
Marilyn
MarilynMann
Andrew B. Chung, MD/PhD
> FDA memo discussing Avandia heart risks:
>
> http://www.citizen.org/documents/AvandiaMemo.pdf
Heart failure risk is a different issue from the risk of MI.
May GOD continue to heal our hearts with HIS living water so that we
can love our neighbors a little more and LORD Jesus Christ a whole lot
more, dear neighbor Marilyn whom I love unconditionally.
MarilynMann
<ach...@emorycardiology.com> wrote:
> On May 23, 7:09 am, MarilynMann <m...@comcast.net> wrote:
>
> > FDA memo discussing Avandia heart risks:
>
> >http://www.citizen.org/documents/AvandiaMemo.pdf
>
> Heart failure risk is a different issue from the risk of MI.
>
You are absolutely right. I should have been more specific.
Marilyn
Andrew B. Chung, MD/PhD
> Andrew, in the Holy Spirit, boldly wrote:
> > On May 23, 7:09 am, MarilynMann <m...@comcast.net> wrote:
>
> > > FDA memo discussing Avandia heart risks:
>
> > >http://www.citizen.org/documents/AvandiaMemo.pdf
>
> > Heart failure risk is a different issue from the risk of MI.
>
> You are absolutely right.
That would not be me but LORD Jesus Christ.
> I should have been more specific.
We all fall short of HIS glory.
The brethren of LORD Jesus Christ are neither absolutely right nor
more special...
... we are simply forgiven:
http://www.interviewwithgod.com/forgiven/
May GOD bless you.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets."
http://HeartMDPhD.com/Love/TheTruth
Brindal
> On May 23, 7:09 am, MarilynMann <m...@comcast.net> wrote:
>
> > FDA memo discussing Avandia heart risks:
>
> >http://www.citizen.org/documents/AvandiaMemo.pdf
>
> Heart failure risk is a different issue from the risk of MI.
>
> May GOD continue to heal our hearts with HIS living water so that we
> can love our neighbors a little more and LORD Jesus Christ a whole lot
> more, dear neighbor Marilyn whom I love unconditionally.
Oh, please! Like prayer is going to be a subsitute for medical care.
"MD/PhD", huh? Where you get your degrees? The University of Total
Idiocy?"
Or maybe you're a time traveller from the Middle Ages.
Brindal
Brindal
>
> > FDA memo discussing Avandia heart risks:
>
> >http://www.citizen.org/documents/AvandiaMemo.pdf
>
> Heart failure risk is a different issue from the risk of MI.
>
> May GOD continue to heal our hearts with HIS living water so that we
> can love our neighbors a little more and LORD Jesus Christ a whole lot
> more, dear neighbor Marilyn whom I love unconditionally.
Oh, please! Like prayer is going to be a subsitute for medical care.
Brindal
>
> > FDA memo discussing Avandia heart risks:
>
> >http://www.citizen.org/documents/AvandiaMemo.pdf
>
> Heart failure risk is a different issue from the risk of MI.
>
> May GOD continue to heal our hearts with HIS living water so that we
> can love our neighbors a little more and LORD Jesus Christ a whole lot
> more, dear neighbor Marilyn whom I love unconditionally.
Oh, please! Like prayer is going to be a subsitute for medical care.
Andrew B. Chung, MD/PhD
> On 23 May 2007 04:09:51 -0700, MarilynMann <m...@comcast.net> wrote:
> > http://groups.google.com/group/sci.med.cardiology/msg/11fa16ed7eb336be?
>
> so much for not cross posting.
In truth, Marilyn crossposted this appropriately to ASD.
Similarly, it is my choice to add the other appropriate NGs.
You remain in my prayers, dear neighbor Mack whom I love
unconditionally.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
tr...@is-better.com
Similarly, it is my choice to add the other appropriate NGs."
It reminds me of the joke:
1st person, "you murdered your wife on may 22".
2nd person, "you are a liar, it was may 23".
In past andrew claimed not to crosspost, as above he claimed "it been
done by him/her". Soon he gave up even that frail excuse and crossposts
freely and often.
It appears an act of revenge. When he gets pushback for his special
notions in a group he makes it a point to crosspost there and to take
single posts from them and add crossposts.
In the diabetic groups the two pound diet got absolutely no traction and
he was asked to stop and not to post personal religious views. The
groups are treated as above.
It is the behavior of the school yard bully who suffers rejection when
there is no adult supervision and who says "you ain't gonna stop me".
James Michael Howard
Rosiglitazone reduces DHEA; this has been known since 2002. Low DHEA has
been connected with heart problems and it is my hypothesis that low DHEA is
involved in thrombosis / strokes. DHEA is low in type 2 diabetes.
I suggest this negative finding regarding rosiglitazone may result from
reductions in DHEA. This may be exacerbated in type 2 diabetes because of
already low DHEA.
James Michael Howard
Fayetteville, Arkansas
MarilynMann
controversy: http://multimedia.thelancet.com/pdf/rosiglitazone_editorial.pdf.
The unsigned editorial suggests that "the FDA, physicians, and
patients can reasonably await the results of RECORD, a phase III trial
designed specifically to study cardiovascular outcomes."
Asked to comment, Journal Watch Cardiology Editor-in-Chief Harlan M.
Krumholz wrote: "Why would you wait when Avandia has never been shown
to avert events or save lives? And now that there is evidence of
potential harm - and there are alternative meds - it seems to me that
the pressure is on the company to show that it is safe and effective."
Marilyn
William Wagner
MarilynMann <ma...@comcast.net> wrote:
Just an observation.
But it seems medicine as a business has eclipsed medicine as an art. I
find more info first in the Wall Street Journal than any where else
besides SMC :)).
So the question becomes what is of import return on investment or the
health of the people. I guess this is a call for a more socialized
human centered approach for fixing our ill's. Cause and remedies and
preventive issues need clarity need a champion.
Bill who wonders if Avandia user's will ever see "Why would you wait
when Avandia has never been shown to avert events or save lives? "
--
S Jersey USA Zone 5 Shade
http://www.ocutech.com/ High tech Vison aid
This article is posted under fair use rules in accordance with
Title 17 U.S.C. Section 107, and is strictly for the educational
and informative purposes. This material is distributed without profit.
Andrew B. Chung, MD/PhD
either.
It remains wiser to lose the visceral adipose tissue (VAT) to cure the
metabolic syndrome (MetS) that is the underlying cause of the excess
of cardiovascular events in type-2 diabetics.
May GOD bless you.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
http://HeartMDPhD.com/Love/TheTruth
MarilynMann
Avandia is in jeopardy because since Dr. Nissen's article patients
have been dropping out of the trial. Who can blame them?
MarilynMann
("Test of Drug for Diabetes in Jeopardy").
Andrew B. Chung, MD/PhD
All glucose lowering medications should be suspected of increasing
risk of acute coronary syndrome (ACS) in the possible manner of
Avandia until proven otherwise.
May GOD bless you in HIS mighty way making you hungrier than ever.
Jim Chinnis
>MarilynMann wrote:
>> Apparently the large clinical trial Glaxo has been conducting on
>> Avandia is in jeopardy because since Dr. Nissen's article patients
>> have been dropping out of the trial. Who can blame them?
>
>All glucose lowering medications should be suspected of increasing
>risk of acute coronary syndrome (ACS) in the possible manner of
>Avandia until proven otherwise.
There are multiple *classes* of glucose lowering medications, including
insulin-sensitizing agents, insulin and its cousins, and those that provoke
increaed insulin production. Avandia belongs to one class within the set of
insulin-sensitizing agents.
Perhaps you are referring only to the insulin-sensitizing agents (which
would include metformin!) or ony to the insulin sensitizing agents similar
in mechanism to Avandia.
--
Jim Chinnis Warrenton, Virginia, USA
Andrew B. Chung, MD/PhD
> Andrew, in the Holy Spirit, boldly wrote:
> >> Apparently the large clinical trial Glaxo has been conducting on
> >> Avandia is in jeopardy because since Dr. Nissen's article patients
> >> have been dropping out of the trial. Who can blame them?
> >
> >All glucose lowering medications should be suspected of increasing
> >risk of acute coronary syndrome (ACS) in the possible manner of
> >Avandia until proven otherwise.
>
> There are multiple *classes* of glucose lowering medications, including
> insulin-sensitizing agents, insulin and its cousins, and those that provoke
> increaed insulin production. Avandia belongs to one class within the set of
> insulin-sensitizing agents.
>
> Perhaps you are referring only to the insulin-sensitizing agents (which
> would include metformin!) or ony to the insulin sensitizing agents similar
> in mechanism to Avandia.
With the understanding that all classes of glucose lowering
medications will lead to episodes of higher sympathetic tone to
compensate for those hypoglycemic events that inevitably occur, all
classes of glucose lowering medications have the potential for
increasing risk of ACS in the manner suspected for Avandia.
May GOD bless you in HIS mighty way making your hungrier than ever.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets."
http://HeartMDPhD.com/Love/TheTruth
Jim Chinnis
>Jim Chinnis wrote:
>> Andrew, in the Holy Spirit, boldly wrote:
>> >MarilynMann wrote:
>> >> Apparently the large clinical trial Glaxo has been conducting on
>> >> Avandia is in jeopardy because since Dr. Nissen's article patients
>> >> have been dropping out of the trial. Who can blame them?
>> >
>> >All glucose lowering medications should be suspected of increasing
>> >risk of acute coronary syndrome (ACS) in the possible manner of
>> >Avandia until proven otherwise.
>>
>> There are multiple *classes* of glucose lowering medications, including
>> insulin-sensitizing agents, insulin and its cousins, and those that provoke
>> increaed insulin production. Avandia belongs to one class within the set of
>> insulin-sensitizing agents.
>>
>> Perhaps you are referring only to the insulin-sensitizing agents (which
>> would include metformin!) or ony to the insulin sensitizing agents similar
>> in mechanism to Avandia.
>
>With the understanding that all classes of glucose lowering
>medications will lead to episodes of higher sympathetic tone to
>compensate for those hypoglycemic events that inevitably occur, all
>classes of glucose lowering medications have the potential for
>increasing risk of ACS in the manner suspected for Avandia.
Statistically, yes. Individuals who maintain tight bg control without
"inevitable" hypoglycemic events should not exhibit increased cardiac risk,
however. Such individuals would include many who treat bg levels primarily
with weight loss, diet, and exercise. Using an insulin-sensitizing agent in
carefully monitored doses shouldn't increase cardiac risks, but should lower
them due to the improvement in bg control.
Some DM diabetics require insulin. It's not reasonable to argue that insulin
increases their risk of cardiac problems. They are likely to die without it,
quite possibly via cardiac causes. There are tradeoffs.
Andrew B. Chung, MD/PhD
What we are witnessing with Avandia is likely a manifestation of these
latter tradeoffs.
May GOD bless you in HIS mighty way making you hungrier than ever.
MarilynMann
Administration to exclude scientists with conflicts of interest from a
panel that later this year will reconsider Avandia's safety. "By
staffing the Avandia advisory committee with scientists from diverse
specialties who are non-conflicted, you will send a message that the
FDA cares about avoiding conflicts of interest and evaluating drugs on
the basis of unbiased scientific findings," the groups said in a
letter to FDA commissioner Andrew von Eschenbach. Signers included the
Center for Science in the Public Interest (Merrill Goozner), Consumers
Union, the Union of Concerned Scientists and six other consumer
groups.
http://cspinet.org/new/pdf/avandia_panel_letter.pdf
Full disclosure: my daughter goes to school and is friends with the
daughters of Mike Jacobson and Bonnie Liebman of CSPI.
Marilyn
MarilynMann
>
> Partial disclosure: My uncritical acceptance of the crappy
> misinterpretaions and skewed science CSPI promotes led to a severe
> decline in my health years ago that immediately reversed once I started
> eating exactly opposite their recommendations.
>
My sympathies. They do tend to oversimplify things.
Andrew B. Chung, MD/PhD
> misinterpretaions and skewed science CSPI promotes led to a severe
> decline in my health years ago that immediately reversed once I started
> eating exactly opposite their recommendations.
Whether a particular diet is right for you will depend on your unique
physiology.
When there is a decrease in appetite, that would be the earliest
indication that a particular diet is wrong for you.
bigvince
Cardiology Editor-in-Chief Harlan M.
Krumholz wrote: "Why would you wait when Avandia has never been shown
to avert events or save lives? And now that there is evidence of
potential harm - and there are alternative meds - it seems to me that
the pressure is on the company to show that it is safe and effective"
.... Why wait indeed when the evidence to now is clear; the FDA
has confirmed Dr. Nissens work.. That the FDA has chosen to wait
shows how broken the system is. It is however not surprising the FDA
has Known about this for several years and has not acted until now.
According to the group Public Citizen an internal FDA memo showed that
staff was concerned about reports of heart failure and recommended
changed s to the label reflecting that fact.It appears that the FDA
never acted. Source: Letter Demonstrating that the FDA Knew About
Avandia Dangers, Urging
Action (HRG Publication #1812) May 22 2007 link
http://www.citizen.org/publications/release.cfm?ID=7523 . The
importance of the committee the FDA selects having no financial ties
to the drug manufactures cannot be overstated,The link you cited
talked about that fact. It is important for public trust that neutral
experts examine the evidence. From " FDA painkiller panel
advisers linked to pharmaceutical firms
10 members worked as paid consultants story published
Gardiner Harris, Alex Berenson, New York Times" Feb 25 2005
Ten of the 32 government drug advisers who last week endorsed
continued marketing of the huge-selling pain pills Celebrex, Bextra
and Vioxx have consulted in recent years for the drugs' makers,
according to disclosures in medical journals and other public records.
If the 10 advisers had not voted, the committee would have voted
12-8 that Bextra should be withdrawn and 14-8 that Vioxx should not
return to the market. The 10 advisers with company ties voted 9-1 to
keep Bextra on the market and 9-1 for Vioxx's return. link
http://sfgate.com/cgi-bin/article.cgi?f=/c/a/2005/02/25/MNGJTBGQ7H1.DTL
publish in the SF Chronical 2/25/05
Thanks Vince
Andrew B. Chung, MD/PhD
cure."
The cure for type-2 diabetes possibly happens when someone loses their
visceral adipose tissue (VAT) when they eat less down to the right
amount:
http://HeartMDPhD.com/HolySpirit/overweight.asp
May GOD bless you in HIS mighty way making you hungrier than ever.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://EmoryCardiology.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
http://HeartMDPhD.com/Love/TheTruth
MarilynMann
in a letter published on The Lancet's web site (www.thelancet.com).
He argues that in ADOPT major cardiovascular events were rare and
heart risks were similar to those of two other diabetes drugs. He
also said DREAM showed "no significant difference" in cardiovascular
events between drug and placebo. Dr. Nissen criticized the letter,
saying Glaxo was referring to such small subsets of data in DREAM and
ADOPT that no firm conclusion could be drawn. "Somebody went back and
looked for something that would support their contention," Dr. Nissen
said. "This is not a scientifically proper way to analyze data."
Marilyn
bigvince
When you read the data and this is the best that Glaxo could find.
rosiglitazone compared to placebo. No difference. Ramipril plus
placebo compared to Ramipril plus rosiglitazome. Many fewer events in
the Ramipril alone group a fact that is characterised as '
unexplained'. No where do I see any evidence of benefit. . Thanks Vince
tellynut
York Times article on how Glaxo tried to intimidate Dr. John Buse when
he raised concerns several years ago about Avandia's cardiovascular
risks, wth a link to Dr. Buse's statement.
http://www.nytimes.com/2007/06/02/business/02drug.html?ref=health
Marilyn
MarilynMann
GlaxoSmithKline has £9.8bn wiped off its market value
An American medical journal will this week publish a major study that
GlaxoSmithKline says will back up its fierce defence of Avandia, its
diabetes treatment whose safety has been called into question.
The results of the GSK-commissioned study of 30,000 diabetes patients
in a real-world setting, to be published as soon as tomorrow, is
expected to show that Avandia has a safety profile similar to rival
treatments. The FTSE 100 drug giant hopes that will mean a reprieve
after a horrid two weeks, in which it has seen 11.8 per cent of its
market value, or £9.8bn, wiped away.
The identity of the American publication was being closely guarded
this weekend because of fears that it would be inundated with calls if
it was revealed. The public interest in the case is high. Avandia was
approved by the US Food and Drug administration in 1999 and is taken
by thousands of patients. Last year it generated £1.6bn in sales.
Its safety has come into doubt since The New England Journal of
Medicine published a study on 21 May that said that Avandia users were
at greater risk of heart attack. Steven Nissen, the chairman of
cardiovascular medicine of the Cleveland Clinic in Ohio, found that
Avandia users were 43 per cent more likely to suffer a heart attack
and 64 per cent more likely to die due to heart complications. Dr
Nissen admitted that his meta-analysis was not comprehensive and
required further study. GSK has fiercely defended the drug. Ronald
Krall, GSK's chief medical officer, published a letter last week in
The Lancet citing other studies that he argued proved its safety.
Investors fear that the company will have to pay out billions in
damages and that sales of its second-best-selling drug will
drastically decline. The FDA said it will assemble a group of experts
to review the drug.
* * *
A "real-world setting"?
Marilyn
MarilynMann
> diabetes treatment whose safety has been called into question.
>
The mystery journal is the New England Journal of Medicine, www.nejm.com.
Marilyn
MarilynMann
Thanks, Marilyn
MarilynMann
a hearing today on the FDA's role in approving Avandia. Go to
http://oversight.house.gov/story.asp?ID=1325 for links to the
testimony by a number of witnesses, including Dr. Buse, Dr. Nissen and
Commissioner von Eschenbach.
Marilyn
David Rind
> What is a "noninferiority trial"?
>
> Thanks, Marilyn
This is actually a fairly complex biostatistical issue that I doubt I
can adequately explain here, but I'll make a brief attempt.
Most studies (superiority trials) set about to prove that a new
treatment is better than an old treatment or no treatment. The default
hypothesis (null hypothesis) is that the new treatment is not better
than the old treatment. Unless a test shows statistical significance,
the new treatment is not considered to have proven itself superior to
the old treatment.
A noninferiority trial sets out to prove that a new treatment is at
least as good as an old treatment. The default hypothesis is that the
new treatment is worse than the old treatment, and specific confidence
interval bounds are set that the new treatment has to exceed to pass the
test that it is not worse than the old treatment.
Placebo controlled trials are always superiority trials. Some trials
comparing a new therapy to an old therapy are conducted as
noninferiority trials. A noninferiority trial typically requires more
patients than a superiority trial, and is a good choice when the
comparator is an old therapy that has been well proven to work. It's a
less good option when the old therapy is of uncertain benefit.
So, for instance, showing that rosiglitazone is not inferior to
metformin/glyburide with regard to CHD outcomes is not necessarily
adequate because there is some evidence that metformin/glyburide may,
itself, cause harmful CHD outcomes. It would be a more believable trial
design if metformin/glyburide had previously been well proven to reduce
CHD events.
--
David Rind
dr...@caregroup.harvard.edu
MarilynMann
MarilynMann
hcrenewal.blogspot.com) comparing a June 18 editorial in the Wall
Street Journal on the Avandia controversy with an article that
appeared in BMJ two days earlier (See Kazi D. Rosiglitazone and
implications for pharmacovigilance: postsurveillance data should be
systematically collected and publicly available. Brit Med J 2007; 334:
1233-4).
Marilyn
MarilynMann
The Lancet 2007; 369:2077
Correspondence
Data and safety monitoring of rosiglitazone trials
Elizabeth G Nabel a, Susan B Shurin a, Denise G Simons-Morton a
and David Gordon a
We write in response to the Correspondence about rosiglitazone from
Ronald Krall of GlaxoSmithKline (June 16, p 1995).1 We would like to
clarify the process of review by the ACCORD and BARI 2D data and
safety monitoring boards (DSMBs) and to correct a possible
misinterpretation. Since these trials began, the DSMBs of both ACCORD
and BARI 2D have carefully monitored the safety of all study
participants, and past DSMB reviews have recommended continuation of
both studies to the US National Heart, Lung, and Blood Institute
(NHLBI).
The NHLBI and the ACCORD and BARI 2D DSMBs are currently reviewing the
ACCORD and BARI 2D data in light of the study by Nissen and Wolski in
the New England Journal of Medicine.2 These discussions and reviews
are ongoing, and the confidential deliberations have not been shared
with outside individuals, as is standard practice for all clinical
trial DSMB reviews. The NHLBI will provide feedback to the study
participants and institutional review boards after this review.
We declare that we have no conflict of interest.
References
1. Krall RL. Cardiovascular safety of rosiglitazone. Lancet 2007; 369:
1995.
2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes. N Engl J
Med 2007; 356: 2457-2471.
Affiliations
a. National Heart, Lung, and Blood Institute, Building 31, Room 5A48,
31 Center Drive MSC 2486, Bethesda, MD 20892, USA
MarilynMann
MarilynMann
http://www.nytimes.com/2007/07/27/health/27avandia.html?_r=1&ref=health&oref=slogin
MarilynMann
http://care.diabetesjournals.org/cgi/content/abstract/30/8/2148
MarilynMann
Another Avandia Mystery: Actos Data
Posted by Anna Wilde Mathews
Call it the case of the reappearing Actos data.
This June, when the medical journal Pharmacoepidemiology and Drug
Safety published a study on the heart safety of GlaxoSmithKline's
diabetes drug Avandia, or rosiglitazone, there was something missing.
People taking Avandia's rival Actos, or pioglitazone, from Japan's
Takeda Pharmaceutical, didn't show up in the analysis.
Today a group of experts will convene outside Washington to advise FDA
what to do with Avandia in light of the possible risk it carries for
heart attacks. The availability of Actos, an alternative that so far
hasn't been fingered for the same side effect, may play a role in the
committee's and the agency's calculations.
Without the Actos patients, the Glaxo analysis looked pretty good for
Avandia. The authors, who were affiliated with Glaxo and its
contractor i3 Drug Safety, a UnitedHealth Group unit, wrote that the
results suggested the risk of cardiovascular problems in people taking
Avandia fell between the risks tied to two older types of drugs, the
sulfonylureas and metformin.
The Glaxo study of Avandia was published soon after the New England
Journal of Medicine ran Cleveland Clinic cardiologist Steven Nissen's
analysis tying the drug to a potential heart-attack risk.
The Glaxo study's authors noted briefly in their paper that because of
"very low usage" of Actos in the Ingenix Research Database during the
study period (2000 to 2004) data on the drug weren't included. But,
according to editors of Pharmacoepidemiology and Drug Safety, someone
else managed to find enough Actos users in the Ingenix database:
Takeda.
In a clarification that will run in the journal, the editors say that
they have recently accepted another study performed in the Ingenix
Research Database, this one sponsored and authored by employees of
Takeda.
In the Takeda analysis, the editors write, the numbers of users of
Avandia and Actos "were extremely close to one another." The editors
note that this "appeared inconsistent" with the statement in the paper
from i3 and Glaxo. Moreover, they write, the Takeda employees' study
say Actos was associated with a lower risk of heart attacks than
Avandia.
In a letter that will appear with the clarification, two of the i3
employees who helped author the Glaxo analysis explain why they left
out Actos, even after an editor of the journal asked for it to be
added. During the time span they examined, there were fewer Actos
users than Avandia users, they wrote, and including Actos would have
diminished the statistical power of the analysis. They have compared
Actos and Avandia using a different database, PharMetrics. Those
results, which Glaxo submitted to a Food and Drug Administration
advisory committee, showed the two drugs with approximately equal
heart safety.
But, the i3 authors write, they now believe that because of increasing
use of Actos, "the constraints would not have been as large as we
imagined" in the Ingenix database. So they're doing a new Glaxo-
approved study in that same database that will include Actos.
The results of the Takeda study may come out Monday. Brian Strom, an
editor for Pharmacoepidemiology and Drug Safety and a professor at the
University of Pennsylvania, says the journal has given the authors
permission to discuss their findings at today's meeting. (Dr. Strom
discloses that he and a co-editor have both been consultants for Glaxo
and Takeda, and are currently funded by Takeda for a study of Actos on
a different issue. Dr. Strom also submitted testimony to a
congressional committee critiquing Dr. Nissen's analysis.)
A spokeswoman for Takeda declined to comment. A spokeswoman for Glaxo
said that "our understanding was that there wasn't enough data on
pioglitazone to do that analysis" in the Ingenix database. She says
Glaxo commissioned the newer analysis comparing the two drugs in the
PharMetrics database. A spokeswoman for i3 couldn't be reached for
comment on Sunday.
Marilyn
MarilynMann
http://www.nytimes.com/aponline/us/AP-Diabetes-Drug.html?_r=1&oref=slogin
MarilynMann
http://www.nytimes.com/2007/07/30/health/30cnd-avandia.html?_r=1&hp&oref=slogin
MarilynMann
MarilynMann
MarilynMann
A Meta-analysis
Sonal Singh, MD; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD
JAMA. 2007;298:1189-1195.
Context Recent reports of serious adverse events with rosiglitazone
use have raised questions about whether the evidence of harm justifies
its use for treatment of type 2 diabetes.
Objective To systematically review the long-term cardiovascular risks
of rosiglitazone, including myocardial infarction, heart failure, and
cardiovascular mortality.
Data Sources We searched MEDLINE, the GlaxoSmithKline clinical trials
register, the US Food and Drug Administration Web site, and product
information sheets for randomized controlled trials, systematic
reviews, and meta-analyses published in English through May 2007.
Study Selection Studies were selected for inclusion if they were
randomized controlled trials of rosiglitazone for prevention or
treatment of type 2 diabetes, had at least 12 months of follow-up, and
monitored cardiovascular adverse events and provided numerical data on
all adverse events. Four studies were included after detailed
screening of 140 trials for cardiovascular events.
Data Extraction Relative risks (RRs) of myocardial infarction, heart
failure, and cardiovascular mortality were estimated using a fixed-
effects meta-analysis of 4 randomized controlled trials (n = 14 291,
including 6421 receiving rosiglitazone and 7870 receiving control
therapy, with a duration of follow-up of 1-4 years).
Results Rosiglitazone significantly increased the risk of myocardial
infarction (n = 94/6421 vs 83/7870; RR, 1.42; 95% confidence interval
[CI], 1.06-1.91; P = .02) and heart failure (n = 102/6421 vs 62/7870;
RR, 2.09; 95% CI, 1.52-2.88; P < .001) without a significant increase
in risk of cardiovascular mortality (n = 59/6421 vs 72/7870; RR, 0.90;
95% CI, 0.63-1.26; P = .53). There was no evidence of substantial
heterogeneity among the trials for these end points (I2 = 0% for
myocardial infarction, 18% for heart failure, and 0% for
cardiovascular mortality).
Conclusion Among patients with impaired glucose tolerance or type 2
diabetes, rosiglitazone use for at least 12 months is associated with
a significantly increased risk of myocardial infarction and heart
failure, without a significantly increased risk of cardiovascular
mortality.
Author Affiliations: Department of Medicine (Dr Singh) and Division of
Public Health Sciences (Dr Furberg), Wake Forest University School of
Medicine, Winston-Salem, North Carolina; and School of Medicine,
Health Policy and Practice, University of East Anglia, Norwich,
England (Dr Loke).