New Studies Link Avandia to Heart Attacks
By Daniel J. DeNoon
WebMD Health News
Reviewed by Louise Chang, MD
Sept. 11, 2007 - New studies link the oral diabetes drug Avandia -- but not the related drug Actos -- to heart attacks.
One of the studies published in The Journal of the American Medial Association is a new analysis of data from Avandia clinical trials by Wake Forest University researcher Sonal Singh, MD, and colleagues.
Using stringent criteria for data selection -- one of the study authors helped write the international guidelines for analyzing side effect data from multiple studies -- the study showed that Avandia increases a diabetes patient's risk of heart attack by 42%.
"Regulatory agencies ought to re-evaluate whether [Avandia] should be allowed to remain on the market," Singh and colleagues conclude. "Health plans and physicians should not wait for regulatory actions. They should avoid using [Avandia] in patients with diabetes who are at risk of cardiovascular events, especially since safer drugs are available."
The 42% increase in heart attack risk seen in the Singh study is nearly the same as the 43% risk found in a controversial earlier analysis led by Cleveland Clinic cardiology chairman Steven Nissen, MD. Unlike the Nissen analysis, however, the new study does not link Avandia to a higher risk of heart death.
"It is absence of evidence, not evidence of absence of an effect on mortality," Singh tells WebMD. "But at least based on this information, we cannot say Avandia increases mortality."
GSK Disputes Avandia Findings
Avandia maker GlaxoSmithKline says the Singh team's conclusions "offer no new information on the safety of Avandia." In a statement, GSK notes that the stringent criteria used in the study results in the use of data from only four studies and "reflects a difference of only 11 events in 14,291 patients" between the Avandia group and a control group.
"On this limited meta-analysis, in the context of all the other evidence, we believe it is inappropriate for the author to advise doctors to disregard the FDA's advice -- which is to keep patients who are effectively controlling their diabetes on Avandia," the GSK statement says.
Singh says the FDA did not conduct a full risk-benefit analysis of Avandia and that its Avandia advisory panel did not evaluate the drug's full risk profile.
"The evidence confirms a significantly increased risk of heart attack with [Avandia] and a doubling in the risk of heart failure compared to other oral [blood sugar-reducing] agents," Singh tells WebMD. "We are waiting for clinical trial evidence suggesting that [Avandia] use leads to a reduction in the morbidity and mortality in patients with type 2 diabetes. Until such evidence becomes available, we stand by our statement that [Avandia] should not be used in diabetic patients at risk for cardiovascular events."
Clinical trials have not yet demonstrated a clear survival benefit or reduction in diabetes complications for patients taking Avandia. But they do show that Avandia helps people with diabetes control their blood sugar.
"We know from clinical studies that effective treatment of diabetes requires intensive, long-term, day-to-day control of blood sugar levels to reduce the risk of serious complications (such as blindness, kidney failure, limb amputation, nerve injury) and ultimately save lives," the GSK statement says. "Avandia is the most widely studied oral medication for type 2 diabetes, and is an important option for physicians who often need to prescribe several different diabetes medicines in combination to help their patients maintain blood sugar control."
Study: Actos Has Heart Attack-Stroke Benefit, Not Risk
The second JAMA study analyzes clinical trial data on Actos. It comes from Cleveland Clinic researchers A. Michael Lincoff, MD, and colleagues -- including Nissen.
The study shows that Actos does not increase risk of heart attack but instead reduces diabetes patients' risk of heart attack, stroke, and death by 18%.
"We can say with confidence that Actos not only does not have the risk seen with Avandia, but has a benefit beyond that," Lincoff tells WebMD. "I am a cardiologist, not a diabetologist. But if a drug of this class is thought to be a good drug for a diabetic patient, Actos has benefit beyond its blood sugar and insulin-resistance indications for reducing death and heart attack and stroke; all reduced about 20%."
An editorial accompanying the studies notes that the two drugs have "strikingly different" effects on heart attack risk. Editorialist Daniel H. Solomon, MD, PhD, is associate professor of medicine at Harvard Medical School and a rheumatologist in the division of pharmacoepidemiology at Brigham and Women's Hospital, Boston.
"While this is by no means definitive -- we don't absolutely know the two drugs are different -- there is increasing evidence the two agents produce different effects regarding [heart attack and stroke] complications. If one is thinking about taking one of these drugs, one should take this into account," Solomon tells WebMD.
GSK takes issue with the Lincoff study. The company notes that much of the data comes from a study funded by Actos maker Takeda Pharmaceuticals.
"No clinical head-to-head trial data specifically evaluates cardiovascular risk between Avandia and Actos; however, the head-to-head data that does exist, and the overwhelming majority of comparative observational data, show no significant differences in cardiovascular events," the GSK statement says. "Analyzed studies show no difference in the [heart attack and stroke] effects of Avandia versus other oral antidiabetic medicines, including Actos."
Lincoff says the new analysis offers new information on Actos.
"The previous study showed the reduction in heart attacks in a high-risk group of patients," he says. "This now includes patients at lower risk, without established risk of heart disease, and we saw the same results. There is the same benefit in all subgroups. All of the data points in the same direction. It is much more reassuring that these results are indicative of the real outcomes in patients."
Robert Spanheimer, MD, Takeda's senior medical director for diabetes, agrees that the Lincoff study strengthens the conclusions of the Takeda-funded study of Actos's heart-related effects.
"This information, combined with the [earlier] study, should give patients the confidence that Actos does not increase heart attack-related events or mortality," Spanheimer tells WebMD.
Actos, Avandia: New Drug Class, New Side Effects
Actos and Avandia are the two available members of a class of drugs called thiazolidinediones, TZDs, or PPAR agonists. They're also called glitazones, after the suffix used in the drugs' generic names.
The drugs activate an important chemical-signaling pathway that controls some of the body's most basic functions. That pathway has several signal boxes, called PPAR receptors. Nobody yet knows all of the things that happen when drugs activate PPAR receptors. But two things happen that are good for people with diabetes: The cells of the body become more sensitive to insulin, and blood sugar levels go down.
Bad things can happen, too. Rezulin, the first FDA-approved glitazone, was taken off the market after three years when it was linked to liver failure. Two similar drugs (called glitazars because they activate two different PPAR receptors) didn't make it through the testing process. Muraglitazar increased heart complications, and tesaglitazar harmed the kidneys.
"This PPAR system is pretty complicated. At this point we don't fully understand it," Solomon says. "I think that whenever a drug is on the market without a well-documented mechanism of action, unanticipated events occur."
Actos and Avandia both increase a patient's risk of heart failure.
In addition to these side effects, Singh notes that patients taking the drugs have an increased risk of bone fractures and increased risk of macular edema leading to blindness.
Takeda's Spanheimer does not dispute that these new adverse events are beginning to appear. He says the company is working hard to understand why they are occurring, when, and in which patients.
"What we are learning about macular edema and bone fractures is it has taken quite awhile -- over 8 million patients -- to see these side effects come out," he says. "You have to be concerned about long-term safety. Some of these side effects, when they appear, are not very strong signals of a drug effect, and it takes a long time for them to be manifest. With any new drug class, you have to look at it two ways -- and one way is we are starting to define the safety profile of this drug."
Lincoff says that from a cardiologist's perspective, the heart benefits of Actos outweigh the heart-failure hazard.
"In general, the heart failure related to these two drugs seems to be reversible -- it seems to be due not to damaging the heart, but to retaining fluid," he says. "But death, heart attack, and stroke are all irreversible. So the benefit of Actos outweighs all these risks from fluid retention."
Singh takes a less rosy view of both drugs.
"What should we tell patients? We look at diabetes control, and either switch them to diabetes drugs that do not have these risks, or switch them to insulin," he says. "I do not switch them from Avandia to Actos. Yes, Actos does not have this increased risk of heart attack. But it does increase risk of heart failure -- true, without increases in mortality -- but heart failure has consequences to patients."
Solomon notes that no drug is absolutely safe.
"Actos and Avandia are very potent at reducing blood sugar, and people with diabetes need something," he says.
Solomon argues for deep change in the FDA's drug approval process:
- Early safety concerns should trigger "strong and clear regulatory actions."
- As a condition of drug approval, manufacturers should commit to timely postmarketing surveillance studies or randomized clinical trials in high-risk patient groups not included in the earlier clinical efficacy studies.
- After several drugs are approved for an indication, new drugs must be approved based on solid clinical endpoints (reductions in disease or death) rather than on markers such as blood sugar levels.
- Continued marketing of a drug should hinge on whether that drug proves as safe and effective as it seemed when approved.
- The risk-benefit calculation for every drug should be clearly defined so that it is obvious when a drug's risks outweigh its benefits.
The Singh and Lincoff studies, and the Solomon editorial, appear in the Sept. 12 issue of the Journal of the American Medical Association.
SOURCES: Singh, S. Journal of the American Medical Association, Sept. 12, 2007; vol 298: pp 1189-1195. Lincoff, A.M. Journal of the American Medical Association, Sept. 12, 2007; vol 298: pp 1180-1188. Solomon, D.H. and Winkelmayer, W. Journal of the American Medical Association, Sept. 12, 2007; vol: 298 pp. 1216-1218. Sonal Singh, MD, assistant professor of medicine, Wake Forest University, Winston-Salem, N.C. A. Michael Lincoff, MD, vice chairman for research, department of cardiovascular medicine, Cleveland Clinic. Daniel H. Solomon, MD, PhD, associate professor of medicine, Harvard Medical School; rheumatologist, division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women's Hospital, Boston. Robert Spanheimer, MD, senior medical director for diabetes, Takeda Pharmaceuticals. Personal communication, GlaxoSmithKline.
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