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An insulin-sensitizer commonly prescribed to patients with type 2 diabetes also reduces the combined risk of heart attack, stroke, and death by 16% in those with a history of heart disease, according to results of the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive).
Previously, pioglitazone (Actos, Takeda/Lilly) has been shown to improve HDL and triglyceride levels1 and to decrease carotid artery wall (intima-media) thickness.2 But PROactive marks the first time an oral glucose-lowering agent has been shown to reduce cardiovascular events and death in a prospective study, according to study chairman John Dormandy, MD, professor of vascular sciences at St. George's Hospital, University of London.
Dormandy presented the data September 12 at the 41st Annual Meeting of the European Association for the Study of Diabetes in Athens, Greece. Study results also were published in the October 8 issue of The Lancet.3 Takeda Pharmaceuticals and Eli Lilly sponsored the research.
The PROactive study took place at centers in 19 countries and included 5,238 patients with type 2 diabetes and evidence of heart disease (meaning a prior major event). Patients were 35–75 years of age, with an average glycated hemoglobin (A1C) >6.5% and a median diabetes duration of 8 years. Sixty percent were smokers, and 25% had neuropathy, 15% nephropathy, and 3% retinopathy.
Investigators were encouraged to optimize use of all other medications, such as statins, aspirin, antihypertensive drugs, and antidiabetic drugs, while subjects were randomized to pioglitazone (titrated up to the maximum allowed dosage of 45 mg) or placebo. Average treatment was 3 years, and the study followed subjects for 175,242 patient-months.
The primary end point, any one of a group of manifestations of cardiovascular disease—death, nonfatal heart attack, stroke, leg amputation, acute coronary syndrome, coronary bypass, or leg artery bypass—occurred in 21% of patients on pioglitazone, compared with 25.5% of the patients on placebo. Pioglitazone's total risk reduction of 10% was not considered statistically significant. The study was powered to show a 20% reduction in the composite of primary end-point events.
However, the principal secondary end point, a combination of the three "most important" cardiovascular events—death, nonfatal heart attack, and stroke—occurred in 12.3% of pioglitazone-treated patients and 14.4% of placebo-treated patients, revealing a statistically significant 16% reduction in these high-risk diabetic patients.
Pioglitazone also was found to reduce A1C by 0.5% more than placebo; increase HDL cholesterol by 19%, compared with a 9% increase with placebo; reduce triglycerides by 11%, compared with a 2% decrease with placebo; and lower blood pressure by a median of 3 mmHg more than placebo.
More than 7 million patients have been treated with pioglitazone since 1999, with approximately 50 million prescriptions, Dormandy says, and the PROactive study "showed no new safety concerns."
But rates of heart failure and edema did raise red flags for some.
CAUSE FOR CONCERN?
Pioglitazone's known side effects, including weight gain, edema, nonserious hypoglycemia, and heart failure, occurred more frequently in the pioglitazone group than in the placebo group, according to Pierre Lefebvre, MD, of the University of Liege in Belgium, who presented the safety data.
Patients on pioglitazone gained a mean 3.6 kg (7.9 lb) in weight. Edema was seen without heart failure in 21.6% of pioglitazone patients and 13% of placebo patients. Heart failure occurred in 10.8% of the pioglitazone group and 7.5% of the placebo group, with 5.7% versus 4.1% being hospitalized, and subsequent death occurring in 0.96% versus 0.84% of the groups, respectively.
The heart failure diagnoses in PROactive were "unadjudicated," says co-investigator Erland Erdmann, MD, of the Medizinishce Klinik III der Universitat zu Koln in Cologne, Germany. "When it came down to hospitalization for heart failure, there was hardly any difference. [With] deaths from heart failure, there was no difference whatsoever between pio[glitazone] and control," Erdmann continues. "So my feeling is that the edema which may have occurred were falsely considered as heart failure."
Asked by the EASD to serve as an independent reviewer of the PRO-active results, Hannele Yki-Järvinen, MD, of the University of Helsinki in Finland, calls it a "brave study" because of the known side effects of glitazones and because most patients were already on cardioprotective drugs.
Looking at the overall impact on health, Yki-Järvinen notes that there were 58 fewer primary end points in the pioglitazone group than in the placebo group, but there were 115 more heart failures.
"The study did not provide answers as to who develops heart failure," says Yki-Järvinen, who also wrote an editorial accompanying the published study results in The Lancet.4 "The patients were quite sick to start with, and only 5% ended up in the hospital because of heart failure. The risk is not very big. If we decide to go with this pill, we need to follow the heart failure signs very closely."
Considering that combination therapy with insulin and TZDs is contraindicated in Europe, she also questions why the subjects were not stratified based on insulin use.
The good news is that pioglitazone reduced the composite end point of all-cause mortality, nonfatal myocardial infarction (MI), and stroke by approximately 16%, Yki-Järvinen says. But the incidence of heart failure was two times greater than the reduction in cardiovascular events, she says, conceding that heart failure may have been overdiagnosed or underdiagnosed.
MEANING FOR THE PATIENT
Extrapolating the results, Dormandy says, "If a primary care doctor has 500 patients similar to the ones in our study, adding pioglitazone to their medication will avoid 10 to 11 first heart attacks, deaths, or strokes in 3 years."
So should all patients with type 2 diabetes—even those who do not yet show evidence of heart disease—be on pioglitazone?
"We haven't looked at pioglitazone in earlier type 2 diabetics, but I would guess that if it works in the far end of the disease it would probably work equally well earlier, if not better," Dormandy says.
When a new drug has an effect that no other drug has on MI, death, and stroke, "I would propose we use it, and I cannot withhold it from my patient," Erdmann says.
Yki-Järvinen is more reserved. "It is at least marginally
beneficial, at least in those patients who did not develop heart
failure." 
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Footnotes
The complete PROactive study results are available online at www.proactive-results.com.
References
2. Langenfeld MR, Forst T, Hohberg C, et al.: Pioglitazone decreases
carotid intima-media thickness independently of glycemic control in patients
with type 2 diabetes mellitus: Results from a controlled randomized study.
Circulation 111:2525–2531, 2005.
3. Dormandy JA, Charbonnel B, Eckland DJ, et al., for the PROactive investigators: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 366:1279–1289, 2005.[Medline]
4. Yki-Järvinen H: The PROactive study: Some answers, many questions. Lancet 366:1241–1242, 2005.[Medline]
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