Pioglitazone benefits high-risk diabetic patients: PROACTIVE is the first study to produce improved cardiovascular outcomes in those with type 2 diabetes.
The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE) is the first study ever to prospectively show that a specific oral glucose-lowering agent can improve cardiovascular outcomes in diabetic patients. Funded by Takeda Pharmaceutical Co. and Eli Lilly & Co., which comarket pioglitazone (Actos) in the United States, the trial was conducted at 321 centers in 19 European countries. The presentation was simulcast on the Internet.
A total of 5,238 patients aged 35-75 years with type 2 diabetes were randomized to either 45 mg pioglitazone or placebo for at least 2.5 years in addition to all their existing therapies, including diet, exercise, lipid-lowering agents, antihypertensives, and antithrombotics.
All had established cardiovascular disease, defined as one or more of the following: MI, stroke, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG) that had occurred at least 6 months in the past (to ensure they were stable), acute coronary syndrome (ACS) 3 months or more in the past, objective evidence of coronary artery disease, or symptomatic peripheral arterial disease or amputation due to ischemia.
Nearly half of the subjects had a prior MI and/or coronary artery disease, and just under one-third had a prior PCI or CABG. In all, 47% of the 2,605 pioglitazone subjects and 49% of the 2,633 in the placebo group had at least two entry criteria, said Massimo Massi-Benedetti, M.D., principal investigator for the Italian PROACTIVE site in Perugia.
At baseline, two-thirds were taking metformin and/or sulfonylurea, while one-third were on insulin, either alone or in combination. In addition, 95% were on at least one cardiovascular medication, including 63% on ACE inhibitors and 55% taking [beta]-blockers. Half were taking lipid-lowering drugs, with about 43% on statins. About a third of the subjects were seen in primary care settings, while the rest were from specialty departments in hospitals.
Of the original randomized cohort, a total of 2,427 pioglitazone and 2,446 placebo subjects had final assessments. However, the entire group was included in the intent-to-treat analysis, said PROACTIVE study chair John Dormandy, M.D., professor of vascular sciences at St. George's Hospital, London.
The primary end point of the study was the time from randomization to the first occurrence of any of the events in the following composite: all-cause mortality, nonfatal MI (including silent MI), stroke, major leg amputation (above the ankle), ACS, CABG or PCI, and leg revascularization. A total of 572 placebo subjects and 514 pioglitazone subjects experienced such events, which translated to 3-year estimates of 23.5% for placebo and 21.0% for pioglitazone, or a nonsignificant 10% relative risk reduction.
However, for the secondary end point--time to first occurrence of all-cause mortality, nonfatal MI (not including silent MI), and stroke--the difference was significant. Here, the 3-year estimates were 14.4% for placebo vs. 12.3% for pioglitazone, comprising a 16% relative risk reduction. This finding is more significant, Dr. Dormandy noted, because "these are frequently used hard end points that are less dependent on the individual physician and that matter most to the patient."
The results favoring pioglitazone did not differ by demographics such as age, gender, body mass index, baseline blood pressure, or duration of diabetes.
When broken down by baseline medication, there was no additional benefit for pioglitazone among statin users compared with nonusers. All other medication and metabolic parameter subgroups appeared to show a benefit for pioglitazone, Dr. Dormandy said.
Presenting the metabolic results, Bernard Charbonnel, M.D., leader of the French study site at Nantes, said the 3-year estimate of progression to insulin use was 22% with placebo, compared with 11% for pioglitazone, a highly significant 50% difference. Compared with placebo, the pioglitazone subjects had a 0.5% drop in hemoglobin [A.sub.1c], a 3-mm Hg reduction in BP, a 13% greater reduction in triglycerides, and a 9% greater increase in HDL cholesterol. These factors all probably contributed to the overall cardiovascular benefit seen with pioglitazone, although the mechanism is still being investigated, he said.
Overall, 46.2% of pioglitazone and 48.4% of placebo subjects had at least one serious adverse event. End point events occurred in 14.9% of pioglitazone and 16.5% of placebo subjects, while non-end point events occurred in 41.4% and 43.7%, respectively.
The fact that nearly half of both groups had serious events "emphasized how sick these patients were" at baseline, noted Pierre Lefebvre, M.D., emeritus professor of medicine at the University of Liege (Belgium) and current president of the Brussels-based International Diabetes Federation.
Heart failure was reported by the patients' individual physicians in 10.8% of the pioglitazone subjects and 7.5% of the placebo group. However, heart failure leading to hospitalization--considered a more accurate measure of true heart failure--occurred in 5.7% of pioglitazone and 4.1% of the placebo groups, a difference of 1.6%. The rates of heart failure leading to death--0.96% with pioglitazone and 0.84% with placebo--were not significantly different, he said.
BY MIRIAM E. TUCKER
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|Title Annotation:||Across Specialties|
|Author:||Tucker, Miriam E.|
|Publication:||Clinical Psychiatry News|
|Date:||Nov 1, 2005|
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