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Pioglitazone for Macrovascular Complications of Diabetes


Am Fam Physician. 2006 Apr 15;73(8):1456-1459.

Although intensive glycemic control decreases microvascular complications of diabetes such as retinopathy and nephropathy, it provides little benefit in macrovascular complications or overall mortality. Persons with type 2 diabetes have a two to four times greater risk of macrovascular events than those without diabetes, and the life expectancy of a 40-year-old person newly diagnosed with diabetes is about eight years less than that of the general population. The pharmacologic actions of pioglitazone (Actos) suggest that this drug could reduce macrovascular changes independently of its effect on glycemic control. Dormandy and colleagues conducted a large, prospective, randomized controlled trial of pioglitazone therapy in patients with type 2 diabetes who had evidence of macrovascular complications.

More than 5,000 patients with type 2 diabetes were recruited from 321 primary care and in-hospital clinics in 19 European countries. Participants were 35 to 75 years of age and had A1C concentrations greater than 6.5 percent despite dietary modification alone or supplemented by oral hypoglycemic agents. About 30 percent of patients also used insulin. Evidence of macrovascular complications included a history of myocardial infarction, stroke, acute coronary syndrome, obstructive arterial disease in the legs, or recent invasive testing or medical procedures.

After baseline assessment, 2,605 participants were randomly allocated to receive oral pioglitazone with their existing management, and 2,633 participants were assigned to placebo. Pioglitazone dosages were 15 mg daily for the first month, 30 mg daily for the second month, and 45 mg daily thereafter. Throughout the study, all medications were adjusted to the clinically optimal dosages. Participants were seen monthly for two months, then every two months for one year, and every three months thereafter. The primary endpoints were time from randomization to death or occurrence of nonfatal myocardial infarction, stroke, acute coronary syndrome, or surgery for coronary or peripheral vascular disease. The principal secondary outcome was the composite of time from randomization to all-cause mortality, myocardial infarction, and stroke. An independent panel regularly reviewed patient records to monitor reporting of all endpoints and adverse events.

The two groups were comparable on entry to the study. Two thirds of the participants were men; 99 percent were white; the mean age was 61.8 years; and the average time since diagnosis of diabetes was eight years. Nearly one half of the patients in each group had a history of myocardial infarction; 19 percent had a history of stroke; almost one half had evidence of two or more macro-vascular complications; and 42 percent had microvascular disease. The average follow-up lasted 34.5 months. Only two patients were lost to follow-up. Pioglitazone was well tolerated: about 90 percent of patients were receiving the 45-mg dosage by the two-month visit, and 93 percent received the highest dosage for the remainder of the study. More than 95 percent of participants were compliant (i.e., used more than 75 percent of the tablets).

Overall, 514 (19.7 percent) of the patients in the intervention group had at least one of the primary endpoints, as compared with 572 (21.7 percent) of the control group. This reduction was not statistically significant. For the main secondary outcomes in the intervention and placebo groups (11.6 versus 13.6 percent, respectively), the difference did achieve statistical significance. The groups also differed significantly in the initiation of insulin therapy: 11 percent of participants in the pioglitazone group who were not already taking insulin began permanent insulin therapy during the study, compared with 21 percent in the control group.

The authors conclude that pioglitazone significantly reduced secondary endpoints and delayed initiation of insulin therapy in patients with type 2 diabetes at high risk of macrovascular complications. Although the difference in primary endpoints was not statistically significant, the authors estimate that treating 1,000 patients with pioglitazone would prevent 21 myocardial infarctions, strokes, or deaths over three years.

Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events). Lancet. October 8, 2005;366:1279–89.

editor’s note: The study by Dormandy and colleagues has profound implications but has raised considerable controversy. The authors stated in a public meeting that oral glucose-lowering medication can prevent macrovascular events, and it was believed that the study results would change clinical practice.1 However, an accompanying editorial2 and an article1 published in the British Medical Journal criticize the study and caution against the general use of pioglitazone (Actos) in type 2 diabetes. The editorial2 expresses significant concerns about underestimation of heart failure and edema in study participants and the lack of information about which patients could benefit from the additional therapy. The article1 is critical of the statistical analysis, concluding that the primary outcome results were not statistically significant and the secondary outcomes do not have sufficient statistical strength to prove an association. The article also questions why, if pioglitazone reduces macrovascular events, it had no apparent effect on all-cause mortality, because more than 350 deaths occurred in the trial. Physicians can expect interest from patients and pressure from pharmaceutical companies to use drugs in this class to reduce the risks of the major causes of mortality in type 2 diabetes.—a.d.w.



1. Freemantle N. How well does the evidence on pioglitazone back up researchers’ claims for a reduction in macrovascular events?. BMJ. 2005;331:836–8.

2. YkiJärvinen H. The PROactive study: some answers, many questions. Lancet. 2005;366:1241–2.



Copyright © 2006 by the American Academy of Family Physicians.
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