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Tulane University Health Sciences Center (V.F., S.A.), New Orleans, Louisiana 70112; and King Edward Medical College (A.J.), Lahore 54000, Pakistan
Address all correspondence and requests for reprints to: Vivian A. Fonseca, M.D., Professor of Medicine and Pharmacology, 1430 Tulane Avenue (SI 53), Tulane University Medical Center, New Orleans, Louisiana 70112. E-mail: vfonseca{at}tulane.edu.
Type 2 diabetes is associated with an increased risk of cardiovascular events that carry a poor prognosis. People with diabetes have not benefited to the same degree as those without diabetes in terms of recent reductions in cardiovascular mortality. Obesity-related insulin resistance, which is accompanied by a cluster of cardiovascular risk factors, is clearly associated with cardiovascular disease and accounts for much of this increased risk of macrovascular disease in people with type 2 diabetes (1). Furthermore, recent data suggest that insulin resistance is associated with a several novel factors that have been implicated in the pathogenesis of cardiovascular disease, including inflammation and endothelial dysfunction (2).
A variety of therapeutic interventions have been developed to treat insulin resistance. The most successful of these has been the peroxisome proliferator-activated receptor (PPAR) agonists such as the thiazolidinediones, also known as glitazones. Although these drugs are only approved for the treatment of diabetes, they have attracted much attention because of their potential for reducing cardiovascular events. They improve insulin sensitivity and directly or indirectly improve a wide array of cardiovascular risk factors, many of which may be pathogenic in inducing cardiovascular events (2).
Although the glitazones improve a number of cardiovascular risk factors, much of these data come from animal studies and small human studies. Ultimately, therefore, the promise of any drug to alleviate human disease must be tested in large outcome-based clinical trials. Several such trials have been initiated, using PPAR agonists in a variety of settings from prediabetes to late-stage diabetes, to examine their role in primary as well as secondary prevention of cardiovascular events (3). The first of these was the Prospective Pioglitazone Clinical Trial in Macrovascular Events Study (PROactive), which recently reported its results and is therefore being viewed with considerable interest (4).
PROactive was a prospective, randomized, controlled trial studying 5238 patients with type 2 diabetes who had evidence of cardiovascular disease. These patients were randomized to pioglitazone, titrated to 45 mg daily, or matching placebo. Importantly, the study drug was taken in addition to the patient’s usual glucose-lowering medications, and therefore this study was designed to assess the pure effect of pioglitazone, independent from any of its effects on lowering blood glucose.
The results of the study show that pioglitazone had only a modest, and not statistically significant, 10% reduction in the risk of the primary composite endpoint, which consisted of all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, and revascularization or amputation. However, the "main secondary endpoint," consisting only of certain of the primary outcome measures, namely all-cause mortality, myocardial infarction, and stroke, was significantly reduced by 16%.
Despite the negative result on the primary endpoint, the primary publication states in its conclusion and the paper subtitle that "pioglitazone reduces mortality, myocardial infarction, and stroke." Such a conclusion is of course noteworthy for a population at high risk for these complications. However, the publication and presentation of the data have also been received with considerable skepticism of the interpretation, as well as condemnation of the methodology used, particularly the statistical analysis (5, 6). It is important for the practicing clinician to put these into perspective so that appropriate, clinically relevant conclusions can be drawn.
The study had major limitations that are likely to impede rapid acceptance in clinical practice. First, it was carried out in a population of mainly Caucasian subjects who were possibly less insulin resistant than the population of the United States and other countries, and who had a relatively high rate of cigarette smoking and a relatively low rate of statin use for patients who had already established macrovascular disease. It is not surprising, therefore, that the event rates were higher than expected, which, coupled with a remarkably higher than expected rate of recruitment, led to the study being concluded somewhat earlier than previously anticipated. A glance at the figures in the primary publication suggest that the Kaplan-Meier curves of the time to primary endpoint only start separating after 18 months, and the 36 months of the trial might not have been adequate to detect a true difference. This is also understandable, given the well-known slow onset of action of this class of drugs, which may be related to their primary mechanism of action.
The design of the study was previously published (7), but the "main secondary endpoint" was not clearly stated at that time, possibly raising a concern that the secondary endpoints may have been "cherry-picked" to obtain a positive result. The use of a secondary endpoint in the presence of a negative primary endpoint has also been severely criticized (6). Although the endpoints chosen as secondary are extremely important in diabetes, the lack of inclusion of silent myocardial infarction (a common problem in diabetes) and congestive heart failure among them do suggest some selection bias. If these endpoints were included, the major secondary endpoint would not have been statistically significant.
The positive effect of pioglitazone is somewhat tempered by an increase in incident congestive heart failure (CHF) in patients treated with pioglitazone. The authors of the primary paper are somewhat apologetic about the reports of heart failure, stating that these were not adjudicated and may have represented edema only and not true heart failure. This is probably an unnecessary denigration of one’s own investigators, just to gloss over what is well recognized in clinical practice, that some patients do indeed get heart failure on a combination of insulin and glitazones, particularly when high doses are used. Two important issues need to be considered in this context. First, pioglitazone is currently not approved in a dose of 45 mg daily for use in combination therapy, particularly in combination with insulin, where widespread use of this dose could lead to harm. Would the result of the trial have been different if a daily dose of 30 mg had been used? Second, patients with New York Heart Association class II–IV heart failure were excluded from the study. In contrast, the drug is approved for use in patients with class II CHF. Would hospitalization and mortality related to CHF been worse had patients with class II CHF been included in the trial? Unfortunately, answers to these questions are not available.
On the other hand, it is indeed reassuring that mortality from heart failure was not increased, suggesting that any heart failure associated with this class of drugs is easily manageable (8). It is also remarkable that liver function tests actually improved during the duration of the trial, providing reassurance about the effects of this class of drugs on the liver where they may actually be beneficial rather than harmful.
The study itself does not provide us with insights into the possible mechanism(s) of the benefit of the secondary endpoint. In the presentation given at the scientific sessions of the European Association for the Study of Diabetes, it was suggested that this may be a result of a number of factors, including the lower hemoglobin AIc (a failure in the execution of the clinical trial protocol and probably too small to be the only explanation), a small but significant reduction in blood pressure, as well as changes in the lipid profile, particularly in the increase in high-density lipoprotein cholesterol and a lowering of triglycerides. The latter has been repeatedly demonstrated with pioglitazone, in contrast with other PPAR
agonists, and has been portrayed as giving this drug a marketing edge. However, it is important to be cautious in attributing the decreased mortality to this change, because muraglitazar, a new drug in this class that has a more profound effect on reducing triglycerides, has recently been shown to possibly increase mortality (9). Other novel cardiovascular risk factors, such as markers of inflammation and, more importantly, insulin sensitivity itself, were not assessed in this trial. By itself, these are minor omissions, as it is often difficult to do mechanistic studies within large clinical trials. Furthermore, adequate clinical data on a wide variety of cardiovascular risk factors are now available.
The lack of an effect of pioglitazone to reduce the need for revascularization is surprising, given the data from preliminary studies and animal studies (2, 3). It is possible that patients in this study had disease too advanced to benefit from any therapy. We must await data from other ongoing studies to address this question.
Another major conclusion of the trial was that pioglitazone delayed the time to permanent insulin use. This, in itself, is not surprising because three oral agents are less likely to be associated with insulin use than two. Emphasis of this point suggests that perhaps insulin therapy is harmful or undesirable, which may not be appropriate considering recent data suggesting that insulin may have antiatherosclerotic properties (10), particularly if used appropriately and to achieve normoglycemia.
Thus, the PROactive trial has provided the impetus for further investigation and at the same time offers some support for the concept that treating insulin resistance will reduce mortality and myocardial infarction. However, it clearly does not conclusively prove this to be the case. Being only the first in many clinical trials, we remain optimistic that the glitazones may ultimately prove their worth in helping reduce the burden of cardiovascular disease in diabetes. Thus, the glass is not half empty, but rather half full.
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Disclosure: Dr. Fonseca and Tulane University have received research grants and consulting fees from Takeda Pharmaceuticals, GlaxoSmithKline, and AstraZeneca.
First Published Online November 22, 2005
Abbreviations: CHF, Congestive heart failure; PPAR, peroxisome proliferator-activated receptor.
Received November 9, 2005.
Accepted November 10, 2005.
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  D. J. Betteridge, R. A. DeFronzo, and R. J. Chilton PROactive: time for a critical appraisal Eur. Heart J., April 2, 2008; 29(8): 969 - 983. [Abstract] [Full Text] [PDF]
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 R. I. Misbin Lessons From the Avandia Controversy: A new paradigm for the development of drugs to treat type 2 diabetes Diabetes Care, December 1, 2007; 30(12): 3141 - 3144. [Full Text] [PDF]
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