Pioglitazone and recurrent myocardial infarction in patients with diabetes and a previous myocardial infarction

Both myocardial infarction (MI) and diabetes are strong predictors of mortality, especially mortality from cardiovascular causes.^1,2 Epidemiologic studies have indicated that the risk of MI is 2 to 4 times greater in patients with diabetes than in those without it.^3,4 Patients with type 2 diabetes and a previous MI are at increased risk for future cardiovascular events, and aggressive strategies should be employed to reduce macrovascular morbidity and mortality in these patients

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Pioglitazone (Actos) improves glycemic control, increases high-density lipoprotein (HDL) cholesterol, lowers low-density lipoprotein (LDL) cholesterol and triglycerides, and may have other beneficial antiatherogenic effects that include modulating the levels of mediators involved in endothelial dysfunction and inflammation.⁵ It has also been shown to reduce the progression of carotid intima-media thickness, a marker of cardiovascular risk, in patients with type 2 diabetes (some of whom had a history of cardiovascular disease).⁶ The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) was a prospective, randomized, multicenter, double-blind, controlled, secondary prevention trial that included patients with type 2 diabetes who had evidence of macrovascular disease. Pioglitazone improved cardiovascular outcome, as shown by a reduction in the composite of all-cause mortality, nonfatal MI, and stroke ( = .027).⁷ There was a nonsignificant decrease in the primary end point of procedure- and disease-related end points ( = .095). The goal of our analysis was to evaluate the effect of pioglitazone on mortality and macrovascular morbidity in a high-risk group of patients with type 2 diabetes and a previous MI.

Subjects and methods

A total of 5238 subjects with type 2 diabetes and macrovascular disease were enrolled in the PROactive Study. Subjects were randomly assigned to receive placebo or pioglitazone, which was titrated from 15 mg to 45 mg, while they continued to take their other glucose-lowering and cardiovascular medications as directed by the International Diabetes Federation 1999 guidelines. Subjects were followed for a mean of 34.5 months.

We analyzed data from the 1804 male and 641 female subjects who had experienced an MI at least 6 months prior to enrollment. Three composite end points were prespecified for this previous-MI subgroup: fatal or nonfatal MI (excluding silent MI); cardiovascular death or nonfatal MI (excluding silent MI); and cardiovascular death, nonfatal MI (excluding silent MI), or stroke.

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Nonfatal MI was defined as survival for more than 24 hours from the start of symptoms and, in the absence of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, at least 2 of the following: (1) symptoms suggestive of MI (ischemic chest pain or discomfort) lasting > 30 minutes, (2) electrocardiographic (ECG) evidence of MI, or (3) elevation of cardiac serum markers; or if there was ECG evidence of MI following PCI or CABG surgery. Time-to-event analyses were performed by fitting a Cox proportional hazards survival model with treatment as the only covariate and previous testing of the validity of the assumption of proportional hazards. Multivariate Cox models were used to identify treatment effects after adjustment for baseline factors prognostic of outcome. Variable selection was performed using a stepwise selection algorithm, and statistical significance was considered < .05.

Table. Effects of pioglitazone on prespecified end points.

Results

Macrovascular morbidities and baseline characteristics were similar between the placebo subjects and the subjects taking pioglitazone. More than two thirds of subjects also had 1 or more other macrovascular conditions (stroke, peripheral arterial obstructive disease, PCI/CABG surgery, or acute coronary syndrome). Baseline use of glucose-lowering and cardiovascular treatments was similar between the 2 groups. Approximately half of the subjects were taking statins at the start of the study, and about 90% were receiving antiplatelet therapy. Some changes were made to medication between baseline and the final visit. For example, there was a decrease in sulfonylurea use and an increase in statin and diuretic use in both groups. Insulin use increased in the placebo group only.

Figure 1. Time to fatal/nonfatal myocardial infarction (MI; excluding silent MI). HR indicates

hazard ratio; CI, confidence interval. (Reprinted with permission from Erdmann E, Dormandy

JA, Charbonnel B, et al; for the PROactive Investigators. The effect of pioglitazone on

recurrent myocardial infarction in 2445 patients with type 2 diabetes and previous myocardial

J Am Coll Cardiol

Copyright Elsevier 2007

infarction. . 2007;49[7]:1772-1780. .)

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The first of the prespecified end points (time to fatal or nonfatal MI) was significantly decreased with pioglitazone (Figure 1), and there were positive trends in the other 2 prespecified end points (Table). In addition, pioglitazone significantly reduced the risk of 2 nonprespecified end points compared with placebo. The occurrence of acute coronary syndrome was reduced by 37% ( = .035), and the composite cardiac end point of nonfatal MI (excluding silent MI), coronary revascularization, acute coronary syndrome, and cardiac death was decreased by 19% ( = .034; Figure 2). The difference in the primary end point defined in the main PROactive study—time to the first occurrence of a macrovascular event (ie, MI, stroke, acute coronary syndrome, coronary or leg revascularization, or amputation above the ankle) or death&mdash;did not reach significance (12% relative risk reduction; = .135). All of the other end points showed positive trends, but did not reach significance.

Figure 2. Time to composite cardiac end point (cardiac death, nonfatal myocardial infarction,

coronary revascularization, or acute coronary syndrome). HR indicates hazard ratio; CI,

confidence interval. (Reprinted with permission from Erdmann E, Dormandy JA, Charbonnel

B, et al; for the PROactive Investigators.The effect of pioglitazone on recurrent myocardial

J Am

Coll Cardiol

Copyright Elsevier 2007

infarction in 2445 patients with type 2 diabetes and previous myocardial infarction. . 2007;49[7]:1772-1780. .)

The results of a multivariate analysis of 25 baseline characteristics showed that increased LDL cholesterol level, increased insulin use, and increased age were predictive factors of a second MI, whereas prior revascularization was a negative predictor. The rate of heart failure requiring hospital admission was higher in the pioglitazone group (7.5%) compared with the placebo group (5.2%), but the fatal heart failure rate was not significantly different between the 2 groups (1.4% in the pioglitazone group vs 0.9% in the placebo group).

Discussion

Compared with the general population, individuals with type 2 diabetes have an increased incidence of MI.³ People with type 2 diabetes without a previous MI have a cardiovascular mortality rate that is comparable to the rate in nondiabetic patients with a previous MI.³ Although interventions such as statin therapy can reduce the excess cardiovascular risk, residual macrovascular morbidity and mortality persist. Thus, it is necessary for clinicians to use aggressive multifactorial management strategies to address the residual risk and to delay or prevent progression of macrovascular disease in patients with diabetes and MI.

The PROactive study examined the effects of pioglitazone taken along with standard therapy on a composite macrovascular end point that included nonfatal MI. There was a significant risk reduction of the disease-related end points of all-cause mortality, nonfatal MI, and nonfatal stroke in the total population included in the study.⁷ This subanalysis of the larger PROactive study assessed 2445 patients with a previous MI (≥ 6 months prior to randomization) and thus at very high risk for a subsequent macrovascular event. This represents one of the largest groups of patients with type 2 diabetes and previous MI to be examined in a prospective randomized study. The results of our subgroup analysis showed that pioglitazone was more effective in preventing recurrent MI than placebo. Treating 1000 patients with type 2 diabetes and MI with pioglitazone in addition to their existing ongoing medication would avoid 22 recurrent MIs over a 3-year follow-up period. The analysis also indicated that pioglitazone reduces the risk of other adverse cardiac outcomes in these patients with previous MI. It is also possible that early and aggressive treatment of early symptomatic heart failure could lead to a relevant improvement in survival.

A recent meta-analysis of the effects of pioglitazone on CV events provides additional strong evidence that there is no increased risk of the composite of death, MI, or stroke with pioglitazone.⁸ This finding persisted when looking at MI in isolation. In contrast, 4 separate meta-analyses performed from very distinct perspectives—the pharmaceutical industry (GlaxoSmith Kline), a regulatory body (FDA), and from within the cardiology community&mdash; reveal that there is a strong suggestive signal that rosiglitazone is associated with increased ischemic cardiac risk (a statistically significant approximate 30%-40% increase).^9-12 As a consequence, the European regulatory authorities have recommended that prescribing information for rosiglitazone be updated to include a warning that, in patients with ischemic heart disease, rosiglitazone should only be used after careful evaluation of each patient's individual risk, and that the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No changes to the prescribing information for medicines containing pioglitazone were considered necessary. To date, there have been no corresponding recommendations from the FDA.

Concern has been raised regarding the use of thiazolidinediones in patients with existing heart failure or at high risk for heart failure. This prompted the American Heart Association and the American Diabetes Association to issue joint guidelines for the use of thiazolidinediones in patients with type 2 diabetes and heart failure. The guidelines recommend that thiazolidinedione treatment should be initiated in patients with heart failure with the lowest possible dose, followed by slow dose escalation based on glycosylated hemoglobin levels.¹³

In our analysis, the rate of serious heart failure leading to hospitalization was higher in the pioglitazone group (7.5%) than in the placebo group (5.2%); however, the rate of fatal heart failure was similar (1.4% and 0.9%, respectively). It should also be noted that nearly all patients (95%) in the pioglitazone group were receiving the maximum dose of 45 mg/day. These findings of a comparable rate of fatal heart failure with pioglitazone and placebo are somewhat reassuring, as patients with an MI are at particularly high risk for heart failure and other cardiovascular diseases. We believe that 3 years of follow-up is a reasonable period in which to judge the clinical effect on the development of heart failure. Our data are supported by a report of more than 23,000 patients, which concluded that pioglitazone does not cause heart failure.¹⁴

Our analysis is limited in that it is from a subgroup of a larger study that did not randomize by history of MI. In addition, the study duration may not have been long enough in view of the chronic nature of treatment. The sample size of nearly 2500 subjects, however, is large, and there were no differences between the 2 treatment groups at baseline.

Conclusions

In our subgroup analysis of the PROactive study among high-risk patients with type 2 diabetes and a previous MI, we showed that the addition of pioglitazone to contemporary goal-driven therapy, with attention to lipid levels, blood pressure, hyperglycemia, and coagulation, further reduced the risk of recurrent MI by 28%, the risk of acute coronary syndrome by 37%, and the risk of the composite cardiac end point of nonfatal MI, coronary revascularization, acute coronary syndrome, and cardiac death by 19%. This suggests that pioglitazone treatment in high-risk patients with diabetes and a previous MI may provide additional, albeit modest, benefit when given in addition to standard care.