Does PERISCOPE Provide a New Perspective on Diabetic Treatment?

Cardiovascular events, particularly acute myocardial infarction and stroke, are the main causes of death in patients with diabetes. Whether stringent glucose control and use of specific glucose-lowering drugs reduce this risk has remained a controversial issue for decades.^{1 - 2} Thus, adequately powered randomized clinical trials are now required to study the effect of new antidiabetic drugs on cardiovascular death, myocardial infarction, and stroke. One of these studies was the Proactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial, which compared pioglitazone with placebo in addition to standard glucose-lowering drugs in more than 5000 patients.³ In the Proactive trial, treatment with pioglitazone failed to reduce significantly the primary composite end point of death, myocardial infarction, stroke, revascularization, and amputation, even though the secondary end point of death, myocardial infarction, and stroke was reduced (hazard ratio [HR]; 0.84, 95% confidence interval [CI], 0.72-0.98; P = .027). A patient-level meta-analysis of the 19 randomized, double-blind controlled trials of pioglitazone showed consistent results for reducing cardiovascular events, with an HR of 0.82 (95% CI, 0.72-0.94; P = .005) but at the price of an excess of serious heart failure (HR, 1.41; 95% CI, 1.14-1.76; P = .002).⁴

Given the role of coronary and cerebrovascular atherosclerosis in the genesis of cardiovascular events, reducing or at least slowing progression of atherosclerosis in the coronary or carotid arteries appears to be an important pathway for preventing cardiovascular events. In this issue of JAMA, Nissen and colleagues⁵ report the results of a randomized trial comparing pioglitazone with glimepiride in 543 patients with type 2 diabetes and coronary artery disease. Patients in whom coronary angiography had identified a segment with mild coronary stenosis (>20% but <50% diameter stenosis) were evaluated with intravascular ultrasound (IVUS) at baseline and 18 months later. The primary end point of the trial—change in percent atheroma volume—increased by 0.73% (95% CI, 0.33% to 1.12%) in the glimepiride group and decreased by 0.16% (95% CI, −0.57% to 0.25%) in the pioglitazone group (P = .002). The results of this study therefore suggest that for patients with type 2 diabetes pioglitazone has the potential to slow or prevent progression of coronary atherosclerosis better than glimepiride, a widely used sulfonylurea.

Several aspects of the PERISCOPE trial must be considered in interpreting the findings. First, IVUS exquisitely delineates changes in coronary atherosclerosis; the PERISCOPE investigators are among the champions of this approach, which they have applied effectively in several previous studies.

Second, the effects observed were on the background of excellent contemporary therapy with statins, renin-angiotensin blockers, and aspirin. However, more than a third of the patients did not complete the study end point assessment, primarily because a repeat IVUS was not obtained. Although the authors used a sophisticated imputation algorithm to reanalyze their results and found essentially consistent outcomes, this high rate of noncompletion raises caution against overinterpreting the results. Another factor is that the target segments selected for ultrasound study were, by definition, segments with apparent mild disease, with exclusion of segments in which a stenosis exceeding 50% was present. Because patients who underwent repeat IVUS also underwent repeat coronary angiography, it would be important to know about the evolution of more severe coronary lesions that may have been present in patients at baseline but were not subjected to percutaneous coronary intervention.

Third, the clinical relevance of the difference achieved, which appears minimal (<1% change in atheroma volume), is unclear, although this effect is well within the range of what is achieved with some therapies demonstrated to improve cardiovascular outcomes, such as high-dose statins.⁶ However, the results from the PERISCOPE trial are consistent with those from several small previous studies suggesting that pioglitazone may have favorable effects on carotid intimal-medial thickness progression⁷ or neointima formation after coronary stenting.^{8 - 9}

Given the small differences in glycemic control and the fact that there is still no evidence that more intense glycemic control is associated with cardiovascular benefits, the authors ascribe the mechanism for the benefit of pioglitazone on progression of atherosclerosis to “nonglycemic” effects. Indeed, not only is there no confirmation that more intensive glycemic control prevents atherosclerosis or cardiovascular events, concerns were raised recently from an interim analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, in which more intensive glucose control was associated with an unexpected increase in the risk of premature death.¹⁰ However, this finding is still unexplained and requires confirmation. Another noteworthy finding is that reduction in atheroma volume was not commensurate with the concentration of low-density lipoprotein cholesterol (LDL-C) achieved, suggesting an LDL-C–independent pathway played a role. Pioglitazone increases high-density lipoprotein cholesterol levels, lowers triglycerides levels and blood pressure, and has a neutral effect on LDL-C levels.³ Therefore, in PERISCOPE, as could be expected, pioglitazone was associated with differential improvement in lipid profile, blood pressure levels, insulin secretion, glucose levels, and markers of inflammation compared with glimepiride, all of which are in the direction of reducing cardiovascular risk. However, it remains difficult to determine the hypothetical mechanism(s) for the benefit observed.

There is a distinct difference between slowing or preventing progression of mild coronary stenoses and improving cardiovascular outcomes. As the authors carefully point out, “clinical outcomes trials, not surrogate end point studies, are the preferred approach to the determination of the benefits of any therapeutic intervention.”⁵ Cardiologists have become aware of the important limitations of trials examining surrogate markers for conditions in which mortality is high. Classic examples include antiarrhythmic drugs effective in suppressing ventricular arrhythmias after myocardial infarction were associated with increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST) trial¹¹ and inotropic drugs improve symptoms in patients with heart failure but may increase mortality.¹² This is particularly relevant to the role of pioglitazone in preventing cardiovascular events in patients with diabetes, for concerns have been raised regarding potential harmful effects of other drugs in the same class.^{13 - 14} In the end, type 2 diabetes is a combination of deficient insulin secretion and excess insulin resistance. Because pioglitazone primarily improves insulin resistance, whereas glimepiride stimulates insulin secretion, a more adequate comparator for pioglitazone might have been metformin, which acts on insulin resistance and is proven to prevent cardiovascular adverse events in type 2 diabetes.¹⁵

The results of the PERISCOPE trial, even though they relate to a surrogate end point, are consistent with the modest clinical benefit demonstrated for the prevention of coronary events with pioglitazone, within PROACTIVE³ and other trials.⁴ However all glitazones share a common adverse effect on heart failure, and other noncardiovascular adverse effects, such as bone fractures. Whether the other widely used glitazone, rosiglitazone, has a neutral, beneficial, or adverse effect on prevention of coronary events should be clarified by the upcoming final results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial.¹⁶ Overall, in the current context of concerns regarding the cardiovascular safety of glucose lowering^{10 ,14} and regardless of the mechanisms involved, PERISCOPE provides a reassuring perspective for patients with type 2 diabetes and high cardiovascular risk.