Cardiovascular outcomes study to evaluate the potential of aleglitazar to reduce cardiovascular risk in patients with a recent acute coronary syndrome (ACS) event and type 2 diabetes mellitus (T2D)

The proposed phase 3 cardiovascular outcomes trial, described in this protocol, will be in patients with T2D following a recent acute coronary syndrome.The available data for aleglitazar, showing clinically meaningful effects on dyslipidemia, glycemic control, peripheral insulin sensitivity as well as on cardiovascular and inflammatory markers (hsCRP, PAI-1, fibrinogen), and moderately favorable effects on blood pressure, does support the potential benefit for aleglitazar for reducing the risk of cardiovascular morbidity and mortality. In the phase 2 dose-ranging study BM17864, 150 μg aleglitazar showed notably greater beneficial effects on the lipid profile than 45 mg pioglitazone, and comparable effects on glycemic control. The changes in hsCRP and PAI-1 for the 150 μg dose of aleglitazar were in the range of those seen with 45 mg pioglitazone, and the decrease in fibrinogen was greater than observed with pioglitazone.Taken together, these data indicate greater beneficial effects on key markers of cardiovascular risk than the comparator pioglitazone at its top dose suggesting the potential for greater benefit on cardiovascular outcomes.Notably, the main lipid benefit of aleglitazar treatment appears to be the marked increase in HDL-C and the marked decrease of TGs. Numerous prospective epidemiological studies have shown a strong inverse relationship between HDL-C levels and the major protein apolipoprotein A-I (apoA-I) and CHD suggesting that a 2-3% reduction in CHD risk could be achieved for each 1 mg/dL rise in HDL-C. The current National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recognize low HDL-C (< 40 mg/dL/ or < 1 mmol/L) as an independent major risk factor for CHD, a component of metabolic syndrome, and a potential target for therapeutic intervention.Lipid-modifying drugs which are most widely used, such as statins and fibrates, generally increase HDL-C levels by up to 5-15% (statins) and 10-15% (fibrates). Niacin has been shown to increase HDL-C (15-35%) but its use is limited by poor tolerability, and in addition it should be used with caution in patients with T2D because it may increase glucose intolerance. The value of raising HDL-C levels in combination with LDL-C lowering was demonstrated by the HDL-Atherosclerosis Treatment Study (HATS). In this trial, combined treatment of simvastatin with niacin in patients with clinical coronary artery disease and low HDL over a 3-year period was associated with decreased progression of atherosclerosis and a 90% reduction in major cardiovascular events .Elevated levels of TGs have also been reported to be associated with an increased risk of recurrent cardiovascular events in patients following an ACS event. PPARα activation decreases TGs levels and shifts the size of LDL-C particles from small, dense particles to larger particles. Thus, the beneficial effects of aleglitazar seen in the phase 2 studies in lowering TGs would be anticipated to further reduce the high residual cardiovascular risk in patients with an ACS event on top of therapy with statins.Importantly, the available data for pioglitazone also suggest beneficial effects of PPARγ agonism on cardiovascular outcomes. The PRO active study compared pioglitazone to placebo on top of standard of care in CHD patients with T2D. While statistical significance was not achieved in the study for the primary composite endpoint of all cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, coronary revascularization, or revascularization of the leg, pioglitazone was shown to reduce the risk of the main secondary composite endpoint of all cause mortality, myocardial infarction, or stroke. The relative risk reduction in PRO active was 16% for the composite endpoint of all-cause death, non-fatal MI excluding silent MI and non-fatal stroke, and 18% for the composite endpoint of cardiovascular mortality, non-fatal MI excluding silent MI and stroke. In addition to PRO active, several other lines of evidence suggest a beneficial effect on cardiovascular outcomes for pioglitazone, including a post-hoc meta-analysis of randomized controlled trials with pioglitazone, and carotid intima-media thickness (cIMT) and intravascular ultra sonography (IVUS) imaging studies. In the post-hoc meta-analysis, there was an 18% relative risk reduction in the composite endpoint of all-cause death, non-fatal MI and stroke, consistent with the above reported results for PRO active. The observed reduction of cardiovascular risk in the PRO active outcome study and the meta analysis of randomized clinical trials with pioglitazone are also in line with the significantly lower rate of progression of atherosclerosis in two imaging studies with pioglitazone, the PERISCOPE randomized controlled trial (by IVUS) and the CHICAGO randomized controlled trial(by high resolution B-mode carotid artery ultra sonography) In summary, in view of the available data for aleglitazar showing beneficial effects on multiple cardiovascular risk factors, and the available cardiovascular outcomes data for pioglitazone, aleglitazar is viewed to have strong potential to provide benefit in improving cardiovascular morbidity and mortality over current standard of care in patients with T2D following a recent ACS. Thus, aleglitazar potentially meets an important unmet medical need in these patients, who are at particularly high risk for there current cardiovascular events despite the currently available treatments.