MD Conference Express AHA 2011 - (Page 16)

n C L I N I C A L T R I A L H I G H L I G H T S Following a dietary lead-in, 398 patients were randomly assigned to one of 10 treatment groups for 12 weeks: placebo; evacetrapib monotherapy (30, 100, or 500 mg/day); or statin therapy (simvastatin, 40 mg/day; atorvastatin, 20 mg/day; or rosuvastatin, 10 mg/day) with or without evacetrapib 100 mg/day. A total of 393 patients received the study drug and were included in the final analysis. The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL [1.42 mmol/L] and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL [3.73 mmol/L]. As monotherapy, evacetrapib produced dose-dependent increases of HDL-C of 30.0 to 66.0 mg/dL [0.78 to 1.71 mmol/L] (53.6% to 128.8%) compared to a decrease with placebo of -0.7 mg/ dL [-0.02 mmol/L] (-3.0%; p<0.001 for all compared with placebo). Decreases in LDL-C were -20.5 to -51.4 mg/dL [-0.53 to 1.33 mmol/L] (-13.6% to -35.9%) compared to an increase with placebo of 7.2 mg/dL [0.19 mmol/L] (3.9%; p<0.001 for all compared with placebo; Figure 1). Figure 1. Percent Changes in HDL-C and LDL-C. Placebo 150% 30 mg evacetrapib 100 mg evacetrapib 10% 3.9% increased cardiovascular death and had off-target effects (increase in aldosterone) that led to increases in blood pressure [Barter PJ et al. N Engl J Med 2007]. However, the outcomes from this and other Phase 2 trials with anacetrapib and dalcetrapib suggest promise for second generation CETP inhibitors as cardioprotective agents. Two large cardiovascular outcome studies (dal-OUTCOMES [Schwartz GG et al. Am Heart J 2009] and REVEAL HPS-3 TIMI-55 [Melloni C et al. Am Heart J 2010]) are ongoing to determine whether CETP inhibitors can further reduce the substantial residual risk of cardiovascular disease still observed in patients with established coronary artery disease despite the use of existing lipid therapies. Further reading: Nicholls SJ et al. JAMA 2011. AIM-HIGH: Niacin Provides No Added Benefit for Statin Users With Well-Controlled LDL Written by Anne Jacobson 500 mg evacetrapib 128.8% * 120% 94.6% * 0% Percent Change Percent Change 90% * -10% -13.6% 60% 53.6% -20% * 30% -22.3% * 0% -3.0% -30% Add-on therapy with high-dose extended-release (ER) niacin provides no additional reduction in cardiovascular (CV) events in patients with dyslipidemia and a history of cardiovascular disease (CVD) who are treated to target low-density lipoprotein (LDL) levels with a statin, according to findings from a randomized trial. -35.9% -30% Treatment Group *p<0.001 compared with placebo. -40% Treatment Group * Reproduced with permission from S. Nicholls, MBBS, PhD. In combination with statin therapy, evacetrapib, 100 mg/day, produced absolute increases in HDL-C of 42.1 to 50.5 mg/dL [1.09 to 1.31 mmol/L] (78.5% to 88.5%; p<0.001 for all compared with statin monotherapy) and absolute decreases in LDL-C of -67.1 to -75.8 mg/dL [1.74 to 1.96 mmol/L] (-11.2% to -13.9%; p<0.001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reduction in LDL-C (p<0.001), but no greater increase in HDL-C (p=0.39). Evacetrapib was well tolerated, with a low rate of treatment-related adverse events or discontinuation of therapy. No evidence of adverse blood pressure or mineralocorticoid effects was observed as was seen previously with torcetrapib. The development of CETP inhibitor drugs to increase HDL-C levels has been challenging and marked by failure with the first agent developed. In the ILLUMINATE trial, torcetrapib 16 January 2012 William E. Boden, MD, University of Buffalo, Buffalo, New York, USA, presented the final analysis of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes trial [AIM-HIGH; NCT00120289]. The AIM-HIGH trial was stopped prematurely in May 2011 after an interim analysis revealed futility (lack of efficacy with niacin) for the primary endpoint and an unexpected higher rate of ischemic stroke in the niacin group. Despite the beneficial effects of statins on LDL levels, patients with dyslipidemia face residual CV risk that is associated with low high-density lipoprotein (HDL) levels. AIM-HIGH was designed to evaluate whether raising HDL levels with ER niacin would reduce CV events in patients who are treated aggressively to low LDL levels with a statin (target 40 to 80 mg/dL [1.03 to 2.07 mmol/L]). The AIM-HIGH trial included 3414 patients aged ≥45 years with a history of coronary heart disease (CHD), cerebrovascular disease, or peripheral artery disease. Patients also had low HDL cholesterol (<40 mg/dL www.mdconferencexpress.com  http://www.mdconferencexpress.com http://www.mdconferencexpress.com

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