Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol: A Randomized Controlled Trial
What are the biochemical effects, safety, and tolerability of evacetrapib, a cholesteryl ester transfer protein inhibitor (CETPi), as monotherapy and in combination with statins, in patients with dyslipidemia?
This randomized controlled trial was conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) (based on Adult Treatment Panel III guideline) or low high-density lipoprotein cholesterol (HDL-C) (<45 mg/dl for men and <50 mg/dl for women) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe. Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks.
Baseline variables in the monotherapy evacetrapib and in combination with statins were similar: mean age about 57 years, >50% were female, mean body mass index was 29 kg/m2, >30% had hypertension, and about 5% had diabetes. The mean baseline HDL-C level was 55.1 mg/dl, and the mean baseline LDL-C level was 144.3 mg/dl. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0-66.0 mg/dl (53.6% to 128.8%) compared with a decrease with placebo of −0.7 mg/dl (−3.0%; p < 0.001 for all compared with placebo) and decreases in LDL-C of −20.5 to −51.4 mg/dl (−13.6% to −35.9%) compared with an increase with placebo of 7.2 mg/dl (3.9%; p < 0.001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1-50.5 mg/dl (78.5% to 88.5%; p < 0.001 for all compared with statin monotherapy) and decreases in LDL-C of −67.1 to −75.8 mg/dl (−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 reductions in LDL-C (p < 0.001), but no greater increase in HDL-C (p = 0.39). Although the study was underpowered, no adverse effects were observed.
Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation.
Statin therapy can reduce the LDL-C to targets in most patients with atherosclerosis or increased risk with the exception of those who are statin intolerant and those with genetic mutation-associated hypercholesterolemia. But the reduction in cardiovascular events with statins compared to placebo is in the range of 25%, and HDL-C levels remain a risk predictor on statins. Among the remaining modifiable risk factors, HDL-C is the remaining major risk factor for which there is not yet clinical evidence of a treatment benefit. The AIM-HIGH study failed to show an advantage of niacin + simvastatin versus statins alone; a finding that may be explained by inadequate size, need for longer follow-up, or lack of effect. The CETPi class of drugs including evacetrapib offers the best opportunity to determine the value of increasing the HDL-C and apolipoprotein (apo) A-1, the protein on the surface of HDL that reflects the number of HDL particles.
Editorial Perspective: In an accompanying editorial in the JAMA issue containing the study of evacetrapib by Nicholls et al. (JAMA 2011;306:2153-5), Dr. Chris Cannon reviewed the epidemiologic considerations and biologic plausibility for HDL particles, as reflected by HDL-C levels, having an important counter-regulatory role in atherosclerosis. While it appears that low HDL-C is a major risk factor and high levels are ‘protective,’ the relationship between a low HDL-C and coronary disease is at least in part the association with other risk factors such as in diabetes and the metabolic syndrome. Further, the HDL-C level does not necessarily reflect the functional characteristics of HDL particles for reverse cholesterol transport or other functions including anti-inflammatory and antioxidant effects, improving endothelial function by enhancing nitric oxide synthase, and anticoagulant effects.
The editorial focused on the novel class of CTEP inhibitors which increase the HDL-C level from 30% to 140%, the apo A-1 from 11% to 45%, and significantly reduce LDL-C and apo B as monotherapy as well as when combined with moderate- to high-dose statins. Torcetrapib, the first CETPi to undergo a clinical outcome trial, led to an increase in cardiovascular events and mortality. This was thought to be due to ‘off-target’ increasing synthesis of aldosterone and cortisol in the adrenal cells that resulted in increasing blood pressure, aldosterone levels, and altered electrolytes. None of the three other CETPi agents in development (dalcetrapib, anacetrapib, and evacetrapib) have similar effects. Each will be in clinical trial soon, with the hope that one or more will lead us to the ‘holy grail’ in atherosclerosis treatment and prevention.
Keywords: Fluorobenzenes, Follow-Up Studies, Nitric Oxide Synthase, Coronary Disease, Pyrimidines, Apolipoprotein A-I, Risk Factors, Europe, Mutation, Cholesterol, Dyslipidemias, Cardiovascular Diseases, Niacin, Hypertension, Oxazolidinones, Hydrocortisone, United States, Sulfonamides, Benzodiazepines, Electrolytes, Atherosclerosis, Sulfhydryl Compounds, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quinolines, Lipoproteins, Heptanoic Acids, Hypercholesterolemia, Simvastatin, Metabolic Syndrome X, Pyrroles, Cholesterol Ester Transfer Proteins, Body Mass Index, Diabetes Mellitus
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