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Novel Therapy i..

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The current National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines recommend statins as the gold standard due to a reduction in low-density lipoprotein (LDL) cholesterol and a decreased risk for coronary heart disease (CHD).1 A novel drug class called cholesteryl ester transfer protein (CETP) inhibitors are being developed for the treatment of high LDL and low high-density lipoprotein (HDL), and to potentially provide cardiovascular benefits. CETP inhibitors have shown improvements in atherosclerotic lesions in animal studies, though this has not been established in humans.2 Torcetrapib was the first, but did not make it to FDA approval as an increased risk for cardiovascular events and mortality was noted in preliminary trials.3 Though low HDL is used as a CHD risk factor and raising HDL is theorized to reduce cardiovascular events, the data is unclear as to the clinical outcomes.1

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Nicholls and colleagues studied the safety and efficacy of evacetrapib as monotherapy and in combination with statins as part of a Phase II trial funded by Eli Lilly. This multicenter, parallel, randomized control trial enrolled 398 patients who were 18 years or older, with low HDL (< 45 mg/dL if male and < 50 mg/dL if female) or high LDL. Patients with atherosclerotic disease, hypertension, hyperaldosteronism, uncontrolled diabetes, or significant liver, kidney, cardiac, or neuromuscular disease were excluded. Eligible patients were randomized to receive: evacetrapib 30mg, 100mg, or 500mg daily as monotherapy; atorvastatin 20mg, simvastatin 40mg, or rosuvastatin 10mg daily as monotherapy or in combination with evacetrapib 100mg daily; or placebo for 12 weeks. Evacetrapib at a dose of 100mg daily was used to evaluate monotherapy.2

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The relative HDL increase with evacetrapib 100mg monotherapy was 97.6% (mean 108.6 mg/dL) compared to placebo (mean 51.6 mg/dL, p<0.001). The relative HDL increase was 78.5% to 88.5% for evacetrapib with statin therapy (all p<0.001), when compared to their respective statin monotherapy groups. The relative LDL decrease was 11.2% to 13.9% for evacetrapib with statin therapy (all p<0.01) when compared to their respective statin monotherapy groups. Overall, safety data was similar to placebo with evacetrapib 100mg daily and with the combination statin and evacetrapib groups, including changes in blood pressure, electrolytes or aldosterone. There were no serious adverse events reported that were considered drug-related, though the authors noted that the study was not powered to determine rare adverse effects.2

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Based on this trial, substantial increases in HDL levels with evacetrapib monotherapy were witnessed that seem greater than other standard therapies, (i.e. niacin, fibric acids).1 This is notable as mean baseline HDL levels of these patients were not low (55.1mg/dL). Patients with lower baseline HDL or higher baseline TG seemed to have greater changes with evacetrapib.2 The safety profile of evacetrapib was similar to placebo, though larger Phase III trials are warranted to better evaluate the adverse drug reaction profile, especially as the previous CETP inhibitor never made it to market due to serious adverse outcomes. It is also important to note that other CETP inhibitors are in development, so more information regarding this class of medications is expected. As the LDL reductions with evacetrapib monotherapy are modest compared to our current standards of therapy, it is likely that this medication could be utilized more as adjunctive therapy to achieve improvements in HDL levels once LDL goals are reached. What this study does not tell us is if these high levels of HDL will ultimately translate into significant clinical benefits.

1. Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 2001;285:2486-97.   [PubMed: 11368702]
2. Nicholls SJ, Brewer HB, Kastelein JJP, et al. Effects of the CETP Inhibitor Evacetrapib Administration as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol. J Am Med Assoc 2011;306:2099-2109.   [PubMed: 22089718] ...

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