Background

Familial hypercholesterolemia (FH) is an autosomal dominant disorder manifested by marked elevation in low-density lipoprotein cholesterol (LDL-C) resulting from mutations in the LDL receptor (LDLR), apolipoprotein B (ApoB), or proprotein convertase/subtilisin kexin 9 (PCSK9) genes. Statins reduce LDL-C in patients with heterozygous FH, but most patients do not reach optimal LDL-C concentrations. Cholesteryl ester-transfer protein (CETP) inhibitors are a class of drugs that block transfer of cholesterol from high-density lipoprotein (HDL) to LDL particles, leading to decreases in serum LDL-C, remnants, and lipoprotein(a) (Lp[a]) and increases in HDL-C and apolipoprotein A-I (apo A-I). Whether the addition of CETP inhibitors to optimal statin therapy can benefit FH patients is unknown.

Methods

The Randomized Evaluation of Anacetrapib Lipid-Modifying Therapy in Patients with Heterozygous Familial Hypercholesterolemia (REALIZE)¹ study is a double-blind randomized clinical trial of anacetrapib, a CETP inhibitor, that enrolled FH patients on optimal statin therapy with residual LDL-C >2.59 mmol/L (>100 mg/dl) in patients without cardiovascular disease (CVD) and >1.81 mmol/L (>70 mg/dl) in those with CVD. There were no HDL-C criteria for enrollment. Using a 2:1 allocation ratio, 204 patients were assigned anacetrapib 100 mg daily and 102 patients to placebo, and patients were followed for 52 weeks for the primary outcome of percent change from baseline LDL-C.

Results

Baseline LDL-C was ~3.4 mmol/L (131 mg/dl). Anacetrapib conferred significant reduction in LDL-C, with a percent change of -40% compared to placebo (p <0.0001), achieving a mean treatment LDL-C around 2.1 mmol/L (81 mg/dl) versus 3.5 mmol/L (135 mg/dl) with placebo. More patients assigned to anacetrapib achieved targets of <2.59 mmol/L (<100 mg/dl) [82% vs. 18%] and <1.81 mmol/L (<70 mg/dl) [44 vs. 5%]. Anacetrapib also increased HDL-C and apo A-I more than placebo (by +102% and +33%, respectively, p <0.0001) and reduced non-HDL-C, ApoB, and Lp(a) (by -36%, -25%, -28%, respectively, p <0.0001 for all). There were more CVD events in the anacetrapib arm [2% (n = 4 events including one non-fatal MI and three unstable angina) vs. 0% in placebo], but this was not statistically significant (p = 0.15). The proportion of adverse events leading to discontinuation was low, slightly higher in the anacetrapib group, but again not statistically significant. No significant increases in blood pressure (BP) (diastolic BP was actually higher in the placebo group), electrolytes, liver enzymes, or creatine kinase were noted in anacetrapib arm, but more skin-related adverse effects did occur (9% vs. 2%, p <0.016).

Conclusion

Anacetrapib was well-tolerated in FH patients and resulted in significant reductions in LDL-C.

Commentary/Perspective

The Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) trial² previously studied the effects of anacetrapib on lipids and safety parameters in 1,623 patients with coronary heart disease or coronary heart disease risk equivalents on background statin therapy. After 24 weeks of treatment, anacetrapib increased HDL-C by 138% and reduced LDL-C by 40%, relative to placebo. There was no difference in CVD events or BP between the groups in this study.

REALIZE is a smaller study (n = 306) but now evaluates anacetrapib in a population with familial hypercholesterolemia: 91% of participants were confirmed to have a genetic mutation in LDLR, ApoB, or PCSK9. Treatment with anacetrapib 100 mg daily on top of background statin therapy led to significant reductions in atherogenic lipoprotein burden [i.e., LDL-C, ApoB, Lp(a)] and increased concentrations of lipid parameters with potentially favorable antiatherogenic properties (i.e., HDL-C, apo A-I). The small increase in CVD events in the anacetrapib arm was based on few events and not statistically significant, but is a bit concerning, especially in light of the Study Examining Torcetrapib/Atorvastatin And Atorvastatin Effects On Clinical CV Events In Patients With Heart Disease (ILLUMINATE)³ in which another CETP inhibitor (torcetrapib) was associated with increased risk of mortality. Unlike torcetrapib, no increase in BP was seen with anacetrapib. Larger clinical trials of anacetrapib powered for hard outcomes (such as the on-going Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification [REVEAL]⁴ study) are needed to see whether these favorable lipid changes translate to reductions in clinical CVD events.

REALIZE studied FH patients with elevated LDL-C on statins, and the primary outcome was a change in LDL-C (and not HDL-C). However, CETP inhibitors are typically considered as therapeutics targeting HDL-C. On the other hand, the PCSK9 inhibitor class of medications target LDL-C, show even more LDL-C lowering (~50% or more), and have very promising early outcome data and safety data.⁵ PCSK9 inhibitors have been tested in similar FH populations and are also currently under investigation in larger longer-term outcome studies. Based on recommendations by the U.S. Food and Drug Administration (FDA) Advisory Committee, likely PCSK9 inhibitors will receive FDA approval for lipid treatment in FH patients even before the large long-term outcome studies are completed (note that alirocumab has already received FDA approval for the treatment of high LDL-C in adult patients).

References

1. Kastelein JJ, Besseling J, Shah S, et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet 2015;385:2153-61.
2. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15
3. Barter PJ, Caulfield M, Eriksson M, et al.Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
4. U.S. National Institutes of Health. REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (ClinicalTrials.gov website). 2010-2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01252953. Accessed on 6/25/15.
5. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med 2015;163:40-51.

Keywords: Advisory Committees, Angina, Unstable, Apolipoprotein A-I, Apolipoproteins B, Blood Pressure, Cardiovascular Diseases, Cholesterol, Cholesterol Esters, Cholesterol Ester Transfer Proteins, Cholesterol, LDL, Coronary Disease, Creatine Kinase, Double-Blind Method, Electrolytes, Heart Diseases, Heptanoic Acids, Hyperlipoproteinemia Type II, Lipids, Lipoprotein(a), Lipoproteins, HDL, Lipoproteins, LDL, Liver, Longitudinal Studies, Mutation, Oxazolidinones, Pharmaceutical Preparations, Proprotein Convertases, Pyrroles, Quinolines, Receptors, LDL, Subtilisin, Hypercholesterolemia

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