Anacetrapib on Top of Optimal Therapy Provides Large LDL-Lowering Benefit in FH: REALIZE

March 05, 2015

AMSTERDAM, THE NETHERLANDS — For patients with heterozygous familial hypercholesterolemia (FH) well treated with existing medical therapy, including high-intensity statins and ezetimibe (Zetia, Merck/Schering-Plough), the addition of anacetrapib (Merck) for 1 year further reduced LDL-cholesterol levels and other atherogenic lipoproteins, according to the results of a new study[1].

Among 204 patients who received anacetrapib, LDL-cholesterol levels were reduced from 127 mg/dL at baseline to 81 mg/dL at 1 year. For the 102 patients who received a placebo, LDL-cholesterol levels increased slightly over the 52 weeks. Treatment with anacetrapib also resulted in a significant increase in HDL-cholesterol levels, with baseline levels doubling after 1 year of treatment (up from 54 mg/dL to 108 mg/dL).

"Furthermore, compared with placebo, anacetrapib allowed significantly more patients to attain their European Atherosclerosis Society and European Society of Cardiology LDL-cholesterol treatment goals," according to lead investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) and colleagues. "These findings were consistent across subgroups and are an extension of the results of a previous study in patients without the familial-hypercholesterolemia phenotype (the DEFINE study)."

The results of the current study, known as the REALIZE trial, are published March 3, 2015 in the Lancet.

Cautiously Awaiting Results of Outcomes Trial

Anacetrapib is a closely watched cholesteryl ester transfer protein (CETP) inhibitor. As reported by heartwire , the CETP inhibitors have shown a dramatic ability to lower LDL-cholesterol levels but have been dogged by a failure, so far, to translate this reduction into a meaningful clinical benefit, such as a reduction in morbidity and mortality from cardiovascular events. Torcetrapib, the first CETP inhibitor to emerge, was pulled from clinical testing after a large trial revealed an increased risk of mortality and cardiovascular events. Dalcetrapib was another CETP inhibitor that failed after an interim analysis of the major outcomes trial showed no benefit of treatment.

In the Lancet, the REALIZE investigators say anacetrapib was well tolerated, with no reported differences in serious adverse events, drug-related adverse events, or adverse events leading to drug discontinuation between the anacetrapib- and placebo-treated patients. The researchers did not observe any changes in blood pressure among the anacetrapib-treated patients, an off-target effect that was observed with torcetrapib.

Despite the significant reductions in LDL cholesterol, non-HDL cholesterol, and apolipoprotein B, as well as the increases in HDL cholesterol and apolipoprotein A1, Kastelein and colleagues urge caution with the drug. This study was not powered for changes in clinical outcomes, but they did observe a numerically higher, although statistically nonsignificant, number of cardiovascular events among the anacetrapib-treated patients. In total, four patients who received anacetrapib had an adjudicated cardiovascular event (stroke, MI, or unstable angina) vs none in the placebo arm, a finding that warrants watching, say the researchers.

The large morbidity and mortality trial with anacetrapib, known as REVEAL and run by researchers at the University of Oxford, is currently ongoing, and full results are expected in 2017.

An editorial accompanying the study[2], written by Drs Frederick Raal and Dirk Blom (University of Witwatersrand, Johannesburg, South Africa), highlights the need for LDL-lowering therapies in FH patients. The risk and age of onset of atherosclerosis tends to be proportional to extent and duration of increased LDL-cholesterol levels, they write.

Despite the significant reduction in LDL cholesterol with anacetrapib and the CETP inhibitors, Raal and Blom are more bullish on proprotein subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies for FH patients. In heterozygous FH, they note, PCSK9 inhibitors on top of optimal medical therapy reduced LDL-cholesterol levels by 60%, vs the 40% observed with anacetrapib. Regarding the increase in HDL cholesterol, clinical trials with niacin and fibrates have shown that such an increase does not necessarily confer clinical benefit, they add.

"Ultimately, results of cardiovascular-outcome studies with both drug classes are needed, but as familial hypercholesterolemia is a disorder of LDL metabolism, our bet is on PCSK9 inhibition," write the editorialists.

Kastelein is a consultant for Merck, Dezima Pharmaceuticals, Cerenis, the Medicines Company, Commonwealth Serum Laboratories Behring, Amgen, Sanofi, Regeneron, Eli Lilly, Genzyme, Isis Pharmaceuticals, Aegerion, Esperion, AstraZeneca, Omthera, Pronova, Vascular Biogenics, Boehringer Ingelheim, Catabasis, AtheroNova, UniQure, and Novartis. Disclosures for the coauthors are listed in the article. Raal is an advisory board member for AstraZeneca, Pfizer, Merck, Amgen, and Sanofi and a consultant for Sanofi and Amgen. He has received payment for lectures and/or travel and accommodation costs from Pfizer, AstraZeneca, Amgen, Merck, and Sanofi. Blom is an advisory board member for AstraZeneca, Merck, Amgen, Sanofi, and Aegerion and a consultant for Sanofi, Amgen, and Aegerion. He has received payment for lectures and/or travel and accommodation costs from Pfizer, AstraZeneca, Amgen, Sanofi, Aegerion, and Merck.


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