Boston, MA—High-density lipoprotein (HDL) cholesterol as a target for treatment in patients with dyslipidemia remains an unfulfilled promise. Christie Ballantyne, MD, Chief, Section of Cardiology Research, and Chief of Cardiology at Baylor College of Medicine, Houston, TX, presented an update on HDL-raising therapies and other developments in pharmacotherapy for dyslipidemia at the 2012 Cardiometabolic Health Congress.
A large randomized controlled clinical outcomes trial with dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was terminated early because of a lack of clinically meaningful efficacy. The planned follow-up was 4 years, but the trial was stopped early when it became apparent that dalcetrapib would have no effect on the primary efficacy measure—a composite of various cardiovascular outcomes. Unlike with a previous CETP inhibitor torcetrapib, there were no safety concerns with dalcetrapib.
Two other CETP inhibitors are under active investigation, said Dr Ballantyne. Anacetrapib increases HDL cholesterol by 138% compared with placebo and is being studied in the clinical outcomes trial known as Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL). Evacetrapib increases HDL cholesterol by 54% to 129% (vs –3% with placebo) and is also being tested in the clinical outcomes trial A Study of Evacetrapib in High-Risk Vascular Disease (ACCELERATE), which is in progress.
“These agents profoundly reduce low-density lipoprotein [LDL] cholesterol along with raising HDL, so they won’t give us a clear answer with regard to the HDL hypothesis,” said Dr Ballantyne.
A recent analysis of genome-wide association studies (Voight BF, et al. Lancet. 2012;380:572-580) showed no association between gene variants that are related exclusively to HDL cholesterol and the reduction in the risk of coronary heart disease (CHD).
“The gene that had the greatest impact on HDL, endothelial lipase, had no impact on CHD,” he said. “There are 6 genes related to HDL metabolism that are associated with CHD, but all 6 of them also have some impact on triglycerides or LDL. So, it really calls into a little more complexity to target HDL.”
In addition, 2 studies expected to be reported in 2013 should offer some answers about the HDL hypothesis, said Dr Ballantyne. One study is testing an agent that increases apolipoprotein (apo) A1 transcription, and the other is using infusions of synthetic HDL. Neither study is looking at the effect of the therapies on outcome end points.
Interim Safety Results from HPS2-THRIVE
An interim safety and tolerability analysis from the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study shows that 24.0% of patients randomized to niacin plus laropiprant at a median follow-up of 3.4 years compared with 15.4% of those assigned to placebo. Flushing was responsible for 0.8% of withdrawals from the laropiprant arm compared with 0.1% of the placebo arm. Other skin-related reasons (mainly pruritus and rash) caused discontinuation in 5.1% of patients who were randomized to niacin/laropiprant and in 1.2% assigned to placebo. Gastrointestinal problems also caused more withdrawals in the niacin/laropiprant arm than in the placebo arm (3.6% vs 1.6%, respectively).
An emerging profile that is appearing in global studies of some lipid-modifying therapies is a difference in pharmacokinetics and side effects in Asian populations versus the rest of the world, said Dr Ballantyne. In HPS2-THRIVE, although myopathy was rare, occurring in 0.54% of the niacin plus laropiprant arm, it occurred approximately twice as often (1.13%) in the study participants in China. Elevations in liver enzymes were also more common in Chinese patients who were assigned to niacin plus laropiprant compared with those from other countries.
The outcomes from HPS2-THRIVE will be released in April 2013.
Omega-3 Fatty Acid Gains FDA Approval
Icosapent ethyl (Vascepa), an ultra-pure omega-3 fatty acid product, gained approval from the US Food and Drug Administration (FDA) over the summer, as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (>500 mg/dL). An outcomes trial called the Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE IT) has been initiated with icosapent in addition to statin therapy in patients with CHD and mixed dyslipidemia, with the goal of getting an additional indication for the treatment of patients with mixed dyslipidemia.
Potential Treatments for Familial Hypercholesterolemia
Homozygous familial hypercholesterolemia (FH) is the most severe form of FH, and it has few options for treatment, Dr Ballantyne pointed out. Two investigational agents with potential indications for the treatment of patients with homozygous FH are lomitapide capsules and mipomersen injection. The manufacturers of each of these drugs were seeking indications for each agent as adjuncts to other maximally tolerated lipid-lowering agents, and both agents were the subject of FDA advisory committee meetings in October 2012. The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee endorsed that approval of lomitapide capsules by a vote of 13 to 2 and endorsed mipomersen by a vote of 9 to 6.
Lomitapide is a microsomal triglyceride transfer protein inhibitor that lowers LDL cholesterol by approximately 40% while also reducing levels of total cholesterol, apo B, triglycerides, non-HDL cholesterol, very-low-density lipoprotein (VLDL), and lipoprotein(a) (Lp[a]). Elevations in alanine transaminase greater than 3 times the upper limit of normal occurred in 38% of lomitapide recipients in a pivotal trial.
Mipomersen is an apo B antisense drug that inhibits the release of apo B-100, an important structural and functional component of lipoproteins, from the liver. Blocking apo B-100 release blocks the production of VLDL, LDL, and Lp(a). Concern has been raised with mipomersen over increases in serum transaminases and in hepatic fat in phase 3 trials.
Monoclonal Antibody Substantially Lowers LDL
Proprotein convertase subtilisin/ kexin 9 (PCSK9) is a hepatic regulator of the LDL receptor. PCSK9 in the plasma binds to LDL receptors, reduces recycling, effectively downregulating LDL receptor activity, thus resulting in increased plasma LDL cholesterol.
Injectable human PCSK9 monoclonal antibodies bind to PCSK9 to block its effect and to prevent the degradation of LDL receptors.
In a phase 2 study of the PCSK9 monoclonal antibody SAR236553/ REGN727 released earlier in 2012, LDL cholesterol reductions as high as 72% were achieved in patients already being treated with atorvastatin.