Triglyceride-rich lipoproteins play causal role in CV risk

Issue: December 2016

BOSTON — Genetic and observational studies have demonstrated that triglyceride-rich lipoproteins play a causal role in CV risk, and raising high-density lipoprotein (HDL) has no effect on CV outcomes, a speaker said at the Cardiometabolic Health Congress.

This challenges previous assumptions that HDL plays a causal role in protection against CV risk. As adjustment for HDL attenuates the estimate of triglycerides contribution to cardiovascular risk, many have assumed that triglyceride-rich lipoproteins, that tend to vary inversely with HDL, merely reflect low HDL, according to Peter Libby, MD, the Mallinckrodt Professor of Medicine at Harvard Medical School, cardiovascular medicine specialist at Brigham and Women’s Hospital and section editor of the Vascular Medicine section of the Cardiology Today Editorial Board.

The assumption that HDL played a crucial role in reducing CV risk derived from consistent evidence that higher levels of HDL associated with lower risk for CVD, Libby said.

“The problem is that … genetic data really cast doubt of the protective effect of [HDL],” Libby said. He noted that people with genetically acquired lifelong elevated HDL showed no reduced CV risk.

Additionally, he said, “drugs that increase HDL have failed to reduce cardiovascular events in clinical trials, and genetic variants that lead to lifelong elevation in HDL don’t seem to translate to less heart disease.”

The FDA has withdrawn indications for two drugs that raise HDL: extended-release niacin and delayed-release fenofibric acid.

Some observational studies that showed that adjusting for HDL attenuates the effect of triglyceride-rich lipoproteins on CV risk were flawed because the adjustment included non-HDL, which captures triglyceride-rich lipoproteins, according to Libby. “Adjusting a risk factor for itself necessarily attenuates the risk estimate,” he said.

However, in a recently published 22-year follow-up of the BIP study, elevated triglyceride levels, fully adjusted for confounders, conferred an increased risk for all-cause mortality in patients with CHD, with particularly high risk shown in those with triglyceride levels > 500 mg/dL (P < .0001), Libby said.

Recent genetic studies have identified causal roles for apolipoprotein A5, apolipoprotein C3 and ANGPTL4, a gene inhibiting lipoprotein lipase whose loss of function is associated with lower triglycerides and reduced risk for CAD, he said.

“To make it simple, ANGPTL4 is a bad guy that inhibits lipoprotein lipase and causes an increase in triglyceride-rich lipoproteins … APOC3 is another bad guy that works by some of the same mechanisms and is pro-inflammatory … and APOA5 is a good guy which can accelerate lipoprotein lipase action and decrease the concentration in triglyceride-rich lipoproteins,” he said. “There’s a very high degree of concordance between the observational epidemiology and the genetics. Things all go in the right direction with four different genetic targets, ANGPTL4, APOC3, APOA5 and lipoprotein lipase itself.”

Libby argues that HDL is a marker for CV risk, not a causal factor, and at least some triglyceride-rich lipoproteins are causal factors, and that previous assumptions may have “bet on the wrong variable by correcting triglycerides for HDL.”

Trials of HDL-raising agents failed to meet their primary endpoints, but some agents performed well in patients with high triglyceride-rich lipoproteins. With that in mind, PROMINENT, a study of pemafibrate (Kowa Pharmaceuticals), a selective PPAR-alpha modulator, will begin soon to evaluate whether reducing triglyceride-rich lipoproteins and apolipoprotein C3 levels in patients with diabetes improves CV outcomes, Libby said.

“It’s going to be a pretty exciting time as we try to marshal resources and gear up for personalized medicine initiatives,” he said. “The goal we are aiming for is to take patients post-MI and allocate them to therapies that will be tailored to their particular residual risk profile.” – by Erik Swain

Reference:

Libby P. Triglycerides on the Rise: Should We Swap Seats on the Seesaw? Presented at: Cardiometabolic Health Congress; Oct. 5-8, 2016; Boston. Libby P. Triglycerides on the rise: Should we swap seats on the seesaw? Eur Heart J 2015; 36(13):774-776.

Disclosure: Libby reports receiving research support from Novartis; serving on scientific and serves on advisory boards for Amgen, Athera, Interleukin Genetics, Kpwa, Medimmune, Novartis and Sanofi/Regeneron; and serving as an unpaid consultant or steering committee member or executive committee member for trials sponsored by Amgen, Esperion, Kowa Pharmaceuticals, Novartis, and Pfizer. He does not accept personal compensation from drug or device companies.