Melissa Walton-Shirley


March 19, 2017

I attended a session entitled "Harnessing the power of genetics to prevent ASCVD," chaired by Dr Henry Ginsberg of New York and Dr Michael Shapiro of Portland, OR. With the FOURIER trial, the field of lipidology has been the favored child for this meeting, so I felt compelled to look more deeply into lipidology. Don't let the word "genetics" put you off—I've broken this dense topic into bite-sized nuggets so that you, dear reader, can peruse what you like and skip the rest (as everyone does at these meetings). Here are some of the topics discussed.

Leveraging Genetic Epidemiology to Understand CV Risk: What Have Nature's RCTs Taught Us?

"LDL causes atherosclerotic CV disease. That goes along with the slightly exuberant expectations of the FOURIER trial," Dr Brian Ference (Wayne State University School of Medicine, Detroit, MI) said, noting the remarkable concordance between randomized genetic studies and FOURIER. He then flashed a slide from his study on the causal and cumulative effect of LDL-C,[1] showing a log scale of the proportionate risk reduction associated with genetically lower LDL-C. At a natural untreated level of 16 mg/dL lower than other cohorts in the study, there was an approximate 25% risk reduction.

Ference remarked that "yesterday's [FOURIER] results followed precisely what the biological levels showed. Lowering LDL by any mechanisms should reduce events." He also mentioned the IMPROVE-IT results, which showed that 6-year treatment with ezetimibe on top of a statin lowered LDL-C by 15 mg/dL and yielded a 15% lower risk of CV events.

Still Bothersome Issues With the LDL Hypothesis. Dr Ference alluded to questions regarding causality of LDL cholesterol and CV events in the ACCELERATE trial. "Is LDL really it?" he asked, rhetorically.

In that failed CETP inhibitor placebo-controlled trial, evacetrapib (Lilly) increased HDL-C by 130% and reduced mean LDL-C by 37% but had no impact on the primary end point of CV death, MI, stroke, revascularization, or hospitalization. Like the molecule's failed sister torcetrapib, evacetrapib was also associated with a small increase in systolic BP. In addition, inflammatory markers were increased in the treatment arm but were reduced in the placebo group in ACCELERATE.

Ference also spoke of the "bothersome fibrate trials" but didn't have time to go into details. ACCORD[2] came to mind, where adding fibrate to a statin actually increased adverse events in women despite LDL lowering, HDL raising, and improvement in triglyceride levels.

Severe Hypercholesterolemia: Does the Genotype Matter?

Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) focused his talk on when to consider testing for familial hypercholesteremia (FH), given the 26-fold increase in CV events with an FH mutation. He described a case of a young gentleman in his 30s who coded while walking in a park and required urgent revascularization due to diffuse coronary arteriopathy. The patient had no family history of CAD and was a nonsmoker.

He reviewed a study from the Geisinger Health system[3] that showed a prevalence of FH between 1:118 for unselected and 1:256 for cath-lab recruited individuals, the second highest extracted from the EHR record and the lowest from "other sites" within the system. While the price of testing is dropping, Ballantyne cautioned that it may not be covered. "US patients aren't usually tested," he said.

He noted that not all patients with xanthomas and high cholesterol have FH, and treatment strategies vary. For example, patients with phytosterolemia, an autosomal recessive condition that leads to unusually high plasma plant-sterol levels, may also exhibit subcutaneous xanthomas on the hands and the Achilles as well as arthritis, splenomegaly, and hemolytic episodes. Reducing dietary intake of oils, olives, and avocados as well treatment with statins have failed to reduce sterol levels in sufferers. In the early days, ileal bypass and bile-acid resin binders were utilized, but in 2002 ezetimibe received FDA approval for treatment.

Dr Ballantyne recalled another patient who was tested for FH only because his wife was pregnant. He had already undergone genetic testing that was positive for LDLR variant 798T>A, which is associated with a 50% chance of having a coronary event by age 50 and a 20-fold increase in risk of CHD. This expectant father's lipid levels were an LDL-C of 261 mg/dL, triglycerides of 232 mg/dL, a total cholesterol of 350 mg/dL, and HDL-C of 43 mg/dL. Because he has now been diagnosed, he stands a better chance of meeting his grandchildren.

There are some practice-changing nuggets here. I plan to start testing more patients for FH and referring them to formal lipid clinics when appropriate. It was suggested by one of the presenters that all patients with LDL-C levels ≥190 mg/dL be tested. I've never used fibrates much and probably never will, but in the world of medical research, the word "never" is always waiting for the next big trial.

You might have found a better way to spend your Saturday morning, but sitting in this session counts as fun for me. I will have more nuggets from these excellent presentations. Stay tuned.


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