The Role of Genetics in Cardiovascular Risk Reduction: Findings From a Single Lipid Clinic and Review of the Literature.

BACKGROUND: Genetic information is not routinely obtained in the management of most lipid disorders or in primary or secondary prevention of cardiovascular disease (CVD). We sought to determine the prevalence of pathogenic variants associated with lipoprotein metabolism or coronary artery disease (CAD) in a single lipid clinic and discuss the future use of genetic information in CVD prevention. METHODS: Genetic testing was offered to patients with hypertriglyceridemia (defined as pre-treatment fasting triglycerides ≥150 mg/dL), elevated LDL-C (defined as pre-treatment ≥190 mg/dL), low HDL-C (defined as ≤40 mg/dL), elevated lipoprotein (a) (defined as ≥50 mg/dL or 100 nmol/L) or premature CAD (defined as an acute coronary syndrome or revascularization before age 40 years in men and 50 years in women) using next-generation DNA sequencing of 327 exons and selected variants in 129 genes known or suspected to be associated with lipoprotein metabolism or CAD. RESULTS: 82 of 84 patients (97.6%) were found to have a variant associated with abnormal lipid metabolism or CAD. The most common pathogenic or likely pathogenic variants included those of the LDL receptor (15 patients) and lipoprotein lipase (9 patients). Other common variants included those of apolipoprotein A5 (14 patients) and variants associated with elevated lipoprotein (a) (25 patients). CONCLUSIONS: The majority of patients presenting to a single lipid clinic were found to have at least one variant associated with abnormal lipoprotein metabolism or CAD. Incorporating genetic information, including the use of genetic risk scores, is anticipated in the future care of lipid disorders and CVD prevention.

The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Sterol Absorption Markers in a Cohort of Real-World Patients.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in multiple tissues, including the small intestine. The effect of PCSK9 inhibition on cholesterol absorption is not known. OBJECTIVES: Measure serum cholesterol absorption markers before and after initiation of PCSK9 inhibitors. METHODS: Single-center retrospective cohort of patients administered evolocumab and alirocumab between July 2015 and January 2017. Paired t tests were used to compare mean serum cholesterol marker concentrations, and ratios to total cholesterol, before and after PCSK9 inhibitor initiation. Analyses were repeated for those taking and not taking statins and taking or not taking ezetimibe at both initiation and follow-up, for each PCSK9 inhibitor, and based on follow-up time (<60, 60-120, and >120 days). RESULTS: There were 62 possible participants, 34 were excluded for lack of data or unknown PCSK9 inhibitor initiation date. Average follow-up was 92.5 days. Mean campesterol (before 3.14 µg/mL, 95% CI: 2.79-4.38 µg/mL; after 2.09 µg/mL, 95% CI: 1.87-2.31 µg/mL; P < .0001), sitosterol (before 2.46 µg/mL, 95% CI: 2.23-2.70 µg/mL; after 1.62 µg/mL, 95% CI: 1.48-1.75 µg/mL; P < .0001), and cholestanol (before 3.25 µg/mL, 95% CI: 3.04-3.47 µg/mL; after 2.08 µg/mL, 95% CI: 1.96-2.21 µg/mL; P < .0001) all significantly decreased at follow-up. There was no significant change in absorption marker to total cholesterol ratios. Findings were not influenced by statin or ezetimibe use or nonuse, which PCSK9 inhibitor was prescribed, or time to follow-up. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 inhibition was associated with decreased cholesterol absorption markers.

How Genomics Is Personalizing the Management of Dyslipidemia and Cardiovascular Disease Prevention.

PURPOSE OF THE REVIEW: To summarize advances in genomic medicine and anticipated future directions to improve cardiovascular risk reduction. RECENT FINDINGS: Mendelian randomization and genome-wide association studies have given significant insights into the role of genetics in dyslipidemia and cardiovascular disease (CVD), with over 160 gene loci found to be associated with coronary artery disease to date. This has enabled the creation of genetic risk scores that have demonstrated improved risk prediction when added to clinical markers of CVD risk. Incorporation of genomic data into clinical patient care is on the horizon. Genomic medicine is expected to offer improved risk assessment, determination of targeted treatment strategies, and improved detection of lipid disorders causal to CVD development.

Evolution of Omega-3 Fatty Acid Therapy and Current and Future Role in the Management of Dyslipidemia.

Omega-3 fatty acids have shown modest benefit in certain subgroups at higher cardiovascular risk. Ongoing trials are investigating cardiovascular event rate reduction with newer, more efficacious formulations with a focus on these higher risk patients. This article focuses on the previously demonstrated benefits of omega-3 fatty acid therapies, currently available formulations, and their current and future role in reducing cardiovascular risk.

Omega-3 carboxylic acids monotherapy and combination with statins in the management of dyslipidemia.

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management placed greater emphasis on statin therapy given the well-established benefits in primary and secondary prevention of cardiovascular disease. Residual risk may remain after statin initiation, in part because of triglyceride-rich lipoprotein cholesterol. Several large trials have failed to show benefit with non-statin cholesterol-lowering medications in the reduction of cardiovascular events. Yet, subgroup analyses showed a benefit in those with hypertriglyceridemia and lower high-density lipoprotein cholesterol level, a high-risk pattern of dyslipidemia. This review discusses the benefits of omega-3 carboxylic acids, a recently approved formulation of omega-3 fatty acid with enhanced bioavailability, in the treatment of dyslipidemia both as monotherapy and combination therapy with a statin.

The future of n-3 polyunsaturated fatty acid therapy.

PURPOSE OF REVIEW: This article focuses on the potential role by which a complex mixture of omega-3 fatty acids (OM3-FAs) may beneficially modify cardiovascular risk by modifying the cholesterol composition of atherogenic lipoproteins. This hypothesis is being tested in the STRENGTH trial, which is enrolling 13 000 patients on statins at high cardiovascular risk with hypertriglyceridemia and low HDL cholesterol (HDL-C) treated with an OM3-carboxylic acid. RECENT FINDINGS: Complex mixtures of OM3-FAs containing predominately eicosapentanoic acid and docosahexanoic acid in combination with statins lowers non-HDL by reducing triglyceride-rich lipoprotein cholesterol (TRL-C) while shifting small LDL cholesterol (LDL-C) to large LDL-C. Recent genomic and epidemiological studies have implicated TRL-C and small LDL-C as causal for cardiovascular disease. Therefore OM3-FAs containing both eicosapentanoic acid and docosahexanoic acid in combination with statins may beneficially modify the high residual risk for patients with hypertriglyceridemia and low HDL-C. SUMMARY: Although outcome trials are underway, subgroup analyses of data from previous randomized controlled trials are suggestive of a reduction in coronary artery disease and atherosclerotic cardiovascular disease event rates with triglyceride and TRL-C lowering therapies, particularly if accompanied by low HDL-C. Although the limitations of such data are acknowledged, clinicians must make treatment decisions while awaiting more definitive results from well-designed large-scale randomized controlled trials.

The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter?

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects.