Statins: Beyond Treatment for Low-Density Lipoprotein Cholesterol

Statins may aid in extensive lipid changes beyond low-density lipoprotein cholesterol (LDL-C), according to new metabolomic profiling data published in the Journal of the American College of Cardiology.

While stains have become a mainstay therapy for dyslipidemia and cardiovascular disease risk, little is known about the molecular effects on metabolic pathways.

Researchers analyzed metabolic profiles in 4 population-based cohorts from the United Kingdom and Finland, based on serum nuclear magnetic resonance metabolomics at 2 time points (2.5 years and 23 years of follow-up). A total of 5590 patients were included—716 of whom started statin therapy and 4874 of whom were “persistent nonusers.” During follow-up, concentration changes in 80 lipid and metabolite measures were compared between the 2 groups.

Remnant cholesterol was substantially lowered (80% relative to LDL-C), but triglycerides were only moderately lowered (25% relative to LDL-C). Omega-6 achieved the lowest levels of the fatty acids (68% relative to LDL-C) and other fatty acids were only “modestly affected.” Circulating amino acids, ketones, and glycolysis-related metabolites were not significantly affected.

To better understand pharmacological effects of statins, researchers used Mendelian randomization to analyze a genetic variant, rs12916, known to mimic inhibition of HMG-CoA reductase (HMGCR; the intended drug target) with the same 80 lipids and metabolites identified in the 4 original cohorts, but in a much larger population: 27 914 individuals from 8 cohorts.

The authors wrote, “Although Mendelian randomization of drug targets has been used previously, our study was the first to our knowledge to combine the concept with observational results across a wide range of cardiometabolic biomarkers.”

They discovered the metabolic changes associated with statins closely matched the association pattern with rs12916 in the HMGCR gene (R²=0.94; slope 1.00 ± 0.03).

“Starting statins was associated with minor lowering of large- and medium-sized VLDL [very-low-density lipoprotein] particle concentrations (11% to 20% relative to the LDL-C-lowering effect), whereas substantial lowering of the smallest VLDL particles (71% relative to LDL-C) was observed.”

In addition, total cholesterol, non-HDL-C (high-density lipoprotein), and IDL-C (intermediate-density lipoprotein) were all lowered (92% to 100%), similar to LDL-C.

In the future, molecular effects of drugs may be better understood via metabolic profiling and genetic proxies that mimic pharmacological action.

Reference

Würtz P, Wang W, Soininen P, et al. Metabolomic profiling of statin use and genetic inhibition of HMG-CoA reductase. J Am Coll Cardiol. 2016;67(10):1200-1210. doi: 10.1016/j.jacc.2015.12.060.