Metabolomics and Genomics Study Shows How Metformin Reduces LDL Cholesterol

By Anne Harding

NEW YORK - A new metabolomic and genomic study demonstrates how metformin may reduce levels of LDL cholesterol and possibly reduce cardiovascular disease risk.

"We speculate that metformin intake affects the levels of LDL cholesterol via AMPK, leading to a down-regulation of the genes FADS1 and 2," Dr. Rui Wang-Sattler and Dr. Stefan Brandmaier of Helmholtz Zentrum Munchen in Neuherberg, Germany, two authors of the study, told Reuters Health in an e-mail interview.

While metformin has been used to treat diabetes for over half a century, its mechanism of action is still not fully understood, the researchers note in their report published online August 5 in Diabetes Care.

To better understand the drug's pleiotropic effects, the investigators analyzed metabolomic and genomic data from the population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort, which included 4,261 individuals between the ages of 25 to 74 year old, of which 3,080 participated in a follow-up investigation.

They replicated their findings in two independent studies, the Erasmus Ruchphen Family study, of 3,000 individuals, and the Netherlands Twin Register, which includes 175,000 people.

Fasting serum metabolite profiling, targeting more than 130 metabolites, identified 6 metabolites linked to metformin treatment in the KORA follow-up cohort. Replication studies and sensitivity analyses narrowed the list to three metabolites, all of which were acyl-alkyl phosphatidylcholines (PCs).

A longitudinal study of the KORA cohort confirmed that levels of the three acyl-alkyl PCs were decreased in patients who began metformin treatment during follow-up. The reduction of these 3 metabolites was associated with decreased LDL cholesterol levels.

Genomic analysis identified 17 genes that were significantly associated with variations in the three metabolites, including FADS1 and FADS2. Metformin activates AMPK in liver cells, the authors note, leading to the inhibition of FADS1 and FADS2 synthesis.

"The underlying mechanism is most likely the metformin-induced activation of AMPK and the consequent suppression of SREBP1c and FADS, which leads to reduced levels of PUFA and LDL-C," the researchers write. "Our findings suggest a pharmaco-epidemiologic mechanism by which metformin may exert beneficial effects to prevent CVD."

The study was supported by multiple noncommercial sources.

SOURCE: https://bit.ly/1TerCj8

Diabetes Care 2015.

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