Metformin May Also Lower LDL Cholesterol: Study Suggests How

Marlene Busko

August 13, 2015

Metformin, which has been used to lower blood glucose levels in patients with type 2 diabetes for more than 50 years, appears to also lower LDL-cholesterol levels, possibly by a complex mechanism, according to new research.

In a study published online August 5 in Diabetes Care, Dr Tao Xu, from Helmholtz Zentrum Munchen, in Neuherberg, Germany, and colleagues describe how they analyzed levels of 131 serum metabolites as well as genomic data in three large cohorts of participants with treated or untreated type 2 diabetes, prediabetes, or no diabetes.

They found that patients who were taking metformin had lower levels of three metabolites and LDL cholesterol, senior author Dr Rui Wang-Sattler, from Helmholtz Zentrum Munchen and the German Center for Diabetes Research, told Medscape Medical News.

It appears that "metformin intake activates AMP-activated protein kinase (AMPK) and consequently suppresses fatty-acid desaturase (FADS) genes, which leads to reduced levels of lipid metabolites and LDL cholesterol," she added.

This mechanism may partly explain how metformin may lower LDL-cholesterol levels in patients with type 2 diabetes and potentially lower their risk of cardiovascular events, she said.

The researchers now plan to continue this line of research to better understand how metformin works.

Pleiotropic Effects of Metformin

Earlier research has suggested that metformin has pleiotropic effects and may lower LDL-cholesterol levels and reduce the risk of cardiovascular disease and cancer.

The drug appears to upregulate the cytoplasmic 5-AMPK pathway (which is involved in stimulating glycolysis and fatty-acid oxidation and inhibiting gluconeogenesis and fatty-acid synthesis). To date, researchers have identified six metabolites that metformin acts on.

In this latest work, Dr Xu and colleagues aimed to specifically investigate the effects of metformin on levels of metabolites and LDL cholesterol in patients with type 2 diabetes.

They analyzed data from more than 2000 individuals living in the community who participated in the Cooperative Health Research in the Region of Augsburg (KORA) study from 1999 to 2001 with follow-up during 2006–2008.

The patients were classified into five groups: normal glucose tolerance (2129), impaired glucose tolerance or prediabetes (375), type 2 diabetes and no antidiabetic therapy (169), type 2 diabetes and metformin therapy (90), or type 2 diabetes and insulin therapy (24).

The researchers determined serum levels of 131 metabolites, including six that metformin is known to act on.

Compared with the other participants, those with type 2 diabetes who were receiving metformin had much lower concentrations of the six metabolites — independent of multiple variables (sex, body mass index, physical activity, alcohol intake, smoking, systolic blood pressure, HDL cholesterol, triglycerides, HbA1c, fasting glucose, and use of statins, beta-blockers, ACE inhibitors, and angiotensin-receptor blockers).

After adjustment for these variables and for the duration of type 2 diabetes, the levels of three of the metabolites — 3 acyl-alkyl phosphatidylcholines (PCs), which are composed of at least one polyunsaturated fatty acid (PUFA) — were still much lower in the 90 patients with type 2 diabetes who used metformin.

When the analyses were repeated in the Erasmus Rucphen family cohort and the Netherlands Twins cohort, levels of the same three metabolites were also lower in patients with type 2 diabetes who were receiving metformin.

Metformin use was linked with lowered levels of LDL cholesterol, and 17 genes (including FADS1 and FADS2) were associated with the three metabolites.

"Our study suggests that metformin might indeed have an additional beneficial effect with regard to cardiovascular diseases among the [type 2] diabetes patients," Dr Xu summarized in a statement from their institution.

This work is helping to unravel the molecular mechanism of action of metformin.

"Until now the exact mechanism is unclear. Thus, we want to continue our contribution to its decryption," co–first author Dr Stefan Brandmaier, from Helmholtz Zentrum Munchen, added.

And importantly, the researchers conclude, their work indicates "a novel approach to identify pleiotropic effects of medication using multilevel 'omics' data."

Diabetes Care. Published online August 5, 2015. Abstract

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