Metformin potentially cardioprotective in nondiabetic adults

Treatment with metformin yields reductions in total (TC) and low-density lipoprotein (LDL-C) cholesterol levels in individuals without diabetes, even providing an additional triglyceride (TG)-lowering effect among those with polycystic ovary syndrome (PCOS), according to the results of a meta-analysis.

“Although the lipid-lowering effects of metformin were not as good as the general lipid-lowering agents, these findings” point to the potential cardiovascular benefits of metformin in nondiabetic adults and contribute to a growing body of literature on the benefits of the antihyperglycaemic drug in this population.

The meta-analysis included 45 articles encompassing 5,731 participants. Of these trials, 25 involved individuals with obesity (body mass index ≥30 kg/m²) and 20 involved patients with PCOS. Metformin dosage used ranged from 500 to 3,000 mg daily, with treatment lasting between 3 months and 3.2 years.

Pooled data revealed that antihyperglycaemic drug had significant, favourable effects on TC (mean change, −6.57 mg/dl, 95 percent confidence interval [CI], −9.66 to −3.47; p=0.000) and LDL-C (mean change, −4.69 mg/dl, 95 percent CI, −7.38 to −2.00; p=0.001), but not on high-density lipoprotein cholesterol (HDL-C; mean change, −4.33 mg/dl, 95 percent CI, −9.62 to 0.96; p=0.109) and TG (mean change, −0.85 mg/dl, 95 percent CI, −0.36 to 2.06; p=0.169). [Endocrine 2020;67:305-317]

There were significant heterogeneities seen for all lipid profiles (HDL-C: I², 85.5 percent; LDL-C: I², 59.9 percent; TC: I², 75.3 percent; TG: I², 67.1 percent).

Metformin also yielded a notable TG-lowering effect in the subgroup of patients with PCOS, with a mean reduction of 8.15 mg/dl (95 percent CI, −15.16 to −1.14).

The pooled effects of the drug on serum lipid profiles had been shown to be stable in sensitivity analysis. Publication bias estimated using funnel plots or Begg’s tests (HDL-C, p=0.933; LDL-C: p=0.860; TC: p=0.904; TG: p=0.567) was not significant.

“The profits of metformin on blood lipid profiles may be explained by several mechanisms, one of them is through the regulation of AMP-activated protein kinase (AMPK),” the investigators explained.

“As an activator of AMPK, metformin exhibits an antilipogenic effect through suppressing hepatic expression of lipogenic-related protein, acetyl-CoA carboxylase (ACC)… Therefore, with the direct phosphorylation of ACC, metformin could lead to an increased fatty acid oxidation and decrease the synthesis of TGs,” they added. [J Biol Chem 2004;279:47898-47905]

Additionally, the drug not only helps upregulate plasma glucagon-like peptide-1 expression to slow gastric motility and emptying, but also reduce appetite by suppressing neuropeptides associated with feeding. [Curr Opin Endocrinol Diabetes Obes 2014;21:323-329]

Despite the favourable results, the investigators acknowledged several limitations to the study. “It is crucial to highlight that all conclusions we draw are about metabolic profiles,” and whether or not the lipid improvements translate to cardiovascular benefits depend on additional trials.