An increase in body mass index (BMI) partially mediates the greater risk of type 2 diabetes observed with efforts to lower low-density lipoprotein (LDL) cholesterol, suggesting a need to improve weight gain prevention in patients taking LDL-lowering medications. These findings were published in Diabetes Care.

The study included an assessment of human genetic data to investigate the hypothesis that the T2D-inducing effect of lowering LDL cholesterol is mediated through elevated BMI. Investigators relied on summary-level data from 3 genetic studies comprising 921,908 individuals of European descent to perform univariable and multivariable Mendelian randomization (MR) analyses. The researchers then performed individual-level MR analyses to replicate the results in 92,532 individuals from 14 observational studies.

In univariable MR analyses, the researchers found that a 1-standard deviation (SD) reduction in genetically predicted LDL cholesterol increased T2D odds by 12% (95% CI, 1.01-1.24; P <.001) and increased BMI by 0.07 SD units (95% CI, 0.02-0.12; P <.001).


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Less evidence of a direct effect of lowering LDL cholesterol was observed in T2D through BMI in the multivariable MR analysis (OR, 1.04; 95% CI, 1.01-1.08) “with a proportion mediated of 38% of the total effect,” the researchers wrote (P =.03). The investigators found that the total and indirect effect estimates were comparable across several different sensitivity analyses. Additionally, the individual-level MR analyses verified the total indirect effect of reducing LDL cholesterol related to T2D through BMI with an estimated proportion mediated of 8% (P =.04).

The researchers suggest their findings may be biased by bidirectional or pleiotropic effects of the variants that were modeled as instrumental variables, despite the robustness of MR to confounding and measurement error compared with conventional observational methods.

“Our findings support that elevated BMI partially mediates the diabetogenic effects of observed with lowering LDLc,” the researchers concluded. “Further exploration of this mechanism may yield insights into adipose tissue and type 2 diabetes pathophysiology, and targeted weight control strategies may be investigated to mitigate the increased risk of type 2 diabetes among individuals taking LDLc-lowering therapies.

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Wu P, Moon JY, Daghlas I, et al. Obesity partially mediates the diabetogenic effect of lowering LDL cholesterol. Diabetes Care. Published online November 17, 2021. doi:10.2337/dc21-1284