Abstract
BACKGROUND: Dyslipidemia is a recognized risk factor for type 2 diabetes (T2D), yet the genetic basis and causal nature remain unclear, particularly in Chinese populations. OBJECTIVES: The authors investigated the causal effects of genetically predicted lipid levels on T2D risk and explored the potential effects of lipid-modifying drugs. METHODS: Leveraging data from the Kunshan Community cohort in China, we analyzed the associations between low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides (TGs) with T2D risk using genetic risk scores, 1-sample univariable, multivariable, and nonlinear Mendelian randomization (MR) analyses. Two-sample MR using summary-level data from Global Lipid Genetics Consortium and Biobank Japan was used for validation. Drug-target MR was used to examine the impact of lipid-modifying drug targets on T2D. RESULTS: Lower genetic risk scores of LDL-C (OR per SD: 0.97 [95% CI: 0.95-0.99]; P = 0.010) and TGs (0.96 [95%CI: 0.94-0.98]; P = 0.002) were associated with increased T2D risk. Univariable MR revealed that genetically predicted lower LDL-C (0.78 [95% CI: 0.65-0.93]; P = 0.006) and TG levels (0.76 [95% CI: 0.66-0.89]; P < 0.001) were linked to a higher T2D risk, validated by 2-sample MR. Multivariable MR demonstrated a direct inverse association between LDL-C (0.80 [95% CI: 0.66-0.97]; P = 0.020) and TG (0.80 [95% CI: 0.66-0.97]; P = 0.022) with T2D. No evidence was found for nonlinearity. Among lipid-modifying drugs, genetic mimicry of apolipoprotein C3 (APOC3) inhibition increased T2D risk (OR per 1 mmol/L reduction in TG: 1.38 [95% CI: 1.10-1.75]; P = 0.007). CONCLUSIONS: Our findings suggested potential adverse effects of lower LDL-C, TG levels, as well as long-term use of APOC3 inhibitors on T2D risk in Chinese populations. These findings highlight the need for cautious lipid management strategies in T2D prevention.