Numerous prospective studies have demonstrated that reduced high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride (TG) levels, but not low-density lipoprotein cholesterol levels (LDL-C),^1-4 are independent risk factors that are associated with type 2 diabetes (T2D). However, causal evaluation based on these studies is limited owing to the potential for unmeasured confounding and reverse causality. Hence, the relevance of each of these lipoprotein fractions in association with T2D is actively debated.

There are several prior studies that have provided conflicting evidence on the direction and quantitative correlation of major lipid fractions in association with the risk for T2D. The most contentious discussion involves the role of LDL-C in relation to T2D. While numerous prospective epidemiological studies have shown that LDL-C levels are log-linearly associated with the risk for coronary heart disease (CHD) independent of TG and HDL-C levels,⁵ no such association of LDL-C level with T2D has been observed.^1-4 However, evidence from a meta-analysis of randomized clinical trials has shown that reduction of LDL-C by statin treatment, compared with placebo, led to a higher, but very small absolute, risk for T2D.⁶ While this observation was argued to be due to survival bias among statin users, off-target effects of high statin dose, or chance, further sensitivity analyses conducted in this meta-analysis did not find any evidence of such biases. In support of this observation, Swerdlow et al⁷ subsequently reported that genetic variants associated with reduced expression of 3-hydroxy-3-methylglutaryl-CoA reductase, the target of statins, and reduced LDL-C levels were associated with increased risk for T2D. Thus, the observation that statins increase T2D risk is likely to be real, but the small increased risk for diabetes is surpassed by the large risk reduction of cardiovascular disease achieved by statin therapy.