In genetic analysis, statin-induced LDL decline linked to new-onset diabetes
In a Mendelian randomization analysis, LDL reduction associated with statin use was linked to elevated odds of type 2 diabetes, but not with other pleiotropic effects.
The researchers devised a weighted genetic risk score based on variants in HMGCR that affect LDL to determine whether it had any relationship to observed pleiotropic effects of statins.
“There are naturally occurring variants in the gene HMGCR that encodes the enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase, that statins target. Because those genetic variants are inherited randomly and remain unchanged, a Mendelian randomization approach may be less vulnerable to reverse causation and residual confounding and might provide evidence consistent with a causal effect between statin treatment and candidate outcomes,” Ge Liu, MS, statistical genetic analyst in the department of biomedical informatics at Vanderbilt University, and colleagues wrote.
The researchers developed the score in 53,385 unrelated adults of European ancestry from the BioVU biobank (mean age, 60 years; 56% women) and validated in 30,444 unrelated adults of European ancestry from the eMERGE research consortium (mean age, 69 years; 55% women). The threshold for statistical significance was P < .002 in the BioVU cohort and Bonferroni-adjusted P < .05 in the eMERGE cohort.
According to the researchers, a HMGCR risk score equivalent to a 10 mg/dL decline in LDL was associated with elevated likelihood of type 2 diabetes (OR in BioVU cohort = 1.09; 95% CI, 1.04-1.15; P = 5.58 x 10-4; OR in eMERGE cohort = 1.09; 95% CI, 1.01-1.17; P = .02).
There was no correlation between HMGCR risk score and any of the other non-CV phenotypes analyzed. There was a trend toward a 10 mg/dL decline in LDL conferring elevated likelihood of Parkinson’s disease (OR = 1.3; 95% CI, 1.07-1.58; P = .007) and kidney failure (OR = 1.18; 95% CI, 1.05-1.34; P = .008) in the BioVU cohort, but the trends were not replicated in the eMERGE cohort, the researchers wrote.
“The cardiovascular benefits of statins in clinical practice outweigh the small increased risk of type 2 diabetes,” Liu and colleagues wrote. “Nevertheless, particularly for patients with high type 2 diabetes risk (eg, patients with overweight or obesity), health care professionals could encourage a healthy diet and lifestyle and consider clinical monitoring for the development of type 2 diabetes.”