Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study

Diabetologia. 2015 Dec;58(12):2774-80. doi: 10.1007/s00125-015-3762-x. Epub 2015 Sep 26.


Aims/hypothesis: Statins and niacin (nicotinic acid) reduce circulating LDL-cholesterol (LDL-C) levels by different mechanisms. Yet, both increase the risk of diabetes mellitus. Our objective was to relate blood LDL-C concentrations and a genetic risk score (GRS) for LDL-C to the risk of incident diabetes in individuals not treated with lipid-modifying therapy.

Methods: We evaluated participants of the Framingham Heart Study who attended any of Offspring cohort examination cycles 3-8 and Third Generation cohort examination cycle 1 (N =14,120 person-observations, 6,011 unique individuals; mean age 50 ± 11 years, 56% women), who were not treated with lipid-modifying or antihypertensive medications and who were free from cardiovascular disease at baseline. Incident diabetes was assessed at the next examination.

Results: The GRS was significantly associated with LDL-C concentrations (sex- and age-adjusted estimated influence 0.24, p < 0.0001). On follow-up (mean 4.5 ± 1.5 years), 312 individuals (2.2%) developed new-onset diabetes. In multivariable models, a higher LDL-C concentration was associated with lower risk of diabetes (OR per SD increment 0.81, 95% CI 0.70, 0.93, p = 0.004). The GRS was associated with incident diabetes in a similar direction and of comparable magnitude (OR per SD increment 0.85, 95% CI 0.76, 0.96, p = 0.009).

Conclusions/interpretation: Among individuals not treated with lipid-modifying therapy low LDL-C concentrations were associated with increased diabetes risk. These observations may contribute to our understanding of why lipid-lowering treatment may cause diabetes in some individuals. Additional studies are warranted to elucidate the molecular mechanisms underlying our observations.

Keywords: Diabetes risk; Low-density lipoprotein concentrations; Mendelian randomisation; Untreated individuals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cholesterol, LDL / blood*
  • Cohort Studies
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / epidemiology*
  • Diabetes Mellitus / genetics*
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk
  • Risk Factors
  • Triglycerides / blood


  • Cholesterol, LDL
  • Triglycerides