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

Charlotte Andersson, Asya Lyass, Martin G. Larson, Sander J. Robins, Ramachandran S. Vasan

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2774-2780
Number of pages7
Issue number12
StatePublished - Sep 26 2015
Externally publishedYes


  • Diabetes risk
  • Low-density lipoprotein concentrations
  • Mendelian randomisation
  • Untreated individuals

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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