Insulin resistance does not seem to increase CVD risk in elderly without diabetes

Contrasting associations of insulin resistance with diabetes, cardiovascular disease and all-cause mortality in the elderly: PROSPER long-term follow-up

Literature - Welsh P et al., Diabetologia. 2014

Welsh P, Preiss D, Lloyd SM, et al.,  
Diabetologia. 2014 Dec;57(12):2513-20. doi: 10.1007/s00125-014-3383-9


It is unclear to what extent moderate metabolic perturbations in advance of diabetes are associated with cardiovascular disease (CVD). While it has been proposed that insulin resistance and the consequent hyperinsulinaemia may promote atherosclerosis, has been challenged by observations that insulin can be protective in some animal models [1].
Recent meta-analyses suggested that the association of HOMA-IR and fasting insulin with CVD are probably modest (although based on studies with limited power) [2,3]. The relation between insulin resistance and CVD risk remains particularly unclear in the elderly, even though is this one of the most important patient groups considering population CVD burden.
This study benefitted from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial cohort [4,5] to examine the association of HOMA-IR with CVD and all-cause mortality in older people (70-82  years old) with pre-existing CVD or at high risk of CVD, and with in-trial diabetes to verify that HOMA-IR measured propensity to develop diabetes.

Main results

  • During 3.2 years of within-trial follow-up, 283 out of 5033 participants were diagnosed with diabetes.
  • HOMA-IR and fasting insulin were both strongly associated with incident diabetes, also after adjustment for CVD risk factors and BMI. Persons in the highest vs the lowest tertile of HOMA-IR had a 4.80 (95%CI: 3.14-7.33, P<0.0001) higher risk of developing diabetes and comparison of the highest with the lowest tertile of fasting insulin yielded a 2.43 (95%CI: 1.65-3.58) higher risk.
  • Over 8.6 years of follow-up, 1943 persons died (all-cause). When adjusting for randomised treatment and country, HOMA-IR and fasting insulin showed trends towards an inverse association with all-cause mortality. No such association was left after further adjustment for other risk factors. Nor were any trends observed to an association between HOMA-IR or fasting insulin and CHD mortality and all CVD.


Analysis of the PROSPER cohort of older people without diabetes revealed that HOMA-IR and fasting insulin were strongly associated with risk of developing diabetes within the 3.2 years of in-trial follow-up. Interestingly, long-term follow-up (8.6 years) provided no compelling evidence for an association between HOMA-IR and all-cause mortality, CHD mortality and CVD events. These observations suggest that insulin and insulin resistance are unlikely to be important CVD risk factors in elderly people without diabetes.

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1. Tsuchiya K, Tanaka J, Shuiqing Y et al (2012) FoxOs integrate pleiotropic actions of insulin in vascular  endothelium to protect mice from atherosclerosis. Cell Metab 15:372–381
2. Sarwar N, Sattar N, Gudnason V, Danesh J (2007) Circulating concentrations of insulin markers and coronary heart disease: a quantitative review of 19 Western prospective studies. Eur Heart J 28:2491–2497
3. Gast KB, Tjeerdema N, Stijnen T, et al (2012) Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS ONE 7:e52036
4. Shepherd J, Blauw GJ, MurphyMB et al (2002) PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360:1623–1630
5. Lloyd SM, Stott DJ, de Craen AJ et al (2013) Long-term effects of statin treatment in elderly people: extended follow-up of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). PLoS ONE 8:e72642

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