Neutral effect of ezetimibe addition to statin therapy on glucose metabolism

Statin therapy with or without ezetimibe and the progression to diabetes

Literature - Barkas F et al., J Clin Lipid 2016

Barkas F, Elisaf M, Liberopoulos E, et al.
Journal of Clinical Lipidology 2016;10:306–313


Recently, the relationship of statins with the development of diabetes (DM) has received a lot of attention based on data showing that:
  • individuals receiving rosuvastatin had a 25% higher risk for new-onset DM compared with those taking placebo [1]
  • individuals treated with simvastatin or atorvastatin are at increased risk for DM [2-4]
  • there is a dose-dependent effect between statins and DM risk [5]
  • more potent statins increase the DM risk more compared with less potent statins [6]
Ezetimibe on the other hand, has been reported to improve metabolic markers such as hepatic steatosis and insulin resistance [7], however, there are not enough data evaluating the relationship between ezetimibe and the development of DM.
In this retrospective study it was assessed whether statin therapy with or without ezetimibe was associated with the development of diabetes in 877 dyslipidaemic individuals with normoglycaemia or prediabetes at baseline, during a median follow-up of 7 years.

Main results

Individuals with pre-diabetes at baseline exhibited a higher risk of incident diabetes compared with those having normal fasting glucose levels (OR: 11.71; 95% CI: 7.09–19.35; P < 0.05).
  • A higher risk of incident diabetes was observed in pre-diabetic individuals receiving high-intensity statin therapy compared with those on moderate intensity statin therapy (adjusted OR: 2.12; 95% CI: 1.06–4.24; P < 0.05) or those not taking a statin (adjusted OR: 4.90; 95% CI: 1.16–20.66; P < 0.05)
  • Addition of ezetimibe to statin treatment did not increase the risk of incident diabetes in pre-diabetic individuals (adjusted OR: 0.89; 95% CI: 0.36–2.22; P > 0.05), nor in normoglycaemic individuals (OR: 1.05, 95%CI: 0.34-3.23, P>0.05).
  • In multivariate analysis, the following factors were strong predictors of new-onset diabetes: baseline fasting glucose (OR: 1.09; 95%CI: 1.07–1.12; P < 0.05), presence of metabolic syndrome (OR: 3.49; 95% CI: 1.92–6.35; P < 0.05), family history of diabetes (OR: 3.03; 95% CI: 1.62–5.66; P < 0.05), duration of follow-up (OR: 1.08; 95% CI: 1.02–1.15; P < 0.05), high-intensity statin therapy (OR: 2.04; 95% CI: 1.18–3.54; P < 0.05).


In pre-diabetic individuals, high-intensity statin treatment was associated with a higher risk of incident diabetes. The addition of ezetimibe to statin therapy had a neutral effect on glucose metabolism.

Find this article online at J Clin Lipid


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2. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet.2003;361:1149–1158
3. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA.2005;294:2437–2445
4. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins. Atherosclerosis. 2011;215:1–8
5. Dormuth CR, Filion KB, Paterson JM, et al. Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases. BMJ. 2014;348:g3244
6. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a metaanalysis. JAMA. 2011;305:2556–2564
7. Zafrir B, Jain M. Lipid-lowering therapies, glucose control and incident diabetes: evidence, mechanisms and clinical implications. Cardiovasc Drugs Ther. 2014;28:361–377

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