Do statins cause diabetes?

Statins may increase the risk of diabetes in some patients, an effect that may vary by the statin type and dosage used.^1–3 Package inserts for most statins, except pravastatin, report an increased risk of elevated glucose, HbA1C, and, in some cases, new-onset diabetes compared to placebo.^4–10 

In the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, 17,603 people without preexisting cardiovascular disease or diabetes were followed for up to five years. Patients randomly assigned to take rosuvastatin had a 27% increased risk of new onset diabetes compared to placebo.¹¹ The West of Scotland Coronary Prevention Study (n=5,974), in contrast, found a 30% lower risk of diabetes among patients taking pravastatin compared with placebo.¹² To evaluate the effects of different statins, Carter et al. conducted a retrospective cohort study from a national diabetes database to examine the rates of incident diabetes among elderly (age >66) patients who had initiated statins prior to the diagnosis.² Over the 14-year study period, 471,250 patients without diabetes were newly treated with a statin. Compared to treatment with pravastatin, fluvastatin, or lovastatin, treatment with higher potency atorvastatin or simvastatin appeared to be associated with an approximately 20% higher risk of new-onset diabetes.

The actual risk, however, is low. When reported in manufacturer’s product information, the frequency of new-onset diabetes is higher in statin-users than placebo (4.2% for simvastatin vs 3.6% for placebo; 2.8% for rosuvastatin vs 2.3% for placebo).^8,9

The effect may be particularly true for those at higher baseline risk of diabetes before statins are initiated.^13,14 Ridker et al. compared incidence of physician-reported diabetes in patients taking rosuvastatin 20 mg (n=8,901) versus placebo (n=8,901) using data from the JUPITER trial.¹⁴ Study inclusion criteria included the presence of elevated hs-CRP, which is a marker for insulin resistance. 41% of study participants had the metabolic syndrome. The number of people with new-onset diabetes was 0.6% higher in patients taking rosuvastatin compared to placebo. People with diabetes risk factors (metabolic syndrome, impaired fasting blood glucose, BMI >30 kg/m², or HbA1c >6%) on rosuvastatin had a 28% increase in incident diabetes compared to those with risk factors taking placebo. There was no increase compared to placebo in incident diabetes in individuals without risk factors. The authors also calculated the cardiovascular benefit among those on statins. For individuals with diabetes risk factors, 134 vascular events were avoided for every 54 new cases of diabetes.

Among 15,056 patients with cardiovascular disease but without diabetes, Waters et al. compared incidence of new-onset diabetes in patients taking high intensity atorvastatin (80 mg/day) with lower-dose statin therapy (atorvastatin 10 mg/day or simvastatin 20 – 40 mg/day).¹³ The presence of two or more diabetes risk factors (baseline fasting blood glucose >100 mg/dL, fasting triglycerides >150 mg/dL, BMI >30 kg.m², or history of hypertension) increased the risk of new-onset diabetes by 24% in the high-intensity statin users, compared to the low-intensity statin users. The risk of new-onset diabetes was not statistically different among high- vs low-intensity statin users, when there was zero or one risk factor for diabetes at baseline. Cardiovascular events were significantly reduced with high-dose atorvastatin.

Navarese et al. conducted a systematic review and meta-analysis of 17 randomized controlled trials that reported incident new-onset diabetes in studies that compared different statins to placebo or high-intensity statins with lower-intensity statins (total n=113,394).¹ Pravastatin therapy was associated with the lowest rate of new-onset diabetes, and rosuvastatin was associated with the highest. Although studies are small, pitavastatin has demonstrated a neutral or favorable effect on glucose control in patients with type 2 diabetes.^15,16

According to current guidelines of the American Heart Association, the American College of Cardiology, the American College of Endocrinology, and the American Association of Clinical Endocrinologists, the modest increased risk of new-onset diabetes is not considered a contra-indication for initiation of statin therapy because the benefits of statins outweigh this small risk.^17,18 Lifestyle changes and weight loss are recommended for all individuals at risk for diabetes.¹⁹

^References

1. Navarese EP, Buffon A, Andreotti F, et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol 2013; 111 (8): 1123-1130.
2. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013; 346 : f2610.
3. Preiss D, Welsh P, Murphy SA, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 2011; 305 (24): 2556-2564.
4. Pitavastatin [package insert]. Tokyo, Japan: Kowa Pharmaceuticals; 2012.
5. Pravastatin [package insert]. Princeton, NJ: Bristol Myers.
6. Fluvastatin [package insert]. East Hanover NJ: Novartis Pharmaceuticals; 2012.
7. Atorvastatin [package insert]. Dublin Ireland: Pfizer Parke-Davis; 2009.
8. Simvastatin [package insert]. Cramlington UK: Merck, Sharpe & Dohne, LTD; 2010.
9. Rosuvastatin [package insert]. Wilmington DE: AstraZeneca Pharmaceticals; 2010.
10. Lovastatin [package insert]. Morgantown WV: Mylan Pharmaceuticals.
11. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008; 359 (21): 2195-2207.
12. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103 (3): 357-362.
13. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol 2013; 61 (2): 148-152.
14. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380 (9841): 565-571.
15. Yamakawa T, Takano T, Tanaka S, Kadonosono K, Terauchi Y. Influence of pitavastatin on glucose tolerance in patients with type 2 diabetes mellitus. J Atheroscler Thromb 2008; 15 (5): 269-275.
16. Yokote K, Saito Y. Influence of statins on glucose tolerance in patients with type 2 diabetes mellitus : subanalysis of the collaborative study on hypercholesterolemia drug intervention and their benefits for atherosclerosis prevention ( CHIBA Study ). J Atheroscler Thromb 2009; 16 (3): 297-298.
17. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol. J Am Coll Cardiol 2018.
18. Jellinger PS, Handelsman Y. AACE 2017 Guidelines: American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention. Endocr Pr 2017; 23 (April).
19. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New Engl J Med 2002; 346 (6): 393-403.