Over the past five years, a large amount of data has emerged suggesting an association between statin use and incident type 2 diabetes mellitus. In 2012, the U.S. Food and Drug Administration approved a safety label change for statins advising consumers of a possible increase in the risk of elevated blood glucose and new-onset diabetes associated with these medications.¹ Since then, a significant amount of attention has been drawn to this subject with numerous articles being published in major newspapers and magazines. Patients frequently ask physicians about the magnitude of this risk and if the benefits truly outweigh the potential harms from statin use.

In 2013, the American Heart Association (AHA) and the American College of Cardiology (ACC) published new guidelines for cholesterol treatment.² These guidelines identify four statin benefit groups and recommend a new risk assessment tool. Some have reported a potential overestimation of risk with the use of the new risk estimator³ and a significant increase in the number of individuals who may be eligible for statin therapy,^4,5 in particular within the group of patients receiving a statin for primary prevention of atherosclerotic cardiovascular disease (ASCVD). For this group, the guidelines indicate that the risk estimate should be the start, not the end, of discussion; a risk estimate should not translate into an automatic statin prescription. The guidelines emphasize the importance of clinician-patient risk discussion, examining the statin benefits in ASCVD reduction, the potential for adverse effects and drug-drug interactions, and implementation of healthy lifestyle habits among other components.

For an effective patient-clinician discussion, an accurate estimation of benefits from statin treatment should be made. The risk of ASCVD events over a defined treatment period should be determined based on the patient's risk factor profile. Subsequently, the relative and absolute reductions in ASCVD risk with treatment as compared to no treatment should be determined. This will vary with moderate- versus high-intensity statins. The patient should also be informed of potential harms and risks of pharmacologic therapy.

In this specific case, it is important to further emphasize that patients with statin-associated dysglycemia appear to derive the same benefits as those without it in terms of prevention of macrovascular events.⁶ Furthermore, in a recent study, Nielsen et al. found no long-term microvascular consequences from statin-associated diabetes.⁷

Statins are one of the most effective and highly evidence-based treatment options in the prevention and treatment of ASCVD in a diverse group of patients. On average, a moderate- and high-intensity statin will reduce LDL-C by 30-50% and ≥50%, respectively. For every 1 mmol/L (39 mg/dL) LDL-C lowering with statin therapy reduces the risk of major coronary events, coronary revascularization procedures, and stroke by ~20%, and of all-cause mortality by ~10%.⁸ The benefits are greatest with the use of higher doses of higher intensity statins leading to more prominent LDL-C reduction.⁹

Figure 1

Generally there is an additional relative reduction in the risk of major vascular events of ~15% with more intense statin therapy. We expect to prevent more events in groups that will likely have the most events. As such, high-risk populations tend to derive the most absolute benefit from any therapy. However, the relative risk reduction per LDL-C lowering remains the same irrespective of the baseline LDL-C and even those starting with low baseline levels may benefit from statin therapy.

Despite the above-mentioned benefits, the risk of statin-induced dysglycemia is of concern. A number of statin trials, meta-analyses,¹⁰ and observational studies by well-respected researchers^11,12 have shown a modest association between statin use and incident diabetes. The magnitude of risk appears to vary with different medications within this class and be higher with higher doses of higher intensity statins.^13,14 The mechanisms behind this association and heterogeneity of effect have not been fully elucidated. There has been no consistent correlation with the degree of LDL-C lowering; however, a recent study by Swerdlow et al. suggests the statin associated-dysglycemia could at least in part be associated by HMG Coenzyme A reductase (HMGCOAR) inhibition. The group showed an association of HMGCOAR single nucleotide polymorphisms, increased body weight, and incident diabetes.¹⁵ Overall, rosuvastatin appears to carry the greatest association with incident diabetes, whereas pravastatin has the best safety profile; however, the more potent rosuvastatin had the greatest relative risk reduction in cardiovascular events of any of the primary prevention trials.

Most studies report a 10-20% increase in the relative risk of diabetes. According to the 2013 AHA/ACC guidelines, this would translate into a 0.1 and 0.3 excess cases of diabetes per every 100 patients treated for one year with a moderate- and a high-intensity statin.² In their meta-analysis, Sattar et al. calculated that 5.4 deaths or myocardial infarctions or nine vascular events, could be prevented for every additional case of diabetes associated with statin use.^10,16 Importantly, the Justification for the use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) showed that the risk was greatest for those individuals with one or more risk factor for the development of diabetes.¹⁷ Moreover, statin therapy only accelerated the diagnosis of diabetes by an average of 5.4 weeks as compared to control in the JUPITER trial.

In conclusion, although the association of statin therapy with incident diabetes exists, the benefits in terms of prevention of ACSVD and all-cause mortality will tend to outweigh this risk in the majority of the population for whom statins are considered, with an estimated five to nine incident ASCVD events prevented per case of diabetes diagnosed. In individuals with low baseline ASCVD risk, such as an estimated 10-year ASCVD risk of 5% or less but with diabetes risk factors, a clinician-patient risk discussion becomes especially critical. The risk discussion should focus in particular on lifestyle modifications, which will decrease the risk of future ASCVD as well as diabetes. Counseling on regular brisk exercise, healthier dietary habits and weight loss should accompany each statin prescription; this will negate any tendency for statin-induced increases in blood sugar. Lastly, more research is needed to clarify the short- and long-term consequences of development of statin-induced dysglycemia, including further quantifying risk of micro- and macrovascular events in this population.

References

1. U.S. Food and Drug Administration. FDA Expands Advice on Statin Risks (FDA website). 2014. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm. Accessed 12/17/2014.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
3. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762-5.
4. Ioannidis JP. More than a billion people taking statins?: potential implications of the new cardiovascular guidelines. JAMA 2014; 311:463-4.
5. Pencina MJ, Navar-Boggan AM, D'Agostino RB, Sr., et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med 2014; 370:1422-31.
6. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol 2011;57:1535-45.
7. Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol 2014;2:894-900
8. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
9. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
10. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42.
11. Danaei G, Garcia Rodriguez LA, Fernandez Cantero O, Hernan MA. Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential survival. Diabetes Care 2013;36:1236-40.
12. Zaharan NL, Williams D, Bennett K. Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol 2013;75:1118-24.
13. 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;111:1123-30.
14. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305:2556-64.
15. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2014 Sept 24. [Epub ahead of print]
16. Cannon CP. Balancing the benefits of statins versus a new risk-diabetes. Lancet 2010;375:700-1.
17. Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-71.

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