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Meta-analyses of numerous randomized trials have demonstrated that treatment to reduce low-density lipoprotein cholesterol (LDL-C) by inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) with a statin reduces the risk of coronary heart disease (CHD) and other major vascular events.^1,2 The clinical benefit of treatment with a statin in these trials appears to be log-linearly proportional to the absolute reduction in LDL-C. Each 38.67 mg/dl (1.0 mmol/L) reduction in LDL-C during treatment with a statin was associated with an approximately 20% reduction in the risk of major cardiovascular events, regardless of a patient's age, gender, LDL-C level, history of cardiovascular disease, or presence of other comorbidities.^1-5

Based largely on data from the statin trials, the recently updated 2013 American College of Cardiology (ACC) and American Heart Association (AHA) Joint Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults has substantially expanded the number of persons who are eligible for treatment with a statin.⁶ Indeed, as compared to the previous iteration of the guidelines, it has been estimated that new ACC/AHA guidelines for the management of cholesterol would increase the number of adults who would be eligible for statin therapy by 12.8 million, from 43.2 million to 56.0 million or almost 50% of U.S. adults between the ages of 40 and 75.⁷ The scale of this proposed increase in the use of statin therapy has raised concern that it may also lead to a substantial increase in the incidence of statin-induced side-effects, particularly an increase in the incidence of new-onset type 2 diabetes mellitus.

Treatment with a statin appears to be associated with an increased risk of developing type 2 diabetes. In a meta-analysis of 15 randomized trials including a total 96,418 persons without diabetes at the time of randomization, treatment with a statin was associated with a 0.33 kg increase in body weight and an 11% increase in the risk of new-onset diabetes as compared to treatment with placebo (or usual care).^8,9,10 In a subsequent meta-analysis of five additional randomized trials including a total of 19,212 persons without diabetes at the time of randomization, treatment with high-dose statin as compared to moderate-dose statin therapy was not associated with any additional weight gain but was associated with a further 12% increase in the risk of new-onset diabetes, suggesting that the effect of statins on the risk of developing diabetes may be dose-dependent.¹⁰ Based largely on these data, the U.S Food and Drug Administration issued a Drug Safety Communication in 2012 changing the safety labelling of statins to include an increased risk of elevated glucose and new-onset diabetes.¹¹

The mechanism by which statins appear to increase the risk of diabetes is not clear. One hypothesis is that inhibiting HMGCR, the target of statins, may itself lead to dysglycemia and an increased risk of new-onset type 2 diabetes. This hypothesis was recently tested in a Mendelian randomization study that evaluated the association between polymorphisms in the HMGCR gene that mimic the LDL-C lowering effect of statins and the risk of diabetes.¹² Polymorphisms in the HMGCR gene (like all other genetic polymorphisms) are inherited approximately randomly at the time of conception in a process sometimes referred to as Mendelian randomization. Therefore, inheriting an HMGCR allele associated with lower LDL-C is analogous to being randomly assigned to treatment with a statin at birth, while inheriting the other allele is analogous to being randomly assigned to usual care. Comparing the risk of adult-onset type 2 diabetes among persons with and without such a polymorphism is, thus, analogous to a long-term randomized trial comparing statin treatment with usual care and should provide an unconfounded, naturally randomized estimate of the causal effect of HMGCR inhibition on the risk of developing diabetes.

The study included data on up to 224,463 persons, and found that each copy of a common polymorphism in the HMGCR gene (rs17238484) was associated with a 2.3 mg/dl (0.06 mmol/L) lower LDL-C, 0.30 kg higher body weight and a corresponding 2-3% increase in the risk of type 2 diabetes (p = 0.016, when combined with publically available data).¹⁰ A second common polymorphism in the HMGCR gene (rs12916) in low linkage disequilibrium (r² = 0.368) with this polymorphism was also associated with a similar pattern of effect on LDL-C, body weight and risk of diabetes.¹⁰

Comparing the randomized trial data with the naturally randomized genetic evidence allows several conclusions to be drawn. First, the small 0.33 kg increase in body weight associated with statin treatment as compared to placebo cannot explain the relatively large 11-12% increased risk of new onset diabetes. This conclusion is strengthened by noting that intensive-dose as compared to moderate-dose statin therapy was associated with an apparently dose-dependent further 12% increase in the risk of diabetes but no additional weight gain. By contrast, the small 2-3% increase in lifetime risk of diabetes associated with each copy of an LDL-C lowering allele in the HMGCR gene can be explained entirely by the 0.30 kg increase in body weight associated with these polymorphisms. Taken together, therefore, these data would suggest that the effect of statins on the risk of developing new-onset diabetes is not entirely due to statin-induced weight gain or to inhibition of HMGCR itself, but could also be related to an "off-target" effect of statin therapy. This conclusion is important, because it suggests that other therapies that lower LDL-C, such as ezetimibe or the new monoclonal antibodies directed against PCSK9, may not similarly increase the risk of diabetes.

It is important to note that although treatment with a statin does appear to cause an increased risk of developing new-onset type 2 diabetes, the cardiovascular benefit of statins appears to far outweigh this small increased risk. Indeed, among those persons without diabetes at the time of randomization in the statin trials, persons who subsequently developed diabetes during follow-up experienced the same proportional reduction in the risk of major cardiovascular events per mmol/L reduction in LDL-C as did persons who did not develop diabetes during follow-up.^8,9,10 In addition, in a meta-analysis of 14 statin trials including 18,686 persons with diabetes (17,220 of whom had type 2 diabetes) and 71,370 persons without diabetes at the time of enrollment, persons with diabetes at baseline experienced the same proportional reduction in the risk of major cardiovascular events per mmol/L reduction in LDL-C as did persons without diabetes.³ The totality of the evidence indicates that persons without diabetes, persons who develop diabetes during treatment with a statin and persons with diabetes at the time statin therapy is initiated all appear to experience a similar and substantial 20% reduction in the risk of major cardiovascular events per mmol/L lower LDL-C during treatment with a statin. Therefore, the risk of developing diabetes, the development of diabetes during treatment with a statin or the presence of diabetes at baseline should not be used as a rationale to avoid or to discontinue treatment with a statin. Further research is needed to determine the long-term non-cardiovascular effects of statin-induced type 2 diabetes.

References

1. 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.
2. Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L. 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.
3. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117-25.
4. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
5. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials. Lancet 2015;S0140-6736(14)61368-4.
6. 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.
7. Pencina MJ1, 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.
8. 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.
9. 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.
10. 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;S0140-6736(14)61183-1.
11. U.S. Food and Drug Administration. FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs (FDA website). 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed 2/4/2015.

Keywords: Dyslipidemias, Secondary Prevention, Primary Prevention, Adult, Alleles, American Heart Association, Antibodies, Monoclonal, Azetidines, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Comorbidity, Coronary Disease, Diabetes Mellitus, Diabetes Mellitus, Type 2, Glucose, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Incidence, Linkage Disequilibrium, Lipoproteins, LDL, Oxidoreductases, Polymorphism, Genetic, Risk Factors, Weight Gain, Random Allocation

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