Statins and the Risk of Diabetes: What’s a Clinician to Do?

Editor's Note: Commentary based on 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]

Background

Statin therapy is associated with a small but significant increased risk of diabetes and appears to be dose dependent.1,2 In 2012, the U.S. Food and Drug Administration mandated safety label updates to statin medications warning of a class effect increase in hemoglobin A1C (HbA1c) and fasting blood glucose concentrations.3 Despite this increased risk of incident diabetes, the overall benefit of statin therapy appears to outweigh the risk, and statins continue to play a fundamental role in the primary and secondary prevention of atherosclerotic cardiovascular disease.4,5 The biologic mechanism(s) through which statins exert their diabetogenic effect remain unclear and may relate directly to the drugs intended inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and/or off-target effects. In this peer-reviewed publication, Dr. Swerdlow and colleagues use Mendelian randomization to better understand the relationship between HMGCR inhibition and the biologic changes observed in the development of diabetes.

Methods

Using data from 42 genetic studies including 223,463 individuals, study investigators selected two single nucleotide polymorphisms (SNPs) in the HMGCR gene (rs17238484 and rs12916) associated with low-density lipoprotein cholesterol (LDL-C). Variations in these SNPs result in lower LDL-C levels, thus mimicking the effect of statin pharmacotherapy. Investigators examined the association of each SNP with body weight, waist circumference, plasma insulin and glucose concentrations, and risk of type II diabetes. Investigators then compared these data with an updated meta-analysis of 20 randomized controlled trials (n = 129,170 individuals) of statin versus placebo or high-intensity versus moderate intensity therapy.

Results

The rs17238484-G and rs12916-T alleles are associated with lower LDL-C (mean decrease of 0.06 mmol/L, 95% CI 0.05–0.07 and 0.08 mmol/L, 0.07-0.10 per allele respectively), increased bodyweight (0.30 kg, 0.18–0.43 and 0.20 kg, 0.04-0.36) and waist circumference (0.32 cm, 0.16–0.47 and 0.30 cm, 0.10-0.50). Both alleles appear to be associated with higher risk of type II diabetes (odds ratio per allele 1.02, 1.00–1.05 and 1.06, 1.03–1.09 respectively). Only the rs17238484-G allele was associated with higher plasma insulin and glucose concentrations. Comparatively, meta-analysis of clinical trial data indicate statin therapy is associated with reduced LDL-C (0.92 mmol/L, 0.18–1.67 at one-year follow-up), increased bodyweight (0.24 kg, 0.10–0.38) and increased risk of developing diabetes (OR 1.12, 1.06–1.18).

Conclusion

HMGCR inhibition is associated with increased weight gain and confers an elevated risk of type II diabetes.

Commentary/Perspective

Data presented by Swerdlow and colleagues leave little doubt that HMGCR inhibition is in part responsible for an increased risk of diabetes and development of phenotypic features seen in the metabolic syndrome. Whether or not patients and clinicians should be concerned about this risk is a more contentious issue. Robust clinical trial data indicate that despite the increased risk for development of diabetes, the cardioprotective effect of statins including reduced mortality and morbidity far outweigh potential risks.1,6 These benefits extend to patients with diabetes and those with risk factors for development of ASCVD.7-9 Clinically speaking, the risk of developing new onset diabetes appears greatest in patients already at risk for developing diabetes, and there is no compelling evidence available at this time to suggest that patients who develop diabetes following initiation of statin therapy are at higher risk for cardiovascular events.10-12

What remains uncertain is if the diabetogenic effect of statins are mediated solely through HMGCR inhibition or whether a more complex set of cellular and physiologic interactions are at work. Emerging research implicates several potential off-target interactions that lead to metabolic changes seen in type II diabetes13,14 The advent of PCSK9 inhibitors offer an alternative approach to reduce LDL-C through a mechanism distinct from HMGCR inhibition; however, it remains to be seen if these medications are clinically effective at reducing major adverse cardiovascular and cerebrovascular events without unintended side-effects.

This paper confirms that the risk of diabetes is an inherent part of statin therapy related directly to HMGCR inhibition (or indirectly through its effects on other parameters such as body weight). All patients should be made aware of this risk and screened regularly. The risk of diabetes should not deter physicians from initiating therapy but should prompt physicians to re-emphasize the importance of healthy lifestyle in conjunction with statin therapy to reduce risk of cardiovascular events.15

References

  1. 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.
  2. Preiss D, Seshasai SRK, 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.
  3. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs (FDA website). 2014. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. 2012. Accessed 10/30/2014.
  4. 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. Circulation 2014;129(25 Suppl 2):S1–45.
  5. American Diabetes Association. 8. Cardiovascular Disease and Risk Management. Diabetes Care 2015;38(Suppl 1):S49–S57.
  6. Taylor F, Huffman MD, Macedo AF. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013;1:1–97.
  7. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, et al. 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.
  8. Ridker PM, Olteanu A, Cook NR, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293–304.
  9. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, 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.
  10. 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;61:148–52.
  11. 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.
  12. Ridker PM, Ridker PM, Danielson E, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207.
  13. Sampson UK, Sampson UK, Linton MF, Linton MF, Fazio S, Fazio S. Are statins diabetogenic? Curr Opin Cardiol 2011;26:342–7.
  14. Sattar N, Taskinen MR. Statins are diabetogenic--myth or reality? Atheroscler Suppl 2012;13:1-10.
  15. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2960–84.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet

Keywords: Alleles, Biological Products, Blood Glucose, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Diabetes Mellitus, Type 2, Fasting, Follow-Up Studies, Hemoglobin A, Glycosylated, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Insulins, Lipoproteins, LDL, Metabolic Syndrome X, Pharmaceutical Preparations, Polymorphism, Single Nucleotide, Random Allocation, Research Personnel, Risk Factors, Secondary Prevention, United States, Weight Gain, Waist Circumference, United States Food and Drug Administration


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