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Elderly Women at Higher Risk of Developing Diabetes While Taking Statins

The risks may be outweighing the benefits, but only to a point.

Statins, the inhibitors of HMG-CoA reductase, have long been an important piece in the prevention and treatment of atherosclerotic cardiovascular disorders.  By reducing production of low-density lipoprotein cholesterol (LDL-C), the risk of developing cardio- and cerebrovascular events has been significantly reduced in patients with and without diabetes.  Statins are fairly well tolerated, with the major use limiting side effect being myalgias, which are largely associated with increases in statin dosage and potency, as well as prolonged periods of use. Since the discovery and increased use of statin therapy, development of diabetes has also been linked to their use, in varying degrees.

Several studies over the years have proposed mechanisms by which statins promote diabetes, including decreasing insulin secretion and insulin sensitivity, but the consensus remains open. This could be due to variation among the class itself. For example, pravastatin has been shown to be less likely to cause diabetes than the other statins, whereas atorvastatin, simvastatin, and rosuvastatin have the most profound effects on insulin secretion and sensitivity. It is not surprising that the mid- to high-range doses of atorvastatin and rosuvastatin are considered to be high potency, carrying the largest effect on lowering LDL-C, with higher dose simvastatin being moderate potency.  Further clouding the issue is the finding that the most dramatic reduction of insulin sensitivity occurred in patients who were normoglycemic, suggesting that development of statin associated diabetes is not limited to people with prediabetes, but rather seen in all comers. However, the benefits imparted by statins have long outweighed the risks of diabetes.

The Australian Longitudinal Study on Women’s Health (ALSWH), which commenced in 1996, has collected health data on over 58,000 women in three different age cohorts (18-23, 45-50 and 70-75) to date. Focus on the oldest cohort was given, as most statin trials lacked significant representation of this gender and age group. A recent survey of the data contained in ALSWH was performed looking for the prevalence of new onset diabetes in elderly women who were taking statin therapy for all indications, not just cardiovascular risk, as the primary outcome. Statin prescribing information was gathered for the period between July 1, 2002 and August 31, 2013. The patients evaluated were 8,372 Australian women born between 1921 and 1926, who were alive on January 1, 2003, and did not have diabetes prior to initiation of statin therapy.  Multivariable Cox regression was used to determine the risk of statin exposure and developing new onset diabetes.

In the 10-year study period, 49% (n=4102) of the patients had records of filled statin prescriptions, and 5% (n=418) had started medication for new onset diabetes. Analysis showed that statin exposure carried a 33% increase in the risk for development of diabetes (HR 1.33; 95% CI 1.04-1.70, p = 0.024). This correlated with a number needed to harm (NNH) 131 patients on statins for five years to produce one new case of diabetes (95% CI 62-1079).  It was also determined that this risk was dependent on statin dose and increased as statin dosage increased, with the hazard ratio ranging from 1.17 (95% CI 0.84-1.65) for the lowest doses to 1.51 (95% CI 1.14-1.99) for the highest doses.

The reported conclusion was that prolonged statin use in women over 70 increased the risk of new onset diabetes up to 51%, seen with use of higher doses.  The investigators go on to suggest that these patients should not be exposed to statins at all, where any active prescriptions should be discontinued.  This is an alarming recommendation, considering that not all elderly women at risk for cardiovascular events are taking the highest of statin doses.  When taking a closer look at the reported statistics, the lowest range of doses has a hazard ratio of 1.17, suggesting a 17% increase in diabetes risk.  However, the 95% confidence interval for this HR is 0.84-1.65, crossing zero, which suggests that the lower doses of statins may actually impart a protective effect against developing new onset diabetes (that is, patients on the lower end of the confidence interval have a 16% reduction of risk). There is merit to evaluating each case of statin use in elderly women and making recommendations based on individual findings, but the sweeping statement of absolutely no statins in this demographic is perhaps rather hasty. There will be a healthy number of cases where the cardiovascular benefits indeed outweigh the diabetic risk.

Practice Pearls:

  • Statin therapy remains a cornerstone in the reduction of cardiovascular risks in people with and without diabetes.
  • Elderly women appear to be at increased risk for development of statin-induced new onset diabetes.
  • Most increases in risk of diabetes are associated with higher statin doses, and lower doses may actually impart a protective effect against new onset diabetes.

References:

Jones M, Tett S, Peeters GM, Mishra GD, Dobson A. New-Onset Diabetes After Statin Exposure in Elderly Women: The Australian Longitudinal Study on Women’s Health. Drugs Aging. 2017;34(3):203-9.

Laakso M, Kuusisto J. Diabetes Secondary to Treatment with Statins. Curr Diab Rep. 2017;17(2):10.

 

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD