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Date of release: 19 March, 2012

Statins and diabetes mellitus risk: WHI Study results and FDA warning


Due to the importance of this study, we received two commentaries, one published last week, and the current one.


 


Culver and colleagues [1] recently analyzed the use of statins and the risk of diabetes mellitus in postmenopausal women who participated in the Women’s Health Initiative (WHI) observational study. This investigation included 153,840 women without diabetes mellitus and no missing data at baseline (age 50–79 years, recruited at 40 clinical centers across the United States during 1993–1998, with follow-up until 2005). At baseline, 7% reported taking statin medication. There were 10,242 incident cases of new-onset, self-reported diabetes mellitus over 1,004,466 person-years of follow-up. An increased risk of 71% for diabetes mellitus in the postmenopausal women taking any statin was recorded, when users were compared to non-users. Multivariate adjustments for confounders still showed an increased risk of 48%. The investigators concluded that this may be a medication class effect, which undoubtedly is both statistically and clinically significant. Soon after the publication of these results, in February 2012, the Food and Drug Administration (FDA) announced that several changes to the label of statins became effective, indicating that incident diabetes mellitus and increased blood glucose are possible outcomes of statin use and that usually minor and reversible cognitive side-effects may occur as well. Interestingly, the FDA said it is also eliminating the recommendation that patients on statins undergo routine periodic monitoring of liver enzymes, because this approach is ineffective in detecting and preventing the ‘rare and unpredictable’ serious liver injuries related to statins [2].

Comment

Does this mean than diabetic or pre-diabetic menopausal women should not use any statin? The increased relative risk of diabetes mellitus with statins, according to the FDA, is only about 10% (9–13% in various meta-analyses), less than with other risk factors like obesity, and much less than the risk of cardiac events in patients with hyperlipidemia. In a pooled analysis of five major statin trials (in the general population), Preiss and colleagues [3] calculated the following absolute risk numbers in statin users: one additional patient developed diabetes mellitus for every three patients protected from a major cardiovascular event. The number needed to harm per year for intensive-dose statin therapy was 498 for one additional case of new-onset diabetes mellitus, while the number needed to treat per year was 155 in order to prevent one cardiovascular event. Treatment of 255 persons (95% confidence interval 150–852) for 4 years resulted in one extra case of diabetes mellitus. Another interesting finding was that a dose-dependent effect was recorded, with a 12% higher risk for developing diabetes mellitus while on intensive-dose statin therapy compared with moderate-dose therapy. 
 
Preiss published a later review [4] that is summarized as follows: the cardiovascular benefits of statin therapy clearly outweigh the risk of developing diabetes mellitus. However, the data suggest a need for patients to become aware of this possible risk, while monitoring the patients for potential development of diabetes mellitus, especially while taking high-dose therapy. When the global risk of cardiovascular events is high (Framingham risk score of 20% or more), or the cholesterol level is high, or multiple cardiovascular risk factors exist, and in certain clinical scenarios such as depression, metabolic syndrome, fatty liver, diabetes mellitus or chronic renal disease, the cardiovascular benefits of statins are much more important than the low relative and absolute risks for developing diabetes mellitus. Needless to say, of course, statins remain obligatory for the secondary prevention of cardiovascular disease. Patients who are treated with statins should be monitored regularly for diabetes mellitus (measuring fasting glucose and glycoHbA1c), and should be encouraged to eat healthily and to be engaged in regular physical activity, quit smoking, and take all other measures to reduce the impact of concomitant risk factors.

Comentario

Enrique Sánchez-Delgado
Internal Medicine-Clinical Pharmacology, Vice President of ANCYM, Hospital Metropolitano Vivian Pellas, Managua, Nicarágua

    References

  1. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Womens Health Initiative. Arch Intern Med 2012;172:144-52.
    http://www.ncbi.nlm.nih.gov/pubmed/22231607

  2. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs.
    http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm

  3. 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.
    http://www.ncbi.nlm.nih.gov/pubmed/21693744

  4. Preiss D, Sattar N. Statins and the risk of new-onset diabetes: a review of recent evidence. Curr Opin Lipidol 2011;22:460-6.
    http://www.ncbi.nlm.nih.gov/pubmed/21897230