Statins and Diabetes: Real Concern or Much Ado About Nothing?

Updated at 7 PM with a detailed comment at the bottom from C. Michael Minder of Johns Hopkins–

In a New York Times Op-Ed piece on Monday, Eric Topol comments on last week’s announcement by the FDA that it was changing the label for statins. Topol focuses on the new warning that statins raise the risk of diabetes. He opens with a provocative statement:

We’re overdosing on cholesterol-lowering statins, and the consequence could be a sharp increase in the incidence of Type 2 diabetes.

Topol does the math and calculates that 20 million Americans taking statins equates to 100,000 new statin-induced diabetics:

Not a good thing for the public health and certainly not good for the individual affected with a new serious chronic illness… If there were a major suppression of heart attacks or strokes or deaths, that might be justified. But in patients who have never had heart disease and are taking statins to lower their risk (so-called primary prevention), the reduction of heart attacks and other major events is only 2 per 100. And we don’t know who the 2 per 100 patients are who benefit or the one per 200 who will get diabetes! Moreover, the margin of benefit to risk is quite narrow.

Topol then concludes that statins are beneficial for secondary prevention in people with a history of heart disease or stroke but for “the vast majority of people who take statins — those who have never had any heart disease — there should be a careful review of whether the statin is necessary, in light of the risk of diabetes and the relatively small benefit that can be derived.”

On his blog on Forbes, pharma reporter Matt Herper writes that with the editorial Topol “has broken ranks with many other heart doctors.” It should be noted, though, that statins for primary prevention have been the subject of intense debate in the past, most recently in an exchange in the Wall Street Journal between cardiologists Rita Redberg and Roger Blumenthal, and that the FDA action and Topol’s piece relied on long-available data.

In a comment highlighted by Herper on his blog, Sanjay Kaul looks at the same numbers as Topol and concludes that “the patients who develop diabetes (1 in 200) are more likely to have elevated fasting blood sugar at baseline, and these patients are also likely to benefit from satins (2 in 100).”

In his own blog on Forbes, John LaMattina, who was the president of Pfizer Global Research and Development in Lipitor’s prime, also disputes Topol’s conclusions. He points out the presence of “a very compelling clinical trial showing the value of one statin, Lipitor (atorvastatin), in Type 2 diabetes – the Collaborative Atorvastatin Diabetes Study  – known as CARDS.” The study was stopped early when it showed large reductions in acute coronary events and mortality for atorvastatin when compared with placebo in diabetics with no history of cardiovascular disease.

Update, Monday 7 PM: Dr. C Michael Minder, a colleague of Roger Blumenthal at Johns Hopkins, sent the following perspective on this issue:

Dr. Topol’s remarks echo the recent FDA warning about statins, but neither come as a surprise since we have been aware of the association with diabetes and statin primary prevention for a number of years.  In 2008, JUPITER showed a 26% increase risk of diabetes in patients randomized to high dose rosuvastatin.  In 2010, Sattar et al published the results of a meta-analysis of 13 trials (including JUPITER) and over 91,000 patients.  The results demonstrated that statins are associated with a small but statistically significant 9% increase (OR 1.09; 95% CI, 1.02-1.17) in the incidence of diabetes.  That translates to 1 new diabetes event per 1000 person years of treatment. On the other hand, over a 4-year period, one could prevent 9 vascular events for the harm of 1 incident case of diabetes.  Drs. Blumenthal, Santos, and I believe that the cardioprotective effects of statins outweigh the harms when statins are prescribed appropriately to patients without known coronary heart disease but at high risk for developing heart disease due to hypertension, diabetes, tobacco use, high cholesterol, and strong family history.

While it’s true that statins are associated with an increased incidence of diabetes, we must not forget that they have tremendous benefit in these high risk patients in reducing cardiovascular morbidity and possibly even mortality.  A 2009 meta-analyses by Brugts et. al and a 2011 Cochrane review by Taylor et al. examining the benefits of statin primary prevention demonstrated modest reductions in mortality (12-17%) and considerable reductions in morbidity (30% reduction in coronary events, 19% reduction in cerebrovascular events, 44% reduction in non-fatal heart attacks, and 33-34% reduction in revascularizations). The cardiovascular benefits of statins appear to outweigh any existing harm, even in cases of high dose statin medication (where Dr. Topol focuses much of his discussion).  According to Preiss et al., compared to moderate dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events.

What’s clear is that there is an association between statins and new onset diabetes, however, we lack firm proof that statins are actually causing diabetes.  While an increased incidence of diabetes was detected in JUPITER, diabetes was not rigorously screened for in study participants and there were no standardized ascertainment protocols.  Furthermore, results may be skewed by frequent testing or screening biases.  Another possibility to explain the increased risk of incident diabetes may be related to patients with underlying metabolic syndrome.  The majority of patients with metabolic syndrome already have glucose intolerance and it would not be surprising if they went on to develop diabetes.  JUPITER included a high proportion of patients with metabolic syndrome (~ 40%) which may explain the higher rates of incident diabetes compared to other trials.  A recent study by Waters et al. demonstrated that the risk of developing diabetes with statin therapy increased with increasing number of metabolic syndrome criteria lending credence to this hypothesis.

While we agree that their is an association of new-onset diabetes in patients taking statin medication for primary prevention, we cannot definitively say that statins are to blame in all cases.  What’s more likely is that patients who develop incident diabetes have glucose intolerance at baseline and subsequently develop diabetes either as natural progression of their disease or perhaps as a consequence of some as-of-yet uncharacterized property of statins.  What is clear is that high risk primary prevention patients stand to gain significant benefit from statin therapy, and the harms of new onset diabetes are outweighed by the reduction in cardiovascular morbidity and mortality.  We emphasize that the benefits of statin primary prevention apply to higher risk patients and should not be applied to all primary prevention patients.

C. Michael Minder, M.D.

Department of Internal Medicine

Johns Hopkins Hospital

References:

Preiss, D., Seshasai, S. R. K., Welsh, P., Murphy, S. A., Ho, J. E., Waters, D. D., DeMicco, D. A., et al. (2011). Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA, 305(24), 2556–2564. doi:10.1001/jama.2011.860

Ridker, P. M., Danielson, E., Fonseca, F. A., Genest, J., Gotto, A. M. J., Kastelein, J. J., Koenig, W., et al. (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. The New England journal of medicine, N Engl J Med, 359(21), 2195–2207. doi:10.1056/NEJMoa0807646

Sattar, N., Preiss, D., Murray, H. M., Welsh, P., Buckley, B. M., de Craen, A. J., Seshasai, S. R., et al. (2010). Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet, Lancet, 375(9716), 735–742. doi:10.1016/S0140-6736(09)61965-6

Brugts, J. J., Yetgin, T., Hoeks, S. E., Gotto, A. M., Shepherd, J., Westendorp, R. G., de Craen, A. J., et al. (2009). The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ, BMJ, 338, b2376.

Taylor, F., Ward, K., Moore, T. H., Burke, M., Davey Smith, G., Casas, J. P., & Ebrahim, S. (2011). Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev, Cochrane Database Syst Rev, (1), CD004816. doi:10.1002/14651858.CD004816.pub4

Waters, D. D., Ho, J. E., DeMicco, D. A., Breazna, A., Arsenault, B. J., Wun, C.-C., Kastelein, J. J., et al. (2011). Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. Journal of the American College of Cardiology, 57(14), 1535–1545. doi:10.1016/j.jacc.2010.10.047