Statins and Risk for Diabetes: Weighing the Evidence

Statins are great drugs, aren’t they? In fact, many of us were poised to recommend they be added to the drinking water. But then came the dreaded caveat. Results of recent analysis of key statin trials-the West of Scotland Coronary Prevention Study (WOSCOPS),^1,2 the Justification for the Use of Statins in Primary Prevention (JUPITER) trial,³ and the EUROASPIRE Survey⁴-suggested that statins lower cholesterol at the expense of increasing new-onset diabetes mellitus (DM). The FDA required revised class labeling to this effect in 2012 after several years of speculation. 

How seriously should we take this warning?

Let’s look at one of the incriminating studies, the EUROASPIRE.^1,4 The study involved 22 countries over 12 years. During the study period, there was an increase in statin use by a factor of 67.8%. Statin therapy decreased elevated cholesterol levels from 94.5 % to 46.2% of initial levels, but during the interval also raised DM incidence from 17.4% to 28%. So, should we hold statins in individuals who are at risk for or already have DM? Not yet. Let’s look at some critical rebuttals first.   

Waters and coworkers⁵ studied 15,056 persons enrolled in the Treat to New Targets (TNT) and Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trials. These patients had coronary disease at baseline, but not diabetes. The authors were particularly interested in 4 identifiers previously associated with the development of new onset diabetes: fasting glucose >100 mg/dL; fasting triglycerides >150 mg/dL; BMI  >30 kg/m²; and a history of hypertension. Among the 8825 persons across both trials that had 0 to 1 of these risk factors, DM developed in 142 of the 4407 ingesting 80 mg of atorvastatin daily. DM developed in 148 of 4418 taking either atorvastatin 10 mg or simvastatin 20 or 40 mg. In the remaining 6231 subjects, with 2 to 4 of the incriminating risk factors for DM, 448 of 3128 in the 80-mg atorvastatin limb and 368 of 3103 in the aforementioned lower-dose cohort developed DM.  At the same time, cardiovascular (CV) events were significantly reduced with 80 mg of atorvastatin daily in both groups that developed DM.

What’s the message in these numbers?

Compared with lower-dose statin therapy, atorvastatin 80 mg/d did not increase the incidence of DM in patients with 0 to 1 of the specified risk factors; the high-dose treatment, however, did increase the incidence of DM by 24% among patients with 2 to 4 DM risk factors. The number of CV events was significantly reduced with atorvastatin 80 mg in both groups at risk for DM. In short, the Waters study reveals that patients with a low risk for DM accrue CV benefits from statins, but are not prone to new-onset DM. Those with more risk factors also experience CV protection. 

There are 2 additional papers that add valuable insight into this important debate. Michael B. Rocco, MD, of the Cleveland Clinic observed that the trials implying statins increase the risk of DM were not designed to look for DM.⁶ He concurs with the results of Waters’ study, that is, that statin therapy at most may uncover DM only in people at risk for DM in the first place. In a 2010 paper by Sattar,⁷ it was calculated that 255 patients have to be treated for 4 years before a statin-induced case of DM is precipitated. Simultaneously, treating the same 255 persons with a statin would prevent 9 vascular events, translating into a 9:1 benefit to risk ratio.
 
Do not stop writing for statins based on the DM scare.

Do be aware that persons at significant risk for DM before initiating statin therapy may develop DM on therapy. But also remember that CV events are being prevented at the same time.
 

References
1. Sattar N, Taskinen M-R. Statins are diabetogenic-myth or reality? Atheroscler Suppl. 2012;1:1-10.
2. Freeman D, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Trial. Circulation. 2001;103:357-362. 
3. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
4. Kotseva K, Wood D, De Backer G, et al. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, III surveys in eight European countries. Lancet. 2009;373:929-940.
5. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy. JACC. 2013;61:148-152.
6. Rocco MB. Statins and diabetes risk: fact, fiction and clinical implications. Cleve Clin J Med. 2012;79:883-893.
7. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010;375:735-742.