Two Studies Address Diabetes Risks With Statins--One Good News, One So-So

May 24, 2013

TORONTO, ON — The debate about the potential risks of new-onset diabetes in statin-treated patients is addressed in two separate studies published by Canadian researchers looking at patients treated with the LDL-lowering drugs[1,2]. While one study is reassuring for older patients treated with statins, with researchers finding no evidence of an increased risk of diabetes in acute coronary syndrome (ACS) patients, the other suggests that the more potent statins, such as rosuvastatin (Crestor, AstraZeneca), atorvastatin, and simvastatin, do pose an increased risk compared with pravastatin.

In a study published online May 14, 2013 in Circulation: Cardiovascular Quality and Outcomes, Dr Dennis Ko (Sunnybrook Health Sciences Center, Toronto, ON) and colleagues explain that while clinical-practice guidelines for ACS patients advocate for the use of intensive-dose statin therapy, the data suggesting an increased risk of diabetes with the drugs have raised some concerns.

The group analyzed data of more than 17 000 patients 65 years of age and older hospitalized with MI in Ontario, Canada, between 2004 and 2010. Just over 52% of the ACS patients were treated with intensive statin therapy, defined as atorvastatin >40 mg, rosuvastatin >20, and simvastatin>60 mg. Atorvastatin <40 mg, rosuvastatin <20 mg, simvastatin <60 mg, and any dose of fluvastatin, lovastatin, and pravastatin, were considered moderate-dose statin therapy and prescribed to 48% of the treated patients.

In total, 8540 matched pairs who had a similar likelihood of receiving intensive-dose or moderate-dose statin therapy were included in the analysis.

Five years after hospitalization for ACS, 13.6% of patients who received intensive statin therapy had a new diagnosis of diabetes. Comparatively, 13.0% of patients prescribed moderate-dose therapy had a new diagnosis of diabetes. The difference was not statistically significant. Intensive-dose statin therapy did result in a significantly lower risk of repeat hospitalizations for ACS or death compared with moderate-dose therapy (44.8% vs 46.5%, respectively; p=0.04). The reduction in ACS alone was also statistically significant (22.2% vs 23.5%; p=0.04), while differences in mortality risk at five years were not.

In a statement, Ko said the study "provides evidence that shows intensive statins are underutilized in older patients," and the data should reassure physicians and encourage them to treat more patients with high-dose statin therapy.

FDA Mandates Label Change in 2012

In 2012, as reported by heartwire , the US Food and Drug Administration mandated a labeling change to the entire drug class , issuing a warning that statins can raise blood sugar and HbA1c levels (pravastatin was exempted from the label change). The risk of diabetes began to gain traction first with the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, where investigators reported a 27% increase in the risk of diabetes in patients taking rosuvastatin compared with placebo.

Other analyses and meta-analyses confirmed the increased risk with statins in JUPITER, with an analysis from the Women's Health Initiative (WHI) showing a 48% increased risk of diabetes among women, while an analysis of PROVE-IT, A to Z, TNT , IDEAL, and SEARCH showed that high-dose statin therapy increased the risk of diabetes by 12% . In addition, a similar meta-analysis found that statin therapy increased the risk of diabetes by 9% .

Higher Risks Compared With Pravastatin

While Ko et al suggest it safe to treat older patients with intensive statin therapy, another study, this one published May 23, 2013 in BMJ, does find that patients are at an increased risk of new-onset diabetes when treated with rosuvastatin, atorvastatin, and simvastatin compared with those treated with pravastatin.

Led by Dr Aleesa Carter (Toronto General Hospital, ON), the researchers explain that despite concerns about the risk of new-onset diabetes among statin-treated patients, pravastatin is exempt from the FDA label change. In fact, pravastatin was associated with a 30% lower risk of diabetes compared with placebo-treated patients in the West of Scotland Coronary Prevention Study (WOSCOPS).

Over a 14-year period, the researchers identified from provincial databases 471 250 patients with no history of diabetes treated with a statin. Of these, just under half were treated with a statin for primary prevention, while 51.7% received a statin for secondary prevention. The patients were older--median age at the start of treatment was 73 years--and more than half were women. Atorvastatin was the most commonly prescribed medication, accounting for half of all new prescriptions, followed by rosuvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin.

Compared with pravastatin, atorvastatin, rosuvastatin, and simvastatin were associated with a 22%, 18%, and 10% increased risk of new-onset diabetes, respectively. There was no risk observed with fluvastatin or lovastatin. In a subgroup analyses, the results were consistent in the primary- and secondary-prevention cohorts.

Analysis of Diagnosis of Diabetes With New Users of Statins

Statin Outcomes per 1000-person years Adjusted hazard ratio (95% CI)
Pravastatin (n=38 470) 22.64 Reference
Atorvastatin (n=268 254) 30.70 1.22 (1.15–1.29)
Fluvastatin (n=5636) 21.52 0.95 (0.81–1.11)
Lovastatin (n=6287) 21.80 0.99 (0.86–1.14)
Rosuvastatin (n=76 774) 34.21 1.18 (1.10–1.26)
Simvastatin (n=75 829) 26.22 1.10 (1.04–1.17)

There was also an increased risk of new-onset diabetes among those treated with moderate-dose statins (hazard ratio 1.22; 95% CI 1.19–1.26) and high-dose statins (HR 1.30; 95% 1.20–1.40) compared with low-dose therapy. The researchers note that the risk associated with rosuvastatin appears to be dose related and dependent on the duration of treatment. "The increased risk with rosuvastatin significantly decreased after covariate adjustment and became nonsignificant once dose was taken into consideration," write Carter et al.

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