Risk of incident diabetes among patients treated with statins: population based study

To the Editor:
Important Considerations in Choosing Specific Statin Treatments
Carter AA, et al’s paper is timely important in delineating a controvercial issue regarding new-onset diabetes of statin therapy in patients.1 Compared with pravastatin (the reference drug in all analyses), there was an increased risk of incident diabetes with atorvastatin (adjusted hazard ratio 1.22, 95% confidence interval 1.15 to 1.29), rosuvastatin (1.18, 1.10 to 1.26), and simvastatin (1.10, 1.04 to 1.17). Overall, moderate (adjusted hazard ratio 1.22, 95% confidence interval 1.19 to 1.26) and high doses (1.30, 1.20 to 1.40) were associated with an increased risk of incident diabetes compared with low doses of statins. When considering potency, (high potency statins (rosuvastatin, atorvastatin) adjusted hazard ratio 1.22, 1.15 to 1.29; moderate potency statins (simvastatin) 1.11, 1.04 to 1.18; low potency statins (fluvastatin, lovastatin) 0.97, 0.87 to 1.09) were observed.

Nonetheless, statins are very important to prevent cardiovascular events in patients with high risk or even low risk of vascular disease. However, unfortunately, over the decade the unwanted effect of statins to induce type 2 diabetes have been neglected. Further, whether this unwanted effect of statin is class effect or dose-dependent has been disputed. Several experimental studies have demonstrated that pravastatin has favorable effect compared with others and this unwanted effect of statin is dose-dependent, however, these important issues have not completely been investigated in humans.2 We first reported that high-dose simvastatin and atorvastatin therapy may have greater adverse effects on glucose homeostasis than low dose therapy in hypercholesterolemic patients.3,4 Hypercholesterolemic patients receiving high dose atorvastatin (80 mg) developed greater insulin resistance, higher fasting insulin levels, and higher HbA1c levels when compared with patients receiving the low dose atorvastatin (10 mg) or placebo. Recently, we observed significantly differential metabolic effects of pravastatin vs simvastatin5 or rosuvastatin6 with equally lipid-lowering dosage in hypercholesterolemic patients.

We speculate that long-term adverse effects of new-onset diabetes may generate a relative increase in deaths. Indeed, a recent large scaled randomized clinical trial confirms our speculation. In individuals with one or more risk factors for diabetes, statin was associated with a 39% reduction in the primary endpoint, but in individuals with no major diabetes risk factors, statin was associated with a 52% reduction in the primary endpoint.7

One should consider that higher-dose (high potent) statin therapy may cause more adverse effects and therefore lead to differences in routine clinical care between those treated with higher-dose and low-dose (low potent) regimens. Pravastatin might have a preferential
benefit among primary prevention patients at high risk of diabetes.Thus, it is important to consider the cardiovascular and metabolic context and natural histroy of diseases when choosing statin therapy for optimal individual patient health over the long-term.8

Funding: None, Disclosures: None

REFERENCES
1. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013;346:f2610.

2. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins. Atherosclerosis 2011;215:1-8.

3. Koh KK, Quon MJ, Han SH, et al. Simvastatin improves flow-mediated dilation but

reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes

Care 2008;31:776-82.

4. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol 2010;55:1209-16.

5. Koh KK, Quon MJ, Han SH, et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis 2009;204:483-90.

6. Koh KK, Quon MJ, Han SH, et al. Differential metabolic effects of rosuvastatin and

pravastatin in hypercholesterolemic patients. Int J Cardiol 2013;166:509-15.

7. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.
Lancet 2012;380:565-71.

8. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2012 Nov 15. doi:pii: S0167-5273(12)01412-X. 10.1016/j.ijcard.2012.10.037. [Epub ahead of print]