Statins and the Risk of Diabetes: Evidence From a Large Population-Based Cohort Study

Giovanni Corrao; Buthaina Ibrahim; Federica Nicotra; Davide Soranna; Luca Merlino; Alberico L. Catapano; Elena Tragni; Manuela Casula; Guido Grassi; Giuseppe Mancia

Disclosures

Diabetes Care. 2014;37(8):2225-2232. 

In This Article

Conclusions

The results show that compared with patients who used statins for a small portion of the follow-up period, those who exhibited a more continuous use of statins had a 32% excess risk of new-onset diabetes. Furthermore, the results show that an increased risk of new-onset diabetes is related to all available statins at all doses. The results failed to show, however, significant evidence that high-potency statins exert a stronger action on diabetes development than low-potency statins. In summary, this population-based study supports the notion that continuous use of statins is associated with a nonmarginal increase in the risk of developing diabetes in a real-life setting.

Comparison With Available Evidence

The current findings confirm and extend the results of the JUPITER trial, which was the first to find that new-onset diabetes was 27% more common in patients treated with statins than in those receiving placebo,[5] as well as the results of the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial, which showed that new-onset diabetes increased by 30% in the pravastatin group compared with the placebo group.[21] Even more clear-cut risk excesses (+20% and +48%) have been reported from observational investigations.[8,19,23] Meta-analyses of clinical trials, however, showed a weaker increased risk of new-onset diabetes by ~10%.[7,8,23] Finally, the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial showed that high-dose atorvastatin treatment compared with placebo is associated with a 37% excess risk of diabetes.[24]

The current findings differ from those of a large cohort study, bolstering the suggestion that statin-induced diabetes is likely a class effect,[8] and of a meta-analysis of clinical trials showing that intensive- versus moderate-dose statin therapy is associated with a greater risk of diabetes.[25] Two large randomized trials, however, consistently showed that atorvastatin 80 mg daily is associated with a weak and nonsignificant excess of diabetes compared with atorvastatin 10 mg daily (HR 1.10 [0.94–1.29]) or simvastatin 20 mg daily (HR 1.19 [0.98–1.43]).[24]

Plausibility

The mechanisms underlying the diabetogenic influence of statins are incompletely understood. Atorvastatin and simvastatin have been shown to decrease glucose uptake in adipocyte cell lines[26] and insulin sensitivity,[27] respectively. Simvastatin and atorvastatin have been shown to decrease insulin secretion in β-cells.[28] The inhibition of isoprenoid synthesis may explain some of the observed dysglycemic effects of statins.[26] Finally, it has been hypothesized that statins may influence muscle or liver insulin sensitivity directly, but there is no specific experimental evidence to support this hypothesis.[29]

Strengths and Weaknesses

The current study is unique in several respects. First, the investigation was based on data from a very large unselected population, which was made possible because of a cost-free health-care system for virtually all Italian citizens. Second, the drug prescription database provides highly accurate data because report of prescriptions by the pharmacies is essential for reimbursement, and filing of an incorrect report about dispensed drugs has legal consequences.[30] Third, patients were identified from the point of the initial lipid-lowering therapy, and the complete sequence of the subsequent prescriptions for statins was available. Fourth, we were able to include patients without previous clinical evidence (drug treatment and/or hospitalization) of diabetes so that the data relate to the effect of statin use on new-onset of diabetes. Finally, a number of sensitivity analyses were performed, which increased the robustness of the findings.

The study has a number of potential limitations. First, evaluation of statin adherence was based on pharmacy-dispensing information. This method assumes that the PDC by a prescription corresponds to the proportion of days of medication use. Small, insignificant differences between the assessed number of dispensed pills and the actual pill count were reported by a study investigating adherence to statin therapy over 12 months.[31] Furthermore, data on dispensing history have been shown to be consistent with other adherence measures, drug serum levels, and clinical drug effects.[32] Nevertheless, the use of medication dispensing as a measure of adherence remains a source of uncertainty in our estimates.

Second, because of privacy regulations, identification codes of prescription records were not available for analysis, so drug-based diagnoses of diabetes cannot be scrutinized and validated. However, it seems highly unlikely that diagnostic errors could differentially affect patients according to their adherence to statins. Moreover, the adherence-diabetes relationship was confirmed, and indeed amplified, when a more stringent diagnostic criterion for new-onset diabetes was used, which raises the possibility that the statin-dependent risk of developing diabetes might be greater than that resulting from the primary diagnostic criterion we adopted. It should also be mentioned that the improved diagnostic specificity obtained with the stricter criterion minimizes bias of a risk estimate that includes diagnostic misclassification.

Third, our estimates might be affected by detection bias; that is, patients with long-term adherence to statin therapy may have been more likely to receive a diagnosis of diabetes. However, we found a clear relationship between adherence with statins and risk of diabetes, even among patients who did not undergo laboratory examinations or outpatient specialist visits. Thus, the excess risk of diabetes also concerned patients with low use of health services, making it unlikely that detection bias explains the main findings.

Finally, whether the observed findings are a result of our inability to fully account for higher adherence to statin therapy in patients at higher risk of diabetes is the more relevant question in interpreting the findings. Baseline fasting serum glucose and other components of the metabolic syndrome, such as triglyceride level, BMI, and hypertension,[24] might be more frequent in individuals with high rather than low adherence to statin treatment. Because our databases have a limited amount of clinical information, we dealt with confounding in several ways. First, only statin users were included in the cohort to compare the duration of statin therapy, whereas inclusion of nonusers would be for observational investigations.[8,19] In this way, the potential for confounding is reduced by actively comparing patients with the same indication at baseline.[33] Second, our estimates were adjusted for a number of available demographic, therapeutic, and clinical characteristics, such as cotreatment with antihypertensive and other agents, history of CV disease, and categories of Charlson comorbidity index score. Third, the statin-diabetes relationship was observed within each stratum of frequency of laboratory examinations and outpatient specialist visits. Because medical attention might be considered a proxy of clinical profile and other unmeasured risk factors for diabetes, this further protects our conclusions, although residual confounding cannot be excluded. For this reason, we also performed a sensitivity analysis and showed that the association between adherence to statin treatment and the risk of diabetes was not annulled after correction for an unmeasured confounder of great importance for the development of diabetes, obesity. It should be emphasized that beyond obesity, no other unmeasured factor is able to annul the investigated relationship, even if it is characterized by very-high prevalence (i.e., up to 37.5%), strongly affects the outcome (i.e., up to threefold increased diabetes risk), and is markedly more diffuse among adherent patients (i.e., up to twofold more than in those with little adherence to statin therapy). In such conditions, an increased risk of diabetes weaker than that found in our main analysis is expected. This possibly explains the stronger association generally reported by observational investigations than reported in clinical trials.

Implications for Benefits of Statin Treatment

Assuming that 1) the diabetes incidence rate among patients with very-low adherence to statin therapy represents the baseline rate of new-onset diabetes because diabetes is unlikely to develop during very-short-term statin use and 2) diabetes develops in patients with high adherence to statins at a rate 1.32-fold faster than the baseline rate, we expected that ~280 patients would have to be continuously treated to induce one case of diabetes every year. In a meta-analysis of seven randomized controlled trials of statin use versus control in patients with diabetes, statins decreased major CV and cerebrovascular events every 40 patients treated.[34]

Consistent with our calculation, a meta-analysis reported that treating 255 patients with statins for 4 years would induce one case of diabetes, but in the meantime, it would prevent 5.4 coronary deaths or myocardial infarctions for each millimolar reduction in serum LDL cholesterol.[6] Thus, the CV protection offered by statins appears to markedly outweigh the increased incidence of diabetes, although the adverse effect of diabetes on CV risk[35] suggests that the original statin-dependent protection might decline with time. The decline might be less than predicted based on epidemiological data on diabetes and CV morbidity and mortality, however, because whether the prognostic value of drug-induced diabetes is equivalent to that of native diabetes is still uncertain.[36] This has been reported to be the case in some studies,[37,38] whereas in other studies, a few years or even long-term exposure to diabetes induced by antihypertensive drugs was not found to increase CV morbid or fatal events.[24,39]

Conclusion

This large population-based cohort study extends earlier findings of an increased risk of diabetes with statin therapy by providing evidence of a clear-cut association between adherence to statin therapy and risk of new-onset diabetes in a real-world setting. It appears from event-based investigations that benefits of statins in reducing CV events clearly overwhelm the diabetes risk.

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