Statins are lipid-lowering drugs used to prevent cardiovascular diseases. They act by inhibiting the catalysis of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) into mevalonate by HMG CoA reductase, thus reducing cholesterol synthesis by the liver. Beside this effect on cholesterol reduction, statins reduce inflammation and oxidative stress and up-regulate endothelial NO-synthase activity, thereby improving endothelial functions and stabilizing the atherosclerotic plaque (1). Benefit of statins have been shown for both secondary and primary cardiovascular prevention (2–4). Statins are among the most commonly prescribed drugs worldwide (5). Around 200 million people take a daily statin worldwide, including over 30 million people in the United States alone (6). In France, about 5 million people were using such drugs in 2014 (7).

Statins have already been shown to increase the risk of diabetes through endocrine mechanisms related to HMG-CoA reductase activity (2, 8, 9). Steroid hormones are produced from cholesterol of low-density lipoproteins, which is used as a substrate of steroidogenesis in adrenal cortex and gonads (10, 11). By inhibiting cholesterol synthesis, statins could be responsible of a reduction of steroid hormones synthesis and thereby cause adrenal insufficiency (AI). Today, only a few studies concerning a limited number of patients showed contradictory results on steroid hormone synthesis (12–14).

In this context, we conducted a large, nationwide study based on French claims data to investigate if the use of statin is associated to occurrence of AI.

The source cohort included 27 028 250 participants eligible for case and control selection. A total of 4 496 AI cases were identified, of which 4 492 cases were finally matched to 44 798 controls ( Figure 1 ). Participants included in the analyses had a median age of 66 years (IQR 52-78), and were mostly women (58.2%). Around 75% had at least one dispensing of systemic corticosteroids or of topical corticosteroids within the three years prior to index date and 40% of inhaled corticosteroids.

Cases appeared to present with a higher burden of comorbidities and a higher use of drugs, potentially confounders in the association between statins and adrenal insufficiency ( Table 1 ).

Given the very low frequency of tyrosine kinase inhibitors, interferon or ribavirin and immunotherapy (less than 0.1% of controls), these covariates were not included in the DRS. Among the remaining covariates, all showed standardized differences lower than 0.1, except the covariate “radiotherapy, local tumors and related procedures that can lead to a secondary adrenal insufficiency”. This covariate was, as a result, excluded from the DRS and included into the final model for adjustment. Validation information about DRS is detailed in Supplementary Data , Figure S1 and Table S4 .

Analyses showed no association between statin use and the risk of adrenal insufficiency after adjustment for potential confounders. This absence of association was found regardless of the definition of statin exposure used (statin use, statin history of use, statin cumulative use, or intensity of last statin dispensed). A non-significant increase in AI risk was observed with a cumulative use of]0-1] year (OR 1.09, 95%CI 0.97; 1.27) and for new users (OR 1.12, 95%CI 0.81; 1.55) compared with non-users of statin ( Table 2 ). Stratified analyses on sex, age or corticosteroid use did not show any association in some subgroups of patients ( Table 3 ).

The results of sensitivity analyses assessing the impact of lag-time length variation and hospital stays longer than three weeks were consistent with those of the main analyses ( Supplementary Data , Table S5 ). The negative exposure analysis using low-dose aspirin as exposure confirmed also our negative results ( Supplementary Data , Table S6 ).

We found no relevant association between statin exposure and AI risk after multivariate adjustment for potential confounders and regardless of statin definitions of exposure we used. This result is consistent with those of a recent study describing drug-induced AI using pharmacovigilance reports (17). Our results showed a non-significant increase in AI occurrence for new users of statins and for cumulative use of statins lower than one year. This risk, if any, seems to be very limited given the risk estimates not exceeding 1.15. This non-significant association observed when treatment with statin was initiated may be due to a residual detection bias rather than to an effect of statin on AI. From a biological and physiological viewpoint, a cumulative dose-effect would rather have been expected.

London et al. had shown in their study of 14 patients that a single treatment with a lipophilic statin reduced the production of some glucocorticoid precursors (12). This effect could have a clinical impact but it is possible that a compensatory phenomena allow glucocorticoid synthesis to be maintained or regulated.

Our study presents with strengths and limitations common to all studied performed from medico-administrative databases. As for their strengths, the nationwide healthcare database of the French population is frequently used for safety studies owing to their interest in terms of data exhaustiveness, and representativeness of the population (15, 18–20). Our study hence focused on data relating to beneficiaries of the major health insurance scheme, which concern about 80% of the French population. As for their limitations, this database only informs on reimbursed dispensings for prescribed drugs, which is only a proxy of patients’ exact use. As for the strengths specific to our study, the multivariate adjustment including a DRS succeeded in considering for a big part of confounding as it removed the association initially found with the crude analysis. In addition, all performed sensitivity analyses were consistent, including the analyses using low-dose aspirin as negative tracer exposure which eliminates a possible indication bias. As for the limitations of our study, the way we identified AI has not been validated elsewhere, and did not used steroid levels. However, it has been internally discussed with clinical experts in endocrinology and hospital coding. In addition, other studies on the same topic have used similar identification algorithm (AI ICD codes associated with hydrocortisone use) to define AI in claim databases (21, 22). Finally, our study only involved adult subjects, whereas in heterozygous familial hypercholesterolemia statin treatment can be initiated at a very young age. The impact of such treatment at this young age on steroid hormone synthesis could not therefore be studied here and would require further investigations, even if clinical trials conducted in this population have been reassuring (23, 24).

To the best of our knowledge, our study is the first to investigate the risk of AI associated with statin use in nationwide data. Our results do not indicate an increase in the occurrence of AI associated with statin use, either at initiation, with high cumulative use or high intensity treatment. The risk of AI related to statin exposure, if any, seems to be very limited and does not compromise statin treatment. Further studies could be carried out to assess the impact of these drugs on steroid hormone synthesis in more at-risk population or young patients.

The data analyzed in this study is subject to the following licenses/restrictions: French law to access SNDS. Requests to access these datasets should be directed to https://www.health-data-hub.fr.

SM: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. AJ: Conceptualization, Formal Analysis, Methodology, Writing – review & editing. AP: Conceptualization, Methodology, Supervision, Writing – review & editing. TD: Conceptualization, Methodology, Writing – review & editing. LD: Conceptualization, Methodology, Writing – review & editing. JB: Conceptualization, Methodology, Supervision, Writing – review & editing.