Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non‐case study in the French pharmacovigilance system database

Abstract

Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33-48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25-2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57-112)), disopyramide (OR 32 (22-46)), nifedipine (OR 2.16 (1.32-3.51)), diltiazem (OR 1.76 (1.01-3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16-3.16)) and frusemide (OR 1.89 (1.31-1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5-1.4) and 1.2 (0.7-2.2), respectively). The same was found for other drugs except cibenzoline. Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.

A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

“…Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6,8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively).…”

“…Previous experience with reporting of hypoglycaemia with ACEIs had raised the possibility of confounding by indication [8], at a time when data-mining tools were not generally available. Such signals can now easily be generated by automated methods that are widely used for the detection of new adverse drug reactions.…”

“…Exposure was considered as the presence in a report of the drug of interest, whether or not it was suspected of causing the reaction [8]. For each drug of interest, reporting odds ratio (ROR: ratio of the odds of exposure in reports of cases and noncases) and their 95% confidence intervals (95% CI) were computed [15].…”

“…The indications and uses of angiotensin receptor blockers (ARBs) are similar to those of ACEIs.We therefore tested the French pharmacovigilance database for a signal of hypoglycaemia associated with ARBs, using the same methodology as used previously for ACEIs in a similar context [8].…”

Drug dependence associated with triptans and ergot derivatives: a case/non-case study

“…The problems associated with the recruitment of controls for case/control studies do not apply to case/non-case studies, for all reports not identified as cases are non-cases. Several studies using the case/non-case method have been published on this database applying to different fields of drug safety [24][25][26]. One limitation of the pharmacovigilance database and consequently of the case/non-case method [20,26] lies in the selection and notoriety bias due to the spontaneous notification system, which depends on the cooperation and goodwill of healthcare professionals [25][26][27][28].…”