Antihypertensive Drug Class Interactions and Risk for Incident Diabetes: A Nested Case–Control Study

Background We aimed to determine how single and combination antihypertensive therapy alters risk for diabetes mellitus ( DM ).Thiazide diuretics ( TD ), β blockers ( BB ), and renin–angiotensin system blockers ( RASB ) impact DM risk while calcium channel blockers ( CCB ) are neutral. DM risk associated with combinations is unclear. Methods and Results We enrolled nondiabetic patients from K aiser P ermanente N orthwest with a fasting plasma glucose ( FPG ) <126 mg/dL between 1997 and 2010. DM cases were defined by a FPG ≥126 mg/dL, random plasma glucose ≥200 mg/dL, HbA 1c ≥7.0%, or new DM prescription (index date). We used incidence density sampling to match 10 controls per case on the date of follow‐up glucose test (to reduce detection bias), in addition to age and date of cohort entry. Exposure to antihypertensive class was assessed during the 30 days prior to index date. Our cohort contained 134 967 patients and had 412 604 glucose tests eligible for matching. A total of 9097 DM cases were matched to 90 495 controls (median age 51 years). Exposure to TD ( OR 1.54, 95% CI 1.41 to 1.68) or BB ( OR 1.19, 95% CI 1.11 to 1.28) was associated with an increased DM risk, while CCB and RASB exposure was not. TD + BB combination resulted in the fully combined diabetogenic risk of both agents ( OR 1.99, 95% CI 1.80 to 2.20; interaction OR 1.09, 95% CI 0.97 to 1.22). In contrast, combination of RASB with either TD or BB showed significant negative interactions, resulting in a smaller DM risk than TD or BB monotherapy. Conclusions Diabetogenic potential of combination therapy should be considered when prescribing antihypertensive therapy.