Dementia Risk With Combined Statin and Antihypertensive Drugs That Increase Versus Decrease Angiotensin-II Formation: Findings From the 45 and Up Study.

摘要

BACKGROUND: Hypertension and dyslipidaemia are key modifiable risk factors of dementia, and the combined use of statins and antihypertensive medications (AHMs) may offer protective benefits. However, evidence on specific combinations remains limited. This study examined associations between dementia risk and the use of statins with angiotensin-II (Ang-II) promoting AHMs (drugs that increase Ang-II formation) compared with statins combined with Ang-II suppressing AHMs (drugs that decrease Ang-II formation). METHODS: This was a prospective study using data from the 45 and Up Study cohort, a large population-based cohort in New South Wales, Australia. Participants aged ≥ 45 years with hypertension and dyslipidaemia were included if they had concurrent statin and AHM use. Exposure groups were defined as either users of statins and Ang-II promoting AHMs (angiotensin II receptor blockers [ARBs], thiazides, and dihydropyridine calcium channel blockers [DHP CCBs]) or statins and Ang-II suppressing AHMs (angiotensin-converting enzyme inhibitors [ACEIs], beta-blockers [BBs], and non-DHP CCBs). Medication exposure was determined based on a proportion of days covered (PDC ≥ 80%). Baseline characteristics of the two groups were balanced using 1:1 pair propensity score matching. The Cox proportional hazards model was used to estimate hazard ratios (HRs) adjusted for diet, physical activity, comorbidities, and concomitant medications. RESULTS: Among 34,610 matched participants (17,305 per group; a mean age [standard deviation (SD)] of 65.8 (8.8) years; a mean follow-up (SD) of 12.4 (5.1) years), use of a statin plus Ang-II promoting AHM was associated with a 12% lower dementia risk (HR, 0.88; 95% CI, 0.79-0.98) and 13% lower all-cause mortality (HR, 0.87; 95% CI, 0.82-0.93) compared to statin plus Ang-II suppressing AHM combinations. Combinations of rosuvastatin or atorvastatin with Ang-II promoting AHMs (HR, 0.43; 95% CI, 0.36-0.50 and HR, 0.74; 95% CI, 0.64-0.84, respectively) conferred greater benefit compared with simvastatin combined with Ang-II promoting AHMs. The effects were consistent across both sexes, with the protective association observed only in the 65-74-year age group, and combinations involving ARBs demonstrated superior benefit compared to those with ACEIs. Findings were robust across sensitivity analyses, including applying a competing-risks model for death. CONCLUSIONS: Combined therapy with a statin plus Ang-II promoting AHMs, particularly rosuvastatin or atorvastatin with an ARB, was associated with lower dementia risk, suggesting cognitive benefits may inform therapy selection. Future randomised trials should confirm these findings and explore underlying mechanisms.