Association of Angiotensin II–Stimulating Antihypertensive Use and Dementia Risk

Figures

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  Figure 1. Interaction of Different Antihypertensive Types With the Renin–Angiotensin System Thiazides and dihydropyridine calcium channel blockers (DiCCBs) increase renin. β–blockers (BB) reduce β1-mediated renin production. Long-acting forms of verapamil and diltiazem (non-DiCCBs) either do not affect or reduce renin. Renin generates angiotensin I (Ang-I), which is converted into angiotensin II (Ang-II) by angiotensin-converting enzyme (ACE), which exerts physiologic effects by binding to AT1 or AT2 or may be further metabolized into Ang-IV, which binds to AT4. ACE inhibitors (ACEI) directly inhibit ACE activity, thereby inhibiting angiotensin II production. Angiotensin receptor 1 blockers (ARBs) inhibit angiotensin II activity directly at the AT1 receptor, but leave angiotensin II production intact. Angiotensin hypothesis: ACE reportedly degrades β-amyloid (Aβ), a major component of the cerebral neuritic plaques associated with Alzheimer disease. ACEIs may inhibit this degradation, thus facilitating Aβ plaques accumulation. ARBs selectively inhibit Ang-II at angiotensin receptor 1 (AT1) without inhibiting ACE, allowing ACE to degrade Aβ. Moreover, Ang-II and Ang-IV activity have been…

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  Figure 2. Study Flow Chart *Only individuals using antihypertensive drug (AHD) types from thiazide(-like), angiotensin 1 receptor blocker, angiotensin-converting enzyme inhibitor, calcium channel blocker, and β-blocker classes were included because loop and K-sparing diuretics are generally not prescribed as stand-alone treatments for hypertension. There were no individuals using renin antagonists.

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  Figure 3. Hazard Ratio (HR) and 95% Confidence Interval (CI) of Dementia, Mortality, and Dementia/Mortality as Combined Outcome for Each Possible Dichotomous Categorization of Antihypertensive Classes in the Study Depicted are the HR and 95% CI (y-axis) for each individual possible random combination of antihypertensive subclasses (thiazides, dihydropyridine calcium channel blockers [DiCCBs], non-DiCCBs, angiotensin receptor 1 blockers [ARBs], β-blockers [BBs], angiotensin-converting enzyme inhibitors [ACE], K-sparing and loop diuretics), in order of HR for the event from low to high on the x-axis. Each individual blue dot represents a possible combination. Only the HRs associated with the angiotensin II–stimulating medication (Ang+) combination hypothesized by this study (in red) and the individual antihypertensive classes on their own (gray) are marked. Within parentheses are the numbers of events followed by the number of individuals in the particular category at baseline. Note that the combined outcome of dementia/mortality is most useful for interpreting whether differences in dementia risk are due to differences in the competing risk of mortality. Models adjusted for systolic blood…