Just published in The Lancet: Antihypertensive medication classes and risk of incident dementia in primary care patients: a longitudinal cohort study in the Netherlands 2024
Compared to ACEi, ARBs [HR = 0.86 (95% CI = 0.80–0.92)], beta blockers [HR = 0.81 (95% CI = 0.75–0.87)], CCBs [HR = 0.77 (95% CI = 0.71–0.84)], and diuretics [HR = 0.65 (95% CI = 0.61–0.70)] were associated with significantly lower dementia risks. Regarding competing risk of death, beta blockers [HR = 1.21 (95% CI = 1.15–1.27)] and diuretics [HR = 1.69 (95% CI = 1.60–1.78)] were associated with higher, CCBs with similar, and ARBs with lower [HR = 0.83 (95% CI = 0.80–0.87)] mortality risk.
Moreover, a recent network meta-analysis suggested that specific AHM-classes, particularly angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs), reduce dementia risk beyond their BP lowering effects.
Dementia risk was similar within CCB subclasses (dihydropyridine/non-dihydropyridine), and within diuretic subclasses (thiazide/loop/K-sparing) versus ACEi.
Within diuretic subclasses, mortality risk was lower for thiazides (HR = 0.87; 95% CI = 0.83–0.93), and higher for loop (HR = 3.05; 95% CI = 2.89–3.22) and K-sparing (HR = 1.50; 95% CI = 1.42–1.59) diuretics versus ACEi
Among patients receiving AHM, ARBs, CCBs, and Ang-II-stimulating AHM were associated with lower dementia risk, without excess mortality explaining these results. Extensive subgroup and sensitivity analyses suggested that confounding by indication did not importantly influence our findings. Dementia risk may be influenced by AHM-classes’ angiotensin-II-receptor stimulating properties. An RCT comparing BP treatment with different AHM classes with dementia as outcome is warranted.
The lower dementia risks associated with ARBs and beta-blockers compared to ACEi slightly attenuated with increasing age. This may be a chance finding. Alternative explanations are speculative. Possibly, some classes, such as ARBs, rely more on neuroprotective properties that are particularly exerted before extensive neuropathological changes associated with late life dementia develop, thereby potentially extending their therapeutic benefits, especially in younger age groups. Alternatively, ARBs might particularly reduce the risk of dementia with (micro-)vascular origin, which could represent a larger proportion of dementia cases in younger patients.
Several hypotheses suggest how individual AHM-classes might reduce dementia risk beyond BP lowering effects. For example, dihydropyridine CCBs may prevent neuronal cell death and AD neuropathology by regulating cellular calcium influx, and ARBs may reduce inflammation, oxidative stress, and AD neuropathology by improving cerebral blood flow. The more recent “angiotensin hypothesis” suggests that several AHM-classes lower dementia risk by stimulating the angiotensin-II-receptors type (ATR) 2 and 4, involved in cerebral ischemia and memory function (Fig. 1). ARBs directly block ATR1, increasing ATR2 and ATR4 stimulation, and upregulating angiotensin-II production. Thiazide diuretics and dihydropyridine CCBs stimulate ATR2 and ATR4 by increasing renin and thereby angiotensin-II production. BBs and non-dihydropyridine CCBs decrease renin and thereby angiotensin-II production. Finally, ACEis inhibit angiotensin-II production, inhibiting ATR2 and ATR4, and may also decrease cerebral Amyloid-Beta degradation wherein ACE is involved. This would fit with ACEi generally being associated with the highest dementia risk, ARBs versus ACEi most consistently with lower dementia risk, and the consistent results of studies evaluating Ang-II-stimulating versus inhibiting medication, discussed above. Our results do not fully support the angiotensin hypothesis. This could be attributed to residual confounding within the observational data or to other, as-yet-unknown mechanisms that might also influence the differential associations between antihypertensive medication classes and the risk of dementia.
Moreover, a large meta-analysis reported that the association between blood pressure lowering with AHM and lower risk of dementia or cognitive decline was not affected by baseline blood pressure or cumulative systolic blood pressure change. Finally, in a different cohort with similar characteristics where BP values were available, we found no apparent differences in BP values between AHM-classes. Therefore, we expect that the differential associations in our study represent class-specific mechanisms affecting dementia risk beyond BP lowering effects.
ARBs, CCBs, and thiazide diuretics were associated with lower dementia incidence rates compared to ACEi-use, without excess mortality. Combined with previous studies, our study makes a compelling case for differential associations between AHM-classes and dementia risk, particularly for lower risks associated with ARBs versus ACEi and Ang-II-stimulating versus Ang-II-inhibiting AHM-classes.
The HRs are even better in those who started medication before age 60:
Quite an amazing paper!
Unfortunately, they did not address combinations well. So we don’t know if the effects are additive, and therefore the HR multiplicative, which, for example, would give, in the best-case scenario, for the combination of ARB + dihydropyridine CCB + Thiazide(like): 0.85x0.79x0.75 = 0.50 for dementia. If among each of these classes there is a best-in-class drug that reduces dementia risk even more and if the effects are still additive then we might have an HR for the combination as low as 0.3 (the proof is left as an exercise to the reader 
).
