Telmisartan protective against dementia in hypertensive, T2D patients?

Use of the angiotensin receptor blocker (ARB) telmisartan in an East Asian population with hypertension and type 2 diabetes (T2D) was associated with a lower risk of dementia and any ischaemic stroke events compared with other ARBs, a nationwide cohort study has shown.

Compared with angiotensin-converting enzyme inhibitors, ARBs can further reduce dementia risk owing to their distinct effect on angiotensin type I receptors and angiotensin IV signalling. [J Intern Med 2018;284:620-642] ARBs also have RAAS*-modulating effects and may deliver pleiotropic protection on cognition. [Cerebrovasc Dis 2008;26:106-112]

At a clinical dose, telmisartan is the only ARB that has modulating effects on PPAR-γ**, which may be neuroprotective. [Drug News Perspect 2010;23:241-256; Future Cardiol 2017;13:279-296] Telmisartan may also protect against cognitive decline via TrkB/BDNF*** upregulation in the hippocampus. [J Cardiol 2012;60:489-494]

“Telmisartan has also been shown to have sufficient BP-lowering potency [and] adequate blood-brain barrier (BBB) penetration and to reduce BP variability, all of which can influence the cognitive protective effects,” said the researchers.

Of the 65,511 eligible patients from the Taiwan NHIRD^#, 11,400 were divided into the telmisartan and the non-telmisartan ARB arms (n=2,280 and 9,120, respectively) after propensity-score matching. [PLoS Med 2021;doi:10.1371/journal.pmed.1003707]

Compared with those in the non-telmisartan arm, telmisartan recipients had a lower risk of dementia diagnosis (2.2 percent vs 3.2 percent; hazard ratio [HR], 0.72; p=0.03) and any ischaemic stroke (6.8 percent vs 8.6 percent; HR, 0.79; p=0.008) during long-term follow-up.

“[P]atients registered as having any ischaemic stroke may have had minor strokes or silent infarctions, which were observed when patients were receiving brain imaging for dementia surveys. This could also be a possible explanation for the lower incidence of dementia in the telmisartan arm,” the researchers explained.

The risk of dementia diagnosis remained lower among telmisartan vs non-telmisartan recipients even after adjusting for ischaemic stroke occurrence (subdistribution HR, 0.70; p=0.022) or all-cause mortality as a competing factor (subdistribution HR, 0.71; p=0.029).

“The impact of hypertension treatment on the risk of dementia occurrence in T2D patients is a valid question worthy of further investigation,” said the researchers. Chronic hypertension can trigger vascular remodelling, changes in the BBB, and regional cerebral flow reduction, which may subsequently lead to cognitive impairment and stroke incidence. [Hypertension 2016;68:e67-e94] In T2D, the neurodegenerative risk may be attributed to vascular changes, insulin signalling, and alterations in glucose metabolism. [J Alzheimers Dis 2017;59:393-403]

Patients with comorbid T2D and hypertension are thus more susceptible to stroke and dementia. [Lancet 2012;380:601-610; Nat Rev Endocrinol 2018;14:591-604] “[T]herefore BP control is an important issue in these patients … Our data suggest an association between a lower occurrence of dementia diagnosis and telmisartan use in T2D patients. [These] could guide further clinical trials to verify our findings,” they said.

“[While] the results remain insufficient to give conclusive answers of a high evidence level … our findings may help inspire future studies on dementia risk reduction in hypertensive T2D patients,” the researchers pointed out. Further investigation is thus warranted to ascertain the protective effects of telmisartan against dementia and the possible underlying mechanisms of action.

Potential study limitations are selection bias, use of electronic health records, and drug adherence, combinations, or switching. Causal effects of the drugs must also be interpreted with caution. Whether the findings can be generalized to other ethnicities also remains unclear.