|
Hypertensive patients at high risk of cognitive decline
|
Telmisartan versus other ARBs versus centrally acting ACEi versus non-centrally acting ACEi
|
Polymorphisms in ACE have been linked to Alzheimer’s disease [60] but whether central ACE inhibition will protect or harm is unclear. ACEi but not ARBs might accelerate beta-amyloid pathology by blunting ACE activity on non-angiotensin pathways and by inhibiting AT2 and AT4 receptors. One ARB in particular, telmisartan, has additional activity on PPAR gamma that might protect against neurodegeneration [61]
|
A network meta-analysis concluded that ARBs had more benefit on cognition than ACEi drugs (adjusted effect size 0.47 +/– 0.17, p = 0.04) [62]. Yet hypertension management with centrally acting versus non-centrally acting ACEi was associated with 25 % slower functional decline in Alzheimer’s patients [63]. A Phase II trial is underway to compare telmisartan to perindopril in patients with comorbid hypertension and Alzheimer’s (Table 1). Additional comparisons are needed
|
|
Hypertensive patients at risk of cognitive decline
|
Amlodipine or nifedipine versus other DHP CCBs
|
Most DHP CCBs are likely to penetrate the brain except for amlodipine. Nilvadipine and nitrendipine but not amlodipine decreased beta-amyloid accumulation and blunted apoptosis in a mouse model of Alzheimer’s. DHP CCBs varied in their capacity to increase amyloid clearance from the brain [64]. Effects on the brain may vary depending on their selectivity for different calcium channels [65]
|
In a small trial in hypertensive patients with MCI, nilvadipine versus amlodipine slowed cognitive decline and improved cerebral blood flow despite similar effects on blood pressure [34]. Nitrendipine and nimodipine, have clinical data to suggest utility for the prevention or treatment of dementia, respectively, while nifedipine was associated with an increased risk of cognitive decline (reviewed in [64]). A Phase III trial is underway to test nilvadipine as a treatment for Alzheimer’s (Table 1)
|
|
Diabetes patients at risk of cognitive decline
|
Centrally penetrant versus non-penetrant GLP-1 agonists
|
GLP-1 agonists have been shown to protect against hippocampal synapse loss, lower beta-amyloid pathology and related damage, reduce neuroinflammation, and promote neurogenesis. While exenatide, liraglutude, and lixisenatide cross the blood–brain barrier, albiglutide and dulaglutide are large proteins unlikely to reach the brain [18]
|
Treatment with liraglutide blocked decline in cerebral glucose metabolism over 6 months in Alzheimer’s patients in a Phase II trial [66]. Additional trials are underway to repurpose these drugs to treat cognitive impairment (Table 1) but not to compare cognitive outcomes of CNS-penetrant versus non-penetrant GLP-1 agonists for diabetes treatment
|
|
Diabetes patients with or without comorbid dementia
|
Choice of drugs to minimize the risk of severe hypoglycemia
|
Severe hypoglycemia can trigger acute cognitive impairment and possibly accelerate long-term cognitive decline [67]. The choice of drugs used to manage diabetes may alter the risk of severe hypoglycemia in some patients
|
Nursing home patients with both dementia and diabetes had up to 8× higher risk of severe hypoglycemia when treated with sulphonylurea instead of insulin analogs [68]. More research is needed on how the choice of drugs alters risk in diverse patient populations
|
