A call for comparative effectiveness research to learn whether routine clinical care decisions can protect from dementia and cognitive decline

Dacks, Penny A.; Armstrong, Joshua J.; Brannan, Stephen K.; Carman, Aaron J.; Green, Allan M.; Kirkman, M. Sue; Krakoff, Lawrence R.; Kuller, Lewis H.; Launer, Lenore J.; Lovestone, Simon; Merikle, Elizabeth; Neumann, Peter J.; Rockwood, Kenneth; Shineman, Diana W.; Stefanacci, Richard G.; Velentgas, Priscilla; Viswanathan, Anand; Whitmer, Rachel A.; Williamson, Jeff D.; Fillit, Howard M.

doi:10.1186/s13195-016-0200-3

Alzheimer's Research & Therapy

Table 1 Examples of clinical trials testing neuroprotective properties of an anti-hypertensive or anti-diabetic drug

From: A call for comparative effectiveness research to learn whether routine clinical care decisions can protect from dementia and cognitive decline

Drug	Class	Primary clinical use	Trials underway to evaluate the use to treat or prevent dementia or cognitive decline	Putative primary mechanism of action	Estimated completion
Nilvadipine	Calcium channel blocker	Hypertension	NILVAD Phase III trial evaluating if this calcium-channel blocker can improve cognitive function in mild-moderate Alzheimer’s disease (NCT02017340)	Beta-amyloid clearance and cortical perfusion	2017
Telmisartan versus Perindopril	ARB versus ACE inhibitor	Hypertension	SARTAN-AD Phase II head-to-head comparison of perindopril and telmisartan in Alzheimer’s patients with hypertension, using brain atrophy as an experimental surrogate marker (NCT02085265)	Beta-amyloid production and catabolism	2017
Candesartan or Losartan	ARB	Hypertension	A Phase II trial with candesartan in MCI (NCT02646982) and Losartan in Alzheimer’s (ISRCTN93682878)	Neurovascular injury, blood-flow, beta-amyloid pathways	2021 & 2017
Metformin	Biguanide	Diabetes	A Phase II in Alzheimer’s (NCT02409238) and a Phase II trial in MCI (NCT01965756) are underway	Restore insulin signaling in the brain	2017 & 2016
Pioglitazone, mini-dose	Thiazolidinedione	Diabetes but at a different dose	Phase 3 trial testing a very low-dose formulation of pioglitazone to reduce the risk MCI due to Alzheimer’s (NCT01931566)	Metabolism and inflammation	2019
Liraglutide	Incretin mimetic (GLP-1 agonist)	Diabetes	Two Phase II trials underway or recently completed in Alzheimer’s (NCT01843075; NCT01469351). A third trial is underway in aging adults at high risk of dementia (NCT02140983) and a fourth Phase III trial is underway on cognitive dysfunction in major depressive disorder or bipolar disorder (NCT02423824)	Restore insulin signaling in the brain to slow Alzheimer’s pathology	2015–2017
Exenatide (Exendin-4)	Incretin mimetic (GLP-1 agonist)	Diabetes	A Phase 2 safety trial in patients with Alzheimer’s or mild cognitive impairment with secondary outcomes of behavioral and cognitive performance, ADAS-cog and CDR, and biomarkers related to Alzheimer’s disease and dementia (NCT01255163)	Restore insulin signaling in the brain to slow Alzheimer’s pathology	2018

Examples of clinical trials underway to evaluate whether a drug approved for hypertension or diabetes could be repurposed to treat or prevent Alzheimer’s disease or cognitive impairment. Many other trials have already been completed. In all cases, the putative mechanism of action involves a direct effect on the brain rather than an indirect effect through treatment of the primary indication. Other repurposing efforts are underway with drugs approved for depression, epilepsy, and erectile dysfunction. Very few studies are designed for CER, i.e. to compare the cognitive outcomes from treatments that are clinically equivalent for their currently approved indication
ACE angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, MCI mild cognitive impairment

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ISSN: 1758-9193

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