Table 1.

Summary of the clinical outcomes for diabetic drugs for AD.

Classes of Diabetic Drugs Being Repurposed for AD	Specific Drugs in the Class Being Explored for AD	Summary of Clinical Studies
metformin		A cohort study from Singapore in 365 participants showed that long-term metformin use was associated with a 50% risk reduction for cognitive decline A Finnish case–control study indicated that long-term use of metformin was associated with lower incidence of AD A pilot clinical trial in MCI showed improvements on the SRT
Insulin		Administering 20 IU intranasal insulin twice a day for 21 days improves attention, story recall, and function in those with MCI or AD Craft et al. ran a longer pilot clinical trial to investigate the effect of intranasal insulin on cognition, function, cerebral glucose metabolism, and CSF biomarkers in 104 adults with either AMCI (n = 64) or mild to moderate AD (n = 40) over the span of 4 months. The outcomes demonstrated an improvement in delayed memory in the 20 IU group (p < 0.05), as well as preserved caregiver-rated functional status at both insulin doses (p < 0.01) and general cognition assessed by the ADAS-cog score in younger patients and functional abilities assessed by the ADCS-ADL scale for adults with AD (p < 0.05) Intranasal insulin was used in a randomized clinical trial of 289 adults with MCI or AD over a span of 12 months; it showed no cognitive or functional benefits compared to the placebo group but there were lingering concerns about the delivery system
Incretins/GLP1 Receptor Agonists	Liraglutide, semaglutide, exenatide	ELAD, Evaluation of Liraglutide in the treatment of Alzheimer’s Disease, was a phase IIb double blinded, randomized, placebo-controlled trial conducted in multiple centres in the UK, where 204 adults with mild to moderate AD received subcutaneous injections of either LRGT or placebo once daily for 12 months The results demonstrated no difference between treatment and control in cerebral glucose metabolic rate, the primary endpoint [104]; however, there was improved cognitive function in LRGT-treated participants measured by ADAS-EXEC (ADAS-Cog with Executive domains of the Neuropsychological Test Battery). Currently, two large phase III clinical trials, evoke and evoke+ are underway. Each study has 1840 amyloid-positive participants with MCI or mild AD dementia who will be randomized to receive either daily oral semaglutide (14 mg, escalated via 3- and 7- mg over 8 weeks) or daily oral placebo over a period of 156 weeks The REWIND trial was a randomized, double-blind placebo-controlled trial conducted in 24 countries which examined the effect of once weekly subcutaneous injection of either DGT or placebo in participants aged 50 or more and diagnosed with T2DM on cardiovascular risks of T2DM, such as non-fatal MI, non-fatal stroke, or death from cardiovascular causes. After adjustment, the hazard of substantial cognitive impairment was reduced by 14% in the DGT-treated arm in comparison to placebo arm (HR 0.86 95% CI: 0.79–0.95 p = 0.0018), indicating that DGT may be a potential drug used to curb MCI in T2DM
DPP4 Inhibitors	Linagliptin, sitagliptin, saxagliptin, vildagliptin	A 2-year study of DPP4 inhibitors preserved cognition in diabetics with MCI A randomized trial of sitagliptin in 253 with T2DM showed MMSEs improved in the sitagliptin group
p-par gamma agonists	Rosiglitazone, piaglitazone	Piaglitazone associated with improved glucose metabolism and blood flow Rosiglitazone pilot associated with improved attention and delayed recall and ADAS. Efficacy signal selectively in ApoE 4 noncarriers Large phase III trial of rosiglitazone did not show a sustained efficacy signal
SGLT2 Inhibitors	Empagliflozin, cangliflozin, dapagliflozin	SGLT2 inhibitors lowered dementia risk by 42% Long-term improvement on the RBANS