TABLE 3.

Overview of clinical trials of diabetic drugs and herbal medicines in treatment of AD.

Objective of study	Types of antidiabetic drugs	Types of clinical trials	Outcome characteristics	References
T2DM, dementia	Metformin	A population-based investigation	Metformin improved cognitive performance and decreased the risk of dementia	Cheng et al.
MCI due to AD	Metformin	A paired study	Patients with metformin had higher levels of Aβ and lower levels of tau and p-Tau in CSF. Metformin might reduce hippocampus and cortical atrophy to cognitive improvement.	Pomilio et al.
Abnormal glucose metabolism and NDVCI	Metformin	A randomized controlled trial	The performance function was increased. The levels of fasting insulin and IR index is significantly decreased in the metformin-donepezil group than that in the acarbose-donepezil group.	Lin et al.
AD, T2DM	Metformin	A population-based nested case-control study	Metformin was significantly associated with an increased risk of AD.	Ha et al.
AD, MCI, and DM	Metformin	A prospective research	Worse cognitive performance was associated with metformin use.	Moore et al.
AD	Exenatide	A double-blind randomized placebo-controlled Phase II clinical trial	Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal EV except for a reduction of Aβ42 in EVs.	Mullins et al.
AD	Liraglutide	A randomized study	Liraglutide highly significantly raised the blood-brain glucose transfer capacity (T (max)) estimates of cerebral cortex compared to placebo.	Gejl et al.
AD	Liraglutide	A randomized, placebo-controlled double-blinded clinical trial	Liraglutide prevented the decline of glucose metabolism. There was no firm conclusions from the Aβ load or cognition measures.	Gejl et al.
Subjective cognitive complaints	Liraglutide	A placebo-controlled study	Significant improvement in intrinsic connectivity within the DMN was observed in liraglutide group relative to placebo by fMRI.	Watson et al.
Cognitive impairment in T2DM	Dulaglutide	A randomized, double-blind placebo-controlled trial	The hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide.	Cukierman-Yaffe et al.
MCI, T2DM	DPP4is	A population-based cohort study	DPP4 activity was negatively associated with BDNF. The risk for MCI increased with higher levels of DPP4 activity.	Zheng et al.
DM and AD-related cognitive impairment	DPP4is	A retrospective investigation	The DPP4is group had lower global amyloid burden, lower regional amyloid burden in temporo-parietal areas, and a slower longitudinal decrease in MMSE score and memory recall subscore.	Jeong et al.
Memory-impaired adults with AD or amnestic MCI	Insulin Therapy	A randomized controlled trial	Intranasal insulin improved verbal memory and acutely increased plasma Aβ42 levels.	Reger et al.
T2DM, AD	Curcumin	A 12-week randomized controlled trial	Participants with prediabetes who consumed 180 mg of curcumin daily had significantly reduced GSK3β and IAPP in serum samples after 12 weeks compared with placebo groups, reducing insulin resistance and the risk of developing AD and DM.	Thota et al.
/	Curcumin	A randomized, double-blind, placebo-controlled trial	Healthy older people with solid lipid curcumin have significantly better memory performance and mood.	Cox et al.
AD	Curcumin	A randomized, placebo-controlled, double-blind, pilot clinical trial	Curcumin can help patients with AD decrease the accumulation of Aβ in the brain, although Aβ levels in serum were no significant difference.	Baum et al.
/	Resveratrol	An interventional study	Supplementary resveratrol could improve memory function, accompanied by increased hippocampal functional connectivity and glucose metabolism.	Witte et al.
AD	Resveratrol	A randomized, double-blind, placebo-controlled trial	The treatment of resveratrol had no benefits in biomarkers of AD and glucose metabolism. And brain volume loss was increased in the resveratrol group.	Turner et al.
T2DM with normal cognition or AD	Metformin, DPP4is	A retrospective investigation	In normal cognition (NC) (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), DPP4is use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4is use among APOE epsilon4 carriers.	Wu et al.
T2DM and AD or mixed-pathology dementia	Metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and DPP4is	A prospective open-cohort study	Compared to non-users, prevalent users of metformin and DPP4is experienced a slower cognitive decline with time. Secondly, compared to DPP4is, the use of insulin and sulfonylureas was associated with larger point-wise decrements in MMSE with annual intervals.	Secnik et al.
DM with or without AD	Sitagliptin, metformin, and insulin	A prospective and observational study	Besides its effects similar to those of insulin and metformin in glycemic control and in reducing need for insulin, 6-month sitagliptin therapy may also associated with improvement of cognitive function in elderly DM patients with and without AD.	Isik et al.
Dementia, T2DM	DPP4is, metformin, TZD, sulfonylurea, and insulin	A meta-analysis	Patients with T2DM under treatment with DPP4is presented with the lowest risk of dementia, followed by those treated with metformin and TZD, while treatment with insulin was associated with the highest risk.	Zhou et al.
Dementia	SGLT2is, DPP4is	A retrospective study	The use of SGLT2 is associated with lower risks of dementia compared with DPP4is use.	Mui et al.
Dementia	SGLT2is, DPP4is	A retrospective study	SGLT2is showed an association with lower dementia risk compared with DPP4is. Dapagliflozin exhibited the lowest risk, followed by empagliflozin, whereas canagliflozin showed no association.	Wu et al.