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Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials

Alzheimer's Research & Therapy volume 16, Article number: 272 (2024) Cite this article

Abstract

Objective

To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D).

Methods

Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI).

Results

A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer’s disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo.

Conclusion

Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D.

Introduction

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by insulin resistance and relative insulin secretion insufficiency, which result in persistent hyperglycemia and corresponding damage to multiple organs [1, 2]. Due to the rising prevalence of obesity, and the gradual intensification of population aging, T2D has imposed a significant global disease burden, influencing over 573 million individuals worldwide [2]. Currently, with the optimization of T2D treatment strategies, the life span of patients was greatly prolonged. Diabetic complications which significantly impact long-term quality of life have therefore garnered increasing attention, among which cognitive dysfunction serves as a particularly important concern [3, 4].

Dementia is a spectrum of diseases manifested by different degrees of cognitive function decline, which could be generally categorized as Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, and frontotemporal dementia etc., according to specific causes and pathological changes [5, 6]. Dementia primarily generates from neurodegeneration and cerebral angiopathy [7, 8], while T2D promotes these neural injuries through multiple pathophysiological mechanisms. The persistent hyperglycemia caused by T2D would exacerbate the accumulation of advanced glycation end products (AGEs), which induced β-amyloid protein deposition and neurofibrillary tangles, subsequently leading to neuronal damage [9]. Additionally, insulin resistance could also affect insulin signaling in neuronal cells, weakening the inhibition of β-amyloid production and tau (τ) protein hyperphosphorylation, thereby accelerating the development of cognitive impairment in patients [10, 11]. Meanwhile, endothelial injuries and atherosclerosis in cerebral vasculature in patients with T2D also contribute to hypoperfusion of corresponding brain regions, which further promote the progression of cognitive function decline [12]. Compared to individuals without T2D, patients with T2D were with 151% higher risks of developing dementia [13]. Moreover, after adjusting the effects of blood glucose and diabetic complications, the risks of dementia in patients with diabetes were still greater than healthy populations [14]. Accordingly, anti-diabetic agents are assumed to be able to improve the cognitive function by ameliorating T2D progression and perhaps through their unique mechanisms independent of glycemic control [15].

Neuroprotective effects have been indicated in many anti-diabetic agents by in vivo experiments, including metformin [16], thiazolidinediones (TZD) [17], α-glycosidase inhibitors (AGI) [18], glucagon-like peptide-1 receptor agonists (GLP-1RA) [19], dipeptidyl peptidase-4 inhibitor (DPP-4i) [20], and sodium-dependent glucose transporters-2 inhibitor (SGLT-2i) [21]. However, clinical observations exhibited inconsistent results. Recently, GLP-1RA was demonstrated effective in early Parkinson’s disease, which indicated its protective impact on neurodegenerative disease [22]. Moreover, although the risks of dementia were significantly decreased in patients with T2D under GLP-1RA [23] and SGLT-2i [24] treatment in several randomized controlled trials (RCTs), some studies indicated increased risks of Alzheimer’s disease in sulfonylurea users compared to DPP-4i [25]. Meanwhile, previous meta-analyses on this topic simply include only observational studies or RCTs [26, 27], or investigated only one anti-diabetic agent [28, 29], which also warrant replenishment. Therefore, we designed and conducted a systematic review and network meta-analysis concerning all available anti-diabetic agents to further explore the association between the use of anti-diabetic agents and the risks of dementia in patients with T2D.

Methods

Study design and registration

This systematic review and network meta-analysis was designed and conducted conforming to the recommendation of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 protocol [30] and PRISMA extension statement of network meta-analysis [31]. Registration was accomplished on International Prospective Register of Systematic Reviews (PROSPERO) platform with the number of CRD42022379082.

Data sources and searches

We implemented a comprehensive literature retrieval in PubMed, Embase, Web of Science, Cochrane Library and Clinicaltrial.gov website for observational studies and RCTs which applied anti-diabetic agents in patients with T2D from the inception to March 2024, in line with the instructions from the Cochrane Handbook for Systematic Reviews and Meta-analysis. To fully include available and eligible studies, we also screened the references of published relevant studies.

We implemented literature searches by the strategy of both applying medical subject headings (MeSH) and free terms. The retrieval terms were as follows: anti-diabetic agents, biguanides, metformin, sulfonylurea, glibenclamide, glimepiride, glipizide, gliquidone, gliclazide, glinides, nateglinide, repaglinide, mitiglinide, thiazolidinediones, rosiglitazone, pioglitazone, englitazone, α-glycosidase inhibitor, miglitol, acarbose, voglibose, glucagon-like peptide-1 receptor agonist, liraglutide, albiglutide, dulaglutide, exenatide, efpeglenatide, lixisenatide, semaglutide, taspoglutide, dipeptidyl peptidase-4 inhibitor, sitagliptin, omarigliptin, alogliptin, linagliptin, saxagliptin, tenegliptin, anagliptin, vildagliptin, gemigliptin, sodium-dependent glucose transporters-2 inhibitor, dapagliflozin, empagliflozin, canagliflozin, luseogliflozin, ertugliflozin, sotagliflozin, bexagliflozin, Ipragliflozin, insulin, glucokinase activators, doragliatin, glucagon-like peptide-1/gastric inhibitory polypeptide dual agonists, tirzepatide, glucagon-like peptide-1/glucagon receptor dual agonists, glucagon-like peptide-1/gastric inhibitory polypeptide/glucagon receptor triple agonists, type 2 diabetes, cognitive disorder, dementia, Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, Parkinson’s dementia, observational studies, cohort studies, case-control studies, cross-sectional studies. Specific search strategies were summarized in Texts S1.

Study selection and data extraction

The inclusion criteria in this network meta-analysis were: (1) studies which were observational studies (including cohort studies, case-control studies, and cross-sectional studies) or RCTs; (2) studies conducted in adult patients with T2D; (3) studies compared an anti-diabetic agent with another anti-diabetic agent or placebo; (4) studies with reports of dementia events.

Two investigators (ZL and CL) independently inspected the searched articles by their titles, abstracts, and full manuscript, excluded the duplicate and ineligible studies, assessed the quality and evaluated the risks of bias of the remaining studies, and extracted data from eligible studies. The extracted data included: (1) Study information [study design, medication exposure, study durations, sample size in experimental and control groups, publication data (first author and published year)]; (2) Baseline characteristics of patients [mean age, body mass index (BMI), sex ratio, baseline glycosylated hemoglobin A1c (HbA1c), HbA1c change]; (3) incidence of different types of dementia (overall dementia, Alzheimer’s disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson’s dementia).

Dementia events were primarily obtained from the main text or attached supplementary files of each article. When the data of dementia incidence were not available in main texts or supplementary files, Clinicaltrials.gov website served as the subsequent data source. Disagreements were resolved by reaching a consensus with another joint investigator (XC).

Risks of bias assessment

Evaluation for risks of bias in observational studies were performed by the Newcastle-Ottawa Scale (NOS) [32], which specifically assessed the following domains of non-randomized studies as selection of the study groups, comparability among different groups, and ascertainment of either the exposure or outcome of interest. The total scores of NOS range from 0 to 9. For RCTs, the risks of bias in randomized controlled trials were evaluated with the Cochrane Collaboration’s tool [33]. The evaluating measurements include random sequence generation, allocation concealment, blinding of participants and caregivers, missing outcome data, and selective outcomes reporting, and other bias. Each domain was evaluated by degrees as to whether the risks of bias exist, including “definitely yes”, “probably yes”, “definitely no”, “probably no” according to the instruction.

Data synthesis and analysis

The primary endpoints of this network meta-analysis were the association between the use of anti-diabetic agents and the risks of dementia. The incidence of different subtypes of dementia including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies were considered as the exploratory endpoints.

Primarily, conventional meta-analyses comparing each anti-diabetic agent with other treatments (other types of anti-diabetic agents or placebo) were implemented for both observational studies and RCTs. The results were presented as odds ratio (OR) with confidence interval (CI) for observational studies, as well as risk ratio (RR) with 95% CI for RCTs. Meta-regression analyses assessing the potential correlations between baseline characteristics and the research outcomes for both observational studies and RCTs were also conducted. Afterwards, we conducted network meta-analyses within frequentist graph theoretical framework [34] for observational studies and RCTs. Indirect evidence was estimated using the entire network of evidence, and heterogeneities for included studies in all comparisons were evaluated. Heterogeneity was assessed with the Cochrane Q [35] and the Higgins I2 statistics [36]. When I2 value ≥ 50%, a high heterogeneity was prompted; otherwise, the heterogeneity would be considered relatively low. Due to the potential high level of heterogeneity, the random-effect model was consistently adopted in all analyses. Global incoherence between direct and indirect comparison was evaluated via side-splitting approaches [37]. In the network plots, the node represented as an intervention and the comparisons between two interventions were depicted as connection lines, whose width indicated the quantities of studies in corresponding comparison [38, 39]. Moreover, the probability of being the best intervention was generated with the P-score and surface under the cumulative ranking curve (SUCRA) method [40, 41].

Since some outcome data might be missing due to loss to follow-up, we utilized the “intention-to-treat” analyses set data for studies with prominent missing outcome data during the statistical process to control the influence of missing outcome data. The certainty of study results was evaluated utilizing the schemes recommended by Grades of Recommendations Assessment, Development and Evaluation (GRADE) system. Publication bias was assessed with the funnel plot and Egger’s test [42]. Statistical significance was considered at P < 0.05. Statistical analyses were performed by Review Manager statistical software package (Version 5.3, Nordic Cochrane Center, Copenhagen, Denmark), and STATA statistical software package (Version 16.0, Stata Corp, College Station, TX, USA) [43].

Results

Characteristics and quality assessments of included studies

In total, there were 41 observational studies (including 34 cohort studies, 6 case-control studies and 1 cross-sectional studies) with 3,307,483 participants, and 23 RCTs with 155,443 participants included in the meta-analysis (Fig. 1). The anti-diabetic agents investigated in this research involve metformin, sulfonylureas, glinides, TZD, AGI, GKA, insulin, GLP-1RA, GLP-1/GIP receptor dual agonists, DPP-4i, and SGLT-2i. Baseline characteristics of included studies were summarized in Table S1.

Fig. 1
figure 1

Flow diagram of this network meta-analysis

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The quality assessments for observational studies and RCTs were implemented with Newcastle-Ottawa Scale (NOS) and Cochrane instruments respectively (Table S2, Table S3), which suggested generally low risks of bias in enrolled studies. For observational studies, the average score of NOS was 6.88 in cohort studies and 7.67 in case-control or cross-sectional studies, with 31 (75.6%) observational studies of high quality (score ≥ 7/9). For RCTs, there were 4 RCTs with uncertain bias of randomization sequence generation, 2 RCT with high risks for inadequate allocation concealment, and 4 RCTs with high risks for frequent missing outcome data. No RCT was with high risks of bias in adequate randomization sequence generation, or bias in selective outcome reporting, or bias in masking patients and caregivers, or bias in masking outcome assessors and adjudicators (Figure S1). The incoherence between direct and indirect evidence was evaluated by side-splitting charts, where no prominent incoherence was suggested (Table S4). Publication bias was assessed with funnel plots and Egger’s test. The funnel plots exhibited generally even distribution (Figure S2, Figure S3), and no significant publication bias was indicated by Egger’s test (Table S5).

Conventional meta-analyses

For observational studies, when compared with non-users, the risks of overall dementia were significantly lower in patients receiving metformin (OR = 0.92, 95%CI, 0.89 to 0.96, I2 = 92%), TZD (OR = 0.85, 95%CI, 0.80 to 0.90, I2 = 84%), DPP-4i (OR = 0.95, 95%CI, 0.91 to 0.99, I2 = 92%), SGLT-2i (OR = 0.75, 95%CI, 0.64 to 0.87, I2 = 97%) and GLP-1RA (OR = 0.75, 95%CI, 0.64 to 0.88, I2 = 93%). However, insulin (OR = 1.06, 95%CI, 1.01 to 1.11, I2 = 93%) and sulfonylureas (OR = 1.03, 95%CI, 1.00 to 1.16, I2 = 89%) treatment were associated with an increase in the risk of dementia when compared to non-users (Figure S4). Moreover, patients receiving SGLT-2i treatment were with significantly lower risks of Alzheimer’s disease (OR = 0.63, 95%CI, 0.56 to 0.70, I2 = 0%), when TZD treatment was associated with a reduced risk of Alzheimer’s disease (OR = 0.95, 95%CI, 0.94 to 0.97, I2 = 0%) and vascular dementia (OR = 0.71, 95%CI, 0.68 to 0.75, I2 = 0%). However, insulin treatment was associated with an increased Alzheimer’s disease risks (OR = 1.20, 95%CI, 1.18 to 1.22, I2 was not applicable), when compared with non-users (Figure S4).

In conventional meta-analysis of RCTs, no significant difference on the incidence of dementia were characterized in patients receiving TZD (RR = 0.99, 95%CI, 0.06 to 15.80, I2 was not applicable), DPP-4i (RR = 0.94, 95%CI, 0.53 to 1.68, I2 = 12%), SGLT-2i (RR = 1.55, 95%CI, 0.73 to 3.27, I2 = 0%), GLP-1RA (RR = 1.04, 95%CI, 0.55 to 1.97, I2 = 0%) (Figure S5) when compared with non-users. Similarly, no significant associations were observed among anti-diabetic agent treatment and other dementia subtypes including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies (Figure S5).

We also conducted meta-regression analyses to address the influence of potentially associated factors on study results. For observational studies, age was found negatively associated with the risks of dementia (β = −0.016, 95% CI, −0.028, −0.003, p = 0.014), suggesting that patients who were older would gain more prominent benefits in dementia risks reduction with anti-diabetic treatment. While for RCTs, no baseline characteristic was found to be associated with the risks of dementia in patients with T2D. Further details on meta-regression analyses were summarized in Table S6 .

Network meta-analyses

Network meta-analyses of observational studies

The network diagrams of observational studies are exhibited in Fig. 2 and Figure S6 Compared with non-users, SGLT-2i (OR = 0.56, 95%CI, 0.45 to 0.69), GLP-1RA (OR = 0.58, 95%CI, 0.46 to 0.73), TZD (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were associated with the reduced risk of dementia in patients with T2D. Moreover, the risk of dementia was significantly lower in patient receiving SGLT-2i treatment when compared to those using metformin (OR = 0.56, 95%CI, 0.45 to 0.69), DPP-4i (OR = 0.65, 95%CI, 0.52 to 0.80), GKA (OR = 0.53, 95%CI, 0.29 to 0.99) and AGI (OR = 0.62, 95%CI, 0.39 to 0.97). Besides, patients with GLP-1RA treatment also presented lower risks of dementia compared with metformin (OR = 0.65, 95%CI, 0.51 to 0.83) and DPP-4i (OR = 0.67, 95%CI, 0.52 to 0.86). However, compared with placebo, insulin (OR = 0.85, 95%CI, 0.67 to 1.08) and sulfonylureas (OR = 0.97, 95%CI, 0.84 to 1.12) did not increase the risk of dementia in patients with T2D (Table 1).

Fig. 2
figure 2

Network plots for observational studies (evaluating the risks of dementia). *Abbreviations: PBO, placebo; MET, metformin; TZD, thiazolidinediones; SU, sulfonylureas; AGI, α-glucosidase inhibitor; DPP-4i, dipeptidyl peptidse-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; GKA, glucokinase activator.

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Table 1 League charts of observational studies. League charts of observational studies intercomparing the risks of dementia among different anti-diabetic agents and placebo
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Furthermore, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) treatments were associated with significantly reduced risk of Alzheimer’s disease when compared with non-users. Other than life intervention, the risk of Alzheimer’s disease was reduced in patients treated with SGLT-2i when compared with those receiving metformin (OR = 0.46, 95%CI, 0.31 to 0.68), TZD (OR = 0.52, 95%CI, 0.34 to 0.79), DPP-4i (OR = 0.59, 95%CI, 0.45 to 0.78), insulin (OR = 0.28, 95%CI, 0.15 to 0.53) and sulfonylureas (OR = 0.46, 95%CI, 0.31 to 0.66) (Table 2).

Table 2 League charts of observational studies. League charts of observational studies intercomparing the risks of Alzheimer’s disease among different anti-diabetic agents and placebo
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As for vascular dementia, SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) were associated with a lower risk of vascular dementia compared with non-users. Meanwhile, SGLT-2i conferred greater risk reduction in vascular dementia compared with metformin (OR = 0.32, 95%CI, 0.15 to 0.68), DPP-4i (OR = 0.48, 95%CI, 0.27 to 0.85) and sulfonylureas (OR = 0.32, 95%CI, 0.16 to 0.65) (Table 3).

Table 3 League charts of observational studies. League charts of observational studies intercomparing the risks of Alzheimer’s disease among different anti-diabetic agents and placebo
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In terms of SUCRA evaluation for the dementia, the rank order was SGLT-2i (SUCRA: 94.5, mean rank: 1.5) > GLP-1RA (SUCRA: 92.1, mean rank: 1.8) > TZD (SUCRA: 80.5, mean rank: 3.0) > DPP-4i (SUCRA: 57.4, mean rank: 5.3) > metformin (SUCRA: 54.0, mean rank: 5.6) > AGI (SUCRA: 47.3, mean rank: 6.3) > GKA (SUCRA: 31.1, mean rank: 7.9) > sulfonylureas (SUCRA: 25.7, mean rank: 8.4) > glinides (SUCRA: 24.1, mean rank: 8.6) > insulin (SUCRA: 11.3, mean rank: 9.9), which indicated SGLT-2i and GLP-1RA might serve as the optimal treatments in reducing the risk of dementia in patients with T2D. And regarding benefits in reducing the risk of Alzheimer’s disease, the rank was: SGLT-2i (SUCRA: 94.9, mean rank: 1.4) > GLP-1RA (SUCRA: 81.3, mean rank: 2.5) > DPP-4i (SUCRA: 66.7, mean rank: 3.7) > AGI (SUCRA: 56.7, mean rank: 4.5) > TZD (SUCRA: 55.3, mean rank: 4.6) > metformin (SUCRA: 34.9, mean rank: 6.2) > sulfonylureas (SUCRA: 33.9, mean rank: 6.3) > insulin (SUCRA: 3.9, mean rank: 8.7). As for vascular dementia, the rank was GLP-1RA (SUCRA: 84.3, mean rank: 1.9) > SGLT-2i (SUCRA: 83.4, mean rank: 2.0) > TZD (SUCRA: 75.6, mean rank: 2.5) > DPP-4i (SUCRA: 47.8, mean rank: 4.1) > metformin (SUCRA: 11.8, mean rank: 6.3) > sulfonylureas (SUCRA: 10.8, mean rank: 6.4) (Figs. 3, 4 and 5; Table 4).

Fig. 3
figure 3

SUCRA evaluations of the network meta-analysis for observational studies. SUCRA evaluations of the network meta-analysis for observational studies (anti-diabetic agents and the risks of dementia)

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Fig. 4
figure 4

SUCRA evaluations of the network meta-analysis for observational studies (anti-diabetic agents and the risks of Alzheimer’s disease)

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Fig. 5
figure 5

SUCRA evaluations of the network meta-analysis for observational studies (anti-diabetic agents and the risks of vascular dementia). Abbreviations: TZD, thiazolidinediones; AGI, α-glucosidase inhibitor; DPP-4i, dipeptidyl peptidse-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; GKA, glucokinase activator.

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Table 4 Results of SUCRA probability evaluation for observational studies
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Network meta-analyses of RCTs

The network diagrams of RCTs are shown in Fig. 6 and Figure S7 According to the results, compared with placebo, no significantly altered dementia risks were observed in patients receiving DPP-4i (RR = 1.19, 95%CI, 0.61 to 2.32), SGLT-2i (RR = 0.45, 95%CI, 0.67 to 3.12), GLP-1RA (RR = 1.08, 95%CI, 0.57 to 2.05), TZD (RR = 0.73, 95%CI, 0.09 to 32.74), or sulfonylurea (RR = 1.75, 95%CI, 0.66 to 4.63). With respect to the risks of Alzheimer’s disease, vascular dementia, and dementia with Lewy bodies, no significant associations were observed when intercomparing all anti-diabetic agents and placebo as well. More detailed results were summarized in Figure S8 and Table S6-7.

Fig. 6
figure 6

Network plots for randomized controlled trials (evaluating the risks of dementia)

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Discussion

The impact of anti-diabetic agents for dementia event risks

A large number of anti-diabetic agents were demonstrated with potential cognitive function protective effects through proper glycemic control and other independent mechanisms.

SGLT-2i primarily exert hypoglycemic effects by inhibiting the SGLT-2 protein in renal tubular, thereby reducing the reabsorption of urine glucose, and promoting urinary glucose excretion. In recent years, several pre-clinical researches have revealed additional pharmacological benefits of SGLT-2i beyond glycemic effects, which majorly involved cardiorenal protective traits [44, 45], and gradually extended to cognitive function preserving effects. SGLT-2i was demonstrated able to ameliorate cognitive function decline through multiple mechanisms. SGLT-2i could inhibit acetylcholinesterase (AChE) activity, leading to increased brain acetylcholine levels and therefore protects cognitive function [46]. It was also indicated that SGLT-2i may ameliorate cognitive impairment by improving cerebral atherosclerosis and vascular function, suppressing neuroinflammation, and mitigating neuronal apoptosis [47, 48]. Additionally, SGLT-2i could correct the disrupted circadian rhythm of mammalian target of rapamycin (mTOR) caused by metabolic abnormalities, hence reducing tau protein and β-amyloid protein deposition, which delayed cognitive decline in patients with Alzheimer’s disease [49]. Notably, a recent RCT suggested that empagliflozin significantly postponed the progression of dementia in patients with T2D compared to placebo [24]. According to our study, the network meta-analysis of observational studies indicated that SGLT-2i were associated with significantly reduced dementia risks compared to other antidiabetic agents, and SUCRA evaluated SGLT-2i as the bset rank therapy for lowering the risks of dementia. These findings suggest a highly potential cognitive function protective effect of SGLT-2i in patients with T2D.

GLP-1RA and DPP-4i both act through the GLP-1 related pathway, by directly activating the GLP-1 receptor (GLP-1RA) or inhibiting endogenous GLP-1 degradation (DPP-4i) to enhance the physiological function of GLP-1 and exert glucose lowering effects. GLP-1 could alleviate diabetes by increasing insulin sensitivity, promoting insulin release and suppressing appetite, which would effectively conduce to glycemic control and weight losing [50]. Previous studies showed GLP-1RA could delay the progression of cognitive impairment by inhibiting neuroinflammation and neuronal apoptosis [51]. Some studies also found that GLP-1RA improved cognitive function in animal models by activating the Brain-derived neurotrophic factor (BDNF) and Tropomyosin-related kinase B receptor (TrkB) pathway, therefore accelerated newborn neurons formation and synaptic remodeling [52]. And in clinical studies, dulaglutide and exenatide exhibited significant effects on delaying the progression of dementia in patients with T2D as well [23, 53]. While DPP-4i was deemed to delay dementia progression by inhibiting the degradation of GLP-1, GIP, and exerting similar mechanisms as GLP-1RA [54]. In addition to the GLP-1/GIP pathway, DPP-4i could also inhibit the degradation of several neuroprotective DPP-4 substrates such as SDF-1 (Stromal-derived factor-1), GLP-2 (Glucagon-like peptide-2), NPY (Nerve peptide Y) and GRP (Gastrin release peptide), to mediate cognitive function preserving effects through succeeding amelioration of β-amyloid protein deposition and its neurotoxicity, as well as promoting neuron regeneration and brain vascular endothelial function recovery [54,55,56,57]. Pre-clinical studies suggested that linagliptin alleviated cognitive decline via relieving insulin resistance of neurons in Alzheimer’s disease mice model [58]. A retrospective cohort observed slower memory decline in patients with T2D and Alzheimer’s disease when received DPP-4i treatment [59], while a large RCT found that compared with placebo, DPP-4i did not improve cognitive function in patients with T2D [60]. In network meta-analysis of observational studies, GLP-1RA was associated with significantly lower dementia risks compared with non-users and many other anti-diabetic agents, and may serve as an optimal choice as SGLT-2i in lowering dementia risks by SUCRA evaluation. These discoveries also suggested that both GLP-1RA and DPP-4i are with possible cognitive preserving effects, and among all anti-diabetic agents GLP-1RA is with the largest potential in lowering dementia risks in patients with T2D. More researches should be implemented to validate and in-depth investigate the cognitive protective effects of these two drugs.

TZD, as PPAR-γ agonist, is able to reduce blood glucose majorly by improving peripheral tissue insulin sensitivity, reducing serum free fatty acids (FFA), preserving pancreatic β-cell function, and achieving anti-oxidative stress and anti-inflammatory effects, which contribute to preferable benefits in metabolic profiles for patients with prominent insulin resistance features [61]. And for its cognitive protective effects, TZD might improve the cognitive function of mice by means of glycemic-independent ways as extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) pathways activation subsequent of stimulating PPAR-γ receptor at hippocampus [62]. Significant alleviation of neuropathological progression was also observed in Alzheimer’s disease mice model treated with TZD [63]. However, previous clinical studies exhibited inconsistent results. A RCT suggested both cerebral blood flow and cognitive scores improvement in patients with T2D and Alzheimer’s disease receiving TZD [64], while another study have not observed the cognitive function amelioration effects of TZD [65]. In this study, by network meta-analysis, TZD also ranked third regarding dementia risks reduction and vascular dementia risks. Preceding studies indicated that TZD might inhibit vascular inflammation, as well as macrophages infiltration and smooth muscle cell activation by intercepting PI3K/Akt pathway [66, 67]. Meanwhile, a meta-analysis also suggested that compared with placebo, the flow-mediated dilation (FMD, a parameter measuring endothelial function) in patients receiving TZD was significantly increased [68], which further demonstrated the vascular benefits of TZD. The prospects of TZD remitting vascular damage, and subsequently reducing the risks of vascular dementia warrant further exploration and validation.

Metformin is an extensively applied traditional hypoglycemic agent and exerts glucose lowering function by improving insulin sensitivity and inhibiting hepatic glycogenolysis. Previous researches indicated that metformin could introduce neuroprotective effects through mechanisms independent of glycemic control, as activating adenosine monophosphate activated protein kinase (AMPK) pathway in neurocytes to preserve mitochondria stability [69], and reducing the expression of Beta-secretase 1 (BACE1) protein for both in vivo and in vitro conditions, since BACE1 is responsible for the cleavage and maturation of β-amyloid protein [70]. Moreover, metformin was proved to improve the insulin sensitivity of neuronal cells and prevent neurodegenerative pathological changes induced by insulin resistance [71]. Clinical studies also suggested that patients with T2D receiving metformin combining glibenclamide or rosiglitazone treatment were with significantly improved working memory [72]. However, in patients continually treated with metformin, the incidence of Alzheimer’s disease might render a slightly increasing trend [73, 74], and the association between metformin treatment and the risk of dementia events in patients with T2D have not been fully confirmed yet. According to our study, in network meta-analysis of observational studies, patients receiving metformin were with lower dementia risk compared with non-users. These findings further demonstrated the potential of metformin to reduce the risks of dementia event in patients with T2D.

Regarding AGI and GKA, there are currently limited pre-clinical researches exploring their impacts on cognitive function and relevant mechanisms. However, a retrospective cohort found reduced dementia risks in female patients with T2D receiving acarbose, particularly when combined with metformin or pioglitazone [75]. In this study, according to the conventional meta-analysis of observational studies, no significant impacts on all dementia events were observed for AGI and GKA treatment when compared with non-users. Further researches exploring the therapeutic effects of AGI and GKA in undermining cognitive impairment progression for patients with T2D are yet warranted.

Sulfonylureas, glinides and insulin both play glucose lowering effects in insulin-related manners (by promoting the endogenous secretion of insulin, or directly appending exogenous insulin) [76, 77]. Previous studies have suggested that both sulfonylureas could improve the memory and synaptic plasticity of Alzheimer’s disease mice models by activating the in ATP-sensitive potassium channel in brain cells [78]. Insulin was also illustrated to exert cognitive protective effects through mTOR pathways [79]. However, clinical studies have yielded inconsistent results, with some indicating increased dementia risks and others exhibiting decreased risks in patients using sulfonylureas or insulin [25, 65, 80]. Upon the results of our study, network meta-analysis of observational studies suggested that compared with other anti-diabetic agents, sulfonylureas and insulin treatments were associated with significantly lower reductions of dementia, Alzheimer’s disease and vascular dementia risks in patients with T2D. In corresponding SUCRA evaluation, sulfonylureas, glinides and insulin were ranked worst treatment in reducing dementia event risks. This phenomenon could be accounted for the increased risks of hypoglycemic events associated with sulfonylureas, glinides and insulin, leading to subsequent neural damage and cognitive function impairment. Sulfonylureas, glinides and insulin did not exhibit favorable cognitive preserving effects in patients with T2D, and more researches are still required to validate these findings and further explore possible mechanisms.

Meanwhile, according to the meta-regression analyses, age was negatively correlated with the risks of dementia, suggesting that patients who were older would gain more significant benefits from anti-diabetic agents regarding the reduction of dementia risks. Since dementia serves as a specific age-related disease, whose prevalence is intrinsically low in young populations, the dementia risk improving effects may present prominently in elderly patients. For other potentially associated factors including diabetes duration, sex, BMI and so on, no significant associations between them and study results were observed. Further investigations to explore the influence of baseline characteristics on dementia outcomes are warranted.

Limitations and future prospects

This study has some limitations. First, due to the discrepancies of the included studies in the populations, interventions, and outcomes, the heterogeneities which might influence study results should not be ignored. To control the interference of research heterogeneities, we used random effects model in the analysis. Secondly, the majority of study results was generated from observational studies, which inevitably involved more confounding factors, and at lower evidence grade comparing to RCTs. Furthermore, since there are more pre-clinical and clinical studies indicating the cognitive benefits of GLP-1RA than other anti-diabetic agents, the potential publication bias should be considered. To cope with it, we have correspondingly conducted the visual inspection on funnel plots and performed the Egger’s tests, which suggested low risks of publication bias for included studies. But still, further validation with enriched evidence is needed. Meanwhile, as the follow-up period was not restricted in included studies, it may not be sufficient enough for dementia to develop in a short follow-up time, and evaluation for the impacts of anti-diabetic agents on the risks of dementia events could therefore be interrupted.

Moreover, since the included RCTs were mostly designed for other evaluation outcomes, the reported dementia events were with unclear event disclosure and in lack of adjudication by professionals. The meta-analyses results generated by data from RCTs may not adequately reflect the actual association between anti-diabetic agents and dementia event risks. Currently, there are 2 trials (EVOKE, and EVOKE plus) investigating the efficacy of semaglutide in patients with early Alzheimer’s disease being carried out, which may provide further evidence in this field with high quality. More RCTs concentrating on the anti-diabetic agents and the risks of dementia events should be carried out in the future, and subsequent meta-analysis updated by relevant RCTs are warranted.

This study also provides future directions and prospects for current field of anti-diabetic agents and their cognitive function protective potentials. Concerning the cognitive protective effects of anti-diabetic agents, several previous studies have been carried out. Alvin et al. conducted a conventional meta-analysis for observational studies, which suggested that metformin, TZD, GLP-1RA and SGLT-2i were associated with significant reduction for the risk of dementia in patients with T2D, when GLP-1RA exhibited the strongest effects [81]. While Tian et al. further implemented a network meta-analysis of 3 RCTs and 24 observational studies, whose results indicated that patients with SGLT-2i, GLP-1RA, TZD, and DPP-4i treatment showed a decreased risk of dementia, and the SUCRA ranked SGLT-2i as the best intervention. Compared with these previous meta-analysis of this field [81, 82], our study included more observational studies and RCTs as an update, which provided comprehensive evidence for the association between anti-diabetic agents and dementia in patients with T2D. Meanwhile, we analyzed the data from observational studies and RCTs separately, which also to some extent avoided confounders derived from study design discrepancies and enhanced the interpretability of study results. This meta-analysis found that many traditional and emerging anti-diabetic agents were associated with the reduction of different kinds of dementia event risks in patients of T2D, when large quantities of previous studies have also confirmed the cognitive preserving effects of these anti-diabetic agents through favorable glycemic control and other independent mechanisms. Therefore, it was suggested that the reasonable use of these noted anti-diabetic agents could introduce cognitive benefits in patients with T2D. At the meantime, this study also observed significantly elevated risks of dementia events in patients receiving sulfonylureas and insulin treatment. According to precedent researches, it might be associated with the increased incidence of hypoglycemia, thereby causing energy supply deficiencies and resulting in cognitive impairment. Therefore, upon applying insulin secretagogues and insulin to patients with T2D, it is necessary to concern more about patient’s cognitive function, adopt close follow-up assessments, and as much as possible prevent the occurrence of dementia in patients. Meanwhile, in this study, it was indicated that previous RCTs lacked attention to the risks of dementia events in patients with T2D. Subsequent RCTs designating the primary outcome as dementia event risks in patients with T2D are needed to effectively evaluate the impacts of anti-diabetic agents on the risks of dementia events in patients with T2D with high-quality evidence.

Conclusions

In this study, the network meta-analysis for observational studies suggested that compared to non-users, treatment with SGLT-2i, GLP-1RA, TZD or metformin might be associated with a reduced risk of dementia. By SUCRA evaluation, SGLT-2i and GLP-1RA might be the optimal treatments in reducing the risk of dementia among all anti-diabetic agents. Meanwhile, compared with non-users, treatment with SGLT-2i, GLP-1RA or DPP-4i might be associated with a reduced risk of Alzheimer’s disease, when a lower risk of vascular dementia was observed in SGLT-2i users or TZD users. The network meta-analyses for RCTs did not yield any positive results. Further dedicated RCTs directly evaluating the association between anti-diabetic agents and dementia event risks are required to enrich the evidence.

Data availability

No datasets were generated or analysed during the current study.

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Funding

This work was supported by Beijing Natural Science Foundation (No.7202216) and National Natural Science Foundation of China (No.81970698 and No.81970708). The funding agencies had no roles in the study design, data collection or analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Peking University People’s Hospital, 100044 No.11 Xizhimen South Street, Xicheng District, Beijing China, 100044, People’s Republic of China

    Zonglin Li, Chu Lin, Xiaoling Cai, Fang Lv, Wenjia Yang & Linong Ji

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  1. Zonglin Li
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  2. Chu Lin
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  3. Xiaoling Cai
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Contributions

LJ and XC conceptualized this study and designed the systematic review protocol; ZL and CL performed the study selection and data extraction; ZL and CL performed the statistical analyses; ZL, CL and XC prepared the outlines and wrote the manuscript. FL and WY contributed to the critical revision of manuscript drafts.

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Correspondence to Xiaoling Cai or Linong Ji.

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For financial competing interests, LJ has received fees for lecture presentations and for consulting from AstraZeneca, Merck, Metabasis, MSD, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda; when LJ has no non-financial competing interests to disclose. There are no financial or non-financial conflicts of interests to reveal in any other co-authors. No other support from any organization for the submitted work other than that described above.

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Li, Z., Lin, C., Cai, X. et al. Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials. Alz Res Therapy 16, 272 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13195-024-01645-y

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Alzheimer's Research & Therapy

ISSN: 1758-9193