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Zhou JB, Tang X, Han M, et al. Impact of antidiabetic agents on dementia risk: A Bayesian network meta-analysis. Metabolism. 2020 Aug;109:154265. doi: 10.1016/j.metabol.2020.154265. Epub 2020 May 22. (Systematic review)
Abstract

BACKGROUND: Dementia is more prevalent among people with type 2 diabetes, but little is known regarding the influence of antidiabetic agents on this association.

OBJECTIVE: This study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus.

METHODS: Relevant studies were retrieved from the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. Nine antidiabetic agents were included in the search. Data were pooled via network meta-analysis and meta-analysis.

RESULTS: Nine studies were selected for the network meta-analysis with 530,355 individuals and 17 studies for the meta-analysis with 1,258,879 individuals. The analysis excluded glucagon-like peptide 1 (GLP-1) analogs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors due to the absence of relevant data. The use of dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, thiazolidinedione, and sulfonylurea was associated with a decreased risk of dementia in comparison to no treatment with antidiabetic agents (hazard ratio [HR] for DPP-4 inhibitors, 0.54; 95% confidence interval [CI], 0.38-0.74, HR for metformin, 0.75; 95% CI, 0.63-0.86; HR for sulfonylurea, 0.85; 95%CI, 0.73-0.98 and HR for thiazolidinedione, 0.70; 95% CI, 0.55-0.89, respectively). However, the node-splitting analysis showed the inconsistency of direct and indirect estimates in sulfonylurea (P?=?0.042). DPP-4 inhibitors, metformin, thiazolidinedione, and sulfonylurea exhibited a significant impact on the risk of dementia in diabetics compared with insulin (HR, 0.35; 95%CI, 0.20-0.59, HR, 0.48; 95% CI, 0.30-0.77, HR, 0.45; 95% CI, 0.29-0.73 and HR, 0.55; 95% CI, 0.34-0.88, respectively). DPP-4 inhibitors also exhibited a protective effect on the risk of Alzheimer's dementia compared with the no treatment with antidiabetic agents (HR, 0.48; 95% CI, 0.25-0.92). The meta-analysis demonstrated a protective effect of using metformin and DPP-4 inhibitors on the risk of dementia (HR, 0.86; 95% CI, 0.74-1.00 and HR, 0.65; 95% CI, 0.55-0.76, respectively). Further analysis showed insulin was associated with an increased risk of Alzheimer's dementia (HR, 1.60; 95% CI, 1.13-2.26). Only two case-control studies mentioned GLP-1 analogs and SGLT-2 inhibitors, and the pooled ORs showed no evidence of an association with dementia (GLP-1 analogs: 0.71; 95% CI, 0.46-1.10 and SGLT-2 inhibitors: 0.74; 95% CI, 0.47-1.15).

CONCLUSION: This analysis indicated that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. For the increasing focus on the protective effect on dementia, further specific clinical studies are needed to evaluate the impact of GLP-1 analogs and SGLT-2 inhibitors on the risk of dementia.

Ratings
Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Geriatrics 6 / 7
Neurology 6 / 7
Endocrine 5 / 7
Comments from MORE raters

Endocrine rater

I'm not sure that this adds up to much. There are a lot of confounding factors: social class, choice of therapy that depends on duration and 'severity' of diabetes, and difficulties distinguishing Alzheimer and vascular etiologies of dementia.

Endocrine rater

This is good evidence to support use of DPP-4 inhibitors and metformin but I agree that given most patients are on multiple agents, it would be important to see if use of multiple OHA's and long acting insulin would be better than multi-dose insulin or if benefit is lost with severity of diabetes requiring insulin at all. Also it's important to validate if the effect is lost with multiple OHA's with or without sulfonylureas.

Family Medicine (FM)/General Practice (GP) rater

I think knowing the effect on future dementia would be a minor consideration in selecting treatment for diabetes. The first priority would be to obtain a good A1C, secondly to address other pressing comorbidities, eg, using SGLT2 s in HF.

General Internal Medicine-Primary Care(US) rater

The study assessed the impact of various antidiabetic agents on the risk of dementia among patients with Type 2 diabetes mellitus. Data were pooled via network meta-analysis and meta-analysis.

Geriatrics rater

Despite individual RCTs showing mixed results of diabetic control on dementia risk, this high quality network meta-analysis confirms positive association. However, importantly it is of a differential treatment effect across agents, especially between oral agents and insulin.

Neurology rater

These are encouraging results; although, one is left with the unanswered question of whether the results are entirely explained by a better control of diabetes or whether these drugs possess some intrinsic brain protective property.

Neurology rater

The paper is a meta-analysis on several articles chosen in the literature. The authors concluded that patients with type 2 diabetes under treatment with DPP-4 inhibitors presented with the lowest risk of dementia, followed by those treated with metformin and thiazolidinedione, while treatment with insulin was associated with the highest risk. This finding is crucial in the field, therefore this paper might represent a significant advancement. The manuscript is correctly organized and subdivided into paragraphs. There is no apparent grammar mistakes and the flow is linear. Besides, the text is easily understandable even by non-experts in the field.
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