The pharmacodynamics-based prophylactic benefits of GLP-1 receptor agonists and SGLT2 inhibitors on neurodegenerative diseases: evidence from a network meta-analysis

Abstract

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a new generation of antihyperglycemic agents that operate through mechanisms distinct from conventional diabetes treatments. Beyond their metabolic effects, these medications have demonstrated neuroprotective properties in preclinical studies. While clinical trials have explored their therapeutic potential in established neurodegenerative conditions, their role in disease prevention remains unclear. We conducted a network meta-analysis (NMA) to comprehensively evaluate the prophylactic benefits of these agents across multiple neurodegenerative diseases and identify the most promising preventive strategies.

Methods: We systematically searched PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov through October 24th, 2024, for randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was the incidence of seven major neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease. Secondary outcomes included safety profiles assessed through dropout rates. We performed a frequentist-based NMA and evaluated risk of bias with Risk of Bias tool. The main result of the primary outcome in the current study would be re-affirmed via sensitivity test with Bayesian-based NMA.

Results: Our analysis encompassed 22 RCTs involving 138,282 participants (mean age 64.8 years, 36.4% female). Among all investigated medications, only dapagliflozin demonstrated significant prophylactic benefits, specifically in preventing Parkinson's disease (odds ratio = 0.28, 95% confidence intervals = 0.09 to 0.93) compared to controls. Neither GLP-1 receptor agonists nor other SGLT2 inhibitors showed significant preventive effects for any of the investigated neurodegenerative conditions. Drop-out rates were comparable across all treatments.

Conclusions: This comprehensive NMA reveals a novel and specific prophylactic effect of dapagliflozin against Parkinson's disease, representing a potential breakthrough in preventive neurology. The specificity of dapagliflozin's protective effect to Parkinson's disease might rely on its highly selective inhibition to SGLT2. These findings provide important direction for future research and could inform preventive strategies for populations at risk of Parkinson's disease.

Trial registration: PROSPERO CRD42021252381.

Keywords: GLP-1 receptor agonist; Network meta-analysis; Neurodegenerative disease; Parkinson’s disease; SGLT2 inhibitor.

Fig. 1

PRISMA2020 Flowchart of current network meta-analysis

Fig. 2

A Network structure of the primary outcome: overall events of neurodegenerative diseases. A depicts the structure of the overall network meta-analysis of primary outcome. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network. B Network structure of the primary outcome: subgroup analysis of Parkinson’s disease events. B depicts the structure of the subgroup analysis focusing on Parkinson’s disease. The lines between nodes represent direct comparisons from various trials, with the numbers over the lines indicating the number of trials providing these comparisons for each specific treatment. The thickness of the lines corresponds to the number of trials linked to the network

Fig. 3

A Forest plot of primary outcome: overall events of neurodegenerative diseases. When the effect size (expressed as odds ratio) is less than 1, the specified treatment is associated with fewer neurodegenerative disease events compared to placebo/controls. B Forest plot of primary outcome: subgroup analysis of Parkinson’s disease events. When the effect size (expressed as odds ratio) is less than 1, the specified treatment is associated with fewer Parkinson’s disease events compared to placebo/controls. Dosage definition: canagliflozin (low: 100 mg, and high: 300 mg); ertugliflozin (low: 5 mg, and high: 15 mg); injectable semaglutide (low: 0.5 mg, and high: 1.0 mg); empagliflozin (low: 1–10 mg, and high: 25–50 mg). Abbreviations: 95%CIs: 95% confidence intervals; GLP-1 agonist: glucagon-like peptide-1 agonist; NMA: network meta-analysis; OR: odds ratio; RCT: randomized controlled trial; SGLT2 inhibitor: sodium–glucose cotransporter 2 inhibitor