Glucose-lowering therapies may reduce risk for dementia, but more research needed

Key takeaways:

• Two research teams found that GLP-1 receptor agonists reduced dementia risk, but results differed regarding SGLT2 inhibitors.
• Future GLP-1 receptor agonists may have greater neuroprotective effects.

Glucose-lowering drugs have exhibited neuroprotective effects against cognitive decline, but conflicting results of two studies published in JAMA Neurology suggest the need for additional research.

As Healio previously reported, experts estimate that more than 153 million people worldwide will be living with dementia by 2050, demonstrating the importance of identifying strategies for reducing risk. Previous research suggests that glucose-lowering drugs (GLDs), including GLP-1 receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, may offer a neuroprotective effect against dementia, but this association has yet to be confirmed.

In one of two recently published studies in JAMA Neurology, Allie Seminer, MSc, and Alfredi Mulihano, undergraduate students in the School of Medicine at the University of Galway in Ireland, and colleagues found that GLP-1 receptor agonists significantly reduced the risk for all-cause dementia, but SGLT2 inhibitors did not.

“We report that GLP-1 receptor agonists were linked to a 45% lower risk of dementia compared to control (placebo). A previous study which pooled three trials evaluating GLP-1 receptor agonists found similar results,” Seminer and Mulihano told Healio.

However, a different team found that both GLP-1 receptor agonists and SGLT2 inhibitors lowered the risk for Alzheimer’s disease and related dementias compared with second-line GLDs.

“GLP-1 receptor agonists have already shown promise in reducing inflammation, oxidative stress, and neuronal damage, which are key factors in neurodegenerative diseases,” Diana Thiara, MD, assistant clinical professor of medicine at the University of California, San Francisco, said in a related editorial. “However, their neuroprotective effects will need to be validated through rigorous clinical trials.”

Systematic review and meta-analysis

Seminer and Mulihano and colleagues performed a systematic review and meta-analysis to evaluate if cardioprotective GLDs were associated with a reduced risk for dementia or cognitive impairment compared with controls.

They searched PubMed and Embase for randomized controlled studies published through July 2024 that included adults aged older than 18 years, evaluated GLDs recommended based on guidelines and reported changes in dementia or cognition.

Of 26 trials (n = 164,531; mean age, 64.4 years; standard deviation [SD], 3.5 years; 34.9% women) included in the review, 23 reported on incidence of dementia or cognitive impairment. This included 12 trials focused on SGLT2 inhibitors, 10 focused on GLP-1 receptor agonists and one that evaluated pioglitazone.

The researchers found that, over a mean follow-up of 31.8 months, glucose-lowering therapy was not significantly associated with reduced cognitive impairment or dementia (OR = 0.83; 95% CI, 0.6-1.14). However, when evaluating specific drug classes, GLP-1 receptor agonists were linked to a significant reduction in dementia or cognitive impairment (OR = 0.55; 95% CI, 0.35-0.86), but SGLT2 inhibitors were not (OR = 1.2; 95% CI, 0.67-2.17).

“Our findings may have implications for choice of glucose-lowering therapy in patients with diabetes mellitus and higher risk of dementia. However, large trials should be conducted to specifically study the effect of glucose-lowering therapy on dementia and cognitive decline,” Seminer and Mulihano told Healio.

Target trial emulation study

Huilin Tang, PhD, graduate assistant with the department of pharmaceutical outcomes and policy in the College of Pharmacy at the University of Florida, Gainesville, and colleagues performed a population-based cohort study using a target trial emulation approach to evaluate the association between GLDs and risk for Alzheimer’s disease and related dementias (ADRD).

They used electronic health record data from OneFlorida+ Clinical Research Consortium, a health care data repository, from January 2014 to June 2023.

The study included participants aged 50 years or older with type 2 diabetes and no prior diagnosis of ADRD who initiated a GLD within that period. Tang and colleagues divided the participants into three comparison cohorts: GLP-1 receptor agonist (n = 10,212) vs. other second-line GLD (n = 23,646); SGLT2 inhibitor (n = 10,524) vs. other second-line GLD (n = 23,661); or GLP-1 receptor agonist (n = 11,395) vs. SGLT2 inhibitor (n = 12,6722. All groups were comprised of 49% and 53% women and had a mean age of 63 years to 65 years.

Researchers reported 75 ADRD cases among GLP-1 users over a mean follow-up of 2.22 years, compared with 639 ADRD cases among other GLD users over mean follow-up of 3.74 years.

After weighting the cohorts for inverse probability of treatment, the researchers found that, compared with second-line GLDs, ADRD risk was significantly lower with both GLP-1 receptor agonists (adjusted HR = 0.67; 95% CI, 0.47-0.96) and SGLT2 inhibitors (aHR = 0.57; 95% CI, 0.43-0.75).

However, they found that there was no significant difference between GLP-1s and SGLT-2s regarding ADRD risk (aHR = 0.97; 95% CI, 0.72-1.32), conflicting with the results of the first study.

Future of GLP-1 receptor agonists

In a related editorial, Thiara noted that although Tang and colleagues found that GLP-1 receptor agonists and SGLT2 inhibitors had a similar effect on ADRD, the team “did show that isolating semaglutide, the newest and most potent GLP-1 receptor agonist on the market, showed decreased risk of ADRD compared with SGLT2 inhibitors.”

Both studies had limitations, including short-term follow-up, low dementia event rates and confounding variables, Thiara wrote.

“Importantly, with the advent of more potent GLP-1 receptor agonists like semaglutide, it is crucial to study these newer medications individually rather than grouping them with older drugs in the same class, as their effects may differ significantly,” she added.

As GLP-1s continue to develop, including enhanced mechanisms of action such as dual or triple agonism, they could have even greater neuroprotective effects, Thiara wrote.

“By targeting multiple pathways simultaneously, these next-generation drugs may further enhance brain health, improve vascular integrity and potentially provide stronger protection against conditions like cognitive impairment, vascular dementia and ADRD,” she wrote.

For more information:

Allie Seminer, MSc, and Alfredi Mulihano, undergraduate students in the School of Medicine at the University of Galway in Ireland, can be reached at psychiatry@healio.com.

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