In type 2 diabetes, ‘something brain-friendly’ about GLP-1 receptor agonists


Gerstein HC. Session 8: Stroke and Dementia in Diabetes. Presented at: Heart in Diabetes; June 24-26, 2022; Philadelphia (hybrid meeting).

Gerstein reports receiving consultant fees, grants and honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Cirius, Eli Lilly, Janssen, Kowa, Merck, Novo Nordisk and Sanofi.

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PHILADELPHIA — Diabetes independently increases risk for cognitive decline, yet data from several large trials suggest GLP-1 receptor agonists hold significant promise to mitigate risk for dementia-related events, according to a speaker.

“In addition to age and other risk factors, diabetes is a risk factor for cognitive decline, as is the degree of hyperglycemia,” Hertzel C. Gerstein, MD, MSc, FRCPC, professor and population health institute chair in diabetes research at McMaster University and Hamilton Health Sciences in Ontario, Canada, told Healio before speaking at the Heart in Diabetes CME conference. “We are not sure why this is, but diabetes is a risk factor for many serious health consequences, many of which are related to accelerated aging, so it is not a surprise. The holy grail is to try and find ways of mitigating that risk.”

Diabetes elderly woman 2019

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Several studies have assessed the effect of intensive glucose lowering on risk for cognitive decline and have not shown any definitive associations, Gerstein said. Until recently, no diabetes drug has shown any benefit on cognitive decline in randomized controlled trials.

However, a closer look at GLP-1 receptor agonists shows “tantalizing” evidence that this class may have a particularly beneficial effect on the brain, Gerstein said.

Assessing the data

In a meta-analysis of CV outcomes trials assessing GLP-1 receptor agonists in people with type 2 diabetes published in 2021, including new data from AMPLITUDE-Oresearchers found a particularly large stroke benefit — fatal or nonfatal stroke was reduced by 17% for participants assigned a GLP-1 receptor agonists compared with placebo, with an HR of 0.83 (95% CI, 0.76-0.92; P < .001).

“When one looks at the meta-analyses of the GLP-1 receptor agonists, the biggest benefit seems to be on stoke, an even bigger benefit than on CV outcomes like CV death or MI,” Gerstein said. “It really raises the question, is there is something brain-friendly about GLP-1 receptor agonists?”

Gerstein and colleagues with the REWIND trial assessing the GLP-1 receptor agonist dulaglutide (Trulicity, Eli Lilly), which included more than 9,900 participants followed for a median of 5.5 years, also assessed measures of cognitive function at baseline and after randomization. In a paper published in The Lancet NeurologyGerstein and colleagues demonstrated the drug reduced major adverse CV events, including a greater effect on stroke compared with other components of the composite endpoint. Cognitive analyses showed the drug also reduced risk for substantive cognitive impairment in the 15% to 20% range, Gerstein said.

Subsequently, a pooled analysis of three other large CV outcomes trials with GLP-1 receptor agonists — LEADER, SUSTAIN-6 and PIONEER-6 — showed 47 people were diagnosed with an adverse event related to dementia and a 50% lower risk for dementia-related adverse events among participants assigned a GLP-1 receptor agonist vs. placebo. A database analysis of 120,000 people included in a Danish registry also showed GLP-1 receptor agonists were associated with an 11% reduced risk for dementia, Gerstein said.

“None of these things are proof that GLP-1 receptor agonists protect against dementia, but our finding in REWIND plus the other findings are certainly supportive of the hypothesis,” Gerstein told Healio.

More evidence needed

Two randomized controlled trials, EVOKE and EVOKE Plus, are currently underway assessing the effect and safety of oral semaglutide 14 mg (Rybelsus, Novo Nordisk) compared with placebo in more than 1,800 adults aged 55 to 85 years with mild cognitive impairment and evidence of amyloid plaque indicating early Alzheimer’s disease. The primary outcome is change in clinical dementia rating.

“Other studies are ongoing that may show this drug may have a place in preventing cognitive decline,” Gerstein said.


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