GLP-1s: Going Beyond Diabetes and Obesity

Alcohol-Use Disorder
 

In the US alone, around 178,000 deaths every year can be attributed to alcohol – which can cause liver disease and cardiovascular disease. A significant proportion of people will meet the criteria for alcohol use disorder (AUD) at some point in their lives, but many do not seek or receive treatment.

A small clinical trial led by researchers at the University of North Carolina and the USC Institute for Addiction Science has reported that semaglutide may reduce alcohol consumption and craving in people with AUD under certain conditions.

The trial enrolled 48 non–treatment-seeking adults with AUD in the US, with participants randomized to receive either semaglutide or placebo over nine weeks. The primary endpoint was alcohol self-administration in a lab setting, designed to capture changes in voluntary drinking behavior under controlled conditions. Secondary and exploratory outcomes included weekly self-reported consumption and craving.

Participants who received semaglutide consumed less alcohol during the post-treatment lab session compared to the placebo group. Statistical models indicated medium to large effect sizes for both the quantity of alcohol consumed and peak breath alcohol concentration.

Semaglutide did not reduce the overall number of drinking days or drinks per day in naturalistic settings, but it did significantly reduce the amount consumed on drinking days, with participants saying they had decreased alcohol cravings.

A notable secondary outcome was observed among participants who also smoked cigarettes. In this subgroup, those receiving semaglutide showed a greater reduction in cigarettes per day over time relative to placebo. The researchers cited preclinical studies suggesting that GLP-1 receptor agonists may dampen reward-related behaviors beyond alcohol, including nicotine use.

The study population consisted of individuals with moderate AUD severity who were not actively trying to reduce their drinking, which the investigators argue may better reflect the majority of patients receiving GLP-1 therapies in general practice settings.

“The focus on non–treatment-seeking participants has important considerations, one being that semaglutide-related reductions in drinking quantity occurred absent volitional attempts to reduce drinking,” write the authors. “In contrast to treatment-seeking participants, this sample is arguably representative of the majority of those with AUD exposed to GLP-1RAs in general medical settings . . . In this context, the broad uptake of GLP-1RAs presents an ideal scenario for medication repurposing, with potential to help reduce the wide treatment gap associated with AUD.”

MASH
 

Novo Nordisk’s ESSENCE phase III trial evaluated the efficacy and safety of semaglutide in adults with metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis stages. The study assessed subcutaneous semaglutide 2.4 mg administered weekly over a period of 72 weeks.

The trial met its primary endpoint, with 62.9 percent of patients receiving semaglutide achieving resolution of steatohepatitis without worsening of liver fibrosis, compared to 34.3 percent in the placebo group. A key secondary endpoint, improvement in liver fibrosis by at least one stage without worsening of steatohepatitis, was achieved in 36.8 percent of patients in the semaglutide arm versus 22.4 percent in the placebo arm. An additional composite endpoint – the proportion of patients achieving both resolution of steatohepatitis and improvement in fibrosis – was reached by 32.7 percent of patients treated with semaglutide compared to 16.1 percent of those on placebo.

The safety profile of semaglutide observed in the study was consistent with its known safety characteristics, with gastrointestinal events being the most frequently reported adverse events. The results have been published in The New England Journal of Medicine.

Dementia
 

A meta-analysis conducted by authors in Ireland examined whether glucose-lowering drugs recommended for cardiovascular protection might also lower the risk of dementia. Published in JAMA Neurology, the study reviewed data from 26 randomized clinical trials involving more than 164,000 participants to assess the impact of four drug classes – SGLT2 inhibitors, GLP-1 receptor agonists, metformin, and pioglitazone – on dementia and cognitive impairment outcomes. The authors concluded that while glucose-lowering therapies as a group were not clearly associated with reduced dementia risk, GLP-1RAs warranted further investigation. GLP-1s appeared to be associated with a statistically significant decrease in dementia cases.

Other studies have also suggested a potential link between GLP-1s and a reduced risk of dementia and Alzheimer’s disease. For instance, a phase IIb clinical trial presented at the Alzheimer's Association International Conference 2024 found that liraglutide slowed cognitive decline by 18 percent over one year in patients with mild Alzheimer's disease, compared to a placebo group. The study also reported nearly 50 percent less brain shrinkage in areas related to memory, language, and decision-making among those treated with liraglutide

The mechanisms by which GLP-1RAs might influence dementia risk remain speculative, though animal studies and prior observational research suggest roles for anti-inflammatory effects, reduced oxidative stress, and direct neuroprotection.

“The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart,” said Paul Edison, professor of science from Imperial College London and study lead for the work presented at the conference. “While further research is needed, liraglutide may work through various mechanisms, such as reducing inflammation in the brain, lowering insulin resistance and the toxic effects of Alzheimer’s biomarkers amyloid-beta and tau, and improving how the brain’s nerve cells communicate.”