The benefits of GLP-1 receptor agonists may extend beyond weight management, with results of a large study pointing to their potential role in preventing and treating a wide range of substance use disorders (SUDs).

Investigators found that among individuals with a history of substance abuse, starting a GLP-1 was associated with a 50% lower risk for substance-related death and 39% lower risk for overdose. There was also a decreased risk for suicidal behavior, hospital admissions, and substance-related emergency department visits.

In addition, the findings showed that among those with no history of substance abuse, GLP-1s were associated with an overall 14% lower risk of developing an SUD.

“GLP-1 receptor agonists were associated with lower risks of incident alcohol, cannabis, cocaine, nicotine, opioid, and other SUDs, suggesting potential preventive effects across a broad range of substances,” the researchers led by Ziyad Al-Aly, MD, chief of research and development service at the VA St. Louis Health Care System in St. Louis, wrote.

The study was published online on March 4 in The BMJ.

Beyond Food Cravings

SUDs are common, affecting roughly 16.8% of the US population, yet effective treatments are underutilized. 

GLP-1s activate receptors in the hypothalamus to signal satiety and act on the brain’s reward pathways to reduce food cravings. However, based on his clinical experience and observations Al-Aly began to consider whether the drugs’ effects might extend beyond food and curb other cravings.

In a linked opinion piece, Al-Aly reported that he noticed patients who had previously struggled to quit alcohol, nicotine, and illicit drugs had a “sudden” aversion to these substances when they started using GLP-1s.

“Some of my patients have told me it suddenly felt easier to stop smoking or drinking after starting these drugs,” he wrote.

Emerging evidence supports this observation. Previous research has linked GLP-1s to a number of health benefits including a reduced risk for incident alcohol use disorder, cannabis use disorder, and tobacco addiction.

However, this new study evaluated whether GLP-1s reduced the risk for multiple addictions including cocaine and opioid use disorder in people with no history of SUDs. It also examined clinical outcomes in individuals with preexisting SUDs.

A Novel Trial Design

Using VA electronic health records, investigators emulated eight trials comparing patients with type 2 diabetes who started GLP-1 drugs with those starting SGLT2 inhibitors.

Seven trials assessed the risk of developing alcohol, cannabis, cocaine, nicotine, opioid, and other SUDs, whereas one examined outcomes in patients with an existing SUD.

The study included data on 606,434 US veterans with type 2 diabetes.

The study had two trial protocols. One included veterans with no SUD history who started taking GLP-1s (n = 124,001) or SGLT2s (n = 400,816), and the other protocol included 81,617 individuals with an SUD history who initiated treatment with either a GLP-1 (n = 16,768) or SGLT2 (n = 64,849). Participants were followed for up to 3 years.

Standardized mortality ratio weighting was used to balance baseline characteristics between the groups. The weights were incorporated into Cox survival models to estimate hazard ratios (HRs) and the net 3-year risk difference (NRD) per 1000 people.

Among participants with no history of SUDs, initiating a GLP-1 drug was associated with a lower risk of developing several SUDs.

Compared to SGLT2s, GLP-1 use was linked to a 25% lower risk for opioid use disorder (HR, 0.75; 95% CI, 0.67-0.85) and a 20% lower risk for cocaine use disorder (HR, 0.80; 95% CI, 0.72-0.88). Risks were also lower for nicotine (20%), alcohol (18%), and cannabis (14%). The NRD suggested roughly one to six fewer cases per 1000 people over the 3-year study period.

Results were consistent across subgroup analyses by age, sex, race, BMI, A1c level, and GLP-1 type.

Among those with a history of SUD, initiating a GLP-1 drug was associated with a lower risk for SUD-related mortality (HR, 0.50; 95% CI, 0.32-0.79) and drug overdose (HR, 0.61; 95% CI, 0.42-0.88). GLP-1 use was also linked to fewer SUD-related emergency department visits (31%), hospital admissions (26%), and suicidal ideation or attempts (25%).

The study’s limitations included the fact that it was observational and relied on electronic health records from mostly male US veterans with diabetes and, therefore, the findings cannot prove causation and may not be generalizable.

Not a ‘Magic Bullet’

In an accompanying editorial, Fares Qeadan, PhD, associate professor of biostatistics at the Loyola University Chicago in Chicago, noted that the study design “strengthens causal interpretation through a new user design, an active comparator, extensive confounding control, and negative control analyses.”

But he cautioned that GLP-1s should not be seen as a “magic bullet” or replace established treatments for SUDs.

“These results suggest that when GLP-1 receptor agonists are clinically indicated for cardiometabolic reasons, potential benefits for substance-related outcomes may be an added consideration in shared decision-making,” he wrote.

Instead, he called for randomized trials to determine whether GLP-1 drugs meaningfully improve addiction outcomes.

Also commenting, Marie Spreckley, PhD, research program manager of Prevention of Diabetes and Related Metabolic Disorders in High Risk Groups, MRC Epidemiology Unit at University of Cambridge in Cambridge, England, said that while the findings are “biologically plausible” they should be considered “hypothesis generating,” in a statement from the Science Media Centre.

Like Qeadan, Spreckley underlined the need for randomized trials “before these medicines could be considered treatments for substance use disorders. Established evidence-based SUD treatments remain essential,” she noted.

The study was funded by the US Department of Veterans Affairs. See study for author disclosures.