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From the Journals

GLP-1 Drugs Tied to Lower Addiction Risk

In a target-trial emulation of more than 600,000 veterans, GLP-1 RA initiators saw fewer new substance use disorders—and patients with existing SUDs had fewer overdoses, hospitalizations, and deaths.

Conexiant

Glucagon-like peptide-1 receptor agonists were associated with lower risks of incident substance use disorders and fewer substance-related adverse outcomes among US veterans with type 2 diabetes, according to a large observational study published in The BMJ.

The researchers emphasized that the findings do not support prescribing glucagon-like peptide-1 receptor agonists (GLP-1 RAs) specifically to prevent or treat substance use disorders (SUDs). However, they suggested the findings may be relevant when selecting antihyperglycemic therapy for patients with type 2 diabetes who are at elevated risk for SUDs or who have established SUDs.

The study compared initiation of GLP-1 RAs with initiation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, another commonly used class of diabetes medications. The authors noted that the findings reflect the relative comparison between the 2 drug classes rather than a comparison with placebo or no treatment.

Compared with SGLT-2 inhibitor initiation, GLP-1 RA initiation was associated with a lower risk for the composite endpoint of all incident SUDs (HR, 0.86), translating to about 7 fewer cases per 1,000 patients over 3 years.

Absolute risk differences for individual incident SUDs were modest, ranging from approximately 1 fewer case per 1,000 patients for cocaine and opioid use disorders to between 5 and 6 fewer cases per 1,000 for alcohol use disorder over 3 years.

GLP-1 RA initiation also was associated with lower risks of:

  • alcohol use disorder (HR, 0.82)

  • cannabis use disorder (HR, 0.86)

  • cocaine use disorder (HR, 0.80)

  • nicotine use disorder (HR, 0.80)

  • opioid use disorder (HR, 0.75)

  • other substance use disorders (HR, 0.87)

Among patients with pre-existing SUDs, GLP-1 RA initiation was associated with a lower risk for the composite endpoint of SUD-related emergency department visits, hospital admissions, and mortality (HR, 0.71), corresponding to about 12 fewer events per 1,000 patients over 3 years.

Because patients with established SUDs have substantially higher baseline event rates, the absolute risk reductions in this group were larger than those observed for incident SUD outcomes, even though the relative effects were broadly comparable across both protocols. This may make the harm-reduction signal in patients with existing disease more clinically salient.

GLP-1 RA initiation also was associated with lower risks of:

  • SUD-related emergency department visits (HR, 0.69)

  • SUD-related hospital admissions (HR, 0.74)

  • SUD-related mortality (HR, 0.50)

  • drug overdose (HR, 0.61)

  • suicidal ideation or attempt (HR, 0.75)

“These observational data suggest a potential role for GLP-1 receptor agonists in both the prevention and the treatment of various [substance use disorders], warranting further evaluation,” wrote lead author Miao Cai, of the Clinical Epidemiology Center, Research and Development Service at the VA Saint Louis Health Care System and the Veterans Research and Education Foundation of Saint Louis, and colleagues.

The authors cautioned that the study was observational and therefore subject to possible residual confounding and misclassification. The primary risk estimates were derived from cause-specific hazard models, which treat death as a censoring event; complementary analyses using a Fine-Gray model produced consistent results. The authors also noted limited generalizability because the Veterans Affairs population was predominantly older, male, and white.

The findings regarding suicidal ideation or attempt contrast with postmarketing concerns that prompted a European Medicines Agency safety review in 2023. In April 2024, the agency’s Pharmacovigilance Risk Assessment Committee concluded that available evidence did not support a causal association between GLP-1 RA use and suicidality.

Researchers emulated eight parallel, new-user, active-comparator target trials using electronic health records from the US Department of Veterans Affairs healthcare system. The analyses compared initiation of GLP-1 RAs with initiation of SGLT-2 inhibitors among veterans with type 2 diabetes.

Investigators selected SGLT-2 inhibitors as the active comparator because both drug classes are commonly used in type 2 diabetes, whereas SGLT-2 inhibitors do not have known direct effects on mesolimbic reward pathways implicated in addiction. Additional sensitivity analyses using a sulfonylurea comparator produced findings similar to those of the primary analyses.

From a base population of 606,434 veterans with type 2 diabetes, the primary protocol evaluating incident SUDs included 524,817 patients without prior SUD, including 124,001 GLP-1 RA initiators and 400,816 SGLT-2 inhibitor initiators. Median follow-up was 3 years.

A second protocol evaluated 81,617 patients with pre-existing SUDs, including 16,768 GLP-1 RA initiators and 64,849 SGLT-2 inhibitor initiators.

In adherence analyses using marginal structural models, the associations remained consistent over time, whereas absolute risk differences increased during follow-up.

Subgroup analyses showed similar associations across age, sex, body mass index, glycated hemoglobin levels, race categories, and commonly used GLP-1 RAs, including semaglutide, liraglutide, and dulaglutide. However, exposure to tirzepatide was limited within the cohort, representing approximately 1% of GLP-1 RA initiators.

Additional sensitivity analyses using alternative weighting methods, extended treatment look-back windows, complete-data analyses, and negative control outcomes produced findings consistent with the primary analyses.

The practical relevance, the authors suggested, lies in drug selection for patients who already have a guideline-supported indication for a GLP-1 RA—such as type 2 diabetes—and who are at elevated risk for or living with an SUD, rather than in initiating these drugs to treat SUDs directly. Any such advantage, they noted, must be weighed against the known adverse-event profile of GLP-1 RAs, including gastrointestinal intolerance, gallbladder disease, and pancreatitis, within a shared decision-making process.

The study was funded by the US Department of Veterans Affairs. Yan Xie reported uncompensated consulting for Pfizer. Ziyad Al-Aly reported funding from the US Department of Veterans Affairs. The remaining authors reported no relevant financial relationships.

Source: The BMJ