In US veterans with type 2 diabetes, starting GLP-1 receptor agonists was linked to lower risk of several incident substance use disorders and fewer -related adverse outcomes in those with existing SUDs.
Evidence
An electronic health record target trial emulation of eight active-comparator new-user cohorts in 606,434 veterans followed up to 3 years found lower hazards versus SGLT-2 inhibitors for alcohol, cannabis, cocaine, nicotine, opioid, and other SUDs and for SUD-related emergency visits, admissions, mortality, overdose, and suicidal ideation or attempt.
Caveat
This was observational target trial emulation in veterans, so residual confounding remains and the findings do not prove that GLP-1 receptor agonists prevent or treat SUDs.
Simplified
OBJECTIVES: To investigate whether initiation of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with both reduced risks of incident alcohol, cannabis, cocaine, nicotine, opioid, and other substance use disorders (SUDs) in people with no history of SUDs (protocol 1) and with reduced risk of related adverse clinical outcomes among people with a pre-existing SUD (protocol 2).
DESIGN: Emulation of eight parallel, new user, active comparator target trials using electronic health records: seven trials for each incident SUD outcome (protocol 1) and one trial for adverse outcomes in people with pre-existing SUD (protocol 2).
SETTING: US Department of Veterans Affairs.
PARTICIPANTS: From a base population of 606 434 US veterans with type 2 diabetes, participants were assigned to one of the two protocols and followed for up to three years. Trial 1 (primary trial) of protocol 1 included 524 817 initiators of GLP-1 receptor agonists (n=124 001) or sodium-glucose cotransporter-2 (SGLT-2) inhibitors (n=400 816). Protocol 2 included 81 617 initiators of GLP-1 receptor agonists (n=16 768) and SGLT-2 inhibitors (n=64 849).
MAIN OUTCOME MEASURES: Incident outcomes were alcohol, cannabis, cocaine, nicotine, opioid, other SUDs, and a composite of these outcomes. Adverse outcomes among participants with pre-existing SUDs included SUD related emergency department visits, SUD related hospital admissions, and SUD related mortality, and drug overdose and suicidal ideation or attempt. Hazard ratios and net three year risk difference (NRD) per 1000 people were reported based on inverse probability weighted (standardised mortality ratio weighted) cause specific Cox survival models.
RESULTS: Compared with initiation of SGLT-2 inhibitors, initiation of GLP-1 receptor agonists was associated with reduced risk of disorders related to alcohol use (hazard ratio 0.82 (95% confidence interval (CI) 0.78 to 0.85); NRD per 1000 people -5.57 (-6.61 to -4.53)), cannabis use (0.86 (0.81 to 0.90), NRD -2.25 (-3.00 to -1.50)), cocaine use (0.80 (0.72 to 0.88), NRD -0.97 (-1.37 to -0.57)), nicotine use (0.80 (0.74 to 0.87), NRD -1.64 (-2.19 to -1.09)), and opioid use (0.75 (0.67 to 0.85), NRD -0.86 (-1.19 to -0.52)), and other SUDs (0.87 (0.81 to 0.94), NRD -1.12 (-1.68 to -0.55)) and composite outcome of all incident SUDs (0.86 (0.83 to 0.88), NRD -6.61 (-7.95 to -5.26)). Among people with pre-existing SUDs, initiation of GLP-1 receptor agonists was associated with reduced risk of SUD related emergency department visits (0.69 (0.61 to 0.78), NRD -8.92 (-11.59 to -6.25)), SUD related hospital admissions (0.74 (0.65 to 0.85), NRD -6.23 (-8.73 to -3.74)), and SUD related mortality (0.50 (0.32 to 0.79), NRD -1.52 (-2.32 to -0.72)), and drug overdose (0.61 (0.42 to 0.88), NRD -1.49 (-2.43 to -0.55)) and suicidal ideation or attempt (0.75 (0.67 to 0.83), NRD -9.95 (-13.14 to -6.77)). Analyses of treatment adherence showed directionally consistent results with analyses of treatment initiation for both incident SUDs and adverse outcomes among participants with pre-existing SUDs.
CONCLUSIONS: Use of GLP-1 receptor agonists was consistently associated with reduced risks of developing various incident SUDs, suggesting a broad preventive effect across multiple substance types. Use was also associated with reduced risks of adverse clinical outcomes in people with pre-existing SUDs. These observational data suggest a potential role for GLP-1 receptor agonists in both the prevention and the treatment of various SUDs, warranting further evaluation.
Key numbers
0.82
Reduction in Alcohol Use Disorder Risk
Hazard ratio comparing GLP-1 receptor agonists to SGLT-2 inhibitors.
0.69
Reduction in Emergency Department Visits
Hazard ratio for individuals with pre-existing SUDs.
-5.57
Net Risk Difference for Alcohol Use Disorder
Net three year risk difference per 1000 people.
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GLP-1 Therapies