The excessive and uncontrolled consumption of alcohol, which can culminate in the development of alcohol use disorder or alcoholism, is widespread in many countries worldwide. Individuals diagnosed with alcohol use disorder are often also experiencing other mental health conditions, such as depression or anxiety. Moreover, the excessive use of alcohol is known to increase the risk of developing liver disease and some other health-related problems.
While there are several treatment programs for those struggling with their alcohol consumption, available options are not always effective for all affected individuals. Identifying effective new treatments could thus be highly valuable, as it could help to treat a wider range of patients, potentially limiting the detrimental effects of alcohol on their mental and physical health.
Some studies have gathered evidence suggesting that gut hormones, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), could act on both people’s metabolism and their addictive tendencies. These hormones have so far been primarily used to treat obesity and diabetes, as they can help to control blood sugar levels, appetite and body weight.
Researchers at the National Institute on Alcohol Abuse and Alcoholism in the U.S. recently performed a large-scale analysis of genetic data, aimed at further exploring the potential of these hormones as therapeutic tools to limit excessive drinking and improve liver health. Their findings, published in Molecular Psychiatry, suggest that GLP-1 and GIP-based drugs could in fact help to reduce people’s intake of alcohol, which could inform the future development of alternative treatments for alcohol use disorder.
“Pharmacological modulation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) through dual GIP/GLP-1 receptor agonists, commonly used for diabetes and obesity, shows promise in reducing alcohol consumption,” wrote Joshua Reitz, Daniel B. Rosoff and their colleagues in their paper.
“We applied drug-target Mendelian randomization (MR) using genetic variation at these loci to assess their long-term effects on problematic alcohol use (PAU), binge drinking, alcohol misuse classifications, liver health, and other substance use behaviors.”
As part of their study, Reitz, Rosoff and their colleagues analyzed large amounts of bio-genetic data taken from two large databases, the UK Biobank and the Million Veterans Program dataset. They analyzed this data using a technique known as Mendelian randomization, which can be used to explore the link between specific genes and the effects of drugs or the unfolding of biological processes.
“Genetic proxies for lowered BMI, modeling the appetite-suppressing and weight-reducing effects of variants in both the GIPR and GLP1R loci (“GIPR/GLP1R”), were linked with reduced binge drinking in the primary (β = −0.44, 95% CI [−0.72, −0.15], P = 2.42 × 10−3) and replication data (β = −0.13, [−0.22, −0.04], P = 0.0058),” wrote Reitz, Rosoff and their colleagues.
“HbA1c lowering via GIPR/GLP1R variants was associated with reduced risk of heavy drinking with psychiatric comorbidities versus low-risk drinking (odds ratio [OR] = 0.62, [0.45, 0.85], P = 0.0031), with replication in independent HbA1c data (OR = 0.71, [0.60, 0.84], P = 5.22 × 10−5) and directional consistency with reduced PAU. Analysis of individual loci indicated that both GIPR and GLP1R were protective against heavy drinking, underscoring the importance of both targets.”
Overall, the researchers found that naturally occurring differences in the expression of GLP1R and GIPR genes, which the drugs GLP-1 and GIP act on, were linked to a lower consumption of alcohol. In contrast, these differences were not found to be associated with the intake of tobacco, cannabis or opioids.
“While estimates for other substance use disorders (tobacco, cannabis, opioid) were consistently null, food preference analyses revealed that BMI lowering via GIPR/GLP1R reduced fatty food liking (β = −1.58, [−2.01, −1.14], P = 1.62 × 10−12) and increased vegetarian food liking (β = 2.08, [1.17, 2.99], P = 8.22 × 10−6), implicating metabolic and appetite regulation pathways for the alcohol consumption findings,” wrote the authors.
“For liver health, HbA1c lowering via GIPR/GLP1R was associated with reduced NAFLD (β = −0.34, [−0.50, −0.18], P = 2.74 × 10−5) and lower ALT levels (β = −0.26, [−0.38, −0.15], P = 8.39 × 10−6), with replication supporting these findings. Consistency across multiple MR methods and colocalization analyses strengthened causal inference.”
The GLP1R and GIPR gene-related patterns identified by the researchers were found to be connected not only to a lower consumption of alcohol but also to a preference for less fatty foods, such as vegetarian or lean options. This suggests that drugs acting on GLP1R and GIPR receptors, such as GLP-1 and GIP, could influence both people’s appetite and their cravings for alcohol.
“Mediation analysis suggested reductions in hazardous alcohol consumption partially explain the cardioprotective effects of these agonists,” wrote Reitz, Rosoff and their colleagues. “Multi-ancestry analyses supported directionally aligned relationships in non-European cohorts.”
While this study did not directly assess the effects of GLP-1 and GIP, it suggests that the receptors affected by these drugs play a role in alcohol consumption. In the future, it could thus pave the way for clinical trials assessing the potential of these drugs for the treatment of alcohol use disorder.