Researchers create an atlas of health associations for GLP-1 receptor agonists

By Dr. Priyom Bose, Ph.D.Reviewed by Danielle Ellis, B.Sc.Jan 20 2025

Study of 2.4 million participants reveals potential advantages for cardiometabolic and psychiatric conditions alongside increased risks of gastrointestinal and musculoskeletal issues

A recent study published in Nature Medicine has provided valuable insights into the benefits and potential risks of GLP-1 receptor agonists (GLP-1RAs), a class of drugs commonly used to treat type 2 diabetes and obesity. This study, the first of its kind, examines the effects of GLP-1RAs like semaglutide (Ozempic) and compares them with other widely used antihyperglycemic agents.

What are GLP-1RAs?                          

GLP-1RAs are antihyperglycemic agents with protective cardiovascular and renal properties. They are popularly used to treat type 2 diabetes mellitus (T2DM) and obesity. Over the past decade, there has been a substantial increase in GLP-1RA use, and some research has highlighted its gastrointestinal side effects.

Considering the wide use of GLP-1RAs, it is essential to evaluate their potential efficacy and risks systematically. A comprehensive set of possible outcomes linked to GLP-1RAs would positively help physicians prescribe this class of drug for treatment.

About the study

The current study used a discovery approach to systematically examine and map an atlas to elucidate the efficacy and risks of GLP-1RA in accordance with a set of 175 health outcomes. The US Department of Veterans Affairs databases were used to develop a cohort of people with diabetes who initiated GLP-1RA. This cohort constituted a total of 215,970 candidates who were enrolled between 1 October 2017 and 31 December 2023, consisting mostly of White, older men.

The effect of GLP-1RA use was compared with three commonly used antihyperglycemics: dipeptidyl peptidase 4 (DPP4) inhibitors, sulfonylureas, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. A composite control group containing equal amounts of these three antihyperglycemics was also included, as was a control group of individuals who continued with their non-GLP-1RA antihyperglycemic regimen without additional new therapy (usual care).

The findings are based on analyses of data from 2.4 million participants.

Study findings

The atlas showcased the varying efficacy and side effects of GLP-1RAs versus an antihyperglycemic class. In comparison to sulfonylureas, GLP-1RA use was linked to a lower risk of 23 outcomes, including bronchitis, pneumonia, suicidal ideation, chronic obstructive pulmonary disease (COPD), and coagulopathy, and an increased risk of 14 outcomes, including gastroesophageal reflux disease (GERD) nausea, vomiting, sleep disturbances, abdominal pain, and bone pain.

Compared to DPP4 inhibitor, GLP-1RA use was associated with decreased risks of 30 outcomes, including respiratory failure, pneumonia, anemia, post-thrombotic sequelae, and bacterial infections, and increased risk of 13 outcomes, including sleep disturbances, nausea, vomiting, headaches, hypotension, sleep disturbances, and nephrolithiasis.

Similarly, in comparison to SGLT2 inhibitor, GLP-1RA use exhibited a decreased risk of 20 outcomes, including inflammatory conditions of male genital organs, inflammatory diseases of female pelvic organs, alcohol use disorders, fungal infections, and deep vein thrombosis, and an increased risk of 29 outcomes including anemia, abdominal pain, nephrolithiasis, and GERD.

In comparison to composite control, GLP-1RA use exhibited a decreased risk of 34 outcomes, including pneumonia, respiratory failure, alcohol use disorders, COPD, and suicidal ideation, and an increased risk of 17 outcomes, including abdominal pain, GERD, nephrolithiasis, and sleep disturbances.

The addition of GLP-1RA to a usual treatment plan reduced the risk of 42 outcomes. However, the continuation of an existing treatment plan without GLP-1RA did not have such an effect.

GLP-1RA use has been associated with positive outcomes related to substance-related disorders, including alcohol use disorders, cannabis use disorders, stimulant use disorders, and opioid use disorders. Furthermore, this medication reduced the risk of psychotic disorders, including suicidal ideation, bulimia, and schizophrenia.

GLP-1RA use was associated with a reduced risk of neurocognitive disorders (e.g., dementia and Alzheimer’s disease), seizures, thromboembolic disorders, pulmonary hypertension, chronic phlebitis, coagulopathy, and clotting disorders.

Furthermore, this drug also exhibited a reduced risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. GLP-1RA use also has a positive effect on kidney ailments but was associated with an increased risk of kidney stone formation.

Side effects

Despite its positive effects, GLP-1RA use increased abdominal pain, GERD, nausea, vomiting, and gastritis. It also increases the likelihood of non-infectious gastroenteritis, gastroparesis, hypotension, sleep disturbances, arthralgia, interstitial nephritis, and tendinitis.

Conclusions

The current study presented an atlas that highlighted the benefits and risks of GLP-1RAs in comparison to other non-GLP-1RA anti-hyperglycemic agents. The discovery approach confirms the findings of previous studies and clinical trials that indicated the benefits and risks of GLP-1RAs. It also uncovered certain benefits and side effects that were not previously described.

The present study findings will not only help clinical care but also guide future mechanistic and clinical research to evaluate the broad pleiotropic effects of GLP-1RAs. The researchers hope to determine the absolute risks of GLP-1RAs in future research.