Study of 2.4 million participants reveals potential benefits for cardiometabolic and psychiatric conditions, in addition to increased risks of gastrointestinal and musculoskeletal problems
A recent study published in Naturopathy 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 such as semaglutide (Ozempic) and compares them to other commonly 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, the use of GLP-1RA has increased significantly, and research has highlighted its gastrointestinal side effects.
Given the widespread use of GLP-1RAs, it is essential to systematically evaluate their potential efficacy and risks. An expanded range of possible outcomes linked to GLP-1RAs would positively guide physicians in prescribing this class of drugs 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 according to a set of 175 health outcomes. The US Department of Veterans Affairs databases were used to develop a cohort of people with diabetes who started GLP-1RA. This cohort included a total of 215,970 applicants enrolled between October 1, 2017 and December 31, 2023, consisting primarily of white, older men.
The effect of using GLP-1RA was compared with three commonly used antihyperglycemic agents: dipeptidyl peptidase 4 (DPP4) inhibitors, sulfonylureas and sodium-glucose cotransporter 2 (SGLT2) inhibitors. A composite control group containing equal amounts of these three antihyperglycemic agents was also included, as well as a control group of individuals who continued their non-GLP-1RA antihyperglycemic regimen without additional new therapy (usual care).
The findings are based on analyzes of data from 2.4 million participants.
Findings of the study
The atlas showed the varying efficacy and side effects of GLP-1RAs versus an antihyperglycemic class. Compared to sulfonylureas, use of GLP-1RA was associated with 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 disorders, abdominal pain and bone pain.
Compared to the DPP4 inhibitor, use of GLP-1RA was associated with a reduced risk of 30 outcomes, including respiratory failure, pneumonia, anemia, post-thrombotic sequelae and bacterial infections, and an increased risk of 13 outcomes, including sleep disorders , nausea, vomiting, headache, hypotension, sleep disorders and nephrolithiasis.
Similarly, compared to the SGLT2 inhibitor, use of GLP-1RA showed a reduced risk of 20 outcomes, including inflammatory conditions of male genital organs, inflammatory diseases of female pelvic organs, alcohol use disorders, fungal infections and deep venous thrombosis, and increased risk of 29 outcomes, including anemia, abdominal pain, nephrolithiasis, and GERD.
Compared to the composite control, GLP-1RA use showed a reduced 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 disorders.
The addition of GLP-1RA to a usual treatment plan reduced the risk of 42 outcomes. However, continuing an existing treatment plan without GLP-1RA had no such effect.
Use of GLP-1RA 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. In addition, this drug 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 coagulation disorders.
Moreover, this drug also showed a reduced risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. The use of GLP-1RA also has a positive effect on kidney disease, but was associated with an increased risk of kidney stone formation.
Side effects
Despite its positive effects, GLP-1RA causes increased abdominal pain, GERD, nausea, vomiting and gastritis. It also increases the risk of non-infectious gastroenteritis, gastroparesis, hypotension, sleep disorders, arthralgia, interstitial nephritis and tendonitis.
Conclusions
The current study presented an atlas highlighting the benefits and risks of GLP-1RAs compared to other non-GLP-1RA anti-hyperglycemic agents. The discovery approach confirms the findings of previous studies and clinical trials that demonstrated the benefits and risks of GLP-1RAs. It also revealed certain benefits and side effects that had not been previously described.
The current study results will not only inform 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.