A study in US veterans has enumerated the health benefits and risks of taking semaglutide and friends.
A US team has set out to comprehensively evaluate the upsides and downsides of GLP-1 RAs, the wonder drugs developed for diabetes but popular for weight loss and associated with a multitude of other benefits.
In their study published in Nature Medicine, the team took data from the US Department of Veterans Affairs healthcare databases on diabetic patients taking either GLP-1RAs (215,970), sulfonylureas (159,465), DPP4 inhibitors, (117,989), SGLT2 inhibitors (258,614) or some combination of the latter three antihyperglycaemics (536,068) as well as for 1.2 million on usual care.
The cohort was largely older, White and male, but did include more than a million women, half a million people identifying as non-White and 31,000 people under 40.
The researchers looked for associations between incident GLP-1 use and 175 outcomes using the other groups as comparators.
Overall, the worst effects of GLP-1 RAs were unsurprisingly in gastroenterological symptoms, while increased risks were also seen for hypotension and syncope, sepsis, sleep disturbances, headaches, joint conditions and pancreatitis.
Reduced risks were found for respiratory illness, substance use disorders, neurocognitive and psychiatric disorders, suicidal ideation, clotting disorders, infections and liver and kidney problems.
Vs usual care
- GLP-1RA use was associated with a decreased risk of 42 outcomes including cardiac arrest, respiratory complications and respiratory failure, pulmonary hypertension, thromboembolic disorders, liver failure and liver cancer, stimulant use disorders and bulimia
- GLP-1RA use was associated with an increased risk of 19 outcomes including nausea/vomiting, abdominal pain, GORD, gastritis, noninfectious gastroenteritis, arthritis, arthralgia, headaches and sleep disturbances
Vs sulfonylureas
- Decreased risk of 23 outcomes including pneumonia, bronchitis, COPD, suicidal ideation, and coagulopathy and clotting disorders
- Increased risk of 14 outcomes including nausea and vomiting, gastroesophageal reflux disease, sleep disturbances, bone pain and abdominal pain
Vs DPP4 inhibitors
- Decreased risk of 30 outcomes including respiratory failure, post-thrombotic sequelae, pneumonia, anaemia and bacterial infections
- Increased risk of 13 outcomes including nausea and vomiting, sleep disturbances, hypotension, headaches and nephrolithiasis
Vs SGLT2 inhibitors
- Decreased risk of 20 outcomes including alcohol use disorders, inflammatory conditions of male genital organs, inflammatory diseases of female pelvic organs, fungal infections and deep vein thrombosis
- Increased risk of 29 outcomes including anaemia, nausea and vomiting, nephrolithiasis, GORD and abdominal pain
Vs a combination of antihyperglycaemics
- Decreased risk of 34 outcomes including pneumonia, alcohol use disorders, respiratory failure, COPD and suicidal ideation
- Increased risk of 17 outcomes, including nausea and vomiting, GORD, abdominal pain, nephrolithiasis and sleep disturbances
University of Melbourne epidemiologist and public health medicine specialist Professor Tony Blakely said the results might not apply to non-diabetics “as the interaction of diabetes-related inflammation and such like may be the reason for such wide-ranging GLP agonist effects”.
Dr Georgia Rigas, an obesity doctor at St George Private Hospital in Sydney, said the study showed the “bonus health benefits” of GLP-1 medications, though research in more diverse populations was needed.
“While the findings are observational, they systematically map previously underappreciated outcomes, providing valuable real-world insights,” she said.
“Medications like GLP-1s have been life-changing for people with type 2 diabetes and obesity. This new research suggests they may also lower risks for conditions like dementia, heart disease, and even some lung problems – an exciting discovery for improving overall health.
“[The study] likely won’t change my day-to-day clinical decisions. That said, it reinforces the importance of these treatments and highlights areas for future exploration, helping us better understand their full potential and hopefully ways of determining which patients are likely to respond to treatment.”
Nutritionist Peter Clifton, an Adjunct Research Professor at the University of South Australia, said it was “a fascinating paper which should lead to several new studies trying to examine some of the uncommon effects of GLP1 agonists”.
“Some of the observations may be explained by the kind of patients given GLP-1 agonists and others by the effects of the drugs themselves. For instance, the reduced risks of infections and pulmonary disease and thrombo-embolic disease may be mostly due to the weight loss … while the increased risks of nephrolithiasis may [be] due to reduced fluid intake because of nausea and anorexia. Other associations such as reduced schizophrenia risk may relate to patient selection.
“Interestingly, despite the large size of the study, it still did not detect the rare side effect of nonarteritic anterior ischemic optic neuropathy nor significantly increased gallstone disease, which has been seen in other observational studies.”
