EXPERT REACTION: What are the benefits and risks of semaglutide and its sister drugs?

GLP-1 receptor agonists (GLP1-RA’s) are a new class of highly effective medication to treat Type 2 diabetes (T2D) because they reduce both blood sugars and body weight. They have beneficial cardiovascular and renal effects with emerging evidence of benefit to mitigate the risk of degenerative neurological disorders. 

This study describes a systematic evaluation of 175 health outcomes in patients treated with GLP1-RA’s for the management of type 2 diabetes mellitus, as compared to other commonly used treatments for T2D including Sulphonylureas, dipeptidyl peptidase 4 (DPP4) inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, as well as a usual care control group among individuals with T2D who were new users of these medications drawn from US Department of Veterans Affairs healthcare databases, between October 2017 and December 31, 2023. The total number of individuals included in the cohort were 215,970 GLP1-RA’s users and a total of 1.2 million individuals in various comparator groups. The median duration that individuals were followed was 3.68 years. This allowed a comprehensive evaluation of health impacts both beneficial and adverse.

The key findings indicate that compared to other treatments GLP-1Rs, significantly reduce the risk of numerous health conditions, including cardiovascular events, dementia, substance use disorders, and certain infections. On the flip side they are associated with gastrointestinal adverse effects, sleep disturbance, kidney stones and bone pain. Importantly there was no indication of increased depression or suicide. 

These data highlight the importance of careful ongoing of people using these medications.

This is a fascinating paper which should lead to several new studies trying to examine some of the uncommon effects of GLP1 agonists. The new risks and benefits observed are all from observation and need to be confirmed in targeted studies or additional analysis of completed interventions. Some of the observations may be explained by the kind of patients given GLP1 agonists and others by the effects of the drugs themselves. For instance the reduce risks of infections and pulmonary disease and thrombo-embolic disease may be mostly due to the weight loss induced by the GLP1 agonists while the increased risks of nephrolithiasis may 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.

This is a comprehensive evaluation of the impact of medications used to treat diabetes and obesity. The study in over 2.4 million adults enrolled in the US Veterans Affairs healthcare databases compared health outcomes in people who were prescribed GLP-1RA medications versus other medication categories to manage high blood sugar levels and versus usual care. Follow-up time ranged from 2 to 5.4 years and 175 health outcomes examined. Compared to other medications prescribed t lower blood sugar level, those in the GLP-1RA group had a lower risk of 34 health outcomes, with the top five (accounting for 19.4%) being alcohol-use disorders and lung conditions (pneumonia, respiratory failure, COPD), suicidal ideation, and an increased risk of 17 outcomes (9.7%), with the top five being nausea and vomiting, gastroesophageal reflux, abdominal pain, kidney stones and sleep disturbances. Compared to usual care, addition of a GLP-1RA was associated with a decreased risk of 42 outcomes (24%) and an increased risk of 19 (10.9%).
 
This study is important because it is a real-world dataset of people whose health is being managed over time. This has captured a broad range of health outcomes beyond the data routinely collected in relatively short clinical trial. Overall results show the broad effects of GLP-1RA use on lower risk for outcomes including substance use disorders, heart, kidney and metabolic disorders, seizures, Alzheimer’s disease and dementia, blood clotting disorders, some infectious diseases and lung conditions, liver failure and inflammatory bowel disease. Condition where there was an increased risk included several gastrointestinal disorders, low blood pressure, fainting, arthritis, kidney stones, nephritis and drug-induced pancreatitis.

Overall, this study confirms some finding of the clinical trial but also extends to new finding related to both benefit and risk associated with newer GLP-1RA medication and will stimulate further research and evaluation. This study confirms the importance of comprehensive health evaluation, monitoring and follow-up in order to optimise health improvement and reduce potential side-effect and adverse outcomes. This study is likely to assist physicians in monitoring medication use and associated health and well-being outcomes in individuals long-term and for researchers it will inform future studies.

GLP-1 medications aren’t exactly 'new'—they’ve been transforming care for Type 2 diabetes for over 15 years and obesity for nearly a decade. This latest study highlights their far-reaching potential beyond blood sugar control, including reducing risks for conditions like neurocognitive disorders, respiratory diseases, and cardiometabolic issues. It’s a fascinating step forward!

This study showed that the effects of GLP-1 medications go beyond just managing blood sugar and weight. They may also benefit other parts of the body, like reducing the risks of heart disease, lung problems, and even conditions like dementia. It’s like getting bonus health benefits from a single treatment. While the findings are observational, they systematically map previously underappreciated outcomes, providing valuable real-world insights.
 
The systematic review of nearly two million US veterans confirms the reproducible effectiveness of GLP-1 RAs, extending their benefits beyond what RCTs have established. Though limited by cohort demographics and observational design, these findings add depth to our understanding of GLP-1 therapy’s broader health impacts.

GLP-1 medications, long used to treat Type 2 diabetes and obesity, may have unexpected benefits like reducing risks of Alzheimer’s, certain respiratory conditions, and heart disease. While this study offers exciting insights, more research is needed to confirm these effects in diverse populations.

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.

GLP-1 medications not only help with weight loss and blood sugar control but also have a well-studied safety profile. This large study found that their side effects are consistent with what we already know, giving us even more confidence in their use.

This study shows that GLP-1 medications may offer benefits that go far beyond treating diabetes or obesity. From reducing risks of Alzheimer’s and heart issues to improving lung health, the findings highlight their potential to improve overall well-being.

While this study offers exciting insights into the broader benefits of GLP-1 medications, it’s important to remember it focused on older men in the US. Future research needs to include women and people of all ages and ethnicities to ensure these findings apply to everyone.

If you’re using GLP-1 medications, this study brings good news: these treatments may help in ways we didn’t fully realize before, like lowering the risks of certain diseases. It’s another reason to feel hopeful about managing your health.

This study offers exciting insights into the potential broader benefits of GLP-1 medications, but it’s important to recognize its limitations. The findings are based on a group of mostly older, white men, meaning we need more research in diverse populations to see if these results apply to everyone. Additionally, it’s observational, so it can’t prove cause and effect.

While this research provides valuable new perspectives on how GLP-1 medications might impact other areas of health, it 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.

The paper describes a data-driven approach to studying possible beneficial and adverse effects of GLP-1 agonists like semaglutide (Ozempic), which are widely used to treat diabetes and obesity. The sophisticated statistical data techniques employed by the researchers are like those used to study effects of human genetic variations. In genomic analysis the data come from genome sequencing, but here they come from routine diagnostic, treatment and administrative records of millions of patients.

The researchers compare event rates in users of GLP-1 agonists with those observed in patients selected for other diabetes treatments. Rather than testing prior hypotheses about benefits and harms of these new medicines the analysts look for patterns in the data that might signal previously unsuspected effects. Some of the beneficial effects seen in their data, particularly in neuropsychiatric and substance abuse disorders, are supported by other studies. Some may be related to improvements in control of weight and metabolism, well known effects of the drugs. Others may be due to the play of chance or bias, because of differences between patient groups who are chosen to start different diabetes medications.

This is an observational study, not a randomised trial, and the authors caution against basing treatment recommendations on these data, without further confirmation. Such reticence is justified. Flawed observational studies of another diabetes drug, metformin, concluded erroneously that the drug prevented cancer. Analysis of data from randomised trials disproved that theory. This type of ‘big data’ research will generate lots of statistical associations, some of which will be spurious. It is not yet clear whether these data driven methods for exploring beneficial and harmful drug effects are a genuine advance over traditional inferential approaches.

This large study of diabetics in the US – using Veterans Affairs data – extends the range of diseases that appear to be affected by GLP agonists.  Most effects are positive with reductions of 10% to 15% being common for substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer’s disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. However, there were also increases in some gastrointestinal disorders, hypotension, syncope, arthritic disorders, kidney stones and kidney inflammation, and drug-induced pancreatitis.

The study was not a randomized trial, but thorough adjustment for differences between those receiving GLP agonists and those not, and a range of sensitivity analyses, suggest differences are causal.

For non-diabetics taking GLP agonists for other reasons – most likely reducing body weight – the results of this study may not be applicable as the interaction of diabetes-related inflammation and such like may be the reason for such wide-ranging GLP agonist effects.

This study adds to the growing knowledge are the wide-ranging effects of GLP agonists, that will likely see profound changes going forward in treatment of cardiometabolic disorders and diabetes in the future – and the treatment and prevention of obesity, noting this study was among diabetics only.