Dr Muiris Houston: More trials needed before we pass judgment on GLP-1 drugs

There can be no doubt about the game-changing nature of the latest generation of weight-loss drugs called GLP-1 agonists.Semaglutide, sold under the trade name Wegovy, and tirzepatide, branded as Mounjaro, have been shown in clinical trials to produce an average 15-20 per cent weight loss in people taking the new drugs.The benefits of dropping your body mass index (BMI) by at least two units, such as a reduction in blood pressure and a lowering of cholesterol levels, have been backed up by research. The Select trial, which studied effects of semaglutide on heart disease and stroke in patients who were overweight or obese, found a 20 per cent reduction in major adverse cardiovascular events among those treated with the drug.But, as often happens in medicine, the latest research questions some of these benefits.READ MOREA meta analysis of the latest trial data on GLP-1 drugs, published in the British Medical Journal, has found that they do not meaningfully improve quality of life for patients, and questions the reality of cardiovascular benefits after one year of taking the medication.[ Weight-loss drugs linked to increased risk of hair loss, researchers sayOpens in new window ]A key finding was that the obesity drugs associated with the most weight loss were also generally associated with greater harms, including gastrointestinal symptoms, fatigue, and loss of lean muscle mass, and use of them was more likely to be discontinued by patients. The meta analysis found that subcutaneous semaglutide was the only one of the drugs associated with a reduced risk of death from any cause. It was also the only one associated with a reduced risk of heart attack.However, both semaglutide and tirzepatide were linked with a substantial reduction in the risk of heart failure. And none of the drugs included in the analysis reduced the risk of renal failure.A core issue around GLP-1 agonists is what happens when people stop taking the drugs.A separate meta analysis by researchers at the University of Oxford found that after an average of 39 weeks of treatment, stopping the obesity drugs led to 0.4kg/month of weight regain. This means that, on average, people regain all the weight they lost within just 18 months of stopping the medication.“That’s surprisingly quick – almost four times faster than the weight regain seen after stopping weight-loss programmes based on diet and physical activity,” the authors say. “The health improvements vanish too, with blood pressure, cholesterol and blood sugar levels returning to where they started.”There is also some concern that this rebound weight gain will lead to a pharmaceutical version of “yo-yo” dieting – a repeated pattern of losing weight, regaining it and trying to lose it again. It points to a gap between public expectations and the reality of obesity management.[ It’s time for a reality check about certain ‘weight loss’ drugs, and here’s whyOpens in new window ]Many people understandably hope GLP-1 drugs will offer a permanent solution to their issues. But obesity is increasingly recognised as a complex and chronic health condition, influenced by biology, behaviour and the environment. The authors of the BMJ meta analysis questioning benefits of obesity medicines acknowledge that most trials had relatively short follow-up – which limited their ability to make robust assessments on the long-term safety, quality of life, and effects on cardiovascular and kidney outcomes. Others echo this, pointing out the findings do not show that obesity medications have no wider health benefits.Rather, they highlight that while the evidence for weight loss is strong, evidence for some longer-term outcomes is still developing and differs considerably between individual medications.Marie Spreckley, a weight management researcher at the University of Cambridge, noted the meta analysis provided an overview of the rapidly evolving evidence, but needed careful interpretation. “This is particularly important for cardiovascular outcomes. Many weight loss trials were not primarily designed or sufficiently long to assess outcomes such as heart attacks, heart failure, or mortality,” she said.In other words, we must await the results of more focused trials to pass judgment on the sustained benefits of GLP-1 drugs.mhouston@irishtimes.com