Tirzepatide safe, highly effective for three years

New research suggests the twincretin can safely sustain weight loss and glycaemic control in people with prediabetes and obesity.

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A long-term study of tirzepatide in prediabetes and obesity suggests people can keep weight off and remain diabetes-free for years, with a serious adverse event rate similar to placebo.

GLP-1 receptor agonists and glucose-dependent insulinotropic polypeptide drugs – like tirzepatide and semaglutide – have been shown to be incredibly effective treatments for weight reduction, glycaemic control and a whole host of other things in the short term, but there is a constant desire for more long-term safety and efficacy data.

Now, a new study that investigated the efficacy and safety of tirzepatide in people with both obesity and prediabetes over three years reports that, compared to placebo, patients treated with tirzepatide had a 94% reduction in the risk of developing type 2 diabetes while losing up to 20% of their weight.  

The findings were published in the New England Journal of Medicine.

Professor Elif Ekinci, director of the Australian Centre for Accelerating Diabetes Innovations, said it was equally important to see that patients derived significant health benefits above and beyond sustained weight loss.

“These findings underscore the critical role of long-term therapy in achieving and maintaining weight reduction and associated health benefits,” she said.

Researchers recruited over 1000 patients with both obesity (a BMI of at least 30, or at least 27 with one or more obesity-related complications) and prediabetes (based on the results of at least two tests e.g., glycated haemoglobin level, fasting serum glucose level or serum glucose level as part of an oral glucose tolerance test) as part of the SURMOUNT-1 study, an international, double-blind randomised controlled trial.

The average age of included participants was 48.2 years. At baseline participants had a mean weight of 107.3kg, and the average BMI was 38.8. The recruited sample was predominantly female (63.9%) and White (73.4%).

Patients were randomised to receive weekly subcutaneous injections of 5, 10 or 15mg of tirzepatide – or placebo – for 176 weeks. The treatment period was followed by a 17-week safety follow-up period. All patients also received a lifestyle intervention consisting of counselling sessions with a dietician, a calorie-deficient diet and a minimum of 150 minutes of exercise per week.

Two-thirds of patients remained enrolled in the trial to the end of the safety observation period, and a similar number adhered to the assigned regimen of tirzepatide or placebo injections.

After 176 weeks patients in the 5, 10 and 15mg tirzepatide groups lost, on average, 12.3%, 18.7% and 19.7% of their baseline body weight, corresponding to an average weight loss of 12.4, 20.0, and 21.4kg. In contrast, the placebo group lost 1.3% (0.9kg) of their baseline body weight.  

Less than 2% of patients in each of the tirzepatide groups went on to develop type 2 diabetes, compared to 13.3% of patients who received the placebo. This translates to an adjusted hazard ratio of 0.07 of developing type 2 diabetes after receiving tirzepatide.

A greater proportion of patients receiving tirzepatide also developed normal blood glucose levels by the end of the treatment period (89.9% of the 5mg dose group, 91.2% of the 10mg dose group and 93.3% of the 15mg dose group) compared to placebo (58.9% of patients). 

The researchers highlighted that simultaneously targeting both weight and glycaemic control was important in preventing the progression from prediabetes to type 2 diabetes, with additional mediation analyses suggesting that up to half of the effect of tirzepatide on delaying the onset of type 2 diabetes could be attributed to the medication-induced weight loss.

“[Drugs like tirzepatide] improve glycaemic regulation through multiple mechanisms, including direct effects on glucose-dependent insulin resistance through centrally mediated body weight reduction,” they wrote.

“These results highlight the sustained metabolic health benefits that may be attained with anti-obesity medications that combine proximal effects on islet function with long-term weight reduction that increases insulin sensitivity and reduces beta-cell workload in persons with prediabetes and obesity.”

Patients in the tirzepatide group also displayed reductions in waist circumference, blood pressure and lipid levels compared to the placebo group, as well as improvements in self-reported mental and physical health (as measured by the 36-item Short Form Health Survey [SF-36]).

However, as other emerging studies have demonstrated, the beneficial effects of tirzepatide disappeared once the patients stopped their injections.

Researchers estimated that patients regained 7% of their pre-treatment body weight during the 17-week safety follow-up period, and that 16% of patients reverted from having normal glucose levels back to levels that were indicative of diabetes.

“Collectively, these findings support the concept that to maintain weight reduction and glycaemic improvements, therapies would need to be continued long-term, as is done for other chronic diseases,” they concluded.

Constipation, nausea and diarrhoea were the most commonly reported side effects, with the latter two complaints affecting patients during the dose escalation period of the study.

Serious adverse events – including cancer, pancreatitis, cardiovascular events and gallbladder disease – occurred in 13-15% of patients receiving tirzepatide and in 12% of patients receiving placebo.

The TGA approved tirzepatide “for the treatment of adults with insufficiently treated type 2 diabetes mellitus as an adjunct to diet and exercise” either “as a monotherapy where metformin is not tolerated or contraindicated” or “in addition to other medicinal products for the treatment of type 2 diabetes” almost two years ago.

Last year the PBAC rejected Lilly’s application for tirzepatide to be added to the PBS, expressing concerns around the economic analyses and questioning whether it had a greater effect on weight loss and glycaemic control compared to semaglutide. It has now reviewed a second submission.

NEJM, 13 November 2024