Impressive results from tirzepatide for people with type 2 diabetes and obesity
The findings of the SURMOUNT-2 trial were unveiled in a panel discussion at the American Diabetes Association 83rd Scientific Sessions recently. The study showed that weekly tirzepatide leads to significant weight loss and other health benefits in people with type 2 diabetes and overweight or obesity. Dr Susan Aldridge reports.
Professor W Timothy Garvey of the University of Alabama at Birmingham set the scene by reviewing the current therapeutic landscape for treating obesity in type 2 diabetes. “Up to 90% of people with type 2 diabetes also have overweight or obesity,” he said. “They have two diseases and both should be treated effectively.”
Accordingly, the American Association of Clinical Endocrinology (AACE) guidelines now recommend treating obesity to improve the patient’s health and prevent complications, rather than focusing merely on loss of kilograms. And the AACE/European Association for the Study of Obesity have also come up with a more medical diagnosis of obesity as comprising abnormalities in adipose tissue mass, distribution and function, which create a chronic disease.
Obesity pharmacology ranges from phentermine, back in 1959, to tirzepatide which was approved in May 2022 for glycaemic control in type 2 diabetes, although it is under investigation in many trials, including SURMOUNT, for the treatment of obesity. Tirzepatide is a dual agonist of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors. In clinical trials with patients without diabetes, tirzepatide can produce up to 22% weight loss, compared with just 15% with semaglutide. “I think these two medicines, which give us weight loss of 15% or more, are transformational in terms of what they bring to the table for our ability to improve the health of our patients,” said Professor Garvey.
The amount of weight loss you need to treat obesity-related disease, such as type 2 diabetes, cardiovascular risk, immobility, sleep apnoea and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), ranges from 10% to 35%, and 10% to 25% is now achievable with medication. “This is sufficient to prevent and treat a broad array of diabetes complications,” he continued. “So the health benefits that can accrue from this level of weight loss has led me to propose that these drugs be given the title of second-generation obesity medications because they can safely produce more than 15% weight loss in conjunction with lifestyle intervention.”
Obesity in diabetes
Alongside their glucose-lowering effects, GLP-1 receptor agonists and SGLT-2 inhibitors lead to weight loss of around 3%, save for semaglutide, which produces a greater weight loss. “But if we think we’re treating obesity by putting patients on these drugs at doses to treat diabetes, I think we’re fooling ourselves and not doing the best for our patients,” warned Professor Garvey. Also, people with both obesity and diabetes lose less weight than those with obesity alone. This is true for all obesity medications, except for tirzepatide, where we don’t yet have the data.
Looking at the whole range of weight-loss interventions, at the lower end, lifestyle intervention alone can produce between 2% and 7% weight loss, medication is in the middle with weight loss of up to 22% (in patients without diabetes), while surgery is at the higher end with potential weight loss of 40%. “We really are lacking that ‘sweet spot’ of drugs that can get us into 15% or more weight loss with type 2 diabetes,” said Professor Garvey. “This is what we want to look for in drugs designed to treat obesity in diabetes.”
Rationale of medication based on gut hormones
Professor Matthias Tschöp of the Technical University of Munich has been involved in the development of tirzepatide from the start, with Richard DiMarchi, in a bid to achieve 20% weight loss with a medication. “For this, we need to target more than one signalling pathway,” he said. “The gut-brain pathway offers safe and effective targeting of the brain circuits controlling body weight. We need to target more than one gut hormone receptor in the brain and, in my mind, obesity is a brain disease.”
They needed a gut hormone combination in a single compound, he continued. They found that GIP and GLP-1 receptor agonists had a dose-dependent, synergistic, anti-obesity effect in trials in mice and then clinical trials began in 2016. As far as the mechanism of tirzepatide is concerned, GIP is likely the major player, reaching the brain where the antisatiety effect happens.
Design of SURMOUNT-2
Dr Juan Pablo Frías, Director of Velocity Clinical Research, Los Angeles, noted that tirzepatide has been, and continues to be, studied in a number of metabolic diseases, including type 2 diabetes, obesity, NASH/NAFLD, kidney disease, obstructive sleep apnoea and heart failure with preserved ejection fraction (HFpEF). SURMOUNT-1 was carried out in people without diabetes and showed a 22% decrease in weight over 72 weeks. Other SURMOUNT trials are underway, including SURMOUNT-5, which compares tirzepatide with semaglutide.
The need for a separate study in type 2 diabetes is that people with type 2 diabetes often lose less weight than those without the condition. The SURPASS series showed that tirzepatide significantly reduced body weight versus placebo or active comparators in people with type 2 diabetes, but these trials were mainly focused on glycaemic control. For a weight-loss trial, BMI should be 27 or more, there needs to be a dietitian on board and it should run for more than 52 weeks. So SURMOUNT-2 was designed to assess the safety and efficacy of tirzepatide for chronic weight management in people with type 2 diabetes and obesity or overweight.
The trial involved 798 people with type 2 diabetes at 77 sites in seven countries, who were randomised to 10 mg or 15 mg of tirzepatide or placebo, along with increased exercise and a reduced-calorie diet. Their mean BMI at the start was 36, mean body weight 100 kg, and duration of type 2 diabetes 8.5 years. The primary objective of SURMOUNT-2 was to show that the 10 mg and 15 mg doses were superior to placebo at 72 weeks for percentage change in body weight and achieving 5% or more reduction in body weight. There were a number of secondary objectives – achieving 10%, 15%, 20% or more loss in body weight, reductions in HbA1c and so on.
Findings of SURMOUNT-2
Professor Garvey gave out the headline results – for those on 10 mg tirzepatide, mean weight loss was 13.4% (13.5 kg) and it was 15.7% (15.6 kg) on 15 mg. On the 15 mg dose, well over 80% of participants achieved 5% loss of body weight, 45% lost more than 15% and more than 30% of them lost more than 20%. Even more impressive, more than 17% of the participants lost more than a quarter of their body weight.
“These people are going to need to buy new clothes,” Professor Garvey said, as waist circumference decrease was three to four times greater with tirzepatide than with placebo, while mean change in BMI was around 5.7. “This represents a step down in a whole class of obesity – from Class III to Class II or from obese to overweight,” he continued.
Meanwhile, HbA1c decreased by 2.1%, with a very rapid increase seen by 24 weeks, which then stabilised at the lower level. Close to 90% of the SURMOUNT-2 participants reached the ADA 7% HbA1c target and around 50% even achieved normoglycaemia. All of this was achieved with no severe hypoglycaemia and very little Level 2 hypoglycaemia. Finally, there were also improvements in lipids and blood pressure, so all primary and secondary objectives of SURMOUNT-2 were met.
Professor Naveed Sattar of Glasgow University then took the platform to review the safety issues around SURMOUNT-2. “Adverse events, including serious events, were not elevated in the tirzepatide groups compared with placebo, and most treatment-emergent adverse effects were gastrointestinal,” he said. Also of note was improvement in liver enzymes, especially alanine aminotransferase (ALT), which you could expect with weight loss, and suggests tirzepatide has a beneficial effect on liver health. “In summary, the tolerability and safety of tirzepatide in people with type 2 diabetes and obesity is similar to that seen in the SURPASS trials and others on incretin therapies for obesity,” he said.
SURMOUNT-2 versus SURPASS-3
Dr Ildiko Lingvay of the University of Texas SouthWestern Medical Center, reviewed the clinical implications of SURMOUNT-2. In comparison, the SURPASS trials were diabetes-focused, with a primary endpoint of HbA1c, with weight loss being secondary, lasted for up to 52 weeks, and BMI was not a factor in inclusion. SURMOUNT had an obesity focus, with HbA1c as secondary, lasted for 72 weeks and BMI had to be 27 or more.
The SURPASS-3 trial was the most similar to SURMOUNT-2, except that lifestyle interventions were included in SURMOUNT-2 and baseline weight was around 6 kg less. Comparing body weight loss, these were 13.4% and 15.7% in SURMOUNT-2 and 11.4% and 13.9% in SURPASS-3 for the 10 mg and 15 mg doses of tirzepatide, respectively. “This is pretty close and I will speculate that if you were to extend SURPASS-3 to 72 weeks, you would probably get the same percentage body mass loss,” said Dr Lingvay. “The slightly faster response we see in SURMOUNT-2 is probably because of lifestyle intervention in that trial.”
She then put SURMOUNT-2 into context with other weight-loss drugs. So, for instance, there is STEP-2 with semaglutide, with nearly identical study populations, where the rate of change of weight loss is clearly greater with tirzepatide. And, in the pipeline, there is orforglipron, an oral small-molecule GLP-1 receptor agonist, which looks promising with a 10% reduction in a 26-week Phase 2 trial.
Meanwhile, a Phase 2 trial of the long-acting amylin analogue cagrilintide showed a mean weight loss of 15.2% in participants with type 2 diabetes. Finally, retatrutide, a triple agonist of GLP-1, GIP and glucagon (GCG) receptors produces around 10% weight loss in a Phase 2 trial. “So I am very hopeful about the next generation of weight-loss agents,” said Dr Lingvay. “It’s such great news for our patients as there is a great need for these medications.”
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.