The promise of incretin therapy for obesity and liver disease
Glucagon-like peptide-1 agonists have improved outcomes for people with type 2 diabetes in recent years with their glucose-lowering and weight-loss effects. This has fuelled interest in the therapeutic potential of the incretin hormones in other conditions and an invited review in a recent issue of Diabetologia looks at current research and the future of these therapies in obesity and non-alcoholic fatty liver disease. Dr Susan Aldridge reports.
In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have had a big impact in the treatment of type 2 diabetes owing to their clinically relevant and sustained effects on glycaemic control and body weight, combined with cardioprotection. GLP-1RAs are also being used in the treatment of obesity.
Meanwhile, the therapeutic potential of another incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is now being revealed through its application in a combination therapy. The dual GIP receptor (GIPR)/GLP-1RA tirzepatide has shown superior efficacy to semaglutide in reducing HbA1c and body weight in people with type 2 diabetes. The emergence of co-agonists like tirzepatide, which is already approved for type 2 diabetes, has kindled interest in the actions of these two incretin hormones in metabolically relevant tissues such as the liver, muscle and adipose tissue.
In addition, the discovery of poly-agonist drugs that activate multiple gut-brain pathways may further transform the management of metabolic diseases other than type 2 diabetes, including obesity and non-alcoholic fatty liver disease (NAFLD). A new review by Tina Vilsbøll at the Steno Diabetes Center Copenhagen and colleagues looks at current and future research into the application of incretins beyond type 2 diabetes.
Incretins for obesity
The first incretin-based treatment to be approved for the management of overweight and obesity was liraglutide 3 mg once-daily, followed by semaglutide 2.4 mg once weekly. Meanwhile, Phase III trials on tirzepatide, which has already shown dramatic weight loss in individuals with overweight and obesity, are due to be completed later this year.
The efficacy and safety of liraglutide was investigated in the Satiety and Clinical Adiposity – Liraglutide Evidence (SCALE) programme. These trials included people with overweight (BMI ≥ 27 kg/m2) and one or more weight-related complications, including type 2 diabetes, or people with obesity (BMI ≥ 30 kg/m2) with or without complications. Daily liraglutide 3 mg led to an additional 4-5% weight loss compared with placebo, which was sustained after three years of treatment.
These results were exceeded by weekly semaglutide in the Semaglutide Treatment Effect in People with Obesity (STEP) programme in a similar population with overweight or obesity, where mean weight loss of 6.2% was observed after 68 weeks of treatment in those with type 2 diabetes, while those without diabetes lost as much as 10.3-12.5% of their body weight in the same time. Then, in a head-to-head trial of semaglutide versus liraglutide, the mean total body weight loss was 15.8% versus 6.4%.
There is a continuous decline in body weight for the first 60 weeks of semaglutide treatment, then a stable body weight for up to 104 weeks with continued treatment. However, discontinuation of semaglutide after 20 weeks leads to a regain of body weight, whereas maintaining treatment allows continued weight loss over an additional 48 weeks of treatment. This suggests that lifelong treatment is necessary to maintain weight loss. Recently, semaglutide 2.4 mg weekly has been investigated for the growing problem of childhood obesity. In children receiving lifestyle intervention as well, semaglutide resulted in 16.7% weight loss compared with placebo.
The future of obesity treatment
Research into incretin-based treatment for overweight and obesity is looking at the potential of combining GLP-1 receptor agonism with the targeting of other peptide hormones to achieve synergistic effects. The dual agonist tirzepatide is the trailblazer in this area. In the most recent trial, in which those with diabetes were excluded, tirzepatide produced weight loss of 11.9%, 16.4% and 17.8% with increasing doses of 5 mg, 10 mg and 15 mg, respectively. And 83.5% of those in the 15 mg group lost a clinically significant 10% or more of their body weight.
In another trial, adults with overweight or obesity and type 2 diabetes had a mean weight loss of 12.8% and 14.7% on 10 mg and 15 mg tirzepatide compared with just 3.2% on placebo. And in the group treated with 15 mg tirzepatide, 48% lost 15% or more of their body weight.
Tirzepatide has not yet been compared head-to-head with semaglutide 2.4 mg in those with overweight or obesity, but when compared with semaglutide 1 mg in those with type 2 diabetes, doses of 5 mg, 10 mg and 15 mg tirzepatide achieved significantly greater weight loss. However, it’s still not clear whether the GIPR component of tirzepatide exerts its effects by GIPR agonism or antagonism.
The combined GIPR antagonist and GLP-1RA, AMG 133 (Amgen’s obesity therapy), showed a weight loss of 14.5% after 12 weeks in a recent Phase I trial. This compound is poised to enter Phase II and the results are awaited with interest. Clearly more research is needed into the role of GIPR as a therapeutic target in obesity. Currently, several co- and tri-agonists targeting the GLP-1, GIP and glucagon receptor (GCGR) are in development for metabolic conditions, including obesity. Earlier research has shown a synergistic effect of co-infusions of GLP-1 and glucagon on food intake, so GCGR agonism may provide an additive effect due to increased energy expenditure.
However, balancing the weight-loss effect of glucagon receptor agonism with its hyperglycaemic effect is a challenge, so combining this with the glucose-lowering effect of GLP-1R and GIPR agonism is necessary. The GIPR/GIP-1R/GCGR tri-agonist (known as LY3437943) has been compared with dulaglutide 1.5 mg and placebo in a Phase I study in people with type 2 diabetes. Dose escalation of the tri-agonist to 12 mg once weekly over a period of 12 weeks led to an additional weight loss of 9 kg compared with both the placebo and dulaglutide.
Another approach has been to combine cagrilinitide, a long-acting amylin analogue, with semaglutide. In a Phase I study, this combination (at 2.4 mg of each component) resulted in an impressive 17.1% weight loss compared with 9.8% weight loss with semaglutide 2.4 mg alone.
Incretins for NAFLD
In NAFLD, fat accumulation in the liver can lead to inflammation (non-alcoholic steatohepatitis or NASH) and fibrosis, which can lead to NASH-related cirrhosis, currently the fastest-growing indication for liver transplantation in the Western world. The exact pathophysiology of NAFLD is unknown, but features such as metabolic disturbances, lipotoxicity, the gut microbiome, insulin resistance and inflammation are all involved – and there is a close link with obesity, type 2 diabetes and metabolic syndrome. Unsurprisingly, then, NAFLD is on the increase all around the world.
Currently, there is no pharmacotherapy for NAFLD/NASH, so the condition is managed by lifestyle change and treating cardiometabolic risk factors. Incretin-based therapies may be able to address this urgent unmet need by targeting the underlying hormonal and metabolic pathways thought to be involved in NAFLD/NASH.
In preclinical studies, GLP-1RAs have been shown to improve hepatocyte function and hepatic insulin sensitivity, as well as reducing the lipotoxicity of adipose tissue. These benefits arise from both weight loss and mechanisms that are independent of body weight reduction. This review lists all of the randomised controlled trials to date evaluating the potential of GLP-1RAs in NAFLD/NASH. The largest and longest trial to date includes 320 participants with NASH and fibrosis receiving daily semaglutide 0.1 mg, 0.2 mg or 0.4 mg versus placebo. Semaglutide resulted in a dose-dependent reduction of liver enzymes and greater NASH resolution after 72 weeks of treatment.
Meanwhile, the effects of 2.4 mg semaglutide once weekly are being explored in 1,200 participants in a Phase III trial with a combined primary endpoint of resolution of NASH without worsening fibrosis, improvement of liver fibrosis without worsening steatohepatitis and time to first liver-related clinical event. A recent meta-analysis based on data from randomised controlled trials confirms that GLP-1RAs are associated with reduced liver fat, improved liver enzymes and greater histological resolution of NASH without worsening of liver fibrosis.
GIP has been less well studied in NAFLD/NASH, but 52 weeks of treatment with tirzepatide reduces liver fat and improves liver enzymes compared with insulin degludec. Meanwhile, tirzepatide at 5 mg, 10 mg and 15 mg doses is in a Phase II trial in 196 participants with overweight or obesity and biopsy-confirmed NASH.
GLP-1RAs may work well in combination therapy for NAFLD/NASH because most of their mechanisms do not directly target the liver. Dual and triple agonists have led to improvements in lipid metabolism and hepatic steatosis, and research has shown that they may have additional effects on histological NASH features compared with GLP-1RAs alone and that these may be independent of weight loss. There are also several trials underway of combinations of GLP-1RAs with other peptide agonists or small molecule therapeutics. This review provides a useful overview of clinical trials in this area for readers who wish to take a deeper dive into this area.
So far, the therapeutic potential of GLP-1RAs – either alone or in combination with other peptide agonists – for the treatment of overweight/obesity and NAFLD/NASH appears to be huge, with no major safety concerns. Moreover, based on the reduction in major cardiovascular events that has been observed among people with type 2 diabetes in cardiovascular outcome trials, further trials in overweight and obesity have been initiated. These trials are looking at the ability of semaglutide and tirzepatide to reduce cardiovascular disease and mortality. This will potentially expand the clinical benefit of these therapies and establish a benchmark for overweight/obesity therapies in the future. Indeed, as the development of additional gut hormone poly-agonists progresses, obesity pharmacotherapy may become as efficient as bariatric surgery – currently the gold standard – for weight loss. The authors conclude that developments in incretin-based therapies promise to reshape the treatment landscape and improve outcomes for people with obesity and NAFLD.
To read this paper, go to: Andreasen CR, Andersen A, Vilsbøll T. The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease. Diaebtologia online 27 July 2023. https://doi.org/10.1007/s00125-023-05966-9
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.