Anti-diabetic drug lead to weight loss, providing a much needed impetus in the fight against the rising global obesity epidemic, but are these drugs the silver bullet? Rod Tucker investigates.
According to recent data released by Boehringer Ingelheim and Zealand Pharma, their novel glucagon/GLP-1 receptor dual agonist, BI 456906, designed as an anti-diabetic medicine, gave rise to a 14.9% weight loss in those either obese or overweight compared with placebo.
Though not yet commercially available, BI 45609 is likely to join a long list of anti-diabetic treatments being used in the fight against obesity. Such innovations are urgently needed given the inexorable rise in global levels.
For example, a recent report from the World Obesity Federation described how in 2020, an estimated 2.6 billion people globally had a body mass index (BMI) greater than 25 and therefore classed as overweight. This figure is projected to rise to four billion by 2035.
Obesity therefore represents a major public health concern, especially given how it is associated with as many as 18 co-morbidities including cardio-metabolic disorders and several types of cancer.
The pharmacological management of obesity has always been challenging, with the currently available anti-obesity medications often delivering insufficient efficacy. Part of the problem has been unravelling the complex hormonal milieu that exists in obese individuals and which hormones to target with drugs.
Despite this, an incidental finding in the late 1980’s, paved the way for the current paradigm in obesity management, yet it was to take many more years before researchers fully appreciated the implications of what they discovered.
Anti-diabetic role of GLP-1
In 1998, it was already known that glucagon-like peptide 1 (GLP-1), a hormone that caused the release of insulin from the pancreas and suppressed glucagon release, also produced an anti-diabetic effect through lowering blood sugar. But when researchers gave an intravenous infusion of GLP-1 to healthy young men, it not only lowered blood glucose but enhanced satiety and fullness, reducing energy intake by up to 12% compared to saline.
At the time, researchers failed to understand the importance of these results and it took more than 20 years to understand the weight-lowering effect of GLP-1 agonists. The importance of this effect came to prominence in a 2017 study of the GLP-1 agonist, semaglutide, in those with type 2 diabetes. The drug led to weight losses of up to five kilograms, prompting a further study – this time in overweight and obese patients without diabetes.
The results showed that a weekly injection of semaglutide to people with a BMI greater than 30 led to a mean reduction in body weight of -14.9% compared to only -2.4% with placebo. As an added bonus, the drug also improved cardiometabolic risk factors.
But GLP-1 was not the only hormonal target in obesity. Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone responsible for increasing insulin secretion after the intake of oral glucose. The drug tirzepatide, for example, which is a dual GLP-1-GIP agonist, is able to reduce body weight by more than 20 per cent.
Another somewhat counter-intuitive target is the glucagon receptor. Under normal circumstances, stimulation of this receptor increases the release of glucose, but work in 2009 demonstrated how a glucagon-GLP-1 co-agonist, reduced body weight among diet-induced obese mice. Scientists are now taking this innovation a step further with triple receptor agonist drugs, most recently, LY3437943, which has been shown to decrease body weight.
With anti-diabetic drugs now incorporated into obesity management guidelines, have we at last found the silver bullet to stem the rising tide of obesity? Probably not.
It’s widely acknowledged that these new anti-obesity drugs are only one part of a comprehensive approach to obesity management, alongside diet and exercise. Indeed, NICE recommended use of semaglutide alongside a reduced-calorie diet and increased physical activity as a therapeutic option for weight loss in March 2023.
Furthermore, once stopped, any weight lost with these drugs is quickly regained, largely because the decline in energy expenditure favouring weight regain persists long after the period of weight loss.
Ultimately, perhaps weight loss per se should not be seen as the most relevant metric. Patients who lose weight with anti-diabetic drugs also need to adopt a healthy diet and accept increased physical activity as a life-long norm.
Although some degree of weight regain is inevitable once treatment has stopped, it is recognised that the adoption of healthy lifestyle habits reduce mortality, irrespective of body mass index.