Are anti-diabetic drugs the silver bullet for the obesity epidemic?

5th June 2023

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 ultimate solution? 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.

Obesity management

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.

Multiple sclerosis risk from anti-diabetic medication age dependent

29th November 2022

The risk of developing multiple sclerosis in those prescribed anti-diabetic medication shows an age-related dependent relationship

Patients aged 45 years and older prescribed anti-diabetic medication have an increased risk of developing multiple sclerosis compared to younger patients, but in the younger age group, the risk is actually significantly reduced according to the findings of a study by US researchers based at the university of Arizona.

Globally, an estimated 2.8 million people live with multiple sclerosis (MS) and the prevalence has increased in every world region since 2013, with a pooled incidence across 75 countries of 2.1 per 100,000 persons/year. Moreover, there is a good deal of data to suggest that axonal degeneration is the major determinant of irreversible neurological disability in patients with MS.

Although the precise underlying cause for MS remains to be determined, observational research suggests both genetic and environment influences and which are widely believed to be autoimmune in nature. Nevertheless, one prospective study following people for 9 years, demonstrated a moderate but significant association of type 2 diabetes with MS incidence. In addition, it has also been found that patients with type 1 diabetes have a more than 3-fold increased risk of developing MS.

Given the association with diabetes, the US researchers wondered if the use of anti-diabetic medication might positively impact on the risk of developing MS. The team turned to a US insurance claims database and identified those with type 2 diabetes and set the index data as the first recorded entry of their type 2 diabetes (T2D) diagnosis and the start date of the study, as 12 months after this index date.

For their analysis, researchers categorised participants with T2D as either under or over 45 years of age and propensity matched both cohorts, based on several factors including age, gender and co-morbidities.

Multiple sclerosis risk and use of anti-diabetic medication

A total of 143,613 individuals prescribed anti-diabetic medication (mean age of 30.16 years) and 638,625 (mean age of 61.85) were identified and both groups propensity matched.

Among the younger diabetic cohort, there was a significantly reduced risk of developing multiple sclerosis (relative risk, RR = 0.22, 95% CI 0.17 – 0.29, p < 0.001). In contrast, among the older cohort, the risk of developing MS was actually significantly higher (RR = 1.36, 95% CI 1.25 – 1.47, p < 0.001). The increased or decreased risk was also apparent for both sexes although among older men the risk was only slightly elevated (RR = 1.17, 95% CI 1.01 – 1.37, p = 0.04).

Interestingly, when researchers considered the individual anti-diabetic medicines, the risk was higher (or lower for younger patients) for all classes e.g., insulin, metformin, sulfonylureas, glitazones, DPP4 inhibitors and the combination of metformin and sulfonylureas.

The authors concluded that exposure to anti-diabetic medication in those with type 2 diabetes either increased or decreased the subsequent risk of developing multiple sclerosis and that this elevated or reduced risk was age-dependent.

Citation
Branigan GL et al. Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics. Heliyon 2022.