The Evolution of Weight Loss Drugs: Implications for T2D
Type 2 diabetes (T2D) is a progressive metabolic disorder characterized by insulin resistance, beta-cell dysfunction, and chronic hyperglycaemia with significant risk of renal and / or cardiovascular complications. Given the close relationship between T2D and obesity, weight reduction has long been recognized as a key goal for patients with T2D. Although weight loss of 10-15% is associated with improved insulin sensitivity and glycaemic control, traditional approaches to weight management (i.e. diet and exercise) typically do not achieve durable weight reduction. Indeed, only 1 in 5 individuals with overweight or obesity are successful in sustaining >10% weight loss long-term with lifestyle interventions alone. Importantly, weight regain is paralleled by declines in glycaemic control and T2D progression.
In the past two decades, the development of the glucagon-like peptide-1 (GLP-1) receptor agonists has reshaped the therapeutic landscape of chronic weight management and cardiometabolic diseases, including T2D. These drugs elicit greater weight loss than is achieved by lifestyle intervention alone and lead to wide-ranging cardiometabolic benefits. In this article, we discuss what the rapid evolution of these drugs means for patients with T2D.
Clinical development and efficacy of GLP-1 receptor agonists
GLP-1 receptor agonists (GLP-1 RA) mimic endogenous GLP-1, an incretin hormone that enhances glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying, and promotes satiety via central appetite regulation. Although now widely recognised for their efficacy as weight loss drugs, the first GLP-1RA (Exenatide from Eli Lilly) was initially approved in 2005 as a twice daily injectable for T2D. It wasn’t for another ten years that the daily injectable Liraglutide (Novo Nordisk) was approved for the treatment of obesity. The continued development of this drug class has led to the approval of numerous once-weekly injectable, and one daily oral, GLP-1RAs for patients with T2D. Further innovation in GLP-1 based therapies led to the approval of Tirzepatide (Eli Lilly), a dual glucose-dependent insulinotropic (GIP)/GLP-1 receptor co-agonist, for both T2D and obesity.
Data from multiple large phase three clinical trial series have demonstrated that GLP-1RA reduce HbA1c by 0.9-1.8% in patients with T2D, depending on the agent and dose used. Interestingly, body weight reduction with GLP-1RA treatment is typically lower in patients with obesity and T2D (5-10% weight loss), versus individuals without T2D (~15% weight loss). Notably, dual targeting of GLP-1R and GIPR receptors with Tirzepatide appears even more effective for glycaemic control and weight reduction versus single peptide treatments. Beyond glycaemic control and weight loss, GLP-1RAs have also been shown to reduce the risk of cardiovascular death, stroke, myocardial infarction, and kidney disease in patients with T2D and/or obesity. Clinical trials investigating the efficacy of GLP-1RA against metabolic-dysfunction associated steatohepatitis (MASH), peripheral arterial disease, Alzheimer’s and Parkinsons are also ongoing.
Drawbacks of incretin-based therapies
Despite their significant benefits, incretin-based therapies are not without limitations. The most common adverse events include gastrointestinal issues such as nausea and vomiting, which can negatively impact adherence. A related concern is the requirement for sustained therapy, since, as with most weight loss modalities, treatment withdrawal leads to weight regain and rebound risk of disease progression. Moreover, 25-40% of the weight lost with GLP-1RA treatments is lean mass rather than fat mass. Whilst the functional implications of this are currently unclear, reductions in lean mass are closely associated with decreased energy expenditure and thus likely contribute to the drive for weight regain if treatment is stopped. A major component of lean mass is skeletal muscle, which is especially important for glucose metabolism, mobility and overall metabolic health. The long-term consequences of lean tissue reduction with GLP-1RA therapy in patients with T2D therefore require further investigation, particularly in populations vulnerable to sarcopenia, such as older adults or individuals with pre-existing muscle loss.
Finally, the availability and affordability of newer drugs remain significant barriers, with many healthcare systems and insurance providers offering limited coverage for obesity pharmacotherapy. This raises questions about the feasibility and equitability of the lifelong treatment paradigm needed for continued metabolic benefits. Addressing these challenges will be critical in optimizing the widespread clinical adoption of incretin-based therapies.
Unanswered questions and future directions
Despite the success of incretin-based therapies, there are still important gaps in our understanding. One pressing question is whether preserving lean mass during GLP-1RA treatment could improve outcomes in T2D. Since skeletal muscle is essential for glucose uptake and overall metabolic health, strategies that protect muscle mass during weight loss may further enhance long-term benefits, particularly in high-risk populations (e.g. sarcopenia). Several muscle-preserving compounds are currently under investigation with GLP-1RA as potential combination therapies, including agents targeting the activin and apelin signalling pathways.
The introduction of Semaglutide and Tirzepatide has already prompted shifts in treatment paradigms, with the American Diabetes Association guidelines now prioritizing these agents for weight loss and glycaemic goals in patients with T2D. Looking ahead, several new therapies are in development, potentially pushing the boundaries of metabolic treatment even further. For example, Retatrutide (Eli Lilly) is a triple agonist that targets the GLP-1, GIP, and glucagon receptors, and has shown early promise for even greater weight loss and metabolic improvements than Tirzepatide. Meanwhile, Amgen’s investigational once-monthly injectable drug MariTide has shown significant promise in Phase two trials, resulting in 17% weight loss and a 2.2% drop in HbA1c in patients in T2D. Paradoxically, this drug combines a GLP-1RA with a GIP antagonist, highlighting that our understanding of incretin biology is still evolving.
As newer therapies continue to emerge, and our understanding of patient responses expands, it may become possible to refine treatment strategies based on individual metabolic phenotypes or genotypes. Future research should focus on personalized medicine approaches, optimizing drug selection for different patient subgroups to maximize efficacy while minimizing side effects. As the field continues to evolve, the next generation of metabolic therapies may not only improve glycaemic control but also address broader aspects of body composition and long-term metabolic health. For healthcare professionals, staying informed about these developments is crucial for optimizing treatment decisions and ensuring that patients with T2D receive the most effective and individualized care possible.
Written by Morgan Reid and Dr Christopher Shannon – Diabetes Complications Research Centre, UCD
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