Beyond Blood Sugar: Why the Next Generation of Obesity Medicines May Go Beyond GLP-1
For years, we have tended to think about metabolic disease through one main lens: blood sugar. If glucose is too high, we lower it. If HbA1c improves, the treatment is working.
But obesity is much more complicated than that.
Someone can live with significant obesity without having diabetes. They can have insulin resistance, fatty liver disease, high blood pressure, sleep apnoea and increased cardiovascular risk while their blood glucose still looks relatively normal. So perhaps it is time to ask a different question:
Are we treating the right problem?
From glucose control to controlling appetite and weight. The arrival of GLP-1 medicines changed the conversation. Drugs such as semaglutide were initially associated with diabetes treatment, but their impact on appetite and body weight quickly became impossible to ignore. GLP-1 receptor agonists can help people feel fuller, reduce appetite and slow the movement of food through the stomach.
That is important because obesity isn’t simply about eating too much.
Our appetite is controlled by an incredibly complex network of hormones and signals between the gut, brain, pancreas, liver and adipose tissue. Modern food environments, meanwhile, give us almost unlimited access to highly palatable, calorie-dense food.
For some people, simply being told to “eat less and exercise more” is therefore an inadequate response to a biological problem.
GLP-1 medicines gave clinicians a way of addressing some of that biology directly.
And that may only be the beginning.
Why stop at one pathway?
This is where the next generation of medicines becomes particularly interesting.
Rather than stimulating just the GLP-1 receptor, newer medicines can target more than one metabolic pathway.
Tirzepatide, for example, activates both the GIP and GLP-1 receptors. It is therefore a dual agonist rather than a traditional GLP-1-only medicine. And there is a reason to believe that targeting multiple pathways could matter.
In the SURMOUNT-5 trial, tirzepatide produced significantly greater weight loss than semaglutide in adults with obesity who did not have diabetes. That is an important finding.
It suggests that the additional biological pathway isn’t simply helping with blood glucose. It may be contributing to a more powerful effect on the underlying biology of obesity.
The focus is shifting from:
“How do we lower glucose?”
to:
“How do we change the biological drivers of excess weight?”
What could a triple agonist add?
The really interesting possibility is what comes next. Researchers are investigating medicines that target three receptors at once: GLP-1, GIP and glucagon. The idea makes biological sense.
GLP-1 can help reduce appetite and improve glucose regulation. GIP may complement GLP-1 activity and contribute to metabolic effects.
Glucagon is different. Among other effects, it can influence energy expenditure and lipid metabolism.
Put those mechanisms together and you potentially have a medicine that does more than simply reduce blood glucose or suppress appetite. It could potentially reduce energy intake while also influencing how the body uses and expends energy. That is a very attractive concept in obesity medicine.
But there is an important caveat.
Triple agonists are still an emerging area of research. We should not assume that three targets automatically mean three times the benefit—or even that they will ultimately be better than dual agonists.
The question has to be answered by clinical trials. And those trials need to look beyond the number on the scales. We need to know what happens to fat mass, lean mass, cardiovascular risk, metabolic health, quality of life, side effects and, perhaps most importantly, what happens when treatment continues for many years.
Obesity isn’t just a glucose problem
This is probably the biggest change in thinking.
For a long time, diabetes and obesity treatment were closely tied to glucose. But obesity can exist long before glucose becomes abnormal.
A person may have excess visceral fat, insulin resistance, fatty liver and substantial cardiovascular risk without meeting the criteria for type 2 diabetes. That means a treatment strategy focused exclusively on glucose can miss a much bigger picture. The goal should be to improve metabolic health, not simply produce a better HbA1c result.
This is increasingly reflected in clinical guidance. The American Diabetes Association now recommends considering therapies with meaningful weight-loss effects for people with diabetes and overweight or obesity, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists. That represents an important shift. Weight loss is no longer just a welcome side effect of treating diabetes. For many patients, weight management is itself a primary therapeutic goal.
The problem with the “eat less” argument
There is another reason this matters.
We live in an environment where high-calorie food is cheap, convenient and everywhere.
Our biology has not evolved to cope with that environment.
The human body is remarkably good at defending its existing weight. When someone loses a significant amount of weight, biological signals can increase hunger and reduce energy expenditure, making weight maintenance difficult.
This helps explain why long-term weight management can be so challenging.
GLP-1 and multi-incretin medicines don’t remove the need for healthy nutrition or physical activity. Instead, they may make those behaviours more achievable by changing the biological background against which a person is trying to lose weight.
That is a very different proposition from simply telling someone to exercise more. But bigger isn’t necessarily better. It is tempting to look at the development of increasingly sophisticated medicines and conclude that the future is simply about adding more receptors. It isn’t. More powerful drugs can also mean more side effects.
Gastrointestinal symptoms are already common with incretin-based therapies. Rapid weight loss also raises questions about nutritional adequacy and preservation of lean mass. Then there are the practical issues: cost, access, long-term adherence and what happens when treatment is stopped. And not every patient will respond in the same way.
The future may therefore be less about finding one “super drug” and more about finding the right metabolic treatment for the right patient.
The bigger change is how we think about obesity. Perhaps the most important thing happening in obesity medicine isn’t the development of a particular drug.
It is the change in the way we understand the disease.
Obesity is increasingly recognised as a chronic disease with a powerful biological component—not simply a consequence of poor choices or lack of willpower. GLP-1 medicines helped change that conversation.
Dual agonists such as tirzepatide have taken it further, showing that targeting more than one metabolic pathway can produce substantially greater weight loss than GLP-1 monotherapy in head-to-head clinical research. Triple agonists could take the concept another step. But the goal shouldn’t be to create the most complicated drug possible.
The goal should be much simpler:
Can we help people lose excess fat, preserve muscle, improve metabolic health and maintain those benefits over the long term?
If the answer is yes, then the future of obesity treatment may look very different from the glucose-centric model we have relied on for decades.
The real opportunity is not simply to lower blood sugar. It is to treat the biology of overnutrition and obesity itself.
References
American Diabetes Association Professional Practice Committee. (2026). 8. Obesity and weight management for the prevention and treatment of diabetes: Standards of care in diabetes—2026. Diabetes Care, 49(Supplement_1), S166–S182. https://doi.org/10.2337/dc26-S008
Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., & Stefanski, A. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387(3), 205–216. https://doi.org/10.1056/NEJMoa2206038
Rubino, D. M., Greenway, F. L., Khalid, U., O’Neil, P. M., Rosenstock, J., Sørrig, R., Wadden, T. A., Garvey, W. T., & SURMOUNT-5 Investigators. (2025). Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine, 393(5), 450–461. https://doi.org/10.1056/NEJMoa2416394
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