GLP-1 Receptor Agonists in the Treatment of Obesity With and Without Diabetes - High-Quality UK SARMs | #1 SARMs Supplier

GLP-1 receptor agonists have become increasingly used for the treatment of obesity and type 2 diabetes (T2D). They offer a way to lose weight by suppressing appetite and better controlling blood glucose by stimulating the release of insulin. Obesity and T2D are separate diseases, but most often, closely linked to one another. Both strongly alter metabolism and affect the way GLP-1RAs affect the body. This article will go over what obesity and T2D are, the health implications of these conditions, how GLP-1RAs can be of benefit and why they affect people differently.

What are Obesity and T2D?

Obesity is a medical condition where there is such a degree of adiposity that the risk of serious health issues such as cardiovascular disease, T2D and cancer are increased. It is typically diagnosed by calculating a person’s body mass index (BMI), where a BMI of ≥30 is considered obese.

Obesity is typically attributed to:

Poor dietary choices and habits: Consuming highly processed food and sugary drinks in excessive quantities.
Inactive lifestyle: A lack of daily activity means that calories are not being expended.
Genetics: Certain genetic factors can influence how the body stores and utilises fat.
Medical conditions and medications: Diseases such as hypothyroidism and polycystic ovary syndrome (PCOS) alter metabolism and promote weight gain, while medications such as antidepressants and antipsychotics can lead to weight gain.
Age: As we age, we lose muscle mass and our metabolism slows, making us more likely to gain weight.

In most cases, the risk of T2D increases as BMI increases. This disease occurs due to the body’s inability to regulate and respond to glucose and a lack of appropriate response to the hormones that would regulate blood glucose levels. It is characterised by persistently elevated blood glucose, which can damage organs and nerves. It is usually caused by excess body fat and inactivity, but other contributing factors include genetics, age and certain other health conditions¹.

How GLP-1RAs and Other Related Drugs Work

GLP-1RAs, such as semaglutide, and other similar drugs such as tirzepatide (a dual receptor agonist) and retatrutide (a triple receptor agonist), all work by mimicking the action of hormones that regulate glucose levels, energy expenditure and the release of other hormones such as insulin. When these drugs are used to treat obesity and T2D, they produce reliable weight loss and improved blood glucose control. Obesity and diabetes remission have been possible for a significant number of patients taking these types of drugs.

Results of Clinical Studies

A review paper looking at the effect of 2.4 mg of semaglutide on adults with and without T2D found that those with only obesity experienced a reduction in weight of an estimated 11.57%, while those with obesity and T2D lost 6.34% of their body weight².

From these results, we can see that people with obesity tend to see greater weight loss results than those with obesity and T2D. This is due to a few different factors, which we will discuss below.

Why T2D Makes Weight Loss More Difficult

Obesity and T2D bring about different types and degrees of metabolic disruption. This can lead to dampened responses to not only endogenous hormones but also drugs that target hormone receptors. This lack of responsiveness is much more evident in those with T2D than in people with only obesity. Some of the main additional factors that determine whether someone develops T2D are the location of the fat, genetics, pancreatic function and responsiveness to hormones.

Fat Distribution

We know that adiposity increases the likelihood of developing T2D, but the location in the body where the fat is being stored can influence how it affects homeostasis. Subcutaneous fat is not usually harmful, while visceral fat is highly metabolically active and inflammatory. It is visceral fat that contributes to the body’s inability to properly respond to insulin³.

One study has put forward a hypothesis that some people’s adipose tissue has a greater capacity to expand to accommodate a surplus intake of energy⁴. Once the adipose tissue has reached its limit, fat is stored in other tissues, becoming the more harmful visceral fat.

Those whose bodies are more inclined to store energy as visceral fat are at higher risk of developing T2D. People of different races tend to store fat differently, with Asians being at a higher risk of accumulating visceral fat⁵, whilst black men are least likely to accumulate visceral fat⁶.

Genetics

Variation in genes involved in insulin secretion and β-cell function can lead to an increased risk of developing T2D. Some of these variations affect fasting glucose levels, triglycerides and cholesterol levels, increasing the risk of coronary heart disease. Variants have been identified that affect insulin sensitivity, reducing insulin-dependent glucose uptake. Several of these variants have been associated with a higher risk of developing metabolic syndrome⁷. A person with these variants is more likely to develop T2D as their BMI increases.

The Pancreas

We know that the functioning of pancreatic β-cells is partly dictated by our genetics, rendering some of us less able to secrete sufficient insulin to keep up with glucose intake. The ability of tissues to respond to insulin is also partly influenced by genetics. Although having these genetic variants does not guarantee a person will develop T2D, it increases their chances of developing the disease if their diet and lifestyle test these lowered limits.

Some people may be able to gain a significant amount of weight in fat before it becomes taxing on the pancreas. The ability of the pancreas to maintain its function determines whether or not T2D develops.

Impaired Response to Incretins

Incretins are gastrointestinal hormones, such as GLP-1 and GIP, that target the same receptors as several weight loss drugs. People with T2D still secrete these hormones, but they are less effective. This means that even when agonising these hormone receptors with the use of drugs, the elicited response will be dampened.

How Does This Affect Weight Loss?

Because of the additional burdens associated with T2D when compared to obesity alone, those with T2D generally have greater difficulty losing weight. Weight loss is not only slower through diet modifications and exercise, but even when assisted by drugs such as GLP-1RAs. Those with T2D are generally less responsive to the hormonal signals upon which these drugs rely to exert their benefit. Despite this, the drugs still produce significant weight loss in patients with T2D and greatly improve blood glucose control. The results in diabetic patients may not be as marked as those seen in patients with only obesity, but they are still beneficial.

Which GLP-1R Targeting Drugs Are Most Effective?

Patients with only obesity have been found to respond very well to 15 mg tirzepatide, with a reduction in weight of 17.8% in 72 weeks being reported in a review paper⁸. This same paper compared other weight loss drugs, including a newer triple receptor agonist, retatrutide, which produced a 22.1% reduction in weight after 48 weeks. The results of a more recent trial reported that participants taking 12 mg of retatrutide for 104 weeks lost an average of 30.3% of their body weight⁹. Since tirzepatide has been on the market for longer, the research supporting its weight loss results is more robust, whilst retatrutide is still in clinical trials and we have fewer studies to draw upon to prove its reliability.

15 mg of tirzepatide in diabetic patients produced a reduction in weight of 12.8% after 104 weeks, although this weight was lost mostly in the first 52 weeks and maintained for the remainder of the study¹⁰. Blood glucose levels were also improved with HbA_1C reducing by 2.59% in patients taking the 15 mg dose. Comparatively, 12 mg retatrutide produced a 15.3% reduction in body weight after 40 weeks, with a 1.94% reduction in HbA_1C¹¹.

Overall, tirzepatide is known to produce strong weight loss results and blood glucose control. Although retatrutide can cause rapid weight loss in diabetics, tirzepatide reduces HbA_1C to a greater extent, even though the weight loss is not as great. A lower HbA_1C is associated with a reduction in diabetes related complications, so it is an important metric that patients should aim to control when treating the disease.

Conclusion

Although obesity increases the risk of developing T2D, there are several factors that determine how high that risk is, some of which are beyond our control. Despite there being predetermined factors affecting risk, several dietary and lifestyle choices can help reduce the risk of developing a full blown disease. Once T2D develops, it becomes more difficult to lose weight in conventional and medically assisted ways. This may be partly due to the uncontrollable factors that conferred an increased risk to begin with, but also due to the changes in the body’s response to hormones and its ability to secrete hormones, which have been caused by the disease. GLP-1RAs, as well as dual and triple receptor agonists that also target this receptor, can significantly reduce weight, improving health outcomes. They are most effective at reducing weight in those with obesity and without T2D because, although they are stimulating the correct hormone receptors, these receptors do not respond normally in those with T2D.

Even though people with T2D do not experience as great a reduction in weight as those without the disease, the benefits are significant and enough to put the disease into remission in some cases. Although weight loss may seem like an uphill battle due to the burden that T2D places upon the body, significant improvements are still experienced, which could vastly improve health outcomes.

References

Klein S, Gastaldelli A, Yki-Järvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metab. 2022;34(1):11-20. doi:10.1016/j.cmet.2021.12.012
Hong B, Kim H, Lee D, Kim K. Weight Loss Effects of Once-Weekly Semaglutide 2.4 mg in Adults with and Without Type 2 Diabetes: A Systematic Review and Meta-Analysis. Pharmaceuticals. 2025;18(7):1058. doi:10.3390/ph18071058
Lee MJ, Kim J. The pathophysiology of visceral adipose tissues in cardiometabolic diseases. Biochem Pharmacol. 2024;222:116116. doi:10.1016/j.bcp.2024.116116
Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome — An allostatic perspective. Biochim Biophys Acta BBA – Mol Cell Biol Lipids. 2010;1801(3):338-349. doi:10.1016/j.bbalip.2009.12.006
Williams R, Periasamy M. Genetic and Environmental Factors Contributing to Visceral Adiposity in Asian Populations. Endocrinol Metab. 2020;35(4):681-695. doi:10.3803/EnM.2020.772
Hill JO, Sidney S, Lewis CE, Tolan K, Scherzinger AL, Stamm ER. Racial differences in amounts of visceral adipose tissue in young adults: the CARDIA (Coronary Artery Risk Development in Young Adults) study. Am J Clin Nutr. 1999;69(3):381-387. doi:10.1093/ajcn/69.3.381
Brown AE, Walker M. Genetics of Insulin Resistance and the Metabolic Syndrome. Curr Cardiol Rep. 2016;18:75. doi:10.1007/s11886-016-0755-4
Moiz A, Filion KB, Toutounchi H, et al. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes. Ann Intern Med. 2025;178(2):199-217. doi:10.7326/ANNALS-24-01590
Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial.
Tirzepatide for the treatment of adults with type 2 diabetes: An endocrine perspective. PubMed Central (PMC). Accessed June 27, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC10087310/
Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. 2026;407(10546):2402-2413. doi:10.1016/S0140-6736(26)00967-0

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