Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a very successful treatment option for both TYpe 2 Diabetes and obesity as they have demonstrated efficacy in blood glucose management, weight reduction, and cardiovascular disease prevention. GLP-1, an incretin hormone,which plays a crucial role in glucose metabolism and appetite regulation. It influences insulin secretion and insulin sensitivity. Its action of slowing and gastric emptying plays an important role in its weight reduction efficacy. The clinical use of GLP-1RAs has evolved, offering a number of options that provide flexibility in their prescribing. Emerging now are three types of medications classified as single dual and now, triple receptor agonists. The first one showing success was Ozempic, now also called Wegovy which is a single receptor agonist. The next Monjauro also called Zepbound is a dual receptor agonist. And the third called retatutride, which has not yet been FDA approved but has shown great efficacy in studies as a triple GLP-1 receptor agonist. These medications all reduce HbA1c levels, facilitate weight loss, and exhibit cardiovascular protective effects. Therefore they are increasingly being recognized n=by clinicians as an integral component of T2DM and obesity management. There seems to be an advantage to dual and triple receptor agonists which may provide both enhanced efficacy as well as a lower rate osf side effects seem to represent the future direction of GLP-1 based therapy. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00361-4/fulltext
How GLP1 medications work?
GLP-1 is a peptide hormone secreted by cells of the small intestine. That secretion is greatly enhanced after the ingestion of food. GLP-1 having been found in taste receptor cells in the oral cavity may also be involved in taste perception.5
GLP-1 receptors are found in the pancreas’ in islet beta cells which produce insulin and these receptors are also found in the central nervous system (CNS). In the brain, GLP-1Rs are found in areas that are thought to control food intake and the regulation of energy balance.
Mechanisms in diabetes
GLP-1 acts directly on the pancreatic β-cells enhancing insulin secretion. GLP-1 also decreases the liver’s glucose production by inhibiting glucagon secretion and increasing insulin sensitivity in the skeletal muscle through an indirect mechanism by increasing microvascular recruitment in skeletal muscles .7 Studies have demonstrated the crucial role that this plays in glucose homeostasis, and the stimulation of the insulin response.8
Along with the transient -short term effect of slowing gastric emptying, there is a marked reduction in the post-meal blood sugar excursion that occurs after food is ingested, thus its efficacy in Type 2 Diabetes. While regard to the effect of GLP-1s effects on the nervous system these do not seem to take part in the body’s glucose regulation but have a separate and distinct central nervous system effect of appetite suppression.6
GLP-1 Medications used in diabetes
Semaglutide
Semaglutide was the first GLP1-RA agonist available in subcutaneous injection and oral formulations. It is structurally similar to liraglutide but with modifications, making it even more resistant to degradation by DDP-4 and with a longer half-life. Semaglutide by subcutaneous injection was shown to be superior to exenatide once weekly, dulaglutide, and liraglutide in lowering HbA1c.19 In its daily oral formulation dose, semaglutide was non-inferior to liraglutide in decreasing HbA1c, in the PIONEER-4 trial.15 However, oral semaglutide more significantly reduced HbA1c than dulaglutide, −1.7% vs. 1.4% (Table 1).21
Comparative trials favor long acting agents (exenatide once weekly, liraglutide, dulaglutide, semaglutide) over short acting agents (exenatide twice daily and lixisenatide) in providing superior glycemic control. Among long acting agents, semaglutide by subcutaneous injection provides the greatest reduction in HbA1c. Liraglutide and dulaglutide seem to provide similar glycemic control, as do oral semaglutide and liraglutide. While oral semaglutide may be a preferred agent for patients adverse to injections, its strict administration requirements, that is 30 min before the first meal, beverage, or other medications, may limit its effective use.
Dual GLP-1/GIP RA
Tirzepatide
A dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RA, with activity at both receptors. The activation of both receptors seems to lead to greater efficacy in glycemic control. Administered in a once-weekly subcutaneous injection, it was shown to significantly decrease HbA1c, up to 2.07% at a maximum dose of 15 mg weekly, compared to placebo (Table 1).23 Studies have shown that Tirzepatide provides greater glycemic control compared to available single agonist agents.28
https://drsobo.com/tirzepatide-superior-to-semaglutide-for-weight-loss/
https://drsobo.com/women-lose-more-weight-than-men-taking-tirzepatide/
Triple GLP-1 RA in development
Retatutride- Triple GLP-1/GIP/glucagon RA. Retatrutide, is a once weekly, triple GLP-1 administered by subcutaneous injection, is under development for treating type 2 diabetes. In a phase 2 clinical trial, retatrutide reduced HbA1c to −2.02%.25
Also under development
Dual GLP-1 RA agonists
Semaglutide 2.4 mg, combined with cagrilintide (CagriSema),nis being developed for treating T2DM. It is administered in a once-weekly subcutaneous injection. In a phase 2 clinical trial, CagriSema significantly reduced HbA1c by −2.2%, compared to −1.8% for semaglutide 2.4 mg alone.24
Retatrutide is currently the triple only receptor agonist under investigation. It enhances obesity treatment by regulating body fat mass, energy homeostasis, and energy intake.53 In a phase 2 randomized, double-blind trial, weekly injections of retatrutide (1 mg–12 mg) led to weight reductions of 7.2–17.5% at 24 weeks and 8.7–24.2% at 48 weeks in individuals with obesity or pre-obesity showing no plateau during this period .53
Thyroid disorders and thyroid cancer
The relationship between risk of thyroid cancer and use of GLP-1 RAs is not well understood. When specific GLP-1 RAs were evaluated compared to placebo and other antidiabetic drugs, liraglutide was found to increase risk of thyroid disorders.70 No effects on risk were noted for semaglutide, lixisenatide, exenatide, nor albiglutide in which relative risks were not significant.70 During its meeting in October 2023, The European Medical Association (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded that the available evidence does not support a causal association between the GLP-1RA liraglutide, dulaglutide, semaglutide, and cancer of the thyroid.71
Gastrointestinal side effects
Gastrointestinal (GI) effects are the most reported by study participants and include nausea, vomiting, diarrhea, constipation, bowel obstruction, biliary disease and slowed gastric emptying. Concerns regarding the risk of regurgitation and pulmonary aspiration due to delayed gastric emptying have resulted in guidance from the American Society of Anesthesiologists (ASA) Task Force for use of these medications prior to procedures requiring general anesthesia.73
Conclusion
The mechanism of action of GLP-1 receptor agonists (GLP-1RAs) offers a multifaceted approach to addressing both type 2 diabetes mellitus (T2DM) and obesity. By enhancing insulin secretion, improving insulin sensitivity, and decreasing hepatic glucose production, GLP-1RAs play a crucial role in regulating blood glucose levels. Additionally, their effects on appetite suppression and satiety contribute to weight loss and management. The wide array of available GLP-1RAs, from short-acting to long-acting formulations, provide clinicians with various options to tailor treatment to individual patient needs. Furthermore, the emergence of novel agents such as tirzepatide, dual and triple hormonal agonists, expands the therapeutic landscape for managing T2DM effectively. While the potential of GLP-1RAs in type 1 diabetes mellitus (T1DM) treatment shows promise, further research is warranted to elucidate their efficacy and safety profile in this population fully. Overall, GLP-1RAs represent a valuable class of medications with diverse applications in diabetes management, offering hope for improved outcomes and better quality of life for patients with diabetes and obesity.
GLP-1 receptor agonists (GLP-1 RAs) in managing obesity have demonstrated significant efficacy in promoting weight loss and improving cardiometabolic parameters. Liraglutide, semaglutide, tirzepatide, orforglipron, retatrutide, and other emerging agents have shown substantial reductions in body weight when used as monotherapy or combined with lifestyle interventions. These agents aid in weight reduction and exhibit beneficial effects on appetite control, glycemic control, and cardiovascular health.
Furthermore, dual and triple receptor agonists, such as tirzepatide and retatrutide, offer additional advantages by targeting multiple pathways involved in energy regulation, resulting in enhanced weight loss and improved metabolic outcomes compared to traditional GLP-1 RAs. Despite the promising efficacy of these agents, it is essential to consider their safety profiles, particularly regarding gastrointestinal adverse effects, which are common but generally transient and manageable. Additionally, concerns regarding the risk of pancreatitis, and thyroid disorders require careful monitoring and further investigation. While current evidence suggests no significant increase in these risks, ongoing research is needed to understand better the long-term safety and efficacy of these medications.
Overall, GLP-1 RAs represent a valuable therapeutic option for individuals with obesity, offering not only significant weight loss but also potential benefits for cardiometabolic health. Continued research and clinical monitoring will help optimize their use and maximize patient outcomes in managing obesity and related metabolic conditions.
