Next-gen GLP-1 Breakthroughs: Revolutionizing Diabetes and Obesity Treatment at ADA 2024

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of medications used to treat type 2 diabetes mellitus (T2DM) and obesity by lowering serum glucose levels and managing metabolism in affected patients. Companies are continuously striving to improve approved therapies and develop next-generation obesity treatments. These efforts include combining GLP-1 with other entero-pancreatic hormones that have complementary actions and synergistic potential, such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin. These therapies are currently undergoing investigational trials aimed at enhancing the weight loss and cardiometabolic benefits of GLP-1 receptor agonists.

From June 21 to June 24, 2024, the American Diabetes Association (ADA) held its 84th Scientific Sessions, highlighting groundbreaking research from leading companies aiming to revolutionize obesity and diabetes treatment. Key players such as Lilly, Jiangsu Hengrui Pharmaceuticals, and Altimmune showcased initial, updated, and final results through High Priority Late-Breaking Abstracts, Oral Presentations, and Poster Presentations.

In this context, DelveInsight has carefully curated and emphasized some of the most significant abstracts. These abstracts represent promising advancements that have the potential to transform patient care significantly, shaping a more effective treatment landscape for both obesity and diabetes and beyond them.

1. Retatrutide: Enhancing Pancreatic Function and Insulin Sensitivity

The Abstract 266-OR, presented during the ADA conference focused on exploring the mechanism by which retatrutide enhances glycemic control. 

Retatrutide, a single peptide conjugated with a fatty diacid moiety, functions as a triple-agonist targeting GIP, GLP-1, and glucagon receptors. It demonstrates a higher affinity for the GIP receptor compared to glucagon and GLP-1 receptors. This interaction suggests a synergistic mechanism: inhibiting glucagon-induced gluconeogenesis through GLP-1/GIP and enhancing glucagon’s role in energy expenditure, coupled with the appetite-suppressing effects of GLP-1/GIP, thereby promoting weight loss.

In two Phase II double-blind, randomized, placebo-controlled trials involving 281 individuals with type 2 diabetes (36 weeks) and 338 obese subjects (48 weeks), retatrutide demonstrated significant efficacy. It reduced HbA1c levels by up to 2.2% in type 2 diabetes patients and achieved weight reductions of up to 17% by week 36 in diabetics, and 24% by week 48 in obese subjects without diabetes.

In assessing retatrutides’s (RETA) impact on glycemic control mechanisms, fasting biomarkers from two Phase 2 double-blind randomized placebo-controlled trials: T2D (281 subjects over 36 weeks) and OB (338 subjects over 48 weeks) were analyzed. The results revealed significant improvements in insulin resistance, with the HOMA2-IR index reduced by 39% in type 2 diabetes and 52% in obesity with 12 mg of retatrutide. Adiponectin levels, which indicate insulin sensitivity, increased by up to 52% in type 2 diabetes and 70% in obesity. Beta-cell function, measured by the HOMA2-B index via C-peptide, improved by up to 88% in type 2 diabetes but showed no significant increase in obesity. Additionally, markers of beta-cell stress and dysfunction, such as proinsulin and proinsulin/C-peptide ratios, decreased by up to 71% and 62%, respectively, in type 2 diabetes. This research provides a deeper understanding of retatrutide’s mechanisms, clarifying its primary outcomes.

These findings are particularly significant for individuals with type 2 diabetes who manage complex medication regimens to control blood sugar. New treatments like retatrutide offer the potential to simplify these therapeutic approaches, providing hope for more streamlined and effective diabetes management.

2. Breaking Boundaries: HRS9531 Pioneers Dual GLP-1/GIP Agonist for Obesity

HRS9531 demonstrated a promising result in obese patients with a significant reduction in weight among Chinese adults in the 1861-LB abstract presented at the conference. Treatment using HRS9531, a dual agonist targeting GLP-1 and GIP receptors, successfully led to reductions in body weight, blood pressure, blood glucose levels, and triglycerides, accompanied by a favorable safety profile in obese adults without diabetes.

In a randomized, double-blind, placebo-controlled Phase II trial, 249 Chinese adults with a BMI ranging from 28 to 40 kg/m² were evenly assigned to five groups: receiving once-weekly subcutaneous injections of HRS9531 at doses of 1.0 mg, 3.0 mg, 4.5 mg, and 6.0 mg, or placebo over 24 weeks. The primary objective was to evaluate the percentage change in body weight by Week 24.

The result published demonstrated significant weight loss benefits among individuals treated with HRS9531 compared to those receiving a placebo. After the 24-week intervention, participants in the 1.0 mg, 3.0 mg, 4.5 mg, and 6.0 mg HRS9531 groups experienced weight reductions of 5.4%, 13.4%, 14.0%, and 16.8%, respectively, in contrast to a minimal 0.1% reduction in the placebo group. Additionally, a substantial proportion of participants achieved a ≥5% weight reduction: 52.0%, 88.2%, 92.0%, and 91.8% in the respective HRS9531 dosage groups, compared to only 10.2% in the placebo group.

Obesity significantly increases the risk of chronic conditions such as type 2 diabetes and cardiovascular disease, underscoring the critical need for effective weight management strategies. While lifestyle interventions alone often have limitations, the emergence of HRS9531 presents a promising therapeutic option for addressing obesity. By facilitating weight loss, HRS9531 not only offers potential health benefits but also aims to reduce the societal burden associated with obesity-related health issues. This underscores its potential to improve overall health outcomes and mitigate the significant health challenges posed by excess weight.

3. GZR18: Pioneering Weight Loss with an 18.6% Reduction in Obesity Trials

Gan & Lee Pharmaceuticals recently presented promising findings from a phase Ib/IIa clinical trial of GZR18 Injection, a glucagon-like peptide-1 (GLP-1) receptor agonist, in an abstract 1858-LB presented at a conference. 

The study focused on evaluating GZR18’s efficacy in reducing weight among obese and overweight individuals in China. Over a 35-week treatment period, the once-weekly administration of GZR18 resulted in a mean weight reduction of 16.5 kg from baseline, corresponding to an 18.6% placebo-adjusted weight change. Similarly, the bi-weekly regimen showed a mean weight reduction of 11.3 kg, equating to a placebo-adjusted change of 13.5%. Furthermore, safety assessments indicated that GZR18 Injection was well tolerated, with no instances of serious hypoglycemia or drug-related serious adverse events reported among the obese participants. These findings underscore GZR18’s potential as an effective and safe treatment option for weight management in the Chinese population.

While not a direct comparative study, GZR18 demonstrated superior weight reduction capabilities compared to Semaglutide and Tirzepatide, based on published data from similar study durations. Additionally, GZR18 offers a longer duration of action, potentially requiring administration only once every two weeks, positioning it as a promising candidate for future obesity treatment options.

4. Pemvidutide: A Promising Dual Receptor Agonist in the Fight Against Obesity

The promising results from the Phase II MOMENTUM trial of pemvidutide, a peptide-based GLP-1/glucagon dual receptor agonist, were highlighted at the American Diabetes Association conference. This trial included 391 participants with obesity or overweight conditions, with at least one co-morbidity and no diabetes. Participants were randomly assigned in a 1:1:1:1 ratio to receive 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide or a placebo, administered weekly for 48 weeks alongside diet and exercise.

At Week 48 of the study, subjects receiving pemvidutide experienced significant mean weight losses of 10.3% at 1.2 mg, 11.2% at 1.8 mg, and 15.6% at 2.4 mg doses, compared to a 2.2% reduction with placebo. Notably, the 2.4 mg dose exhibited a near-linear continued weight loss by the end of treatment. Additionally, pemvidutide led to substantial reductions in serum lipids and improvements in blood pressure, with no observed imbalances in cardiac events, arrhythmias, or clinically significant increases in heart rate.

In conclusion, the trial findings revealed significant weight loss with pemvidutide, alongside an impressive preservation of lean mass. Coupled with its favorable safety profile and potential to improve other obesity-related conditions like dyslipidemia and hypertension, pemvidutide emerges as a highly promising long-term treatment option for various segments of the obese population, offering a safe and effective means of managing body weight.

5. GL0034 (Utreglutide): Weekly Dosing for Safety and Metabolic Impact in Obesity

At the ADA 2024 conference, Sun Pharma presented promising results from its phase I study of GL0034 (Utreglutide), evaluating the drug’s safety, tolerability, and metabolic effects in individuals with a BMI ≥28 kg/m2. Participants were randomized in a 9:3 ratio to receive subcutaneous GL0034 at fixed doses (4 × 680 µg in cohort 1) or escalating doses (680, 900, 1520, 2000 µg in cohort 2), or placebo, administered once weekly over four weeks. 

The study results revealed reductions across all parameters compared to baseline, with significant decreases observed in glucose area under the curve and HbA1c in both groups by day 23. Additionally, in cohort 1 and 2, there were respective reductions in body weight versus baseline of 2.9 kg and 4.6 kg by day 29. Overall, in individuals with obesity, a once-weekly dosing regimen of GL over four weeks led to clinically significant improvements in glucose levels, insulin response, HbA1c, lipid profiles, and body weight, with favorable tolerability.

With obesity rates rising sharply, there is a growing need for effective weight management medications. Drugs like GL0034 (Utreglutide) within the GLP-1 drug category, known for their favorable tolerability and safety profiles, are poised to meet this increasing demand. 

6. Mitigation of Liver Steatosis in Chinese Overweight and Obese Individuals: Mazdutide’s Impact in GLORY-1

Innovent Biologics announced encouraging findings from its phase III clinical trial evaluating mazdutide, a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), in Chinese adults with overweight or obesity. The results were unveiled during the ADA 2024 session.

In the phase 3 GLORY-1 trial (NCT05607680), 610 Chinese adults meeting criteria of a BMI ≥ 28 kg/m² or ≥ 24 kg/m² with at least one weight-related comorbidity were randomly allocated in a 1:1:1 ratio. Participants received once-weekly subcutaneous doses of either mazdutide at 4 mg, mazdutide at 6 mg, or placebo over 48 weeks.

The study’s findings revealed significant efficacy in weight loss with mazdutide: at weeks 32 and 48, both 4mg and 6mg doses surpassed placebo in mean percentage reduction of body weight from baseline. Moreover, a higher proportion of participants achieved ≥5%, ≥10%, and ≥15% reductions in body weight compared to placebo. Notably, among participants with baseline MRI-PDFF ≥10%, those receiving mazdutide 6mg experienced an average 80.2% reduction in liver fat content, contrasting with a mere 5.3% decrease in the placebo group. Importantly, the drug demonstrated favorable tolerability throughout the trial.

In conclusion, mazdutide has shown promising potential as a treatment for obesity and related metabolic disorders, supported by robust clinical evidence from multiple Phase III studies. The exclusive license agreement between Innovent and Eli Lilly and Company underscores a strategic commitment to advancing Mazdutide’s development and potential commercialization in China. With positive outcomes observed across various cardio-metabolic parameters and the acceptance of its first New Drug Application by China’s NMPA, mazdutide represents a significant advancement in addressing the unmet medical needs of individuals with overweight, obesity, and type 2 diabetes in the region.