Obesity is a chronic, manageable neurometabolic condition with an increasing global prevalence, expected to affect approximately 25% of the world's population by the mid-2030s. Weight management is considered critical, especially for treating type 2 diabetes (T2DM) in obese or overweight individuals. While lifestyle modifications are the first-line approach, more effective pharmacological options are often needed. Retatrutide, a novel triple-hormone receptor agonist, has emerged as a promising therapeutic agent for weight loss and metabolic improvement. This article delves into the clinical trial results of retatrutide, highlighting its efficacy, safety, and potential as a leading option for obesity management.
Understanding Retatrutide
Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors. These incretin hormones play a crucial role in nutrient metabolism. Specifically, retatrutide is a weekly single-agent peptide medication comprising a 39-amino acid peptide linked to a C20 fatty diacid moiety. It exhibits agonist activity for GIP, glucagon, and GLP-1 receptors. Compared to natural glucagon and GLP-1, retatrutide demonstrates lower potency at the human GLP-1 receptors and glucagon, while it is more potent at the human GIP receptor. It also shows a prolonged pharmacokinetic half-life and demonstrates favorable pharmacological characteristics.
The conventional view of insulin and glucagon has long been seen as an antagonistic one; however, our current understanding of glucagon action is not so glucose-centric, but involves other mechanisms that could conceivably be useful for diabetes treatment.
Phase 2 Clinical Trials: Key Findings
Findings from two related phase 2 clinical trials looking at the novel triple-hormone receptor agonist retatrutide were presented during a late-breaking symposium at the 83rd Scientific Sessions. The session, Retatrutide (LY3437943), a Novel GIP/GLP-1/Glucagon Receptor Triagonist-Obesity, NAFLD, and T2D Phase 2 Trial Results, can be viewed on-demand by registered meeting participants at ADA2023.org.
Study Design and Patient Population
One of the phase 2, double-blind, randomized, placebo-controlled trials involved adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. We enrolled 338 adults, 51.8% of whom were men.
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Another trial enrolled 281 participants with type 2 diabetes who were randomized to receive 0.5 mg, 4 mg, 8 mg, or 12 mg doses of retatrutide, 1.5 mg of dulaglutide, or placebo for 36 weeks.
Significant Weight Reduction
The study evaluated 338 participants with obesity who did not have type 2 diabetes. "Retatrutide was well tolerated and provided substantial and clinically meaningful reductions in body weight at 48 weeks of treatment," said Ania M. Jastreboff, MD, PhD. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group.
At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. “The highest dose of retatrutide led to an average 24.2% in weight reduction at 11 months, and the weight reduction threshold of greater than or equal to 5% was reached in all participants who received 8 mg or 12 mg of retatrutide,” Dr. Jastreboff said.
Achievement of Weight Loss Targets
At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. This highlights the dose-dependent efficacy of retatrutide in achieving significant weight loss.
Improvements in Metabolic Parameters
In addition to weight loss, retatrutide treatment resulted in significant improvements in key metabolic parameters. Reductions in BMI, waist circumference, FPG, HbA1c, and blood pressure were observed, indicating broad metabolic benefits.
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A meta-analysis of three randomized controlled trials, encompassing 878 patients, showed that retatrutide significantly reduced body weight (mean difference [MD]: −14.33%), body mass index (MD: −5.38), waist circumference (MD: −10.51 cm), fasting plasma glucose (MD: −23.51 mg/dL), hemoglobin A1c (MD: −0.91%), and systolic and diastolic blood pressure (MD: −9.88 mm Hg and −3.88 mm Hg, respectively), all with P values < 0.00001.
“Clinically meaningful reductions in A1C and body weight were achieved with retatrutide 4 mg-12 mg compared with placebo and dulaglutide 1.5 mg,” Dr. Rosenstock said. In terms of the effect of retatrutide on body weight, Dr. David A. D’Alessio, MD, the James B.
“When I look at this data, I can summarize it by saying that retatrutide demonstrated significant, meaningful improvements in glycemic control-up to normoglycemia-that were associated with robust body weight reductions of a magnitude not previously shown with any of the medications previously tested in type 2 diabetes,” Dr. David A. D’Alessio said.
Impact on Liver Fat Content
Arun J. Sanyal, MD, presented findings related to the effect of retatrutide on liver fat content in participants with NAFLD. “All doses of retatrutide showed significantly greater reductions in liver fat content versus placebo through week 24 and week 48 in the NAFLD subset,” Dr. Sanyal said. “Mean relative liver fat reduction was greater than 80% with retatrutide 8 mg and 12 mg, and 80% or more of participants on retatrutide 8 mg and 12 mg had a 70% or more relative reduction in liver fat.
“At the highest dose of retatrutide, more than 90% of participants with obesity and NAFLD achieved normalization of liver fat. This suggests that the addition of glucagon agonism to GIP and/or GLP agonism may result in greater efficacy in people with NAFLD/NASH,” Dr. Sanyal said.
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Safety and Tolerability
The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). “The safety and tolerability profile of retatrutide was comparable to that observed with GLP-1 and GIP/GLP-1-based therapies for the treatment of type 2 diabetes or obesity,” Dr. Jastreboff said.
Compared to placebo, patients receiving retatrutide experienced higher occurrences of nausea, vomiting, decreased appetite, diarrhea, and constipation (Table 4). Despite these side effects, the overall incidence of adverse events leading to discontinuation of treatment was relatively low.
For the 4 mg dose, there was no significant difference compared to the placebo group, with an RR of 1.11 (95% CI: 0.93 to 1.31, P = 0.24). Nonetheless, the 8 mg dose showed a slight increase in adverse events with an RR of 1.23 (95% CI: 1.06 to 1.44, P = 0.007), and the 12 mg dose had a more pronounced increase in adverse events, with an RR of 1.34 (95% CI: 1.16 to 1.55, P < 0.0001).
Meta-Analysis: A Comprehensive Look
A meta-analysis was conducted to evaluate the efficacy and safety of retatrutide in obese patients. The analysis included three randomized controlled trials (RCTs) with a total of 878 patients. The studies compared retatrutide with placebo in obese patients, with or without type 2 diabetes.
Methodology
The meta-analysis followed standard methodologies, including the PRISMA guidelines and the standards of the Cochrane Handbook of Systematic Reviews. The search involved four databases-PubMed, Web of Science, Scopus, and Cochrane-covering articles published up to May 1, 2024.
The inclusion criteria were: (1) a population of patients who are obese or overweight, with or without T2DM; (2) the intervention of retatrutide, assessed at various dosage levels; (3) a control of a placebo group; and (4) outcomes of percent body weight changes, hemoglobin AIC (HbA1c) levels, additional metabolic parameters, or the incidence of adverse effects.
Results
The meta-analysis demonstrated that retatrutide significantly reduced body weight, BMI, waist circumference, fasting plasma glucose, hemoglobin A1c, and systolic and diastolic blood pressure. The overall pooled analysis showed a statistically significant percent reduction in body weight of the retatrutide group when compared to the placebo group after 36 weeks of treatment, with an overall MD of −14.33 (95% CI: −18.27 to −10.39, P < 0.00001).
Compared to placebo, retatrutide showed a statistically significant achievement of ≥5%, ≥10%, and ≥15% weight loss targets after 24 weeks of treatment. The odds ratios (ORs) for achieving these weight loss targets were significantly higher in the retatrutide groups compared to placebo.
Safety Profile
The safety analysis showed varying associations between the incidence of all adverse events and different doses of retatrutide. Compared to placebo, patients receiving retatrutide experienced higher occurrences of nausea, vomiting, decreased appetite, diarrhea, and constipation.
Comparison with Other Antiobesity Medications
When compared with other antiobesity medications, retatrutide appears to offer superior weight loss outcomes. To date, no other phase 2 or 3 trials testing weekly GLP-1 or GIP and GLP-1 receptor agonists have reported this degree of weight loss.
To provide some context, a weight loss of up to about 5% was seen with 4.5 mg of dulaglutide, 7.2% with 2 mg of semaglutide, 10.6% with 2.4 mg of semaglutide in adults with overweight or obesity and T2DM (STEP 2), and 12% with 15 mg of tirzepatide, following treatment periods of 40 to 68 weeks. Additionally, up to 63% of adult participants with overweight or obesity and T2DM treated with retatrutide lost at least 15% of their body weight at 36 weeks, whereas 40% achieved this level of weight loss at 40 weeks with 15 mg of tirzepatide in the SURPASS-2 study.
Potential Mechanisms of Action
Nutrient-stimulated hormone-based pharmacotherapies exploit the body’s natural mechanisms for regulating body fat and energy balance. Jastreboff et al suggested that combining GLP-1 or GIP-GLP-1 agonists with glucagon receptor activation could enhance their effectiveness. This combination might increase impacts on substrate utilization, energy intake, and energy expenditure.
Retatrutide, along with other molecules that have glucagon activity, could potentially improve lipid profiles and reduce liver fat through several possible mechanisms. These include increases in fatty acid oxidation in the liver mediated by glucagon receptors and decreases in hepatic lipogenesis.
Implications for Obesity Treatment
The substantial reductions in body weight and metabolic improvements observed in the clinical trials and meta-analysis suggest that retatrutide has the potential to become a leading option for obesity management, particularly for patients who have not responded adequately to other treatments.
The results of the Jastreboff et al trial demonstrated that participants receiving the 12 mg dose of retatrutide experienced a mean weight reduction of 24.2% after 48 weeks. Notably, weight loss continued throughout the trial period, with no plateau observed. This trial highlighted that retatrutide’s efficacy might be enhanced through the combination of GLP-1, GIP, and glucagon receptor activation, resulting in significant reductions in body weight and imp…
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