Obesity is a dangerous, chronic, and manageable neurometabolic condition expected to affect approximately 25% of the world’s population by the middle of the next decade. Weight management is considered critical for treating type 2 diabetes (T2DM) in obese or overweight individuals. Considering weight loss as a targeted treatment objective in managing T2DM, we prefer to start with lifestyle modification in terms of exercise and weight loss as a first-line approach; if that fails, we use medications like sodium-glucose cotransporter-2 inhibitors or incretins due to their ability to boost weight loss. However, weight loss using these drugs could be stronger, necessitating more effective pharmacological options. Retatrutide, a novel triple agonist targeting the receptors of glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon, has emerged as a promising therapeutic agent. This article delves into the efficacy and safety profile of retatrutide based on recent clinical trials.
Understanding Retatrutide: A Triple Hormone Receptor Agonist
Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are incretin hormones that have a role in nutrient metabolism. Glucagon is secreted from pancreatic α cells. 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. Retatrutide’s unique mechanism of action, simultaneously targeting GLP-1, GIP, and glucagon receptors, sets it apart from other anti-obesity medications. By acting on these three key receptors, retatrutide can potentially enhance impacts on substrate utilization, energy intake, and energy expenditure.
Methodology of the Meta-Analysis
To evaluate the effectiveness and safety of retatrutide, a comprehensive systematic review and meta-analysis were conducted. Standard methodologies were followed, including the PRISMA guidelines and the standards of the Cochrane Handbook of Systematic Reviews, to guarantee the results’ transparency, validity, and reliability. 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. Studies with English full-text that represented randomized controlled trials (RCTs) investigating retatrutide and its different doses were included. Studies on healthy populations, non-English texts, single-arm studies, animal studies, and abstracts were excluded.
The articles obtained through the search strategy were exported, and duplicates were removed using EndNote. Following this, titles and abstracts were screened using Rayyan. The full-text articles were then assessed for eligibility. Two researchers independently evaluated studies to determine their suitability for inclusion. Data were extracted using three carefully designed Excel sheets. The first recorded baseline characteristics, including sample size, age, sex, weight, BMI, waist circumference, fasting plasma glucose (FPG), HbA1c, systolic and diastolic blood pressure, and estimated glomerular filtration rate. The second was a summary sheet containing information on country, study phase, dose, duration, inclusion and exclusion criteria, outcomes, and conclusion. The Cochrane Risk of Bias 2 tool was used to assess the quality of the included RCTs, focusing on bias arising from the randomization process, deviations from intended interventions, missing outcome data, selection of reported results, and measurement of the outcome. RevMan (version 5.4) was used to analyze data extracted from the included studies. Continuous outcomes were combined as mean differences (MD) with corresponding 95% confidence intervals (CI). For categorical outcomes, relative risks (RR) or odds ratios (OR) were calculated along with their 95% CI. For P < 0.1, a random effects model was employed to compute pooled effect size; otherwise, a fixed-effect model was used.
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After searching PubMed, Scopus, Web of Science, and the Cochrane Library, 161 records were identified. After removing duplicates, 97 records were screened for eligibility criteria. Following the title and abstract screening, 32 records were selected for full-text screening. Three RCTs were included in the analysis; two of them included only diabetic obese patients, and the third study was conducted on nondiabetic obese patients. The total number of patients was 878, with 748 receiving retatrutide and 130 receiving placebo. For the analysis of safety and efficacy outcomes, three doses were considered: 4 mg (n = 114), 8 mg (n = 120), and 12 mg (n = 124). The doses were administered subcutaneously once weekly.
Significant Weight Reduction with Retatrutide
The meta-analysis of three randomized controlled trials (RCTs), encompassing 878 patients, demonstrated that retatrutide significantly reduced body weight. 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), with significant heterogeneity between the studies (P < 0.00001, I2 = 95%). The mean differences for the 4, 8, and 12 mg groups were −9.86 (95% CI: −16.97 to −2.76, P = 0.006), −16.31 (95% CI: −21.49 to −11.13, P < 0.00001), and −16.90 (95% CI: −22.37 to −11.44, 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. There was an OR of 43.34 (95% CI: 25.81 to 72.77, P < 0.00001) and no significant heterogeneity (P = 0.05, I2 = 55%) for achieving ≥5% weight loss target, an OR of 89.84 (95% CI: 42.31 to 190.77, P < 0.00001) and no significant heterogeneity (P = 0.24, I2 = 26%) for achieving a ≥ 10% weight loss target, and an OR of 46.93 (95% CI: 20.59 to 106.98, P < 0.00001) and no significant heterogeneity (P = 0.48, I2 = 0%) for achieving a ≥ 15% weight loss target.
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.
Improvements in Metabolic Parameters
In addition to weight loss, retatrutide treatment resulted in significant improvements in key metabolic parameters. The overall pooled analysis showed a statistically significant reduction in BMI of the retatrutide group when compared to the placebo group after 24 weeks of treatment, with an MD of −5.38 (95% CI: −5.74 to −5.01, P < 0.00001) and significant heterogeneity (P = 0.001, I2 = 75%). The MD for the 4, 8, and 12 mg groups were as follows: −4.24 (95% CI: −4.88 to −3.60, P < 0.00001), −5.85 (95% CI: −6.46 to −5.24, P < 0.00001), and −6.00 (95% CI: −6.65 to −5.35, P < 0.00001), respectively.
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The overall pooled analysis indicated a statistically significant decrease in FPG of the retatrutide group compared to the placebo group after 24 weeks of treatment, with an MD of −23.51 (95% CI: −31.33 to −15.69, P < 0.00001) and significant heterogeneity (P < 0.00001, I2 = 90%). The overall pooled analysis showed a statistically significant decrease in HbA1c of the retatrutide group when compared to the placebo group after 24 weeks of treatment, with an MD of −0.91 (95% CI: −1.16 to −0.66, P < 0.00001) and significant heterogeneity (P < 0.00001, I2 = 95%). After 36 weeks of treatment, systolic blood pressure was more significantly decreased in the retatrutide group compared to the placebo group, with an MD of −9.88 (95% CI: −11.39 to −8.37, P < 0.00001) and no significant heterogeneity (P = 0.58, I2 = 0%).
Reductions in BMI, waist circumference, FPG, HbA1c, and blood pressure were observed, indicating broad metabolic benefits. The overall reduction in FPG (MD = −23.51, 95% CI: −31.33 to −15.69, P < 0.00001) and HbA1c (MD = −0.91, 95% CI: −1.16 to −0.66, P < 0.00001) means that retatrutide could be particularly beneficial for diabetic or prediabetic individuals with obesity. Originally, given that weight loss is being increasingly acknowledged as a vital part of the treatment for T2DM, one of the included trials in the efficacy meta-analysis tested retatrutide in patients with T2DM. Despite rising heterogeneity between the two included studies due to different patient populations, this confirmed the efficacy of retatrutide in diabetics and nondiabetics.
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.
Safety Profile and Adverse Events
Three studies reported the safety data of retatrutide versus placebo. The analysis showed varying associations between the incidence of all adverse events and different doses of retatrutide. 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).
Compared to placebo, patients receiving retatrutide experienced higher occurrences of nausea, vomiting, decreased appetite, diarrhea, and constipation. The safety profile of retatrutide was generally favorable, although some adverse events were more common in the treatment groups. Gastrointestinal side effects such as diarrhea, vomiting, and constipation had a higher incidence in the retatrutide groups, particularly at higher doses. Notably, the incidence of nausea was significantly increased across all dose levels. Despite these side effects, the overall incidence of adverse events leading to discontinuation of treatment was relatively low.
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Retatrutide Compared to Other Anti-Obesity 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.
Implications and Future Directions
The findings of this meta-analysis provide robust evidence for the efficacy and safety of the triple-hormone-receptor agonist retatrutide in obesity treatment. Retatrutide’s substantial efficacy in promoting weight loss was evident across different dosages. The observed weight reductions were dose dependent, with higher doses achieving greater weight loss. The incidence of achieving ≥5%, ≥10%, and ≥15% weight loss was significantly higher in the retatrutide groups compared to placebo, with ORs indicating substantial treatment effects. The absence of significant heterogeneity in most subgroup analyses further strengthens the reliability of these findings.
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. These results represent a remarkably high efficacy, comparable to outcomes observed with other antiobesity drugs, suggesting a need to reassess whether a 5% weight reduction is still an optimal target for obesity treatment. Treatment objectives may need to be reevaluated to focus on the magnitude and quality of weight reduction, specific BMI or body fat percentage targets, and related health benefits.
The substantial reductions in body weight and metabolic improvements observed in this 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 approval process for retatrutide by the US Food and Drug Administration is expected to be lengthy, taking several years.