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. 2025 Feb 5;38(3):291–303. doi: 10.1080/08998280.2025.2456441

Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials

Alaa Abdrabou Abouelmagd a, Amro Mamdouh Abdelrehim b, Mohamed Nabih Bashir c, Fares Abdelsalam d, Ahmed Marey c, Yousef Tanas c,e, Duha Milad Abuklish f, Mohamed Mohamed Belal c,✉
PMCID: PMC12026077  PMID: 40291085

Abstract

Background

Retatrutide is a novel triple agonist targeting the receptors of glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon. We sought to assess the efficacy and safety of retatrutide in obese patients with or without diabetes.

Methods

PubMed, Scopus, Web of Science, and Cochrane databases were searched from inception until May 2024. Eligible studies comprised randomized controlled trials that compared retatrutide with placebo in obese patients. We excluded studies on healthy populations, non-English texts, single-arm studies, animal studies, and abstracts. RevMan software (version 5.4) was used for analysis, with subgroup evaluation by dose (4 mg, 8 mg, 12 mg).

Results

Three randomized controlled trials, encompassing 878 patients, satisfied our inclusion criteria. 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. No significant difference in adverse events was observed between the groups (relative risk: 1.11, P = 0.24).

Conclusion

Retatrutide demonstrated significant improvements in body weight and metabolic outcomes among adults with obesity and had an appropriate safety profile. However, additional large and long-term trials are required to establish these results.

Keywords: GIP, GLP-1, glucagon, meta-analysis, obesity, retatrutide

Obesity is considered a dangerous, chronic, and manageable neurometabolic condition that is expected to affect approximately 25% of the world’s population by the middle of the next decade.1 Weight management is considered critical for treating type 2 diabetes (T2DM) in obese or overweight individuals. Losing weight can enhance insulin sensitivity and metabolic abnormalities associated with T2DM and reduce nonmetabolic cardiovascular risks.2 Historically, there has been limited progress in developing pharmaceutical treatments for obesity until recently.

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.3 However, weight loss using these drugs could be stronger, necessitating more effective pharmacological options. Metabolic surgery is beneficial for individuals with T2DM who have a body mass index (BMI) of >35 kg/m2, frequently resulting in diabetes remission and improvement in associated obesity-related conditions.4

Studies of individuals after bariatric surgery show strong evidence of the importance of significant weight loss in improving metabolic disorders. However, challenges such as high initial costs and limited acceptance decrease the generalization of bariatric surgery as a strategy to lower the obesity impact on public health.2

Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are incretin hormones that have a role in nutrient metabolism. Short-acting and long-acting GLP-1 receptor agonists improved blood glycemic control and lowered body weight in individuals with T2DM.2,3 GLP-1 receptor agonists delay gastric emptying, decrease food intake, increase insulin secretion in response to meals, and inhibit glucagon release in hyperglycemic and euglycemic states.5 GIP also increases insulin secretion after meals and aids in lipid clearance.6

Glucagon is secreted from pancreatic α cells. It increases glucose secretion from the liver between meals, reduces appetite, decreases gastrointestinal motility, increases lipolysis and fatty acid oxidation by the liver, and stimulates insulin secretion during hyperglycemia.7–10 Early preclinical studies showed good GLP-1 co-agonist and glucagon effectiveness in reducing body weight in rodents.11 Targeting glucagon, GLP-1, and GIP simultaneously with an agonist may provide better glycemic control and weight loss.12–14

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.14–16 The approval process for retatrutide by the US Food and Drug Administration is expected to be lengthy, taking several years. This is primarily due to the requirement to complete extensive phase 3 trials, projected to continue through 2025.17

Retatrutide demonstrated weight reduction and improved glycemic control in mice.14–16 A study administering a single dose to healthy subjects found that it is well tolerated and significantly affects appetite regulation and weight loss.14–16 In this meta-analysis, we aimed to assess the safety and efficacy of retatrutide in reducing body weight and improving metabolic outcomes in obese patients.

METHODS

We have followed standard methodologies for this systematic review and meta-analysis, including the PRISMA guidelines and the standards of the Cochrane Handbook of Systematic Reviews,18,19 to guarantee the results’ transparency, validity, and reliability. We registered the protocol in the Open Science Framework database with a registration number of 10.17605/OSF.IO/EX2UD.

Search and study selection

Our search involved four databases—PubMed, Web of Science, Scopus, and Cochrane—covering articles published up to May 1, 2024. This strategy used a combination of terms (retatrutide OR LY3437943) investigating the effects of retatrutide at varying doses on obese or overweight patients, with or without T2DM.

We included studies that met four criteria: (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. We included studies with English full-text that represented randomized controlled trials (RCTs) investigating retatrutide and its different doses. We excluded abstracts, animal studies, studies on healthy populations, studies without English full text, and single-arm studies.

The articles obtained through the search strategy were exported, and duplicates were removed using EndNote.20 Following this, titles and abstracts were screened using Rayyan.21 We then assessed the full-text articles for eligibility. Two researchers independently evaluated studies to determine their suitability for inclusion. Conflicts were resolved by discussion or by a senior reviewer.

Data extraction and outcomes

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 third reported outcomes of percent body weight changes, HbA1c levels, other metabolic measures, and reported adverse effects.

Risk of bias and quality assessment

We used the Cochrane Risk of Bias 2 tool to assess the quality of the included RCTs.22 There are five key domains: bias arising from the randomization process, deviations from intended interventions, missing outcome data, selection of reported results, and measurement of the outcome. Each domain is assessed using questions with an overall evaluation of “low risk,” “some concerns,” or “high risk” of bias.

Statistical analysis

We used RevMan (version 5.4) to analyze data extracted from the included studies.23 Continuous outcomes were combined as mean differences (MD) with corresponding 95% confidence intervals (CI). For categorical outcomes, we calculated relative risks (RR) or odds ratios (OR) along with their 95% CI. In cases where significant heterogeneity was identified—I2 > 60% or χ2 P < 0.1—we employed a random effects model to compute pooled effect size; otherwise, a fixed-effect model was used. Results were deemed statistically significant if the P value was <0.05.

RESULTS

After searching PubMed, Scopus, Web of Science, and the Cochrane Library, we identified 161 records. After removing duplicates, we screened 97 records for eligibility criteria. Following the title and abstract screening, we selected 32 records for full-text screening. Ultimately, this systematic review and meta-analysis included three RCTs.24–26 The search strategy and study selection results are shown in Figure 1.

Figure 1.

Figure 1.

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PRISMA flow diagram.

Three RCTs were included in our analysis; two of them included only diabetic obese patients,24,26 and the third study was conducted on nondiabetic obese patients.25 The total number of patients was 878, with 748 receiving retatrutide and 130 receiving placebo. For the analysis of safety and efficacy outcomes, we considered three doses: 4 mg (n = 114), 8 mg (n = 120), and 12 mg (n = 124). The doses were administered subcutaneously once weekly. The detailed study summary and baseline data of the participants are presented in Tables 1 and 2, respectively.

Table 1.

Summary of the included studies on retatrutide

First author, year Year Country Study phase Dose (mg) Treatment duration Outcome assessed Conclusion Inclusion criteria Exclusion criteria
Jastreboff
2023		 2021–2022 USA 2

  • 1

  • 4 (with an initial dose of 2)

  • 4 (with an initial dose of 4)

  • 8 (with an initial dose of 2)

  • 8 (with an initial dose of 4)

  • 12 (with an initial dose of 2)

 48 weeks

  • Percentage change in weight from baseline at 24 and 48 weeks

  • Weight reduction of 5% or more, 10% or more, and 15% or more at 24 and 48 weeks

  • Change from baseline at 24 and 48 weeks in weight, BMI, waist circumference, HbA1c, fasting glucose level, insulin, and lipid levels

  • In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight.

  • Aged 18–75 years with a BMI of 30–50 or 27–<30 in addition to at least one weight-related condition

  • Diabetes, previous or planned surgical treatment for obesity, treatment with medication that promotes weight loss or gain, or a change in body weight of >5 kg within 3 months before screening
Rosenstock
2023		 2021–2022 USA 2

  • 0.5

  • 4 (starting dose 2)

  • 4 (no escalation)

  • 8 (starting dose 2 mg)

  • 8 (starting dose 4)

  • 12 (starting dose 2)

 36 weeks

  • Primary: change in HbA1c from baseline to 24 weeks

  • Secondary: change in HbA1c and body weight at 36 weeks

  • Retatrutide showed clinical improvements in glycemic control and robust reductions in body weight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists.

  • Aged 18–75 years with T2DM and an HbA1c of 7.0–10.5% (53.0–91.3 mmol/mol) treated with diet and exercise alone or with a stable metformin dose (≥1000 mg once daily) for at least 3 months before the first two screening visits

  • Stable body weight (±5 kg for 3 months before randomization) and BMI of 25–50 kg/m2 at the first screening visit

  • T1DM

  • History of ketoacidosis or hyperosmolar state/coma

  • History of diabetic retinopathy

  • History of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months before Visit 1

  • History of acute or chronic pancreatitis or signs and symptoms of acute pancreatitis at screening

  • Known clinically significant gastric emptying abnormality (e.g., severe diabetic gastroparesis or gastric outlet obstruction), have undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery (e.g., Lap-Band), or chronically taking medications that directly affect GI motility

  • Obesity induced by other endocrine disorders (like Cushing’s syndrome or Prader-Willi syndrome)

Urva
2022		 2019–2020 USA 1

  • 0.5

  • 1.5

  • 3

  • 3/6

  • 3/6/9/12

 12 weeks

  • Safety outcomes

  • Efficacy outcomes: changes from baseline in HbA1c and body weight with exploratory pharmacodynamic measures, including waist circumference and oral glucose tolerance test measures (C-peptide, glucagon, glucose, and insulin)

  • In this early phase study, Ly3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once weekly dosing.

  • Aged 20–70 years with T2DM for at least 3 months before screening, HbA1c of 7.0–10.5% at lead-in and screening, BMI of 23–50 kg/m², stable body weight (<5% change during the previous 3 months), without advanced known possible complications of diabetes.

  • Using glucose-lowering medication except metformin within 3 months before screening
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BMI indicates body mass index; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Table 2.

Baseline characteristics of the enrolled patients in the included studies on retatrutide

Study ID Intervention N Male sex
no. (%)		 Mean (SD)
Age (yr) Weight (kg) BMI (kg/m2) WC (cm) HbA1c (%) FPG (mg/dL) SBP
(mm Hg)		 DBP
(mm Hg)		 eGFR
Jastreboff
2023		 Placebo 70 36 (50%) 48.0 (12.5) 109.2 (20.9) 37.3 (5.9) 115.1 (13.9) 5.5 (0.4) 94.9 (9.6) 126.2 (12.6) 83.5 (9.1) 89.4 (17.01)
Retatrutide 1 mg 69 36 (52%) 50.6 (13.3) 106.4 (19.8) 37.5 (5.9) 114.8 (14.7) 5.5 (0.4) 94.3 (9.7) 126.1 (14.6) 79.7 (9.2) 87.9 (18.01)
Retatrutide 4 mg escalation 33 17 (52%) 50.8 (11.9) 108.0 (26.3) 37.3 (5.9) 117.2 (16.6) 5.6 (0.4) 93.6 (7.8) 127.2 (12.4) 80.9 (8.5) 84.5 (18.75)
Retatrutide 4 mg 34 18 (53%) 46.8 (14.1) 107.0 (21.3) 37.4 (4.7) 115.2 (14.2) 5.5 (0.4) 91.4 (10.4) 126.5 (13.3) 81.0 (8.7) 90.91 (14.52)
Retatrutide 4 mg combined 67 35(52.5%) 48.7(13.1) 107(23.7) 37.35(5.2) 116.1(15.3) 5.5(0.4) 92.4(9.2) 126.8(12.7) 80.9(8.5) 87.7(16.8)
Retatrutide 8 mg slow escalation 35 18 (51%) 46.1 (13.5) 106.5 (21.6) 37.4 (6.0) 114.3 (14.3) 5.5 (0.4) 94.1 (11.9) 126.3 (12.8) 82.1 (9.1) 94.8 (15.9)
Retatrutide 8 mg fast escalation 35 18 (51%) 48.7 (11.1) 108.6 (20.9) 37.0 (5.5) 115.6 (12.7) 5.5 (0.4) 94.0 (9.2) 122.3 (12.2) 80.4 (9.3) 92.7 (15.0)
Retatrutide 8 mg combined 70 36(51%) 47.4(12.1) 107.5(21.1) 37.2(5.7) 114.9(13.4) 5.5(0.3) 94.0(10.5) 124.3(12.1) 81.2(9.1) 93.7(15.4)
Retatrutide 12 mg escalation 66 32 (52%) 45.8 (12.2) 108.0 (21.7) 37.4 (6.0) 116.5 (16.4) 5.5 (0.4) 93.2 (9.1) 118.7 (15.5) 78.2 (11.3) 93.6 (18.26)
Rosenstock
2023		 Placebo 45 22 (49%) 57.6 (10.8) 94.6 (16.6) 33.8 (4.9) 108.6 (12.3) 8.4 (1.1) 184.42 (61.4) 131.9 (15.0) 78.6 (9.8) 90.7 (21.1)
Retatrutide 0·5 mg 47 24 (51%) 57.2 (9.7) 96.7 (18.1) 34.7 (5.6) 110.5 (13.1) 8.3(1.2) 175.80 (65.8) 132.0 (11.6) 79.9 (8.0) 95.1 (14.5)
Retatrutide 4 mg escalation 23 15 (65%) 57.7 (8.1) 108.3 (26.7) 36.3 (7.4) 114.3 (24.4) 8.1 (0.9) 168.91 (49.0) 135.4 (9.8) 82.4 (7.3) 91.6 (17.6)
Retatrutide 4 mg 24 12 (50%) 57.6 (10.0) 93.1 (19.7) 34.0 (6.5) 110.5 (16.2) 8.2 (1.2) 174.29 (52.3) 125.8 (12.8) 77.4 (9.9) 91.6 (17.6)
Retatrutide 4 mg combined 47 17(57.5%) 57.6(9.0) 100.5(24.3) 33.1(6.9) 112.3(20.4) 8.1(1.0) 171.6(50.2) 130.4(12.3) 79.8(8.9) 91.6(17.4)
Retatrutide 8 mg slow escalation 26 10 (38%) 57.0 (7.4) 98.4 (21.1) 35.0 (6.4) 111.1 (15.1) 8.3(1.1) 179.60 (50.2) 131.0 (11.9) 78.2 (9.6) 86.0 (21.1)
Retatrutide 8 mg fast escalation 24 9 (38%) 53.8 (9.0) 95.9 (21.0) 34.1 (5.9) 109.3 (11.5) 8.2 (1.3) 152.96 (36.9) 131.6 (11.6) 82.6 (7.2) 90.4 (21.2)
Retatrutide 8 mg combined 50 19(38%) 55.4(8.2) 97.2(20.8) 34.5(6.1) 110.2(13.3) 8.2(1.1) 166.7(45.8) 131.2(11.6) 80.1(8.6) 88.1(21)
Retatrutide 12 mg escalation 46 20 (43%) 54.4 (9.7) 99.9 (22.7) 35.5 (6.9) 113.8 (17.4) 8.3 (1.1) 177.09 (56.6) 124.7 (13.7) 78.7 (8.4) 91.1 (19.2)
Urva
2022		 Placebo 15 3 (20%) 58.8 (6.4) 84.1 (19.9) 32.3 (6.2) 105.8 (17.6) 8.83 (1.06) NA NA NA NA
Retatrutide 0.5 mg 9 4 (44%) 59.2 (6.6) 86.6 (24.1) 33.3 (6.3) 108.1 (13.4) 8.07 (0.74) NA NA NA NA
Retatrutide 1.5 mg 9 3 (33%) 56.8 (5.7) 82.5 (17.3) 32.4 (6.1) 104.1 (12.3) 8.87 (0.79) NA NA NA NA
Retatrutide 3 mg 11 6 (55%) 56.8 (8.0) 84.5 (14.4) 31.7 (5.1) 106.4 (8.9) 8.65 (0.98) NA NA NA NA
Retatrutide 3/6 mg 11 7 (64%) 55.8 (10.7) 92.4 (15.2) 33.7 (3.9) 109.2 (10.4) 9.05 (0.81) NA NA NA NA
Retatrutide 3/6/9/12 mg 12 8 (67%) 61.5 (6.3) 84.7 (14.7) 30.5 (3.6) 103.7 (10.7) 8.45 (0.92) NA NA NA NA
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BMI indicates body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; NA, not available; SBP, systolic blood pressure; WC, waist circumference.

Risk of bias assessment

Based on the Cochrane Risk of Bias 2 tool, two studies had a low overall risk of bias (Figure 2). However, there were some concerns regarding the randomization process in the study of Urva et al, leading to an overall risk of bias categorized as “some concerns.”

Figure 2.

Figure 2.

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Risk of bias assessment.

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). All three doses demonstrated significant heterogeneity between the included studies: P < 0.00001, I2 = 94%, P = 0.003, I2 = 89%, and P = 0.002, I2 = 90%, respectively (Figure 3).

Figure 3.

Figure 3.

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Forest plot of the percent weight reduction in different retatrutide doses.

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. More details are shown in Table 3 and Supplemental Figures S1–S3.

Table 3.

Secondary efficacy outcomes of retatrutide

Outcome variables Retatrutide arm (mg/week) Control arm I2 (%) Pooled effect size P value
Participants achieving
≥15% weight loss		 Retatrutide 4 Placebo 1 OR 22.73 (95% CI: 5.41, 95.52) <0.0001
Retatrutide 8 Placebo 0 OR 61.32 (95% CI: 14.64, 256.88) <0.00001
Retatrutide 12 Placebo 23 OR 70.50 (95% CI: 16.76, 296.52) <0.00001
Total Placebo 0 OR 46.93 (95% CI: 20.59, 106.98) <0.00001
Participants achieving
≥10% weight loss		 Retatrutide 4 Placebo 0 OR 38.75 (95% CI: 11.43, 131.36) <0.00001
Retatrutide 8 Placebo 0 OR 152.79 (95% CI: 40.82, 571.93) <0.00001
Retatrutide 12 Placebo 18 OR 155.28 (95% CI: 39.80, 605.76) <0.00001
Total Placebo 26 OR 89.84 (95% CI: 42.31, 190.77) <0.00001
Participants achieving
≥5% weight loss		 Retatrutide 4 Placebo 47 OR 18.32 (95% CI: 8.81, 38.10) <0.00001
Retatrutide 8 Placebo 34 OR 135.27 (95% CI: 40.85, 447.97) <0.00001
Retatrutide 12 Placebo 0 OR 73.47 (95% CI: 26.96, 200.19) <0.00001
Total Placebo 55 OR 43.34 (95% CI: 25.81, 72.77) <0.00001
Body mass index (kg/m2) Retatrutide 4 Placebo 0 MD − 4.24 (95% CI: −4.88, −3.6) <0.00001
Retatrutide 8 Placebo 20 MD − 5.85 (95% CI: −6.46, −5.24) <0.00001
Retatrutide 12 Placebo 0 MD − 6.00 (95% CI: −6.65, −5.35) <0.00001
Total Placebo 75 MD − 5.38 (95% CI: −5.74, −5.01) <0.00001
Waist circumference (cm) Retatrutide 4 Placebo 6 MD − 8.58 (95% CI: −10.57, −6.60) <0.00001
Retatrutide 8 Placebo 0 MD − 11.36 (95% CI: −13.27, −9.45) <0.00001
Retatrutide 12 Placebo 0 MD − 11.72 (95% CI: −13.87, −9.56) <0.00001
Total Placebo 27 MD − 10.51 (95% CI: −11.67, −9.35) <0.00001
HbA1c (%) Retatrutide 4 Placebo 94 MD − 0.81 (95% CI: −1.77, 0.15) 0.1
Retatrutide 8 Placebo 97 MD − 1.19 (95% CI: −2.59, 0.20) 0.09
Retatrutide 12 Placebo 98 MD − 1.19 (95% CI: −2.77, 0.39) 0.14
Total Placebo 95 MD − 0.91 (95% CI: −1.16, −0.66) <0.00001
FPG (mg/dL) Retatrutide 4 Placebo 70 MD − 17.80 (95% CI: −35.21, −0.38) 0.05
Retatrutide 8 Placebo 92 MD − 28.51 (95% CI: −60.58, 3.56) 0.08
Retatrutide 12 Placebo 97 MD − 35.32 (95% CI: −79.18, 8.53) 0.11
Total Placebo 90 MD − 23.51 (95% CI: −31.33, −15.69) <0.00001
Systolic blood pressure
(mm Hg)		 Retatrutide 4 Placebo 0 MD − 7.89 (95% CI: −10.8, −4.98) <0.00001
Retatrutide 8 Placebo 0 MD − 10.91 (95% CI: −13.51, −8.32) <0.00001
Retatrutide 12 Placebo 0 MD − 10.36 (95% CI: −12.78, −7.94) <0.00001
Total Placebo 0 MD − 9.88 (95% CI: −11.39, −8.37) <0.00001
Diastolic blood pressure
(mm Hg)		 Retatrutide 4 Placebo 63 MD − 2.82 (95% CI: −5.82, 0.17) 0.06
Retatrutide 8 Placebo 79 MD − 4.44 (95% CI: −8.48, −0.40) 0.03
Retatrutide 12 Placebo 66 MD − 4.38 (95% CI: −7.63, −1.12) 0.008
Total Placebo 60 MD − 3.88 (95% CI: −5.57, −2.2) <0.00001
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CI indicates confidence interval; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; I2, statistical heterogeneity (%); MD, mean difference; OR, odds ratio.

Body mass index

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. There was insignificant heterogeneity in all three doses: P = 0.47, I2 = 0%, P = 0.26, I2 = 20%, and P = 1.00, I2 = 0%, respectively (Table 3, Supplemental Figure S4).

Waist circumference

The overall pooled analysis demonstrated that retatrutide was superior to placebo in reducing waist circumference after 24 weeks of treatment, with an MD of −10.51 (95% CI: −11.67 to −9.35, P < 0.00001) and no significant heterogeneity (P = 0.23, I2 = 27%).

For the 4 mg dose subgroup, the MD was −8.58 (95% CI: −10.57 to −6.60, P < 0.00001). The 8 mg dose subgroup had an MD of −11.36 (95% CI: −13.27 to −9.45, P < 0.00001). The 12 mg dose subgroup showed an MD of −11.72 (95% CI: −13.87 to −9.56, P < 0.00001). There was insignificant heterogeneity in all three doses: P = 0.30, I2 = 6%, P = 0.70, I2 = 0%, and P = 0.84, I2 = 0%, respectively (Table 3, Supplemental Figure S5).

Fasting plasma glucose

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%). For the 4 mg dose subgroup, the MD was −17.80 (95% CI: −35.21 to −0.38, P = 0.05), with no significant heterogeneity (P = 0.07, I2 = 70%). The 8 mg dose subgroup had an MD of −28.51 (95% CI: −60.58 to 3.56, P = 0.08), with significant heterogeneity (P = 0.0003, I2 = 92%). The 12 mg dose subgroup showed an MD of −35.32 (95% CI: −79.18 to 8.53, P = 0.11), with significant heterogeneity (P < 0.00001, I2 = 97%) (Table 3, Supplemental Figure S6).

HbA1c

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%). The MD for the 4 mg group was −0.81 (95% CI: −1.77 to 0.15, P = 0.10), with significant heterogeneity observed between studies (P = 0.0001, I2 = 94%). The 8 mg dose subgroup had a MD of −1.19 (95% CI: −2.59 to 0.20, P = 0.09), with significant heterogeneity (P = 0.0001, I2 = 97%). The 12 mg dose subgroup showed the greatest reduction with an MD of −1.54 (95% CI: −2.47 to −1.55, P = 0.14), with significant heterogeneity (P = 0.00001, I2 = 98%) (Table 3, Supplemental Figure S7).

Blood pressure reduction

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%). For diastolic blood pressure, the MD was −3.88 (95% CI: −5.57 to −2.20, P < 0.00001), with significant heterogeneity between the studies (P = 0.03, I2 = 60%) (Table 3, Supplemental Figures S8, S9).

Safety

Three studies reported the safety data of retatrutide versus placebo, summarized in Table 4.24–26 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). All three doses had no significant heterogeneities: P = 0.79, I2 = 0%, P = 0.54, I2 = 0%, and P = 0.51, I2 = 0%, respectively (Table 4).

Table 4.

Safety outcomes of retatrutide

Outcome variables Retatrutide arm (mg/week) Control arm I2 (%) Pooled effect size, RR (95% CI) P value
All adverse events Retatrutide 4 Placebo 0 1.11 (0.93, 1.31) 0.24
Retatrutide 8 Placebo 0 1.23 (1.06, 1.44) 0.007
Retatrutide 12 Placebo 0 1.34 (1.16, 1.55) <0.0001
Vomiting Retatrutide 4 Placebo 38 4.62 (1.03, 20.67) 0.05
Retatrutide 8 Placebo 0 8.13 (1.93, 34.21) 0.004
Retatrutide 12 Placebo 0 8.98 (2.49, 32.34) 0.0008
Nausea Retatrutide 4 Placebo 0 2.69 (1.36, 5.30) 0.004
Retatrutide 8 Placebo 7 4.27 (2.25, 8.08) <0.00001
Retatrutide 12 Placebo 0 4.00 (2.23, 7.17) <0.00001
Headache Retatrutide 4 Placebo 0 1.38 (0.28, 6.76) 0.69
Retatrutide 8 Placebo 0 3.18 (0.81, 12.55) 0.1
Retatrutide 12 Placebo 62 2.31 (0.54, 9.83) 0.26
Dyspepsia Retatrutide 4 Placebo NA 1.06 (0.15, 7.31) 0.95
Retatrutide 8 Placebo 0 2.52 (0.60, 10.67) 0.21
Retatrutide 12 Placebo 0 3.36 (1.02, 11.04) 0.05
Diarrhea Retatrutide 4 Placebo 52 1.64 (0.77, 3.49) 0.2
Retatrutide 8 Placebo 46 2.51 (1.26, 5.00) 0.009
Retatrutide 12 Placebo 11 2.04 (1.06, 3.94) 0.03
Decreased appetite Retatrutide 4 Placebo 18 3.28 (1.41, 7.62) 0.006
Retatrutide 8 Placebo 47 3.68 (1.60, 8.45) 0.002
Retatrutide 12 Placebo 31 4.64 (2.05, 10.50) 0.0002
Constipation Retatrutide 4 Placebo 0 4.41 (1.29, 15.13) 0.02
Retatrutide 8 Placebo 0 4.17 (1.22, 14.28) 0.02
Retatrutide 12 Placebo 0 4.41 (1.50, 12.93) 0.007
AES leading to treatment
discontinuation		 Retatrutide 4 Placebo 67 2.62 (0.63, 10.87) 0.18
Retatrutide 8 Placebo 0 4.45 (1.17, 17.01) 0.03
Retatrutide 12 Placebo 0 6.70 (2.06, 21.85) 0.002
Abdominal pain Retatrutide 4 Placebo 22 1.42 (0.28, 7.23) 0.67
Retatrutide 8 Placebo 0 3.29 (0.82, 13.28) 0.09
Retatrutide 12 Placebo 0 2.23 (0.57, 8.71) 0.25
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AES indicates adverse events; CI, confidence interval; I2, statistical heterogeneity (%); RR, risk ratio.

Compared to placebo, patients receiving retatrutide experienced higher occurrences of nausea, vomiting, decreased appetite, diarrhea, and constipation (Table 4). In terms of dyspepsia, headache, and abdominal pain, there was no significant correlation between the two groups (Table 4).

Heterogeneity

The significant heterogeneity in most of our efficacy outcomes could not be resolved by a leave-one-out test or sensitivity analysis due to the inclusion of only two studies in our efficacy analysis.

DISCUSSION

The findings of our meta-analysis provide robust evidence for the efficacy and safety of the triple-hormone-receptor agonist retatrutide in obesity treatment. Retatrutide demonstrated significant weight reduction and favorable metabolic outcomes across various dosages, indicating its promise as an effective therapeutic option for obesity management.

Efficacy

Retatrutide’s substantial efficacy in promoting weight loss was evident across different dosages. The overall pooled analysis showed a statistically significant MD in percent weight reduction compared to placebo (MD: −14.33, 95% CI: −18.27 to −10.39, P < 0.00001), with notable efficacy at all tested doses. The observed weight reductions were dose dependent, with higher doses achieving greater weight loss. This trend is consistent with the pharmacological profile of retatrutide, which targets multiple hormonal pathways involved in the regulation of appetite and energy balance.

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. This highlights retatrutide’s potential to be a highly recommended therapeutic option for achieving clinically meaningful weight loss in individuals with obesity.

Nutrient-stimulated hormone-based pharmacotherapies exploit the body’s natural mechanisms for regulating body fat and energy balance.27 Jastreboff et al suggested that combining GLP-1 or GIP–GLP-1 agonists with glucagon receptor activation could enhance their effectiveness.25 This combination might increase impacts on substrate utilization, energy intake, and energy expenditure.26 Our results represent a remarkably high efficacy, comparable to outcomes observed with other antiobesity drugs,25 suggesting a need to reassess whether a 5% weight reduction is still an optimal target for obesity treatment.28 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. Given that participants continued to lose weight at the end of our included phase II trials,24,25 it is likely that even greater weight reductions could be seen in extended phase 3 trials (ClinicalTrials.gov number, NCT05882045).

Metabolic improvements

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. 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,29 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. Retatrutide also may stimulate lipolysis in fat tissue through the activation of GIP receptors.30 Additionally, a phase 2 trial demonstrated that once-weekly retatrutide in patients with obesity and metabolic dysfunction–associated steatotic liver disease resulted in a significant reduction in liver fat and an improvement in insulin sensitivity.16

The ability of glucagon and GIP receptor agonism to lower lipid levels in the blood and boost fatty acid oxidation could also help in reducing ectopic fat and enhancing cell health in various tissues.8,31 Further clinical trials will be required to determine the impact of retatrutide treatment on long-term clinical outcomes.

Safety

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. These safety characteristics aligned with those of GLP-1 receptor agonists and tirzepatide.32–34

Comparison with other treatments

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.32–35 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),35 and 12% with 15 mg of tirzepatide, following treatment periods of 40 to 68 weeks.36 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.36 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. A key advantage of retatrutide is the high percentage of weight loss achieved in a significantly shorter study duration of 24 weeks, compared to the 68 weeks in the STEP 2 trial for semaglutide35 and 72 weeks in the SURMOUNT trial for tirzepatide.37

Insights from individual trials

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 improvements in cardiometabolic measures, such as waist circumference, blood pressure, and glycemic control. The safety profile of retatrutide was similar to that of GLP-1 receptor agonists, with transient gastrointestinal events being the most frequently reported side effects.25

In the Rosenstock et al trial, retatrutide showed significant reductions in HbA1c and body weight in participants with T2DM. The study also reported meaningful improvements in blood pressure, triglycerides, and non-HDL cholesterol. The trial’s findings suggest that retatrutide strikes a favorable balance between safety, glucose-lowering efficacy, and weight reduction. The observed body weight reductions were dose dependent and substantial, with the 12 mg dose group achieving a mean weight reduction of 16.94% at 36 weeks. These results underscore retatrutide’s potential as a promising therapeutic agent for managing hyperglycemia and obesity in individuals with T2DM.24

Limitations and future directions

Despite the promising results, several limitations should be acknowledged. The high heterogeneity observed in some analyses indicates variability in study populations and treatment protocols, which may affect the generalizability of the findings. Additionally, the small number of included RCTs, coupled with the small sample sizes across the studies, necessitates caution in interpreting these results. Long-term data on the sustainability of weight loss and the safety of retatrutide are also lacking, emphasizing the need for further research.

Future studies should focus on the long-term outcomes of retatrutide treatment, including its impact on obesity-related complications and quality of life. Investigating the mechanisms underlying individual variability in response to retatrutide could provide insights for personalized obesity treatments. Additionally, head-to-head trials comparing retatrutide with other antiobesity medications would help establish its relative efficacy and safety profile.

CONCLUSION

Our meta-analysis supports the efficacy and safety of retatrutide as a promising therapeutic option for obesity management. The significant weight loss and metabolic improvements observed with retatrutide, coupled with its acceptable safety profile, highlight its potential to address unmet medical needs in obesity treatment. Further long-term studies are warranted to confirm these findings and to fully elucidate the clinical benefits of retatrutide.

Supplementary Material

Supplemental Material
UBMC_A_2456441_SM9316.docx (217.6KB, docx)

Disclosure statement

The authors report no funding or conflict of interest.

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Supplementary Materials

Supplemental Material
UBMC_A_2456441_SM9316.docx (217.6KB, docx)

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