Retatrutide (LY3437943) for metabolic disorders: A systematic review of clinical outcomes in obesity and type 2 diabetes

INTRODUCTION

Type 2 diabetes, often linked to obesity, results from insulin resistance and pancreatic dysfunction.^[1] Obesity worsens insulin resistance and metabolic risks. Effective management emphasises glucose control and 5–15% weight loss, with >10–15% potentially inducing remission and reducing cardiovascular risk. The growing prevalence of both conditions underscores the need for effective treatments.^[2-4] New glucose-lowering drugs, including glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), improve glycaemic control, reduce cardiovascular risk and aid weight loss.^[3] Semaglutide and tirzepatide are revolutionising obesity treatment, with tirzepatide – a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist – showing superior glycated haemoglobin (HbA1c) and weight reduction compared to GLP-1 agonists alone.^[5,6]

Many patients require greater and sustained weight loss, particularly reductions of 15% or more. This highlights the need for novel treatments targeting both hyperglycaemia and obesity. Enhancing GLP-1 or GIP/GLP-1RAs with glucagon may boost weight loss by reducing energy intake and increasing expenditure while improving insulin secretion, sensitivity and metabolic function.^[7-11] Dual GLP-1 and glucagon receptor agonists, including cotadutide, efinopegdutide and pemvidutide, show varying efficacy in type 2 diabetes, obesity and non-alcoholic steatohepatitis, likely due to differing GLP-1/glucagon activation. Triple agonists such as efocipegtrutide and retatrutide are under investigation, while SAR441255 is no longer in development, highlighting ongoing efforts to optimise metabolic treatments.^[8,12,13]

Retatrutide (LY3437943), a novel triple agonist by Eli Lilly, targets GIP, GLP-1 and glucagon receptors. With higher GIP potency and slightly lower GLP-1 and glucagon activity, it has a half-life of 6 days, enabling weekly dosing. Its unique mechanism may offer superior metabolic benefits over current treatments.^[13] Early trials by Urva et al. and Coskun et al. show retatrutide’s potential for weight loss and glycaemic control. However, data remain inconsistent due to varying study designs, populations and outcome measures.^[14,15] A systematic review is needed to synthesise evidence on retatrutide’s efficacy, clarify its therapeutic potential for obesity and diabetes, identify research gaps and guide future clinical trials for improved treatment strategies [Figure 1].

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Figure 1:

Overview of systematic review.

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MATERIALS AND METHODS

RESULTS

Literature search

According to the eligibility criteria, an initial total of 2,648 studies were identified across three distinct databases. After removing 738 duplicates, 1,910 articles remained for preliminary screening. On applying stringent inclusion and exclusion criteria, 1,011 articles were retained for further evaluation. Ultimately, after a thorough assessment of titles, abstracts and full-text articles, four studies were selected for inclusion in this systematic review. The PRISMA flow diagram provides a detailed visualisation of the study selection process [Figure 2].

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Figure 2:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

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Four clinical studies – two phase 2 and two early-phase trials – evaluated the efficacy, safety and pharmacologic profile of the triple-hormone receptor agonist retatrutide (LY3437943) in adults with obesity or type 2 diabetes mellitus (T2DM). All studies administered retatrutide (LY3437943) subcutaneously once weekly, except the single-dose study by Coskun et al., which evaluated pharmacokinetics following a single subcutaneous injection. All doses were administered subcutaneously once weekly, except in the single-dose study by Coskun et al.,^[15] which assessed pharmacokinetics and short-term tolerability. Study details and population characteristics are summarised in Table 1.

Table 1: Study characteristics and participant demographics.

Study (Year, Country)	Phase/Design/Clinical ID	Sample (n)/Key population	Intervention (dose and route)	Comparator	Duration	Primary and key outcomes	Main findings
Jastreboff et al., 2023[16] (USA)	Phase 2 multicentre RCT (NCT04881760)	338 adults 18-75 y; BMI 27-50 kg/m2	Retatrutide 1, 4, 8, 12 mg SC once weekly	Placebo	48 wk+4 wk FU	% change in body weight (24 and 48 wk); BMI and waist circ. change	Dose-dependent weight loss (-8.7 to -24.2% vs. -2.1% placebo); up to 26 kg reduction; 72% reverted to normoglycemia at 48 wk.
Rosenstock et al., 2023[17] (USA)	Phase 2 DB, double-dummy RCT (NCT04867785)	281 T2DM (18-75 y, HbAlc 7-10.5%, BMI 25-50 kg/m2)	Retatrutide 0.5-12 mg SC once weekly	Placebo, Dulaglutide 1.5 mg SC	36 wk+4 wk FU	ΔHbA1c and body weight (24 and 36 wk); safety	HbA1c↓2.1%; weight ↓ 17%; >15% weight loss in up to 58%; well-tolerated GI AEs.
Urva et al., 2022[14] (USA)	Phase 1b DB MAD RCT (NCT04143802)	72 adults T2DM (BMI 23-50 kg/m2)	LY3437943 0.5-12 mg SC once weekly	Placebo, Dulaglutide 1.5 mg SC	12 wk	Safety, PK/PD, weight, glycaemic markers	Half-life≈6 days; dose-dependent weight loss (-9% max); favourable tolerability.
Coskun et al., 2022[15] (Singapore)	Phase 1 single ascending dose RCT (NCT03841630)	47 healthy volunteers 21-65 y (BMI 19-40 kgW)	LY3437943 0.1-6 mg single SC dose	Placebo	6 wk (43 d FU)	Safety, PK, appetite effects	Well-tolerated; t1/2≈≈ 6 days; transient appetite reduction and mild GI AEs.

All interventions were administered subcutaneously (SC) once weekly, except Coskun et al., which used a single SC dose. AEs: Adverse events, BMI: Body mass index, GI: Gastrointestinal, HbA1c: Glycated haemoglobin, PK/PD: Pharmacokinetics/Pharmacodynamics, RCT: Randomised controlled trial, T2DM: Type 2 diabetes mellitus, wk: Weeks

Weight reduction

Across all studies, retatrutide produced consistent, dose-dependent reductions in body weight, with the magnitude of effect increasing proportionally to dose and study duration [Table 2].

Table 2: Reduction in body weight.

Study	Dose groups (mg SC weekly)	Baseline weight (kg)	% Change from baseline	>5% WL (%)	>10% WL (%)	>15% WL (%)	Comparator change
Jastreboff et al., 2023[16]	1/4/8/12	108±21	-7.2/-12.9/-17.5/24.2 (48 wk)	92-100	75-93	60-83	Placebo -2.1%
Rosenstock et al., 2023[17]	0.5/4/8/12	99±4	-3/-10/-13/-17 (36 wk)	61-94	22-80	10-58	Dulaglutide -2%; Placebo -3%
Urva et al., 2022[14]	0.5-12	85±6	-2 to -9 (12 wk)	-	-	-	Placebo+0.3%
Coskun et al., 2022[15]	0.1-6 (single)	88±8	-1 to -4 (6 wk)	-	-	-	No change

SC: Subcutaneously, wk: Weeks

In the phase 2 obesity trial conducted by Jastreboff et al.,^[16] 338 adults with a BMI between 27 and 50 kg/m² received once-weekly retatrutide for 48 weeks. Mean percentage change in body weight ranged from –8.7% with 1 mg to –24.2% with 12 mg, compared with –2.1% for placebo. The absolute mean weight reduction at the highest dose approached 26 kg, and 75–93% of participants achieved ≥ 10% loss. At 48 weeks, more than 40% achieved ≥20% weight reduction, highlighting a potent metabolic effect comparable to or greater than that observed with selective GLP-1RAs.

In the phase 2 diabetes trial by Rosenstock et al.,^[17] 281 participants with T2DM (mean HbA1c 8.3%) received retatrutide 0.5–12 mg once weekly for 36 weeks. Mean weight change ranged from –3% at 0.5 mg to –17% at 12 mg, compared with –3% for placebo and –2% for dulaglutide 1.5 mg. The proportion achieving ≥ 5%, ≥ 10% and ≥ 15% weight loss rose steadily with increasing dose (61–94%, 22– 80% and 10–58%, respectively).

Early-phase trials further supported these findings. In the Urva et al.^[14] phase 1b study, participants receiving retatrutide 0.5–12 mg weekly for 12 weeks lost 2–9% of baseline body weight compared with a 0.3% gain in the placebo group. The Coskun et al.^[15] single-dose study confirmed a similar pattern, with 1–4% weight reduction over 6 weeks and transient appetite suppression.

Collectively, these data confirm that weekly subcutaneous retatrutide produces clinically meaningful, dose-dependent weight loss across a range of metabolic populations and study durations.

BMI and waist circumference

Changes in BMI and waist circumference closely mirrored weight-loss outcomes [Table 3].

Table 3: Changes in BMI and waist circumference.

Study	Dose range (mg SC weekly)	Duration (wk)	Baseline BMI (kg/m2)	Δ BMI (range)	Baseline waist (cm)	Δ Waist (range) (cm)	Comparator change
Jastreboff et al., 2023[16]	1-12	48	37±6	-2.6 to -9.1	115±14	-5.4 to -19.6	Placebo -0.7 BMI, -2.6 cm
Rosenstock et al., 2023[17]	0.5-12	36	34±1	-1.1 to -6.1	111±3	-2 to -13	Dulaglutide -0.6 BMI, -2 cm
Urva et al., 2022[14]	0.5-12	12	32±5	-	106±4	-2 to -7	Placebo -1 cm
Coskun et al., 2022[15]	0.1-6 (single)	6	30±4	-	105±5	-1 to -5	No change

BMI: Body mass index, SC: Subcutaneously, wk: Weeks

In Jastreboff et al.,^[16] mean BMI decreased by 2.6–9.1 kg/m² across the 1–12 mg dose range, while waist circumference declined by 5.4–19.6 cm. By contrast, placebo participants showed minimal change (–0.7 kg/m² and –3 cm, respectively).

The Rosenstock et al.^[17] study demonstrated similar trends among T2DM patients, with mean BMI reductions of 1.1–6.1 kg/m² and waist decreases of 2–13 cm over 36 weeks – again exceeding results seen with dulaglutide (–0.6 kg/m² and –2 cm). Early studies (Urva et al., Coskun et al.) also indicated smaller but directionally consistent reductions (waist –2 to –7 cm and –1 to –5 cm, respectively).^[14,15]

These results confirm that retatrutide’s body-composition benefits extend beyond total body weight, with proportional reductions in central adiposity markers such as waist circumference.

Glycaemic and metabolic parameters

In participants with T2DM, retatrutide also led to robust glycaemic improvements that correlated with weight loss.

In Rosenstock et al.,^[17] mean HbA1c reduction reached –2.1% at 36 weeks for 12 mg weekly, accompanied by dose-dependent decreases in fasting glucose and improvements in Homeostasis Model Assessment of Insulin Resistance indices. Among participants with overweight or obesity but without diabetes (Jastreboff et al.), 72% reverted to normoglycaemia by week 48.^[16]

Secondary analyses across studies demonstrated favourable changes in lipid parameters, including reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, and modest increases in high-density lipoprotein cholesterol. The magnitude of improvement generally paralleled the degree of weight reduction.

Safety and tolerability

Across all trials, retatrutide was well tolerated. The most frequent treatment-emergent adverse events were gastrointestinal symptoms, notably nausea, diarrhoea and constipation, which were typically mild-to-moderate and diminished over time.

Transient increases in heart rate were observed at higher doses but without accompanying cardiovascular events. No major hypoglycaemia or treatment-related discontinuations were reported.

In phase 1b and 2 studies, pharmacokinetic assessments showed a mean elimination half-life of approximately 6 days, supporting once-weekly dosing and stable steady-state exposure after 4–6 weeks. No unexpected safety signals were identified throughout the study durations.

DISCUSSION

This systematic review, conducted following PRISMA guidelines, evaluated the efficacy of retatrutide (LY3437943) in managing diabetes and obesity. A comprehensive search identified relevant studies published by 30 September 2024. Four studies were included, analysed for clinical and pharmacokinetic outcomes related to obesity, cardiometabolic and glycaemic parameters.

Jastreboff et al.^[16] showed significant, dose-dependent reductions in body weight, BMI and waist circumference, especially with higher doses (8 mg and 12 mg). These reductions align with therapeutic goals of 5–15% weight loss, improving glycaemic control and potentially aiding diabetes remission. Retatrutide outperformed placebo and therapies like dulaglutide in achieving weight loss milestones, suggesting its potential in reducing central adiposity and cardiovascular risk. Its triple agonism, dose-dependent effects and longer duration of action support long-term weight management, especially for obesity-related disorders. However, long-term studies are needed to evaluate weight loss durability and the potential need for continuous therapy.^[18] Both Jastreboff and Rosenstock studies showed retatrutide’s significant ability to lower HbA1c, especially at higher doses, highlighting its potential for managing type 2 diabetes. This dual effect on weight and glycaemic control is vital for reducing long-term diabetes complications. Retatrutide’s triple agonism – GLP-1, GIP, and glucagon receptor activation – enhances insulin secretion, improves sensitivity and increases energy expenditure, contributing to HbA1c reductions. A network meta-analysis suggests retatrutide’s greater efficacy compared to other GLP-1RAs, though head-to-head trials are needed for definitive conclusions.^[19]

Urva et al.^[14] observed that while retatrutide improved insulin sensitivity, its effects on fasting insulin and C-peptide were less significant at lower doses. This suggests that higher doses may be necessary for optimal glycaemic control. Dose optimisation is critical, especially for patients with advanced diabetes, and individualised treatment plans are essential to address varying impacts on different glycaemic markers and meet patients’ specific metabolic needs. Novel anti-obesity treatments, especially dual and triple incretin-based coagonists, offer significant weight loss comparable to bariatric surgery without invasiveness. Such reductions could prevent obesity-related conditions like type 2 diabetes. Sex-specific differences in GLP-1 and glucagon physiology, particularly in females, require further investigation with retatrutide.^[20,21] Retatrutide has shown significant effects on weight, glycaemic control and cardiovascular risk factors, including lipid profiles and blood pressure. Both Jastreboff and Rosenstock observed reductions in triglycerides and LDL-C. These improvements align with broader cardiovascular benefits seen in GLP-1RAs and suggest retatrutide’s potential for reducing atherosclerosis risk. Its glucagon receptor agonism enhances lipid oxidation and reduces hepatic fat, contributing to both weight loss and improved lipid profiles, offering a dual benefit for cardiovascular risk management.

Retatrutide demonstrated reductions in both systolic and diastolic blood pressure, especially at higher doses. This effect addresses key metabolic syndrome and cardiovascular risks. The mechanisms likely include weight loss, improved insulin sensitivity and GLP-1 receptor activation, which improve endothelial function. While some studies showed mild heart rate increases, these were similar to those seen with other GLP-1RAs. Further research is needed to assess their clinical significance and postprandial effects on blood pressure and heart rate.^[22] The extended half-life of retatrutide supports its potential for weekly administration, which is a significant advantage in terms of patient adherence and overall treatment efficacy. Retatrutide generally exhibits a favourable safety profile, with mild-to-moderate gastrointestinal symptoms being most common. However, its dose-dependent efficacy and side effects highlight the need for optimised dosing strategies in future studies.

These studies suggest that retatrutide is a promising advancement in obesity and diabetes treatment, especially for patients needing significant weight loss and improved glycaemic control. However, varying responses across doses highlight the need for further research. Direct comparisons with semaglutide and tirzepatide are essential to determine its role in future treatments. Long-term trials are needed to assess safety and efficacy.

CONCLUSION

Retatrutide shows strong potential for treating obesity and metabolic disorders, especially at higher doses, surpassing dulaglutide in weight loss and glycaemic control. Future trials should focus on long-term studies (52+ weeks), comparing retatrutide with semaglutide and tirzepatide, optimising dosing and including cardiovascular, liver, renal and quality-of-life outcomes. Mechanistic studies and flexible dosing regimens should also be explored to better understand its full impact.