Background

Retatrutide (LY3437943) is the first GLP-1/GIP/GCG triple agonist to complete phase 2 trials, with phase 3 studies ongoing for obesity and/or T2D management. It is a 39 amino-acid, single peptide, engineered from a GIP peptide backbone, conjugated to a C20 fatty di-acid moiety to enable albumin binding and extend its half-life [42]. Retatrutide has ≈ 2.5-times lower potency at the GLP-1 receptor than human GLP-1, 8.9-times higher potency at the GIP-receptor than human GIP and 2.9-times lower potency at the GCG-receptor than human GCG [42].

Preclinical Studies

In preclinical trials, retatrutide was administered to male mice models with obesity [42]. The results showed that retatrutide significantly delayed gastric emptying, reduced food intake, and caused dose-dependent WL. The WL was primarily due to reductions in fat mass with less impact on lean mass. Additionally, retatrutide lowered blood glucose and insulin levels, suggesting that retatrutide enhanced insulin sensitivity. Retatrutide further reduced plasma alanine aminotransferase and liver triglycerides, suggesting improvements in liver health [42]. Further studies demonstrated that retatrutide also increased energy expenditure through GCG receptor activation [42]. These findings highlighted retatrutide’s potential as a potent therapeutic agent for obesity and metabolic disorders.

Phase 1 Trials

In a first-in-human, randomized, placebo-controlled, single ascending dose, phase 1 trial in healthy participants, retatrutide demonstrated a favourable safety profile (similar to other incretin-based therapies) and early signs of efficacy with dose-dependent WL [42]. The pharmacokinetic profile supported once-weekly dosing, with a mean half-life of approximately six days. Appetite suppression was observed at doses ≥ 0.3 mg while significant reductions in circulating triglycerides, branched-chained amino-acids and fasting and postprandial glucagon levels were also seen, along with increasing insulin secretion.

Building on these results, a phase 1b trial in individuals with T2D further evaluated the safety, pharmacokinetics, and pharmacodynamics of once-weekly retatrutide over 12 weeks [43]. The medication produced dose-dependent improvements in both glycaemic control and body weight. At the highest dose (3/6/9/12 mg escalation scheme), mean HbA1c was reduced by up to 1.6% and weight by nearly 9 kg, which was significantly greater than placebo. Retatrutide also lowered fasting and postprandial glucose, reduced appetite, and improved lipid profiles, including reductions in low-density lipoprotein (LDL) cholesterol and triglycerides. Adverse events were mostly mild-to-moderate gastrointestinal symptoms, consistent with other incretin-based therapies. A substudy of this phase 1b trial showed also that retatrutide delays gastric emptying in humans, as measured by the acetaminophen test, though this effect lessens over time due to tachyphylaxis [44].

Phase 2 Trials

The findings of phase 1 studies supported the continued clinical development of retatrutide as a promising candidate for the treatment of obesity and T2D. Two phase II trials - one in a population with obesity (without T2D) [45], and a second in a population with T2D and overweight/obesity [46], have recently been published and their key findings are presented below (Table 1).

Table 1 Key efficacy outcomes from the phase 2 studies of retatrutide in individuals with obesity and with type 2 diabetesDesign

In the obesity trial, 338 participants (mean age 48 years, 48% women, mean BMI 37.3 kg/m2) were randomised (2:1:1:1:1:2:2) to retatrutide 1 mg, 4 mg (titration), 4 mg (no titration), 8 mg (slow titration), 8 mg (fast titration), 12 mg or placebo over 48 weeks [45]. All participants received a lifestyle intervention involving regular counselling regarding diet and physical activity. The primary endpoint was change in bodyweight from baseline at 24 weeks, with 48 weeks included as a secondary outcome.

The trial in people with T2D included 281 participants (mean age 56 years, 56% women, mean BMI 35.0 kg/m2, mean HbA1c 8.3%) treated with lifestyle only and/or metformin, with similar intervention arms to the obesity trial, albeit retatrutide 0.5 mg rather than 1 mg, and dulaglutide 1.5 mg was an additional comparator [46]. The trial duration was 36 weeks. The primary endpoint was HbA1c change from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks.

Weight Loss

In both trials, a marked dose-dependent WL was observed. In the obesity trial, maximal WL was achieved with retatrutide 12 mg after 48 weeks: -24.2% vs. -2.1% with placebo, with 64% vs. 1% achieving ≥ 20% WL respectively (Table 1) [45]. Greater WL was seen in women with higher doses of retatrutide (-28.5% WL vs. -21.9% WL in men) and in those with baseline BMI ≥ 35 kg/m2 (-26.5% WL vs. -22.1% WL with BMI < 35 kg/m2).

In the T2D trial, WL was lower than in the obesity trial however the trial duration was shorter (36 weeks) [46]. Participants receiving retatrutide 12 mg experienced − 16.9% WL vs. -3.0% with placebo and − 2.0% with dulaglutide 1.5 mg. These findings highlight the substantial weight-lowering effect of retatrutide, even in a relatively short treatment period and in people with T2D.

Other Metabolic Benefits

In the T2D trial, there were also dose-response reductions in HbA1c: retatrutide 12 mg reduced HbA1c by 2.16% at 36 weeks, corresponding to an estimated difference from dulaglutide 1.5 mg of -0.80% (95% CI: -1.16, -0.44); and estimated difference from placebo of -1.85% (-2.39, -1.31) [46]. Moreover, a greater proportion of participants on retatrutide 8 and 12 mg (77–82%) achieved an HbA1c ≤ 6.5% compared to placebo (5%) and dulaglutide 1.5 mg (43%). The average HbA1c reduction may have been attenuated by ‘floor effect’, as a high proportion of participants approached near-normal glycaemic levels.

Both trials also showed dose-dependent and marked improvements in waist circumference, lipids and blood pressure (Table 1). Furthermore, a substudy of the obesity trial investigated the mean relative change from baseline in liver fat at 24 and 48 weeks in 98 participants with MASLD at baseline. There was a dose-response reduction in liver fat from baseline at 24 weeks with increasing retatrutide doses: -82.4% with 12 mg retatrutide vs. + 0.3% with placebo [47]. At 24 weeks, healthy liver fat levels (< 5%) were achieved by 86% of participants on retatrutide 12 mg and 0% in the placebo group.

A post-hoc analysis of the phase 2 trials also evaluated retatrutide’s impact on kidney function in individuals with T2D or obesity, most of whom had normal kidney function (6–33% had albuminuria; 0–9% had eGFR < 60 mL/min/1.73 m² across trials and arms) [48]. In participants with T2D, retatrutide 12 mg reduced urine albumin-creatinine ratio (UACR) by 37%, however eGFR was unchanged. In those with obesity, retatrutide 12 mg reduced UACR by 31.5% and increased eGFR by 8.5 mL/min/1.73 m². While the clinical relevance of these findings in a population largely free from kidney disease remains uncertain, the reductions in albuminuria, blood pressure, and the favourable safety profile support further investigation of retatrutide’s potential kidney-protective effects in high-risk populations. Indeed, a phase 2 mechanistic trial (NCT05936151) investigating change in eGFR from baseline to week 24 with multiple doses of retatrutide vs. placebo in 120 people with overweight/obesity and chronic kidney disease (CKD) is ongoing.

Adverse Events

In both phase 2 trials, there were no major safety signals with retatrutide use [45, 46]. Side effects were mainly mild-to moderate gastro-intestinal symptoms (nausea, vomiting, diarrhoea) mostly occurring with higher doses of retatrutide and with faster titration (Table 2).

Table 2 Key safety outcomes from the phase 2 studies of retatrutide in individuals with obesity and with type 2 diabetes

In the obesity trial, serious adverse events (SAEs) occurred in 4% of participants with retatrutide use overall (0–6% across groups) vs. 4% with placebo. Moreover, adverse events leading to medication discontinuation were reported by 10% in the overall retatrutide groups (6–16% across groups vs. 0% with placebo).

The T2D trial showed a similar safety profile, with SAEs occurring in 4–8% of participants at the retatrutide groups vs. 7% with placebo and 2% with dulaglutide. Rates of treatment discontinuation varied across dosing regimens from 0 to 17% (vs. 4% with placebo and 2% with dulaglutide).

Ongoing Phase 3 Trials

Several phase 3 trials are underway investigating the efficacy of retatrutide in larger populations (Fig. 2). The TRIUMPH programme will investigate retatrutide in people with obesity and the TRANSCEND-T2D programme is investigating retatrutide in people with T2D and overweight/obesity.

Fig. 2

The pipeline of phase 2 and phase 3 trials investigating the efficacy and safety of retatrutide. T2D: Type 2 diabetes; SGLT-2: Sodium-glucose co-transporter-2; OA: Osteoarthritis; OSA: Obstructive sleep apnoea; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; AHI: Apnoea-Hypopnea Index; MTD: Maximum tolerated dose; ESKD: End-stage kidney disease; eGFR: estimated glomerular filtration rate; CV: Cardiovascular; CVD: Cardiovascular disease; ASCVD: Atherosclerotic cardiovascular disease; BMI: Body mass index; MI: Myocardial infarction; CKD: Chronic kidney disease.

TRIUMPH-1 (NCT05929066) will look at the efficacy and safety of retatrutide in people with overweight/obesity without T2D and will include subsets of participants with knee osteoarthritis (OA) or OSA. The primary endpoint will be bodyweight change (week 80 and 104), change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in the OA subset, and change in Apnoea-Hypopnea Index (AHI) in the OSA subset.

TRIUMPH-2 (NCT05929079) will assess bodyweight change in people with overweight/obesity and T2D and include a subset of participants with OSA, in which AHI will also be investigated as a primary endpoint. TRIUMPH-3 (NCT05882045) will investigate change in bodyweight in people with overweight/obesity and cardiovascular disease, and TRIUMPH-4 (NCT05931367) will assess change in WOMAC score and bodyweight in individuals with overweight/obesity and knee OA.

TRIUMPH-5 (NCT06662383) will compare the efficacy of retatrutide to tirzepatide on bodyweight over 80 weeks in individuals with obesity. Given that obesity is a chronic and relapsing disease, it is important to understand the effectiveness of different strategies to maintain WL: TRIUMPH-6 (NCT06859268) will assess changes in bodyweight at 116 weeks in individuals with obesity who have completed 80 weeks of retatrutide, comparing continued treatment at high or low doses of retatrutide versus switching to placebo for the last 36 weeks. TRIUMPH-OUTCOMES (NCT06383390) will investigate the impact of retatrutide vs. placebo on the time to occurrence of a composite cardiovascular outcome (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death, hospitalization or urgent visit due to heart failure) and a composite renal outcome (end-stage kidney disease, ≥ 40% sustained decline in eGFR, cardiovascular death or renal death) in 10,000 individuals with atherosclerotic cardiovascular disease and/or CKD.

A series of trials in populations with T2D will also be undertaken. TRANSCEND-T2D-1 (NCT06354660) will compare the efficacy and safety of retatrutide compared to placebo in people with inadequately controlled T2D treated with diet and exercise over a period of 11 months. The primary endpoint will be HbA1c change. Investigating the same primary endpoint, TRANSCEND-T2D-2 (NCT06260722) will compare retatrutide to semaglutide in people with inadequately controlled T2D (treated with oral glucose-lowering treatments) over 26 months. Finally, TRANSCEND-T2D-3 (NCT06297603) will compare retatrutide to placebo over 14 months, in people with inadequately controlled T2D and moderate-or-severe renal impairment on basal insulin.

The Potential of Retatrutide

Retatrutide leads to 24.2% mean WL at the highest dose after 48 weeks in people with obesity, with no evidence of plateau and up to 26% of participants achieving ≥ 30% WL - approaching the efficacy Roux-en-y gastric bypass, one of the most effective BS procedures. In the T2D phase 2 trial ≈ 17% WL was observed after just 36 weeks of treatment with the highest dose, also without evidence of plateau.

Although no data from head-to-head trials comparing retatrutide to other currently approved obesity treatments exist, data from the phase 2 studies with retatrutide suggest that at higher doses, retatrutide could lead to greater WL compared to the most efficacious approved treatments for obesity and T2D such as tirzepatide 15 mg and semaglutide 2.4 mg (Fig. 3) [8, 27, 45, 46, 49, 50]. Notably, nearly 50% of the retatrutide phase 2 obesity trial were men, which is higher than in phase 3 clinical trials with tirzepatide (32.5% in SURMOUNT-1 [27]) and semaglutide 2.4 mg (25.9% in STEP-1 [8]). Given these differences in cohort characteristics, and that women appeared to experience greater WL than men with retatrutide, it may suggest that the mean WL might have been even higher with a higher proportion of women in phase 2 retatrutide trials. Moreover, the magnitude of WL with retatrutide also exceeded that seen with other pipeline multi-agonists such as CagriSema (cagrilintide, an amylin agonist, in combination with semaglutide), mazdutide and survodutide (Fig. 4) [8, 27, 35, 36, 45, 46, 49,50,51,52,53]. The TRIUMPH-5 study will provide data for a direct comparison between tirzepatide and retatrutide for WL.

Fig. 3

Weight loss with retatrutide as compared to currently licenced obesity pharmacotherapy. Data from: [8, 27, 45, 49, 46, 50]

Fig. 4

Weight loss with retatrutide as compared to licenced obesity pharmacotherapies and upcoming dual agonists in phase 3 trials in people with obesity and with type 2 diabetes. GIP: Glucose-dependent insulinotropic polypeptide; GLP-1: Glucagon-like peptide 1; GCG: Glucagon; RA: Receptor agonist; qw: once weekly dosing; biw: twice weekly dosing. Data from: [45, 50, 27, 8, 46, 49, 51, 35, 52, 36, 53]

Retatrutide also shows great potential for treating T2D– in the phase 2 trial, it showed superior efficacy to dulaglutide 1.5 mg, a widely used GLP-1 RA with proven cardiovascular benefits, in reducing HbA1c and bodyweight. After just 36 weeks, 77–82% of participants on retatrutide achieved euglycaemia (HbA1c ≤ 6.5%) and 57–63% achieved ≥ 15% WL. Notably, the SOS study showed that in people with T2D, achieving and maintaining ≥ 15% WL over 15 years was associated with reductions in both micro- and macrovascular complications following BS [54]. Reassuringly, only a very small percentage of people with T2D experienced hypoglycaemia in the phase 2 trial which included people on lifestyle interventions or metformin; however, the TRANSCEND-T2D-3 study which includes people with T2D and CKD on basal insulin, will provide further insight into hypoglycaemia risk in high-risk populations.

More broadly, WL through any means has the potential to reduce the severity of obesity-associated complications [55]. Indeed, phase 3 trials are evaluating retatrutide in populations with T2D, OSA, knee OA, CKD and cardiovascular disease who may particularly benefit. Similarly, the substudy of the obesity phase 2 trial showed clear promise for retatrutide in the treatment of MASLD [47], and through its GCG receptor agonism, retatrutide may offer benefits beyond WL, through weight-independent metabolic effects at the liver [40]. These benefits may extend to individuals with MASH, however there are currently no retatrutide trials planned in populations with MASLD/MASH.

Additionally, retatrutide markedly improved lipid profiles in people with T2D or obesity, reducing total cholesterol (~ 15–18%), LDL (~ 12–22%), and triglycerides (~ 35–40%)—surpassing dulaglutide 1.5 mg. Beyond WL, these effects may be partly driven by its triple agonism, particularly glucagon receptor activation, which enhances lipid oxidation and reduces hepatic lipid synthesis [56].

Safety Considerations and Future Outlook

As with all pharmacotherapy for obesity and T2D, establishing cardiovascular safety and demonstrating improvements in meaningful clinical outcomes will be essential, particularly as cardiovascular outcome trials have not yet been completed with multi-agonists (although data are expected soon for tirzepatide: SURPASS-CVOT [T2D] in 2025; SURMOUNT-MMO [without T2D] in 2027). Until such evidence is available for retatrutide, therapies with established cardiovascular and renal benefits—such as semaglutide, supported by SUSTAIN-6 [5] and FLOW [57] trials in people with T2D, and the SELECT trial [58] in people with obesity - should be prioritised in populations with existing cardio-renal disease. The ongoing TRIUMPH OUTCOMES trial will be key in determining the long-term cardio-renal effects of retatrutide in these populations.

Another consideration for GLP-1/GIP/GCG agonists is their potential negative impact on lean mass [32]. GCG can suppress circulating amino-acids [59] and increase protein catabolism, mechanisms thought to contribute to elevated energy expenditure and WL [32, 33, 60]. An extreme example of the effects of GCG on lean mass is in individuals with glucagonoma, which is characterised by very high levels of circulating GCG, low levels of amino-acids, and sarcopenia [61, 62]. Preclinical evidence suggests that increasing protein intake may offset circulating amino-acids reduction, however this may also blunt the increase in whole-body energy expenditure [63]. In the phase 2 trial of retatrutide in individuals with T2D and overweight/obesity, retatrutide caused large reductions in circulating amino-acids, although lean mass and physical function were not directly assessed [46]. However, reassuringly, in the obesity phase 2 trial, self-reported physical function improved with all doses of retatrutide [45]. Additionally, the phase 2 MOMENTUM clinical trial of pemvidutide (a dual GLP-1/GCG agonist) showed that only 21.9% of WL was attributable to reductions in lean mass at 48 weeks (overall WL 10.3–15.6% across doses) [64]. Nonetheless, further data are needed to assess the safety of retatrutide on muscle mass, particularly in populations at risk for sarcopenia, where caution is warranted.

Other GLP-1/GIP/GCG Triple Agonists in Development

Besides retatrutide, several GLP-1/GIP/GCG triple agonists are in early-stage clinical trials (Table 3), though the WL efficacy associated with these medications remains unknown. All medications within these trials are once weekly subcutaneously-administered injections. These agents are likely to vary widely in their affinity and potency at each hormone receptor.

Table 3 Planned or ongoing phase 2 trials involving GLP1/GIP/GCG triple agonists for obesity and/or type 2 diabetes

However, not all triple GLP-1/GIP/GCG agonists are advancing to late-stage clinical trials. For instance, SAR441255—designed with balanced activity across all three receptors—showed some promising early efficacy for glycaemic control in a phase 1 single-dose study and was generally well tolerated [65], however, no further trials have been reported since 2019.

Other Combinations of Triple Agonism in Development

GLP1/GIP/GCG is the only combination of hormone receptor agonism under investigation as a unimolecular triple agonist in phase 2 or 3 trials for obesity. However, DR-10,624, a GLP-1/GCG/fibroblast growth factor 21 (FGF-21) triple agonist is under investigation for individuals with severe hypertriglyceridemia (not limited to individuals with obesity; NCT06555640). Indeed, there may be synergy between FGF-21 and GCG receptor agonism, due to their similar metabolic actions, particularly related to brown adipose tissue differentiation and activation [32], with FGF21 having additional actions in the liver, reducing hepatic lipogenesis and enhancing hepatic insulin sensitivity [66,