Retatrutide‐Associated Improvements in Cardiovascular Risk Biomarkers in Adults With Obesity With or Without Type 2 Diabetes

ABSTRACT

Aims

To further characterise the effects of retatrutide on cardiometabolic risk, lipoprotein and inflammatory biomarkers were assessed post hoc in phase 2 trials of adults with obesity/overweight with or without type 2 diabetes (T2D).

Materials and Methods

Data were analysed from two randomised, double‐blind, placebo‐controlled phase 2 trials. In Study 1, adults with obesity/overweight and T2D received once‐weekly retatrutide (0.5/4/8/12 mg), dulaglutide (1.5 mg) or placebo for 36 weeks; in Study 2, adults with clinical obesity without T2D received retatrutide (1/4/8/12 mg) or placebo for 48 weeks. Fasting blood samples were collected at baseline and during treatment to assess lipids, apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers. Mixed models for repeated measures estimated placebo‐adjusted change from baseline. Statistical significance was defined as a false discovery rate‐adjusted p < 0.05.

Results

Mean body mass index was 35.4 kg/m² (Study 1) and 37.4 kg/m² (Study 2). In both studies, retatrutide was associated with significant reductions in non‐high‐density lipoprotein cholesterol (Study 1: up to −21.0%, Study 2: up to −26.9%), apolipoprotein B (−21.4%, −24.2%), total triglyceride‐rich lipoprotein particles (−22.5%, −33.7%), large triglyceride‐rich lipoprotein particles (−84.4%, −76.6%), triglyceride‐rich lipoprotein cholesterol (−29.4%, −38.6%), total low‐density lipoprotein particles (−19.7%, −23.5%) and small low‐density lipoprotein particles (−32.6%, −32.3%). Retatrutide was associated with significant reductions in high‐sensitivity C‐reactive protein (−54.8%) and interleukin‐6 (−29.6%) in Study 2 but not Study 1.

Conclusions

In adults with obesity/overweight, with or without T2D, retatrutide treatment was associated with reductions in atherogenic lipoproteins and inflammatory biomarkers linked to cardiovascular disease risk.

Trial Registration: ClinicalTrials.gov numbers NCT04881760 and NCT04867785

1. Introduction

Obesity is associated with atherogenic dyslipidaemia and systemic inflammation, key drivers of cardiovascular risk [1, 2]. Several incretin‐based medications approved for the treatment of obesity and/or type 2 diabetes (T2D) have advanced the management of cardiometabolic disease [3, 4]. These drugs include glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, which have been shown to reduce levels of cardiovascular and inflammatory risk biomarkers in patients with obesity [5, 6]. The dual glucose‐dependent insulinotropic polypeptide receptor (GIPR) and GLP‐1R agonist tirzepatide has also been shown to improve the atherogenic lipoprotein and inflammatory profiles in patients with obesity or overweight, with or without T2D, with a larger effect than that of GLP‐1R agonists [7, 8, 9]. In the SURPASS‐CVOT trial, tirzepatide was non‐inferior to the GLP‐1R agonist dulaglutide with respect to major adverse cardiovascular events (three‐point MACE) in patients with T2D and established cardiovascular disease [10]. Tirzepatide was also associated with a numerically lower MACE incidence and a significant reduction in all‐cause mortality versus dulaglutide [10]. In addition, treatment with some dual GLP‐1R and glucagon receptor (GCGR) agonists has been shown to lower weight and improve glycaemic regulation in adults with obesity or overweight [11, 12]. However, the effects of dual GLP‐1R/GCGR agonism on cardiometabolic health remain poorly understood in people with obesity with or without T2D.

Retatrutide (LY3437943) is a synthetic molecule that agonises GIPR, GLP‐1R and GCGR. The additional pharmacological effect of GCGR agonism is proposed to lead to further benefits on lipid and lipoprotein metabolism because glucagon acts primarily in the liver to increase hepatic fatty acid oxidation and inhibit fatty acid synthesis, thereby reducing hepatic lipid accumulation [13]. Retatrutide treatment was associated with marked reduction of liver fat in a phase 2 trial in people with obesity and metabolic dysfunction‐associated steatotic liver disease (MASLD) [14]. Moreover, in a phase 2 trial in adults with obesity or overweight without T2D, retatrutide treatment reduced body weight by up to 24%, compared to 2% with placebo. Similarly, in a phase 2 trial in adults with obesity or overweight with T2D, retatrutide treatment reduced body weight by up to 17% versus 3% for placebo or 2% for dulaglutide. In these phase 2 trials, retatrutide treatment was associated with improvements in glycated haemoglobin (HbA1c), glucose, blood pressure and atherogenic lipids, including triglycerides, total cholesterol and low‐density lipoprotein cholesterol (LDL‐C) [15, 16]. However, the effects of retatrutide treatment on other lipid and inflammatory biomarkers associated with increased risk of cardiovascular disease have not been reported. In this post hoc analysis of these phase 2 trials, we report the association of retatrutide treatment with changes in levels of apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers in adults with obesity or overweight with or without T2D.

2. Material and Methods

2.1. Study Design and Participants

The study designs, methods and primary results have been reported for the phase 2 trial in adults with obesity/overweight without T2D (NCT04881760) and the phase 2 trial in adults with T2D and obesity/overweight (NCT04867785) [15, 16]. Briefly, both trials were double‐blind, randomised, placebo‐controlled trials that included participants with obesity. In the trial in adults with obesity/overweight and T2D (Study 1), participants were randomly assigned to receive once‐weekly subcutaneous injections of retatrutide at maintenance doses of 0.5, 4, 8 or 12 mg, placebo, or dulaglutide at a dose of 1.5 mg for 36 weeks. Eligible participants were adults aged 18–75 years with T2D with a body mass index (BMI) of 25–50 kg/m². In the trial in adults with obesity/overweight without T2D (Study 2), participants were randomly assigned to receive once‐ weekly subcutaneous injections of retatrutide at maintenance doses of 1, 4, 8 or 12 mg or placebo for 48 weeks. Eligible participants were adults aged 18–75 years with obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 and < 30 kg/m²) with at least one weight‐related comorbidity, but without T2D.

In both trials, the 4 and 8 mg maintenance dose arms were subdivided into dose escalation groups with initial doses of 2 mg or 4 mg. Data from the two 4 mg dose cohorts were pooled, as were the two 8 mg dose cohorts, in this post hoc analysis. Both trials were approved by local ethics committees and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All participants provided written informed consent before entering the trials.

2.2. Study Procedures

Fasting blood samples for the exploratory measures reported herein were collected at baseline, week 24 and either week 36 (Study 1) or week 48 (Study 2). Samples collected after treatment discontinuation or use of rescue medication for persistent severe hyperglycaemia were excluded from the analysis. Lipid and apolipoprotein concentrations were measured to evaluate lipoprotein metabolism. Total cholesterol, triglycerides and high‐density lipoprotein cholesterol (HDL‐C) were measured using standard enzymatic methods. LDL‐C was estimated using the Friedewald formula, and non‐HDL‐C was calculated as total cholesterol minus HDL‐C. Apolipoprotein B (ApoB) and apolipoprotein C‐III (ApoC‐III) were quantified using immunoturbidimetric assays. Other apolipoproteins (ApoA‐I, ApoA‐II, ApoA‐IV, ApoC‐I, ApoC‐II and ApoE) were quantified using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay [17]. Lipoprotein particle concentration and mean lipoprotein particle size were measured by nuclear magnetic resonance (NMR) spectroscopy (LabCorp, Burlington, USA), including triglyceride‐rich lipoprotein particles (TRLP), high‐density lipoprotein particles (HDLP) and low‐density lipoprotein particles (LDLP). Triglyceride‐rich lipoprotein cholesterol (TRL‐C)—the cholesterol content of triglyceride‐rich (remnant) lipoproteins, frequently termed remnant cholesterol—was also estimated by NMR spectroscopy [18]. Additionally, C‐reactive protein (CRP) and interleukin‐6 (IL‐6) were analysed by immunoassay to characterise systemic inflammation [8, 9].

2.3. Statistical Analysis

Data were statistically analysed in the modified intent‐to‐treat population, defined as participants with biomarker data available at baseline and at least one post‐baseline visit prior to treatment or study discontinuation. All analyses were conducted post hoc and were not pre‐specified in the original study protocol. Percent changes from baseline were assessed using a mixed model for repeated measures (MMRM) that included treatment, time and treatment‐by‐time as fixed effects, with log‐transformed baseline biomarker level as a covariate. Data are presented as least squares (LS) means with standard errors (SEs) and 95% confidence intervals (CIs). Multiple comparisons were corrected for false discovery rate (FDR) using the Benjamini–Hochberg procedure [19], with corrections applied separately to the analyses of protein and lipid biomarkers. In these exploratory analyses, differences with FDR‐adjusted p‐values < 0.05 were considered statistically significant.

3. Results

3.1. Baseline Characteristics of the Analysis Populations

Baseline demographics, clinical characteristics and lipid profiles were comparable across treatment groups within each study (Tables S1 and S2). However, as expected, the population with T2D was characterised by greater use of statins and higher mean triglyceride and CRP levels at baseline than the population without T2D.

3.2. Lipid Biomarker Profile in Adults With T2D and Obesity/Overweight (Study 1)

Reductions in non‐HDL‐C, ApoB, TRL‐C and ApoC‐III levels were observed with retatrutide compared with placebo and dulaglutide at 36 weeks from baseline (Figure 1). Retatrutide 8 mg and 12 mg were associated with changes in non‐HDL‐C levels of −21.0% (95% CI: −27.3%, −14.1%) and −20.5% (−27.8%, −12.4%), respectively, which were greater than the corresponding changes with placebo (−1.3% [−10.5%, 8.8%]; p < 0.01 vs. both doses) and dulaglutide (−2.4% [−10.3%, 6.3%]; p < 0.01 vs. both doses; Figure 1a). Retatrutide 8 mg and 12 mg were associated with changes in ApoB levels of −21.4% (−28.0%, −14.2%) and −17.7% (−25.5%, −9.0%), respectively, also greater than the corresponding changes with placebo (0.2% [−9.5%, 10.9%]; p < 0.01 vs. 8 mg and p < 0.05 vs. 12 mg) and dulaglutide (2.1% [−6.4%, 11.4%]; p < 0.001 vs. 8 mg and p < 0.01 vs. 12 mg; Figure 1c). Reductions in TRL‐C levels were greater with retatrutide 8 mg (−29.4% [−38.3%, −19.3%]) and 12 mg (−26.7% [−37.3%, −14.3%]) vs. placebo (−2.7% [−16.1%, 12.9%]; p < 0.01 vs. 8 mg and p < 0.05 vs. 12 mg) and dulaglutide (−2.3% [−14.6%, 11.8%]; p < 0.01 vs. 8 mg and p < 0.05 vs. 12 mg; Figure 1e). Changes in ApoC‐III associated with retatrutide treatment were −31.8% (−37.9%, −25.0%) with 8 mg and −33.2% (−40.2%, −25.4%) with 12 mg and were greater than the changes with placebo (−1.0% [−11.4%, 10.6%]; p < 0.001 vs. both doses) and dulaglutide (−8.6% [−17.3%, 1.1%]; p < 0.001 vs. both doses; Figure 1g). Retatrutide was associated with reductions in the levels of other apolipoproteins predominantly carried by TRLPs (ApoC‐I and ApoC‐II) and HDLPs (ApoA‐I, ApoA‐II and ApoA‐IV) vs. placebo (Figure S1).

FIGURE 1.

Percent change from baseline over time in lipid and apolipoprotein biomarkers. Data are from two phase 2 trials of once‐weekly retatrutide in adults with obesity/overweight and T2D (Study 1) and adults with obesity/overweight without T2D (Study 2). Fasting samples were collected at baseline, week 24 and end of treatment (week 36 in Study 1; week 48 in Study 2). Panels show non‐HDL‐C (a, b), ApoB (c, d), TRL‐C (e, f) and ApoC‐III (g, h). Data are LS mean (SE) percent change from baseline from the mITT population (see supplement for samples sizes for each biomarker). FDR‐adjusted p values: *p < 0.05, **p < 0.01, ***p < 0.001 vs. PBO; ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 vs. baseline; ^† p < 0.05, ^†† p < 0.01, ^††† p < 0.001 vs. DULA 1.5 mg. Apo, apolipoprotein; DULA, dulaglutide; FDR, false discovery rate; HDL‐C, high‐density lipoprotein cholesterol; LS, least squares; mITT, modified intent‐to‐treat; non‐HDL‐C, non‐high‐density lipoprotein cholesterol; PBO, placebo; RETA, retatrutide; SE, standard error; TRL‐C, triglyceride‐rich lipoprotein cholesterol.

3.3. Lipid Biomarkers in Adults With Obesity/Overweight Without T2D (Study 2)

Reductions in non‐HDL‐C, ApoB, TRL‐C and ApoC‐III levels were observed with retatrutide relative to placebo at 48 weeks from baseline (Figure 1). Reductions in non‐HDL‐C were dose dependent, with all but the lowest dose being significantly different than placebo: −15.3% (−19.8%, −10.7%) with 4 mg, −22.0% (−25.9%, −17.8%) with 8 mg, and −26.9% (−31.0%, −22.6%) with 12 mg (placebo: −0.4% [−5.8%, 5.4%]; p < 0.001 vs. all doses; Figure 1b). Retatrutide was associated with reductions in ApoB levels of −20.2% (−24.8%, −15.3%) with 8 mg and −24.2% (−29.1%, −18.9%) with 12 mg (placebo: −6.8% [−12.6%, −0.5%]; p < 0.01 vs. 8 mg and p < 0.001 vs. 12 mg; Figure 1d). Retatrutide was associated with greater reductions in TRL‐C levels than placebo: −27.5% (−36.1%, −17.8%) with 4 mg, −36.5% (−43.8%, −28.3%) with 8 mg and −38.6% (−46.3%, −29.7%) with 12 mg (placebo: −5.8% [−17.4%, 7.3%]; p < 0.05 vs. 4 mg and p < 0.001 vs. 8 and 12 mg; Figure 1f). Reductions in ApoC‐III were statistically significant for retatrutide doses of 4 mg (−24.0% [−30.8%, −16.5%]), 8 mg (−37.1% [−42.6%, −31.1%]) and 12 mg (−38.0% [−43.9%, −31.4%]) vs. placebo (−8.8% [−17.2%, 0.4%]; p < 0.05 vs. 4 mg and p < 0.001 vs. 8 and 12 mg; Figure 1h). Retatrutide was also associated with significant reductions in the levels of other apolipoproteins predominantly carried by TRLPs (ApoE and ApoC‐II) and HDLPs (ApoA‐II) vs. placebo (Figure S1).

3.4. Lipoprotein Particles in Adults With T2D and Obesity/Overweight (Study 1)

Retatrutide treatment was associated with improved lipoprotein particle composition and size at week 36 (Figure 2). Retatrutide 8 and 12 mg were associated with changes from baseline in large TRLP of −84.4% (−90.0%, −75.7%) and −61.9% (−77.1%, −36.4%), respectively, greater than the changes with placebo (−13.6% [−46.8%, 40.4%]; p < 0.001 vs. 8 mg and p < 0.05 vs. 12 mg) and dulaglutide (−12.7% [−43.9%, 35.9%]; p < 0.001 vs. 8 mg and p < 0.05 vs. 12 mg; Figure 2a). A greater reduction in the total TRLP concentration of was also observed with retatrutide 8 mg (−22.5% [−32.7%, −10.8%]) vs. dulaglutide (−1.9% [−14.7%, 12.9%]; p < 0.05; Figure 2a). Additionally, retatrutide 8 mg was associated with a change in TRLP size of −16.0% (−20.1%, −11.7%), greater than the changes with placebo (−6.4% [−11.4%, −1.2%]; p < 0.01) and dulaglutide (−4.4% [−9.0%, 0.5%]; p < 0.01; Figure 2b).

FIGURE 2.

Percent change from baseline at week 36 in lipoprotein particle subclasses (Study 1). Study 1 was a phase 2 trial in adults with obesity/overweight and T2D receiving once‐ weekly retatrutide, placebo or dulaglutide 1.5 mg for 36 weeks. Fasting lipoprotein particle measurements were obtained at baseline, week 24 and week 36. Panels show TRLP concentrations (a), TRLP size (b), LDLP concentrations (c), LDLP size (d), HDLP concentrations (e) and HDLP size (f). Large TRLP includes ‘large’ and ‘very large’ particles. Small TRLP includes ‘small’ and ‘very small’ particles. Medium LDLP data are not presented due to > 20% missing data. Data are LS mean (SE) percent change from baseline at week 36 from the mITT population (see the Supplement for sample sizes for each biomarker). FDR‐adjusted p values: *p < 0.05, **p < 0.01, ***p < 0.001 vs. PBO; ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 vs. baseline; ^† p < 0.05, ^†† p < 0.01, ^††† p < 0.001 vs. DULA 1.5 mg. DULA, dulaglutide; FDR, false discovery rate; HDLP, high‐density lipoprotein particles; LDLP, low‐density lipoprotein particles; LS, least squares; mITT, modified intent‐to‐treat; PBO, placebo; RETA, retatrutide; SE, standard error of the mean; TRLP, triglyceride‐rich lipoprotein particles.

Retatrutide 8 mg was associated with a change from baseline in the concentration of small LDLP of −32.6% (−40.9%, −23.1%), greater than the changes with placebo (−2.3% [−15.5%, 12.9%]; p < 0.001) and dulaglutide (−12.0% [−22.8%, 0.4%]; p < 0.05; Figure 2c). Changes in the total LDLP concentration with retatrutide 8 and 12 mg were −19.7% (−26.3%, −12.5%) and −15.9% (−23.9%, −7.2%), respectively, also greater than the changes with placebo (1.0% [−8.1%, 11.0%]; p < 0.01 vs. 8 mg and p < 0.05 vs. 12 mg) and dulaglutide (−4.4% [−12.3%, 4.1%]; p < 0.05 vs. 8 mg; Figure 2c). Retatrutide 8 mg was associated with an increase in average LDLP size of 1.6% (0.9%, 2.3%), significantly greater than the increases observed with placebo (0.3% [−0.5%, 1.0%]; p < 0.05) and dulaglutide (0.5% [−0.2%, 1.2%]; p < 0.05; Figure 2d).

The total HDLP concentration changed by −13.1% (−16.7%, −9.3%) and −8.9% (−13.3%, −4.4%) with retatrutide 8 and 12 mg, respectively, which was more than the concentration changed with placebo (−1.4% [−5.9%, 3.4%]; p < 0.001 vs. 8 mg and p < 0.05 vs. 12 mg) and dulaglutide (−2.6% [−6.6%, 1.6%]; p < 0.001 vs. 8 mg; Figure 2e). Retatrutide 8 mg was associated with an increase from baseline in HDLP size of 2.1% (1.2%, 2.9%), greater than the increase with dulaglutide (0.6% [−0.2%, 1.5%]; p < 0.05; Figure 2f).

3.5. Lipoprotein Particles in Adults With Obesity/Overweight Without T2D (Study 2)

Retatrutide treatment was associated with improvements in lipoprotein particle composition and size at week 48 (Figure 3). The large TRLP concentration decreased from baseline by −74.8% (−83.4%, −61.8%) and −76.6% (−85.2%, −63.1%) with retatrutide 8 and 12 mg, respectively, significantly more than it decreased with placebo (−33.5% [−57.5%, 4.1%]; p < 0.01 vs. both doses; Figure 3a). Reductions of both medium and small TRLP were significantly higher with retatrutide 8 and 12 mg vs. placebo. The total TRLP concentration decreased by −24.5% (−33.6%, −14.2%), −33.6% (−41.3%, −24.8%) and −33.7% (−42.2%, −23.9%) with retatrutide 4, 8 and 12 mg, respectively, significantly more than it decreased with placebo (−4.9% [−16.8%, 8.6%]; p < 0.05 vs. 4 mg and p < 0.001 vs. 8 and 12 mg; Figure 3a). Retatrutide was associated with reductions in TRLP size of −10.9% with 4 mg (−14.3%, −7.4%), −12.8% with 8 mg (−15.9%, −9.5%) and −9.4% with 12 mg (−13.1%, −5.6%), also more than with placebo (−0.4% [−4.3%, 3.6%]; p < 0.01 vs. 4 mg and 12 mg and p < 0.001 vs. 8 mg; Figure 3b).

FIGURE 3.

Percent change from baseline at week 48 in lipoprotein particle subclasses (Study 2). Study 2 was a phase 2 trial in adults with obesity/overweight without T2D receiving once‐weekly retatrutide or placebo for 48 weeks. Fasting lipoprotein particle measurements were obtained at baseline, week 24 and week 48. Panels show TRLP concentrations (a), TRLP size (b), LDLP concentrations (c), LDLP size (d), HDLP concentrations (e) and HDLP size (f). Large TRLP includes ‘large’ and ‘very large’ particles. Small TRLP includes ‘small’ and ‘very small’ particles. Medium LDLP data are not presented due to > 20% missing data. Data are LS mean (SE) percent change from baseline at week 48 from the mITT population (see the Supplement for sample sizes for each biomarker). FDR‐adjusted p values: *p < 0.05, **p < 0.01, ***p < 0.001 vs. PBO; ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 vs. baseline. FDR, false discovery rate; HDLP, high‐density lipoprotein particles; LDLP, low‐density lipoprotein particles; LS, least squares; mITT, modified intent‐to‐treat; PBO, placebo; RETA, retatrutide; SE, standard error of the mean; TRLP, triglyceride‐rich lipoprotein particles.

For LDLP, retatrutide 12 mg was associated with a decrease in the concentration of small LDLP of −32.3% (−40.8%, −22.5%), greater than the decrease with placebo (−14.6% [−25.0%, −2.7%]; p < 0.05; Figure 3c). Retatrutide 8 mg and 12 mg were associated with reductions in total LDLP of −20.9% (−26.2%, −15.1%) and −23.5% (−29.3%, −17.3%), respectively, also greater than the decrease with placebo (−4.9% [−11.8%, 2.5%]; p < 0.01 vs. 8 mg and p < 0.001 vs. 12 mg; Figure 3c). Retatrutide 4 and 8 mg were associated with increases in the average LDLP size of 1.1% (0.6%, 1.7%) and 1.0% (0.5%, 1.5%), respectively (placebo: 0.1% [−0.4%, 0.7%]; p < 0.05 vs. both doses; Figure 3d).

The concentration of small HDLP decreased with retatrutide 8 mg by −13.4% (−19.1%, −7.2%) vs. −3.3% with placebo (−10.1%, 4.1%; p < 0.05; Figure 3e). Retatrutide 8 mg and 12 mg were associated with increases in the average HDLP size of 2.7% (1.8%, 3.6%) and 2.1% (1.1%, 3.0%), respectively, signficantly greater than the increase with placebo (0.6% [−0.3%, 1.5%]; p < 0.01 vs. 8 mg and p < 0.05 vs. 12 mg; Figure 3f).

3.6. Inflammatory Biomarkers in Adults With T2D and Obesity/Overweight (Study 1)

Retatrutide treatment was associated with decreases from baseline at week 36 in CRP and IL‐6 in adults with T2D; however, these changes were not statistically significant compared with placebo or dulaglutide (Figure 4a,c,e,g).

FIGURE 4.

Percent change from baseline over time and at end of treatment in inflammatory biomarkers. Data are from two phase 2 trials of once‐weekly retatrutide in adults with obesity/overweight and T2D (Study 1) and adults with obesity/overweight without T2D (Study 2). Fasting samples were collected at baseline, week 24 and end of treatment (week 36 in Study 1; week 48 in Study 2). Panels show percent changes at end of treatment for CRP (a, b) and IL‐6 (e, f) and over time for CRP (c, d) and IL‐6 (g, h). Data are LS mean (SE) percent change from baseline from the mITT population (see the Supplement for sample sizes for each biomarker). FDR‐adjusted p values: **p < 0.01, ***p < 0.001 vs. PBO; ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 vs. baseline; ^† p < 0.05, ^†† p < 0.01, ^††† p < 0.001 vs. DULA 1.5 mg. CRP, C‐reactive protein; DULA, dulaglutide; FDR, false discovery rate; IL‐6, interleukin‐6; LS, least squares; mITT, modified intent‐to‐treat; PBO, placebo; RETA, retatrutide; SE, standard error of the mean; T2D, type 2 diabetes.

3.7. Inflammatory Biomarkers in Adults With Obesity/Overweight Without T2D (Study 2)

In adults with obesity or overweight without T2D, dose‐dependent reductions from baseline in inflammatory biomarkers were observed with retatrutide at week 48 (Figure 4). Reductions in CRP were significantly greater for most retatrutide doses vs. placebo, with the greatest changes observed with the 8 mg (−54.8% [−62.6%, −45.4%]) and 12 mg (−53.2% [−62.1, −42.1]) doses (placebo: −7.9% [−24.8%, 12.8%]; p < 0.001 for both doses; Figure 4b,d). Additionally, changes from baseline in IL‐6 levels were significantly higher with retatrutide 8 mg (−29.6% [−39.0%, −18.7%]) vs. placebo (−2.1% [−16.2%, 14.4%]; p < 0.01; Figure 4f,h).

4. Discussion

In this post hoc analysis of two phase 2 trials, retatrutide treatment was associated with dose‐dependent improvements in cardiovascular risk biomarkers in people with obesity or overweight, with or without T2D. Across both populations, reductions in all tested atherogenic lipoproteins were observed, including lower levels of serum non‐HDL‐C (up to 27%), ApoB (up to 24%), TRL‐C (i.e., remnant cholesterol, up to 39%) and ApoC‐III (up to 38%). Large TRLP decreased by up to 84% and small LDLP by up to 33%. Taken together, these findings suggest that retatrutide treatment may reduce overall cardiovascular risk in people with obesity or overweight, with or without T2D. These findings build on previous reports that retatrutide reduces body weight, liver fat, blood pressure, HbA1c, fasting glucose and conventional lipid profiles [14, 15, 16]. The present analysis suggests that the lipid‐lowering effects of retatrutide extend beyond standard lipid parameters to a broader set of atherogenic ApoB‐containing lipoproteins. Given the causal role of ApoB‐containing lipoproteins in atherosclerotic cardiovascular disease [20], these changes may be relevant to cardiovascular risk reduction.

Recent clinical trials indicate that incretin‐based therapies have distinct effects on lipids and atherogenic lipoproteins. The GLP‐1R agonist semaglutide was shown to reduce triglycerides and LDL‐C from baseline by 4 and 11 mg/dL, respectively, and some lipoprotein subfractions (very‐low‐density lipoprotein and small LDL particles) by approximately 3% in patients with T2D [21, 22]. In the present analysis, reductions in atherogenic lipoproteins were significantly greater with retatrutide than with the GLP‐1R agonist dulaglutide in participants with T2D. Similarly, the dual GIPR/GLP‐1R agonist tirzepatide was found to be associated with greater improvements in non‐HDL‐C and ApoB than dulaglutide, with percent reductions of up to 25% and 17%, respectively, in people with T2D [9]. Additionally, tirzepatide lowered triglycerides by up to 41% and ApoC‐III by up to 46% from baseline in people with T2D [9]. Compared with tirzepatide, retatrutide was associated with similar reductions in triglycerides and non‐HDL‐C, but a greater reduction in ApoB.

Retatrutide treatment may lower non‐HDL‐C by significantly reducing both TRLP and LDLP. Tirzepatide treatment was also associated with reductions in large TRLP (83%) and small LDLP (32%) in people with T2D [9]. These changes suggest that both tirzepatide and retatrutide contribute to remnant lipoprotein metabolism, possibly by reducing ApoC‐III levels. ApoC‐III directs triglyceride‐rich lipoproteins away from hepatic clearance toward conversion into smaller, more atherogenic LDLP [23]. The reduction in ApoC‐III is unlikely to be solely a consequence of lower triglyceride‐rich lipoprotein concentrations. Hepatic APOC3 expression is suppressed by insulin through FoxO1 and is increased by hepatic steatosis and insulin resistance [24]. Therefore, the marked reductions in liver fat and improvements in insulin sensitivity seen with retatrutide would be expected to lower hepatic ApoC‐III secretion directly, complementing the effect of a reduced triglyceride‐rich lipoprotein pool.

Reductions in ApoC‐III may facilitate more efficient removal of remnant particles and limit their conversion into smaller LDLP. Collectively, these observations indicate that shared GLP‐1R and/or GIPR agonism with tirzepatide or retatrutide may contribute to improvements in TRLP profiles. Moreover, in the present post hoc analysis, modest changes were observed with retatrutide treatment in HDL‐C and HDLP, with decreases in small HDLP in these short‐term studies, which may suggest a limited effect of GLP‐1R, GIPR or GCGR agonism on the metabolism of HDLP [25]. Although these cross‐trial comparisons need to be interpreted cautiously, these findings indicate that triple GLP‐1R/GIPR/GCGR agonism with retatrutide may exert greater effects on lipids and atherogenic lipoproteins than GLP‐1R agonism alone.

GIPR, GLP‐1R and glucagon agonism influences glycaemic control, energy balance and lipid metabolism through overlapping but distinct mechanisms [26]. GLP‐1R activation has been shown to enhance glucose‐dependent insulin secretion, suppress glucagon release, delay gastric emptying and reduce appetite via central nervous system pathways [27]. GIPR agonism, when combined with GLP‐1R agonism, augments pancreatic beta‐cell function and improves insulin sensitivity [28, 29]. GCGR agonism contributes additional benefits by increasing energy expenditure, promoting fatty acid oxidation and inhibiting fatty acid synthesis [13]. GCGR agonism also has been shown to improve dyslipidaemia and reduce hepatic steatosis in animal models [13]. In people with MASLD, retatrutide reduced liver fat and resolved hepatic steatosis to a greater degree than in previous reports with GLP‐1R and GIPR/GLP‐1R agonists [14]. Our group has also shown retatrutide treatment to be associated with reductions of up to 63% in circulating angiopoietin‐like proteins 3 and 8 (ANGPTL3/8) in people with obesity with or without T2D [30]. In vitro studies in primary human hepatocytes showed that GCGR agonism with glucagon or retatrutide selectively inhibited ANGPTL3/8 secretion compared to GLP‐1 and GIP in both the presence and absence of insulin [30]. Because ANGPTL3/8 inhibits lipoprotein lipase activity [31], reductions in these factors would be expected to enhance clearance of TRLP and, in turn, affect the metabolism of LDLP as well [32, 33, 34]. These mechanisms may partially explain how GCGR agonism with retatrutide reduces atherogenic lipoproteins.

Unlike selective gene‐silencing or antibody‐based approaches that target a single pathway, such as the apoC‐III‐directed agents olezarsen and plozasiran or the ANGPTL3‐directed agents evinacumab and solbinsiran [35, 36, 37, 38], retatrutide acts on the upstream metabolic drivers of atherogenic dyslipidaemia (adiposity, hepatic steatosis and insulin resistance) and concurrently improves a broad spectrum of atherogenic lipoproteins. This breadth of effect suggests that patients with obesity‐associated mixed dyslipidaemia with or without T2D may derive greater initial benefit from multi‐receptor agonism than from single‐target therapy. Nonetheless, residual hypertriglyceridaemia or mixed dyslipidaemia persisted in a proportion of participants after retatrutide treatment (21.1% in Study 1 and 6.7% in Study 2 had triglycerides ≥ 150 mg/dL at end of treatment; 23.9% in Study 1 and 27.9% in Study 2 had non‐HDL‐C ≥ 130 mg/dL at end of treatment). In a subgroup of these patients, adjunctive selective approaches targeting apoC‐III, ANGPTL3, ANGPTL3/8 or ANGPTL4 might be considered [32, 35, 36, 37, 38].

Although weight reduction probably contributes to the changes reported here, several observations indicate that the effects may not be entirely weight‐mediated. The reductions in atherogenic lipoproteins were dose‐dependent, were greater than those produced by dulaglutide and exceeded what would be predicted from the degree of weight loss alone, consistent with the known weight‐independent actions of GCGR agonism on hepatic lipid metabolism and on ANGPTL3/8. Moreover, in exploratory analyses of pooled 8 mg and 12 mg arms (Table S3), the magnitude of weight loss correlated only weakly with end‐of‐treatment changes in non–HDL‐C, ApoB, ApoC‐III and TRL‐C and showed weak correlations with changes in CRP and IL‐6. Formal mediation analysis was beyond the scope of this post hoc study.

Our findings show that retatrutide was associated with reductions in inflammatory biomarkers in people with obesity or overweight, with CRP decreasing by up to 55% and IL‐6 by up to 30%. Although CRP and IL‐6 decreased by up to 41% and 30%, respectively, in participants with T2D and obesity, these decreases were not significantly different from the placebo group, where CRP and IL‐6 levels decreased by 16% and 14%, respectively. The anti‐inflammatory changes observed with retatrutide appeared to be dose‐dependent, with higher doses showing greater reductions in inflammatory markers. Elevated levels of inflammatory markers, including CRP, are common in people living with obesity or overweight [39]. Treatment with GLP‐1R agonists has been associated with reductions in inflammatory markers [40, 41, 42]. Although improvements in inflammation may be partially mediated by reduced body weight, the mechanism by which retatrutide improves systemic inflammation warrants further investigation.

The magnitude of ApoB and non–HDL‐C lowering observed here (up to ≈24% and ≈27%) lies within the range associated with clinically meaningful cardiovascular benefit. In Cholesterol Treatment Trialists' Collaboration and Mendelian‐randomisation analyses, each ≈1 mmol/L (≈39 mg/dL) lower concentration of ApoB‐containing lipoproteins corresponds to roughly a 20% lower risk of major vascular events [43, 44], and the absolute ApoB reductions seen here are comparable to those achieved with moderate‐intensity statin therapy. Whether these lipoprotein and inflammatory changes translate into fewer cardiovascular events and the extent to which any benefit is mediated by weight loss as opposed to direct drug effects remain to be established. As discussed above, the potential cardiovascular benefits of GLP‐1R, GIPR and/or GCGR coagonist therapies are likely to derive from both weight‐dependent and weight‐independent mechanisms [45]. The ongoing TRIUMPH‐OUTCOMES trial (NCT06383390) is designed to test directly whether retatrutide reduces major adverse cardiovascular events.

This study has several limitations. All analyses were performed post hoc and were not pre‐specified; although p values were adjusted for the FDR, the exploratory nature of the analyses and the number of biomarkers examined mean that the findings should be regarded as hypothesis‐generating. Because both trials were of less than 12 months' duration, the long‐term durability of these biomarker improvements is currently unknown. With other incretin‐based therapies, weight and cardiometabolic benefits have been largely maintained over 2–4 years of treatment; the longer‐term TRIUMPH‐OUTCOMES trial will assess the durability of retatrutide's effects. The study populations were predominantly White and were enrolled exclusively in the USA, which limits generalizability. Sample sizes for some biomarkers were modest, particularly in the cohort with T2D, which may have limited the power to detect changes in inflammatory markers. Finally, the biomarkers assessed are surrogates of cardiovascular risk; their improvement cannot be equated with a reduction in clinical events, which could be a research question for a dedicated cardiovascular outcomes trial.

5. Conclusion

This post hoc analysis demonstrated that retatrutide was associated with dose‐dependent improvements in atherogenic ApoB‐containing lipoproteins and systemic inflammation in adults with obesity or overweight, with or without T2D. Across both trials, retatrutide was associated with reduced non‐HDL‐C, ApoB, TRL‐C, ApoC‐III, total and small LDLP and large TRLP and lowered CRP and IL‐6, with many of these changes potentially greater than what has been reported for GLP‐1R agonists and, in some cases, for tirzepatide. These findings suggest that retatrutide treatment has the potential to reduce cardiovascular risk. Because these are surrogate biomarkers, a dedicated cardiovascular outcomes trial is needed to determine whether these biomarker improvements translate into fewer clinical events. The effect of retatrutide on cardiovascular outcomes is being evaluated prospectively in adults with obesity, with or without T2D, in the TRIUMPH‐OUTCOMES trial (NCT06383390).

Author Contributions

Giacomo Ruotolo, Charles Harris, Yanzhu Lin, Jonathan Wilson, Valentina Pirro, Kevin L. Duffin, Tamer Coskun, Melissa Thomas, Zvonko Milicevic and Axel Haupt developed the concept and designed the post hoc analysis. Tamer Coskun, Mark L. Hartman, Melissa Thomas, Zvonko Milicevic and Axel Haupt contributed to the design of both studies. Tamer Coskun, Charles Harris and Mark L. Hartman provided medical oversight during the trials. Yanzhu Lin was responsible for the statistical analysis. All authors participated in interpretation of the data and critical review of the manuscript, had full access to all the data in the study and approved this manuscript to be submitted for publication.

Funding

This work was funded by Eli Lilly and Company.

Conflicts of Interest

Giacomo Ruotolo, Charles Harris, Yanzhu Lin, Jonathan Wilson, Valentina Pirro, Kevin L. Duffin, Melissa K. Thomas, Mark L. Hartman, Ciara O′ Neill, Tamer Coskun, Zvonko Milicevic and Axel Haupt are (or were at the time this research was conducted) employees and shareholders of Eli Lilly and Company, which funded this study. Naveed Sattar has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini‐Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics and Sanofi and has received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. Stephen J. Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx and Sanofi‐Regeneron and is also a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi‐Regeneron, Vaxxinity, CSL Sequiris and Novo Nordisk.

Supporting information

Table S1: Baseline characteristics of people with T2D and obesity/overweight (Study 1).

Table S2: Baseline characteristics of people with obesity/overweight without T2D (Study 2).

Table S3: Correlations between percent change in body weight and percent changes in biomarkers.

Figure S1: Percent change from baseline in apolipoproteins.

Ruotolo G., Harris C., Lin Y., et al., “Retatrutide‐Associated Improvements in Cardiovascular Risk Biomarkers in Adults With Obesity With or Without Type 2 Diabetes,” Diabetes, Obesity and Metabolism 28, no. 11 (2026): 10183–10194, 10.1111/dom.71200.

Data Availability Statement

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.