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. 2025 Jul 29;27(10):5985–5995. doi: 10.1111/dom.16661

Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids

Yi Wen 1, Deven Lemen 1, Yanzhu Lin 1, Yan Q Chen 1, Ajit Regmi 1, William C Roell 1, Melissa K Thomas 1, Mark L Hartman 1, Tamer Coskun 1, Zvonko Milicevic 1, Axel Haupt 1, Giacomo Ruotolo 1, Robert J Konrad 1,✉
PMCID: PMC12409240  PMID: 40726454

Abstract

Aims

The aim of this study was to determine if retatrutide, a triple agonist of glucose‐dependent insulinotropic polypeptide (GIP) receptor, glucagon‐like peptide 1 (GLP‐1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low‐density lipoprotein cholesterol (LDL‐C) levels in part by decreasing circulating concentrations of the angiopoietin‐like protein 3/8 complex (ANGPTL3/8).

Materials and Methods

In post‐hoc analyses of two phase 2 retatrutide trials, concentrations of ANGPTL3/8, ANGPTL4/8 complex (ANGPTL4/8), ANGPTL3 and ANGPTL4 were measured using dedicated immunoassays to determine percent changes from baseline. Correlations of ANGPTL protein and complex levels with lipid and metabolic parameters at baseline were analysed. Correlations of the changes in ANGPTL protein and complex levels versus the changes in lipid and metabolic parameters at study endpoints were also analysed. Direct effects of retatrutide itself, GIP, GLP‐1, GCG and a GCG receptor (GCGR) antagonist antibody on ANGPTL3/8 secretion were studied in vitro using primary human hepatocytes.

Results

ANGPTL3/8 reductions were observed with 8 and 12 mg retatrutide doses in participants with type 2 diabetes, and with 1, 4, 8 and 12 mg retatrutide doses in participants with obesity or overweight but without diabetes. In both cases, ANGPTL3/8 decreases paralleled retatrutide‐induced reductions in TG and LDL‐C. In primary human hepatocytes, both glucagon and retatrutide decreased ANGPTL3/8 secretion, and these reductions were blocked with the GCGR antagonist antibody.

Conclusions

Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL‐C levels.

Keywords: angiopoietin‐like protein (ANGPTL), glucagon (GCG), low‐density lipoprotein‐cholesterol (LDL‐C), retatrutide, triglycerides (TG)

1. INTRODUCTION

Triglyceride (TG) metabolism in human beings is a highly complex process that relies upon the interaction of multiple different apolipoproteins (Apo) and angiopoietin‐like proteins (ANGPTL) to regulate the activity of lipoprotein lipase (LPL), an enzyme responsible for TG hydrolysis. 1 , 2 , 3 , 4 , 5 , 6 In particular, the ANGPTL3/4/8 family of proteins plays a critical part in regulating TG metabolism in a tissue‐specific manner, and angiopoietin‐like protein 8 (ANGPTL8) plays a pivotal role in controlling the LPL‐inhibitory activities of ANGPTL3 and ANGPTL4 in a calorically responsive manner. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13

In the adipose tissue after feeding, ANGPTL8 forms a localized complex with ANGPTL4 that reduces the ability of ANGPTL4 to inhibit LPL. 14 , 15 , 16 This ANGPTL4/8 complex (ANGPTL4/8) binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin, which cleaves ANGPTL4/8 itself, thereby releasing a C‐terminal domain‐containing ANGPTL4 fragment (CD‐ANGPTL4) similar to that created by furin‐mediated cleavage of hepatic ANGPTL4. 17 , 18 ANGPTL4/8‐generated plasmin also cleaves other LPL inhibitors such as apolipoprotein C3 (ApoC3) while preserving the ability of the LPL activator apolipoprotein C2 (ApoC2) to stimulate LPL so that LPL can be maximally active in adipose tissue in the postprandial state. 17 This prevents postprandial ectopic fat deposition by enabling TG to be efficiently hydrolysed in adipose tissue so that their fatty acids (FA) can be re‐esterified and stored in adipocytes as intracellular TG.

In the postprandial state in the liver, ANGPTL8 also forms a complex with ANGPTL3 that markedly increases the ability of ANGPTL3 to inhibit LPL. 14 , 15 , 16 This ANGPTL3/8 complex (ANGPTL3/8) is secreted into the bloodstream and works primarily in an endocrine manner to inhibit the activity of LPL in oxidative tissues so that TG can be routed toward the adipose tissue for storage. 16 In the fat, localized ANGPTL4/8‐mediated plasmin generation blocks the ability of ANGPTL3/8 to inhibit LPL in adipose tissue capillaries, enabling efficient TG hydrolysis and subsequent uptake and storage of FA in adipocytes. 17 , 18 Because ANGPTL3/8 is the most potent circulating inhibitor of LPL, serum concentrations of ANGPTL3/8 are highly correlated with serum TG levels. 14 , 19 , 20 ANGPTL3/8 concentrations are also directly correlated with low‐density lipoprotein cholesterol (LDL‐C) levels, presumably because in addition to potently inhibiting LPL activity, ANGPTL3/8 blocks the ability of LPL to facilitate the uptake of cholesterol‐containing lipoprotein particles by hepatocytes. 14

Retatrutide is a triple agonist of the glucose‐dependent insulinotropic polypeptide (GIP) receptor, the glucagon‐like peptide 1 (GLP‐1) receptor and the glucagon (GCG) receptor that is currently under development for the treatment of obesity and type 2 diabetes. 21 , 22 Retatrutide differentiates itself from previous incretin agonists through its agonism on the glucagon receptor (GCGR). 23 Agonism of the GCGR has been reported to be associated with decreased lipogenesis, increased lipolysis and increased FA oxidation. 23 , 24 , 25 Retatrutide has previously been shown to dose‐dependently decrease body weight in study participants with type 2 diabetes as well as in study participants with obesity or overweight but without diabetes, and to improve glycaemic control in study participants with type 2 diabetes. 21 , 22 Treatment with retatrutide was also associated with improvements in fasting glucose and haemoglobin A1c (HbA1c) in study participants without diabetes. 22 In addition to its abilities to improve glycaemic control and reduce body weight, retatrutide has been demonstrated to dose‐dependently decrease circulating TG levels in both studies and decrease LDL‐C concentrations (compared with placebo) in study participants with obesity or overweight but without diabetes. 21 , 22

Owing to the importance of the ANGPTL3/8 complex in modulating TG and LDL‐C levels, we sought to study the circulating concentrations of the ANGPTL3/8 complex in study participants treated with retatrutide. We therefore performed an exploratory, post‐hoc analysis utilizing fasting serum samples from two recently reported phase 2 retatrutide studies, with one conducted in participants with type 2 diabetes and the other in participants with obesity or overweight but without diabetes. 21 , 22 In the current study, we describe circulating ANGPTL3/8 concentrations in participants treated with retatrutide versus placebo and correlate these results with serum TG and LDL‐C levels. To aid in the interpretation of these data, we also study other circulating ANGPTL proteins and complexes, including ANGPTL3, ANGPTL4 and the ANGPTL4/8 complex. In addition, we characterize the direct effects of retatrutide on ANGPTL3/8 secretion from primary human hepatocytes.

2. MATERIALS AND METHODS

2.1. Phase 2 clinical trial participants and samples

Fasting samples from two retatrutide phase 2 trials were analysed in this exploratory, post‐hoc analysis. The first trial included individuals with type 2 diabetes (ClinicalTrials.gov study number: NCT04867785), and the second trial included individuals with obesity or overweight but without diabetes (ClinicalTrials.gov study number: NCT04881760). The study design, participants, procedures and outcomes for both trials have been described. 21 , 22 The study protocols were approved by independent ethics committees and were carried out in accordance with the Declaration of Helsinki and in compliance with current regulations and standards of Good Clinical Practice. All participants provided written informed consent. In the first trial, study participants with type 2 diabetes received once‐weekly injections of placebo, 1.5 mg dulaglutide, or retatrutide maintenance doses of 0.5, 4 (starting dose 2 mg), 4 (no escalation), 8 (starting dose 2 mg), 8 (starting dose 4 mg), or 12 mg (starting dose 2 mg) for 36 weeks. 21 In the second trial, study participants with obesity or overweight but without diabetes received once‐weekly injections of placebo or retatrutide maintenance doses of 1, 4 (starting dose 2 mg), 4 (no escalation), 8 (starting dose 2 mg), 8 (starting dose 4 mg) or 12 mg (starting dose 2 mg) for 48 weeks. 22

For study participants with type 2 diabetes, fasting samples at baseline, week 12, week 24 and week 36 were analysed. For study participants with obesity or overweight but without diabetes, fasting samples at baseline, week 12, week 24 and week 48 were analysed. ANGPTL3/8, ANGPTL4/8, ANGPTL3 and ANGPTL4 concentrations were measured using dedicated immunoassays as previously published. 20 The results of TG, LDL‐C and other lipid and metabolic parameters have been previously reported. 21 , 22 For the purpose of the current study, TG and LDL‐C, at the exact time points that match the ANGPTL analyses, are shown side by side with the ANGPTL data to aid in the interpretation of the results. Lipid and metabolic parameter data were correlated with ANGPTL data at baseline, and baseline‐to‐endpoint changes in each ANGPTL protein or complex measured were correlated with baseline‐to‐endpoint changes in each lipid and metabolic parameter. In addition, fasting proprotein convertase subtilisin/kexin type 9 (PCSK9) and fibroblast growth factor 21 (FGF21) concentrations at baseline, week 24 and study endpoint were measured.

2.2. ANGPTL3/8 secretion from human hepatocytes

Experiments with human hepatocytes were performed as previously described 14 with minor modifications. Briefly, pre‐plated primary human hepatocytes (HepatoPAC) were obtained from BioIVT. Upon receipt, media was replaced with 64 μL of maintenance media (BioIVT), and cells were maintained for 48 h in an incubator at 37°C under an atmosphere of 10% CO2. Afterward, the media was replaced with 64 μL of starvation media (BioIVT) supplemented with 1× penicillin/streptomycin (Gibco), 6.5 μg/mL transferrin (Sigma), 6.5 ng/mL Selenious Acid (Sigma), 6 μg/mL Linoleic Acid (Sigma) and 1% fatty acid free BSA (Thermo‐Fisher). After 16–20 h of incubation, media was replaced with 100 μL fresh starvation media without or with 10 nM human insulin (Sigma), and the cells were incubated with 10 nM GLP‐1, 10 nM GIP or 10 nM glucagon. Subsequent experiments were similarly performed without or with 10 nM human insulin in the presence of either 10 nM native glucagon (Lilly LSN21411) or 100 nM desacyl retatrutide, which was used to minimize the potentially confounding effects of continuous hepatocyte albumin secretion on an acylated compound such as retatrutide. These incubations were performed in the absence or presence of 100 nM of the glucagon receptor antibody LY278689 (GCGR Ab) that blocks glucagon signalling. In each case, at the end of the final incubation period, media were collected and stored at −80°C prior to analyses of samples using the ANGPTL3/8 immunoassay.

2.3. Statistical analyses

Statistical analyses for clinical trial data were implemented using R 4.3.2 and SAS 9.4 software. Analyses were performed on the modified intent‐to‐treat population, with data after study drug discontinuation or rescue drug initiation excluded. Only study participants with non‐missing baseline values and at least one non‐missing post‐baseline value of the response variable were included. Data were assessed using a mixed model with repeated measures, which included treatment, time and treatment‐by‐time interaction as fixed effects.

Each biomarker at baseline was included as a covariate in the models. In study participants within the type 2 diabetes trial, the run was also considered as a covariate as the data were measured by two individual runs. For both trials, the starting dose subgroups for the 4 and 8 mg treatment arms were pooled for analyses, and log‐transformation was applied before the model fitting. Spearman rank correlation was used to explore the association between the biomarkers themselves and compared with the clinical measurements (such as TG and LDL‐C). Correlations in baseline‐to‐endpoint changes were computed from baseline using the observed values and at the post‐baseline time points using the change from baseline values. Spearman non‐parametric correlation analyses were performed to calculate nominal p‐values for an exploratory, correlated‐based analysis without assumptions of causality and without adjusting for potential confounding factors (e.g., weight loss and glycaemic control). Weight loss and other potential confounders were not included as a covariate in the correlation analyses because doing so can cause multicollinearity issues.

For experiments performed with primary human hepatocytes, an unpaired Student t test was used to compare means of ANGPTL3/8 levels for the vehicle control versus each of the various treatment groups, with the vehicle control set at 100% and results expressed as a percent of control. In all cases, a p‐value of <0.05 was considered to indicate statistical significance.

3. RESULTS

3.1. ANGPTL complex concentrations and correlations in retatrutide phase 2 studies

Patient baseline characteristics have been previously published. 21 , 22 In individuals with type 2 diabetes (n = 251), the baseline least‐squares mean concentrations (standard error) for ANGPTL3/8, ANGPTL4/8, ANGPTL3 and ANGPTL4 were 26.1 (0.7) ng/mL, 18.9 (0.7) ng/mL, 239.5 (5.1) ng/mL and 8.1 (0.2) ng/mL respectively. In individuals with obesity or overweight but without type 2 diabetes (n = 309), the baseline least‐squares means for ANGPTL3/8, ANGPTL4/8, ANGPTL3 and ANGPTL4 were 24.2 (0.7) ng/mL, 19.2 (0.7) ng/mL, 194.9 (3.3) ng/mL and 6.7 (0.4) ng/mL, respectively. Correlations between ANGPTL proteins and complexes and lipid and metabolic parameters at baseline are shown in Table 1. ANGPTL3/8 was positively correlated with TG, non‐high‐density lipoprotein cholesterol (non‐HDL‐C), total cholesterol (TC) and insulin in both studies and with LDL‐C in individuals with type 2 diabetes.

TABLE 1.

Baseline correlations of ANGPTL proteins and complexes with fasting lipid and metabolic parameters in individuals with type 2 diabetes and individuals with obesity or overweight but without diabetes.

ANGPTL protein ANGPTL3/8 ANGPTL4/8 ANGPTL3 ANGPTL4
R and p values R value p value R value p value R value p value R value p value
Type 2 diabetes study
ANGPTL3/8 0.38 <0.0001 0.27 <0.0001 −0.04 0.4937
ANGPTL4/8 0.38 <0.0001 0.15 0.0214 0.63 <0.0001
ANGPTL3 0.27 <0.0001 0.15 0.0214 0.15 0.0174
ANGPTL4 −0.04 0.4937 0.63 <0.0001 0.15 0.0174
TC 0.46 <0.0001 0.25 <0.0001 0.46 <0.0001 −0.02 0.7530
HDL‐C −0.01 0.8303 −0.14 0.0317 0.31 <0.0001 −0.15 0.0189
Insulin 0.28 <0.0001 0.23 0.0003 −0.15 0.0158 0.03 0.6515
LDL‐C 0.37 <0.0001 0.15 0.0201 0.41 <0.0001 −0.08 0.2170
Non‐HDL‐C 0.47 <0.0001 0.29 <0.0001 0.40 <0.0001 0.02 0.7612
TG 0.38 <0.0001 0.35 <0.0001 0.10 0.1012 0.17 0.0069
Waist to height ratio 0.19 0.0026 0.22 0.0004 0.12 0.0625 0.33 <0.0001
Body mass index 0.12 0.0507 0.13 0.0369 −0.02 0.7066 0.24 0.0001
Weight 0.03 0.6167 0.11 0.0872 −0.13 0.0396 0.22 0.0004
Obesity study
ANGPTL3/8 0.29 <0.0001 0.24 <0.0001 −0.12 0.0391
ANGPTL4/8 0.29 <0.0001 0.00 0.9536 0.58 <0.0001
ANGPTL3 0.24 <0.0001 0.00 0.9536 0.06 0.2865
ANGPTL4 −0.12 0.0391 0.58 <0.0001 0.06 0.2865
TC 0.18 0.0013 −0.04 0.4864 0.28 <0.0001 −0.15 0.0069
HDL‐C −0.01 0.8158 −0.13 0.0230 0.29 <0.0001 −0.06 0.3095
Insulin 0.41 <0.0001 0.41 <0.0001 −0.09 0.1250 0.13 0.0260
LDL‐C 0.11 0.0546 −0.04 0.5058 0.20 0.0005 −0.15 0.0101
Non‐HDL‐C 0.21 0.0002 0.00 0.9414 0.20 0.0003 −0.15 0.0084
TG 0.35 <0.0001 0.16 0.0043 0.08 0.1441 0.00 0.9775
Waist to height ratio 0.22 <0.0001 0.32 <0.0001 0.17 0.0021 0.26 <0.0001
Body mass index 0.17 0.0024 0.28 <0.0001 0.21 0.0003 0.24 <0.0001
Weight 0.17 0.0031 0.20 0.0003 0.08 0.1653 0.13 0.0197
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In individuals with type 2 diabetes, ANGPTL3/8 levels decreased by 47.4% and 44.2% (both p < 0.0001) in the 8 and 12 mg retatrutide groups, respectively (Figure 1A). No significant decreases were observed with 0.5 mg retatrutide, 4 mg retatrutide (13.9%, p = 0.0754), 1.5 mg dulaglutide or placebo. Because ANGPTL8 forms a circulating complex with ANGPTL4 (ANGPTL4/8), 6 we also measured ANGPTL4/8 levels. In individuals with type 2 diabetes, ANGPTL4/8 significantly decreased in the 4, 8 and 12 mg retatrutide groups (17.8%, p = 0.0068, 32.6%, p < 0.0001 and 24.5%, p < 0.0001, respectively) (Figure 1B). No decreases were observed with 0.5 mg retatrutide, 1.5 mg dulaglutide, or placebo. TG reductions most closely mirrored ANGPTL3/8 decreases (Figure 1C). LDL‐C reductions were less than those for TG, with significant decreases observed with 8 mg retatrutide (13.9%, p = 0.0044) (Figure 1D).

FIGURE 1.

FIGURE 1

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Changes in fasting ANGPTL3/8, ANGPTL4/8, TG and LDL‐C with retatrutide treatment. Numbers at curve ends represent percent changes from baseline for ANGPTL3/8 (A), ANGPTL4/8 (B), TG (C) and LDL‐C (D) in individuals with type 2 diabetes, and for ANGPTL3/8 (E), ANGPTL4/8 (F), TG (G) and LDL‐C (H) in individuals with obesity or overweight but without diabetes. Error bars denote SE.

In individuals with obesity or overweight but without diabetes, ANGPTL3/8 reductions were also observed (Figure 1E). ANGPTL3/8 decreased by 30.2% (p < 0.0001) with 1 mg, 50.7% (p < 0.0001) with 4 mg, 59.9% (p < 0.0001) with 8 mg and 63.4% (p < 0.0001) with 12 mg retatrutide. Similar results were observed for ANGPTL4/8 (Figure 1F). ANGPTL4/8 decreased by 13.3% (p = 0.0071) with 1 mg, 28.1% (p < 0.0001) with 4 mg, 37.8% (p < 0.0001) with 8 mg, and 34.1% (p < 0.0001) with 12 mg retatrutide. TG (Figure 1G) and LDL‐C (Figure 1H) decreases again paralleled ANGPTL3/8 changes, with significant reductions observed with 1, 4, 8 and 12 mg of retatrutide.

3.2. ANGPTL3, ANGPTL4, PCSK9 and FGF21 levels in retatrutide phase 2 studies

No significant endpoint changes in ANGPTL3 or ANGPTL4 were observed in either study except for an 8.4% reduction of ANGPTL4 (p = 0.046) with 4 mg retatrutide in the diabetes study (Figure 2A–D). We also considered other mechanisms involved in lipid metabolism. Hepatic glucagon signalling has been reported to reduce LDL‐C by regulating proprotein convertase subtilisin/kexin type 9 (PCSK9) degradation. 26 No meaningful PCSK9 decreases compared with placebo were observed in either study (Figure 2E,F). Fibroblast growth factor 21 (FGF21) was also studied. FGF21 decreased in all treatment groups and placebo (non‐significant versus 38.5% placebo reduction) in individuals with type 2 diabetes. In individuals with obesity or overweight but without diabetes, FGF21 decreased in 4, 8 and 12 mg retatrutide groups (significant vs. a 24.8% placebo increase) (Figure 2G,H). These results indicated that LDL‐C and TG reductions in individuals with retatrutide treatment were unlikely to be attributable to PCSK9 decreases or FGF21 increases.

FIGURE 2.

FIGURE 2

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Changes in fasting ANGPTL3, ANGPTL4, PCSK9 and FGF21 with retatrutide treatment. Numbers at curve ends represent percent changes from baseline for ANGPTL3 (A), ANGPTL4 (C), PCSK9 (E) and FGF21 (G) in individuals with type 2 diabetes, and for ANGPTL3 (B), ANGPTL4 (D), PCSK9 (F) and FGF21 (H) in individuals with obesity or overweight but without diabetes. Error bars denote SE.

3.3. ANGPTL protein and complex baseline‐to‐endpoint change correlations in retatrutide studies

Baseline‐to‐endpoint ANGPTL protein and complex changes were therefore compared with changes in lipids, waist‐height ratio (WHR), Body Mass Index (BMI) and weight (Table 2). ANGPTL3/8 changes correlated most strongly with changes in insulin, WHR, BMI and weight. ANGPTL3/8 changes also correlated with TG, LDL‐C, non‐high‐density lipoprotein cholesterol (non‐HDL‐C) and total cholesterol (TC) changes. ANGPTL4/8 changes were more modestly correlated with changes in several lipid and metabolic parameters. Despite positive correlations with changes in LDL‐C, non‐HDL‐C, and TC, ANGPTL3 changes were not correlated with changes in WHR, BMI or weight. ANGPTL4 changes exhibited no meaningful correlations, other than modest negative correlations with insulin changes.

TABLE 2.

Correlations of baseline‐to‐endpoint changes in ANGPTL protein and complex levels with baseline‐to‐endpoint changes in fasting lipid and metabolic parameters in individuals with type 2 diabetes at 36 weeks and individuals with obesity or overweight but without diabetes at 48 weeks.

ANGPTL protein ANGPTL3/8 ANGPTL4/8 ANGPTL3 ANGPTL4
R and p values R value p value R value p value R value p value R value p value
Type 2 diabetes study
ANGPTL3/8 0.48 0 0.10 0.1643 −0.16 0.0190
ANGPTL4/8 0.48 0 0.01 0.9401 0.45 <0.0001
ANGPTL3 0.10 0.1643 0.01 0.9401 0.06 0.3481
ANGPTL4 −0.16 0.0190 0.45 <0.0001 0.06 0.3481
TC 0.34 <0.0001 0.32 <0.0001 0.31 <0.0001 0.07 0.2798
HDL‐C 0.04 0.5255 −0.02 0.7384 0.21 0.0024 −0.12 0.0886
Insulin 0.57 <0.0001 0.26 0.0001 −0.01 0.8340 −0.20 0.0046
LDL‐C 0.15 0.0319 0.13 0.0568 0.30 <0.0001 0.05 0.5118
Non‐HDL‐C 0.33 <0.0001 0.32 <0.0001 0.27 <0.0001 0.10 0.1622
TG 0.41 <0.0001 0.36 <0.0001 0.08 0.2282 0.07 0.3171
Waist to height ratio 0.42 <0.0001 0.33 <0.0001 −0.05 0.4573 0.01 0.8903
Body mass index 0.53 <0.0001 0.44 <0.0001 −0.12 0.0915 0.00 0.9552
Weight 0.53 <0.0001 0.42 <0.0001 −0.12 0.0760 0.00 0.9627
Obesity study
ANGPTL3/8 0.50 0 0.31 <0.0001 −0.28 <0.0001
ANGPTL4/8 0.50 0 0.10 0.1069 0.41 <0.0001
ANGPTL3 0.31 <0.0001 0.10 0.1069 −0.10 0.1181
ANGPTL4 −0.28 <0.0001 0.41 <0.0001 −0.10 0.1181
TC 0.48 <0.0001 0.30 <0.0001 0.32 <0.0001 −0.04 0.4998
HDL‐C 0.18 0.0044 0.13 0.0420 0.13 0.0307 −0.01 0.9194
Insulin 0.52 <0.0001 0.33 <0.0001 0.01 0.8217 −0.20 0.0017
LDL‐C 0.38 <0.0001 0.24 0.0001 0.24 0.0001 0.00 0.9489
Non‐HDL‐C 0.46 <0.0001 0.31 <0.0001 0.28 <0.0001 −0.02 0.7907
TG 0.46 <0.0001 0.30 <0.0001 0.25 <0.0001 −0.12 0.0516
Waist to height ratio 0.51 <0.0001 0.35 <0.0001 0.08 0.1964 −0.12 0.0602
Body mass index 0.59 <0.0001 0.42 <0.0001 0.08 0.2197 −0.08 0.2026
Weight 0.60 <0.0001 0.41 <0.0001 0.09 0.1603 −0.09 0.1683
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3.4. ANGPTL3/8 secretion from primary human hepatocytes

The above results suggested that retatrutide‐induced decreases in TG and LDL‐C were at least partly mediated through reduction of hepatic ANGPTL3/8 secretion. To explore which receptor agonism of retatrutide accounted for this effect, we incubated primary human hepatocytes with GLP‐1, GIP or glucagon. Because insulin stimulates hepatocyte ANGPTL3/8 release, 14 we performed these experiments in the absence or presence of insulin. In the absence of insulin, glucagon decreased ANGPTL3/8 secretion to 55.8% of control, while GLP‐1 and GIP had no effect (Figure  3A). In the presence of insulin (which increased ANGPTL3/8 secretion 3.1‐fold) glucagon reduced ANGPTL3/8 secretion to 50.5% of control, while GLP‐1 and GIP were again without effect (Figure  3B).

FIGURE 3.

FIGURE 3

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Glucagon and retatrutide‐induced ANGPTL3/8 secretion from hepatocytes. Primary human hepatocytes incubated without (A) or with (B) insulin were treated with GLP‐1, GIP or glucagon, and ANGPTL3/8 was measured. Results represent the mean ± SD (n = 6) from 2 independent experiments (*p < 0.0001 vs. control). Primary human hepatocytes incubated without (C) or with (D) insulin were treated with glucagon or retatrutide ± GCGR antibody, and ANGPTL3/8 was measured. Results represent the mean ± SD (n = 12–29) from 2 to 4 independent experiments (*p < 0.0001 vs. control). Error bars denote SE.

To confirm that agonism of GCGR by retatrutide contributed to reduced ANGPTL3/8 secretion, we next examined the effect of an anti‐GCGR antagonist antibody (GCGR Ab). In the absence of insulin, glucagon and retatrutide decreased hepatocyte ANGPTL3/8 secretion to 50.3% and 45.4% of control, respectively, and these effects were blocked by the GCGR Ab (Figure 3C). In the presence of insulin (which increased ANGPTL3/8 secretion 4.6‐fold), glucagon and retatrutide decreased ANGPTL3/8 secretion to 54.2% and 50.7% of control, respectively (Figure 3D). These effects were again negated by the GCGR Ab. These percent reductions observed for hepatocyte ANGPTL3/8 secretion were comparable to those observed with the higher retatrutide doses in the clinical studies (Figure 1).

4. DISCUSSION

A key finding in our current study is that reductions of circulating ANGPTL3/8 concentrations occurring with retatrutide treatment paralleled the dose‐dependent decreases in serum TG and LDL‐C levels observed in individuals with type 2 diabetes and in individuals with obesity or overweight but without diabetes. These data suggest that reductions of ANGPTL3/8 levels may represent one of the mechanisms by which serum TG and LDL‐C were lowered in retatrutide‐treated individuals. It should be noted, however, that TG and LDL‐C levels could be decreased through additional mechanisms beyond ANGPTL3/8, as retatrutide reduced appetite, food intake and body weight in preclinical and clinical studies. 21 , 22 , 23 In addition, ANGPTL4/8 levels decreased in a similar manner but with less magnitude than what was observed for ANGPTL3/8. In contrast, serum concentrations of ANGPTL3 or ANGPTL4 did not decrease significantly, suggesting that decreases in ANGPTL3/8 were the result of reduced hepatic expression of ANGPTL8 rather than ANGPTL3.

Activation of the hepatic GCGR has been associated with decreased lipogenesis and increased lipolysis and fatty acid oxidation. 23 , 24 , 25 These reports are consistent with our observation that glucagon and retatrutide markedly reduced ANGPTL3/8 secretion from human hepatocytes because ANGPTL3/8 functions primarily in oxidative tissues to inhibit LPL‐mediated TG hydrolysis that generates FA that can undergo subsequent FA oxidation. 14 The ability of both glucagon and retatrutide to decrease ANGPTL3/8 secretion and the abrogation of this effect by a GCGR Ab that blocks glucagon signalling suggests that the ability of retatrutide to decrease ANGPTL3/8 was mediated through activation of the GCGR. This concept also aligns with the consensus that hepatocytes do not express canonical GIP or GLP‐1 receptors. 27 , 28

Our observations regarding reduced ANGPTL3/8 and LDL‐C levels in individuals with retatrutide treatment are consistent with the concept that ANGPTL3/8 could block LPL‐facilitated cholesterol‐containing lipoprotein particle uptake by hepatocytes. 14 Other potential mechanisms may contribute, however. For instance, hepatic glucagon signalling has been reported to reduce LDL‐C by regulating PCSK9 degradation in preclinical mouse models. 26 Nevertheless, no significant decreases in PCSK9 were observed in individuals with type 2 diabetes, and the modest reductions in PCSK9 in individuals with obesity or overweight but without diabetes were similar to reductions observed with placebo. Finally, it has been hypothesized that GCGR agonism may improve lipid profiles by increasing FGF21 levels. However, FGF21 concentrations were reduced in individuals with type 2 diabetes and in individuals with obesity or overweight but without diabetes, as well as in individuals with metabolic dysfunction‐associated steatotic liver disease treated with retatrutide. 29 These results indicate that LDL‐C and TG reductions in retatrutide‐treated individuals were unlikely to be attributable to decreases in PCSK9 or increases in FGF21.

Our results further highlight the ANGPTL3/8 complex as an important target for the treatment of hyperlipidemia. From a human genetic standpoint, knockout mutations in both ANGPTL3 and ANGPTL8, each of which is required to form the ANGPTL3/8 complex, have been shown to be associated with lower levels of serum TG and LDL‐C, as well as a decreased risk of cardiovascular events. 30 , 31 , 32 , 33 Importantly, the TG‐lowering protein apolipoprotein A5 (ApoA5) has recently been shown to work by selectively suppressing the ability of the ANGPTL3/8 complex to inhibit LPL enzymatic activity. 34 , 35 , 36 , 37 In addition, loss‐of‐function mutations in APOA5 have been shown to be associated with increased TG levels as well as an increased risk of myocardial infarctions. 2 Consistent with these observations, the anti‐ANGPTL3 monoclonal antibody evinacumab, which is approved for the treatment of homozygous familial hypercholesterolemia (HoFH), has been shown to inhibit ANGPTL3/8 more potently than it inhibits ANGPTL3. 38 Furthermore, an anti‐ANGPTL3/8‐specific monoclonal antibody has been shown to lower TG by as much as 90% in hypertriglyceridemic mice and as much as 70% in study participants with mixed hyperlipidemia, while also decreasing LDL‐C by up to 32% in the same individuals. 38 , 39 These observations are consistent with a recent report that utilized human genetic approaches to identify the ANGPTL3/8 complex as the most likely key functional unit in regulating plasma lipid metabolism. 40

Administration of retatrutide caused no significant decreases in HDL‐C levels in either population studied. 21 , 22 This is likely because ANGPTL3 levels were not changed in retatrutide groups. While ANGPTL3/8 can inhibit endothelial lipase (EL), the enzyme which hydrolyses phospholipids in phospholipid‐rich HDL, ANGPTL3 is the most relevant EL inhibitor because it inhibits EL almost as potently as ANGPTL3/8, and serum levels of ANGPTL3 are much greater than those of ANGPTL3/8. 19 , 41 ANGPTL3 loss‐of‐function mutations and therapies targeting ANGPTL3 are associated with reduction in TG, LDL‐C and HDL‐C, since ANGPTL3 inhibits both LPL and EL. 30 , 42 The lack of HDL‐C reduction with retatrutide treatment is therefore consistent with our observations that ANGPTL3/8 (the most potent circulating LPL inhibitor) decreased, while ANGPTL3 (the most important circulating EL inhibitor) was unchanged in retatrutide groups.

Recently, circulating levels of ANGPTL4/8 have been identified as a risk factor for cardiovascular disease. 20 In addition to demonstrating decreases of ANGPTL3/8, our data also show consistent reductions in ANGPTL4/8 occurring with retatrutide treatment. While it is currently unclear why ANGPTL4/8 levels are positively associated with cardiovascular mortality, decreases in ANGPTL4/8 may provide an additional potential benefit, although further studies will be needed to explore this possibility.

As interesting as our data may be, there are several limitations to our current study. Regarding our hepatocyte experiments demonstrating that both glucagon and retatrutide suppress ANGPTL3/8 secretion in vitro, while the retatrutide concentration used (100 nM) was consistent with expected human exposure levels, 23 the glucagon concentration used (10 nM) was much greater than normal plasma glucagon levels (~10–20 pM). 21 , 43 Although this concentration was chosen because portal vein glucagon levels would be expected to be much higher than peripheral levels, caution is needed when attempting to interpret these in vitro findings. It is thus important to note that our hepatocyte experiments lack in vivo validation (such as would be provided by lipolysis assays), which limits their translatability. As a result, more rigorous mechanistic studies, including direct lipolysis assessments, would be required to validate our hypotheses.

Another limitation of our study is that there were some inconsistent correlations across the two populations. For instance, ANGPTL3/8 decreases were more highly correlated with LDL‐C reductions in patients with obesity (r = 0.38, p < 0.0001) than in patients with diabetes (r = 0.15, p = 0.0319). Similarly, ANGPTL3 changes were correlated more with TG declines (r = 0.25, p < 0.0001) in patients with obesity than in patients with diabetes (r = 0.08, p = 0.2282). The reasons behind these observations are unclear but may stem from inherent metabolic differences in the two different cohorts. While TG‐lowering effects observed with retatrutide paralleled ANGPTL3/8 reductions in both cohorts, LDL‐C decreases followed a dose‐response pattern that was less related to decreases in ANGPTL3/8. A possible reason for this could be that ANGPTL3/8 is only one of several drivers of LDL‐C concentrations. Additional studies are thus needed to further clarify the role that ANGPTL3/8 plays in regulating LDL‐C levels.

A further limitation to our study is that while our data convincingly show reductions in ANGPTL3/8 and corresponding lipid parameters, it is unclear if these changes will translate into longer‐term cardiovascular benefits, as there are no data available on cardiovascular outcomes or accepted surrogate markers in the two cohorts studied. A recent report suggested that circulating ANGPTL3/8 levels are associated with increased coronary heart disease risk in a Swedish population, but this result has not yet been replicated in other populations. 44 Our current study is also limited by its post hoc design and potential confounders (such as the effects of retatrutide on glycaemic control and weight loss). Reductions in lipids could result at least partly from weight loss, and thus not only from the decreases observed in ANGPTL3/8. Because of these limitations, future studies, including prospective trials and/or genetic analyses, will be needed to confirm a causal mechanism for the ANGPTL3/8 pathway in mediating the lipid‐lowering effects of retatrutide.

5. CONCLUSION

Taken together, our data suggest that the lipid‐lowering effects of retatrutide observed in phase 2 studies may occur through reduced ANGPTL3/8 complex secretion via hepatocyte GCGR agonism. This concept is supported by the observation that decreases in serum ANGPTL3/8 levels paralleled retatrutide‐induced reductions in TG and LDL‐C levels in individuals with type 2 diabetes and individuals with obesity or overweight but without diabetes. These observations thus highlight an additional possible dimension of retatrutide beyond its efficacy regarding glycaemic control and weight reduction.

AUTHOR CONTRIBUTIONS

Design: Yi Wen, Robert Konrad, Tamer Coskun, Zvonko Milicevic, Mark Hartman, Melissa Thomas, Axel Haupt, Giacomo Ruotolo. Conduct/data collection: Deven Lemen, Yan Chen, Ajit Regmi, William Roell. Analysis: Yanzhu Lin. Writing manuscript and writing—original draft: Yi Wen, Robert Konrad. Writing–review and editing: all authors.

CONFLICT OF INTEREST STATEMENT

All authors are employees and shareholders of Eli Lilly and Company.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16661.

ACKNOWLEDGEMENTS

The authors thank Jonathan Wilson for his expert technical assistance on the measurements of FGF21 and PCSK9, and also thank Halle Higbie for her help with the measurements of ANGPTL3 and ANGPTL4.

Wen Y, Lemen D, Lin Y, et al. Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids. Diabetes Obes Metab. 2025;27(10):5985‐5995. doi: 10.1111/dom.16661

DATA AVAILABILITY STATEMENT

Lilly provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available on 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 for 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 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.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Lilly provides access to all individual participant data collected during the trial, after anonymization, except for pharmacokinetic or genetic data. Data are available on 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 for 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 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.

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