The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity

Abstract

Introduction

Obesity and type 2 diabetes mellitus (T2D) increase the risk of kidney disease. This study assessed changes in kidney parameters with retatrutide, an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors.

Methods

A post hoc analysis of 2 retatrutide studies (dose range: 0.5–12 mg) was performed in participants (estimated glomerular filtration rate [eGFR] ≥ 45 ml/min per 1.73 m²) with T2D (n = 281) and with overweight or obesity without T2D (n = 338). Both studies were placebo-controlled; the T2D study included dulaglutide 1.5 mg as an active comparator. We assessed change from baseline at week 36 (T2D) and week 48 (overweight/obesity) in urine albumin-to-creatinine ratio (UACR) and eGFR derived from creatinine, cystatin C, or both.

Results

At baseline, mean eGFR derived from creatinine and median UACR were 91 ml/min per 1.73 m² and 13 mg/g, respectively in the T2D study, and 90 ml/min per 1.73 m² and 7 mg/g, respectively in the obesity study. In participants with T2D, retatrutide 12 mg was associated with reduced UACR compared with placebo at 36 weeks by −37.0% (95% CI: −57.3 to −7.0); eGFR was unchanged compared with placebo. In participants with overweight or obesity, retatrutide 8 mg and 12 mg, compared with placebo at 48 weeks, was associated with decreased UACR by −28.0% (95% CI: −46.0 to −4.1) and −31.5% (95% CI: −49.3 to −7.4), respectively, and with increased eGFR derived from creatinine by 5.3 ml/min per 1.73 m² (95% CI: 1.9–8.7) and 8.5 ml/min per 1.73 m² (95% CI: 4.9–12.1), respectively. Similar increases in eGFR derived from cystatin C and combined creatinine-cystatin C eGFR were observed. Because most patients had normal albuminuria, the absolute reduction in UACR was modest.

Conclusion

Higher doses of retatrutide were associated with reduced UACR in participants with T2D and obesity, and with increased eGFR in participants with obesity but not in those with T2D.

Graphical abstract

Obesity is common in people with T2D, and both conditions increase the risk of kidney and cardiovascular complications.^1,2 The prevalence of chronic kidney disease (CKD) continues to increase and parallels the global increase in the prevalence of obesity and T2D.³ Management strategies for the treatment of CKD, in particular in the presence of obesity or T2D, include lifestyle modification and blood pressure (BP) reduction with angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers. More recently, sodium-glucose co-transporter 2 inhibitors and a selective mineralocorticoid receptor antagonist, finerenone, have been recommended in clinical practice guidelines to further reduce the risk of kidney failure.^4,5 Despite these newer therapies, the risk of kidney failure remains high, particularly in those whose risk factors are insufficiently controlled.^6,7

GLP-1 receptor agonists promote insulin secretion after meals, improve glycemic control and body weight (BW), and reduce the risk of cardiovascular complications for people with T2D and obesity.8, 9, 10 Moreover, the GLP-1 receptor agonist, semaglutide reduced the risk of a composite kidney end point in a dedicated kidney outcome trial.¹¹ Much progress has been made in the past few years with the introduction of new potent incretin-based therapeutics targeting the pathophysiology of obesity and T2D. Cotadutide, an agonist for the GLP-1 and glucagon receptor reduced albuminuria, hemoglobin A1C (HbA1c), and BW in adults with T2D and CKD.¹² Retatrutide is an agonist of the GIP, GLP-1, and glucagon receptors. In preclinical models, the addition of glucagon receptor agonism to GIP/GLP-1 receptor agonism resulted in maintenance of energy expenditure during weight loss together with decreased calorie intake.¹³ In these models, glucagon receptor activation with retatrutide accounted for 30% to 35% of the observed BW loss in mice as a result of the maintenance in energy expenditure.¹³ In 2 phase 2 dose-finding clinical trials, retatrutide markedly improved BW and glycemic control in participants with T2D and those with obesity without T2D.^14,15 Based on emerging data suggesting that targeting the glucagon receptor may exert direct kidney protective effects,¹⁶ we performed an exploratory analysis of these 2 clinical trials to assess the association of retatrutide treatment with changes in kidney parameters in these 2 patient populations. Renal safety was also evaluated.

Methods

Study Design and Participants

The current analyses are based on data from 2 randomized, double-blind, placebo-controlled, multicenter phase 2 clinical trials in participants with T2D and/or obesity that enrolled adults aged 18 to 75 years. The T2D study included an active comparator, dulaglutide, administered in a double-blind, double-dummy manner. The studies were conducted, respectively, at 42 and 28 research and health care centers in the United States. The principlal findings and trial protocols have been reported previously.^14,15 In brief, in the T2D trial (NCT04867785), eligible participants had T2D treated with diet and exercise alone or with a stable dose of metformin (≥ 1000 mg once daily) for at least 3 months, an HbA1c of 7.0% to 10.5%, and a body mass index of 25 to 50 kg/m². In the obesity trial (NCT04881760), eligible participants had a body mass index of 30 to 50 kg/m² or 27 to < 30 kg/m² with at least 1 weight-related condition and no diabetes. In both trials, participants with kidney impairment, defined as eGFR < 45 ml/min per 1.73 m², were excluded from participation. Ethical approval was obtained from local ethics committees at each site, and the studies were conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences’ International Ethical Guidelines and Good Clinical Practice Guidelines. All participants provided written informed consent before entering the study.

Randomization and Masking

In both trials, for participants randomized to receive retatrutide doses >1 mg, the dose was increased from a starting dose of 2 mg (slow escalation) or 4 mg (fast escalation) every 4 weeks for up to 12 weeks until the maximum dose was reached. In the T2D trial, participants were randomly assigned (2:2:2:1:1:1:1:2) to receive placebo; dulaglutide 1.5 mg; or retatrutide 0.5 mg, 4 mg (slow escalation), 4 mg (fast escalation), 8 mg (slow escalation), 8 mg (fast escalation), or 12 mg (slow escalation). Randomization was stratified according to baseline HbA1c (≤ 8.5% or > 8.5%) and body mass index (< 30 kg/m² or ≥ 30 kg/m²). In the obesity trial, participants were randomly assigned (2:2:1:1:1:1:2) to receive placebo; or retatrutide 1 mg, 4 mg (slow escalation), 4 mg (fast escalation), 8 mg (slow escalation), 8 mg (fast escalation) or 12 mg (slow escalation). Randomization was stratified according to sex (self-reported) and body mass index (< 36 kg/m² or ≥ 36 kg/m²). For the post hoc analyses reported here, the starting dose subgroups for the 4 mg and 8 mg treatment arms were pooled.

Procedures

The T2D and obesity trials consisted of, respectively, a 3- and 6-week screening, a 36- and 48-week treatment period, and a 4-week safety follow-up period. Throughout the treatment period, participants self-administered once weekly subcutaneous injections of placebo, retatrutide, or dulaglutide. Retatrutide and matching placebo were administered using a syringe, whereas dulaglutide and matching placebo were administered using a single-dose pen (Eli Lilly and Company). Detailed descriptions of study visits have previously been reported.^14,15 The primary efficacy end points were changed from baseline to 24 weeks in HbA1c for the T2D trial and percentage change in weight for the obesity trial, as early efficacy assessments.

Outcomes

The current post hoc analyses assessed the association of retatrutide versus placebo and/or versus dulaglutide with changes in kidney parameters, which included percentage change in UACR and change in eGFR derived from creatinine, cystatin C, and the combination of eGFR derived from creatinine and cystatin C, from baseline to week 36 (T2D trial) and week 48 (obesity trial). eGFR was calculated by using the CKD - Epidemiology Collaboration creatinine, cystatin C, and creatinine-cystatin C equations.¹⁷ Urinary albumin and creatinine were measured in single spot urine samples at baseline, week 36 (T2D trial), and week 48 (obesity trial). UACR and eGFR were assessed after a 4-week washout period in the obesity trial but not in the T2D trial. Additional end points included changes from baseline in systolic and diastolic BP.

Statistical Analyses

Sample size calculations for the T2D and obesity trials were previously reported.^14,15 All analyses are considered exploratory because the trials were not enrolled or powered to assess kidney parameters. In both trials, an efficacy estimand was used to assess efficacy of retatrutide compared with placebo, representing the mean treatment effect of retatrutide relative to placebo for all randomized participants, if the treatment was administered as intended. Randomized participants who discontinued the study drug because of inadvertent enrollment, and data after permanent discontinuation of study drug were excluded from the analysis (efficacy analysis set). For the T2D trial, data collected after initiation of rescue medication were also excluded. Safety analyses were conducted on all randomized participants who received at least 1 dose of double-blind study treatment with all data from the start of treatment to the end of study follow-up, unless otherwise specified. Analyses were conducted separately for each trial.

A mixed model for repeated measures was used as the primary analysis model for comparisons among treatment groups relative to continuous measurements assessed over time. Mixed model for repeated measures analysis included randomized treatment, visit, treatment-by-visit interaction, and stratification factors as fixed effects, and the baseline measure as a covariate. An unstructured covariance matrix was used. To assess treatment effects on UACR, we used log-transformation and back-transformed the results to obtain the geometric mean percentage change. All analyses were conducted on the efficacy analysis set unless stated otherwise, including analyses of association with changes in BP (unlike the original publications, where BP was assessed on the safety analysis set).^14,15 We report least-squares means with standard errors and least-squares mean differences with 95% CI, and P-values for treatment comparisons. Correlations among kidney function parameters and BW or systolic BP were analyzed using Spearman correlations. Statistical analyses were done using R (version 4.1.2).¹⁸

Results

Participant Disposition and Baseline Characteristics

In the T2D trial, 281 participants were randomized to receive placebo (n = 45), dulaglutide 1.5 mg (n = 46), or retatrutide 0.5 mg (n = 47), 4 mg (pooled, n = 47), 8 mg (pooled, n = 50), or 12 mg (n = 46). The efficacy population comprised 275 participants after excluding 6 participants who discontinued the study due to inadvertent enrollment. In the safety analyses, all 281 participants were included. In the obesity trial, 338 were randomized to receive placebo (n = 70), or retatrutide 1 mg (n = 69), 4 mg (pooled, n = 67), 8 mg (pooled, n = 70), or 12 mg (n = 62). The efficacy population comprised 335 participants after excluding 2 participants who discontinued treatment because of inadvertent enrollment and 1 participant who was randomized but not treated. In the safety analyses, 337 participants were included. Overall, 79% and 78% of participants in the T2D and obesity trials, respectively, completed the study on treatment.

Baseline characteristics are shown in Table 1. Mean creatinine/cystatin C–based eGFR values were 94.4 and 89.1 ml/min per 1.73 m² for the T2D and obesity trials, respectively. Among participants with available creatinine/cystatin C–based eGFR results, 240 (94%) and 319 (95%), respectively, had values ≥ 60 ml/min per 1.73 m². Geometric mean UACRs were 16.2 and 8.4 mg/g, respectively; 65 (23%) and 33 (10%) participants had a UACR ≥ 30 mg/g.

Table 1.

Baseline clinical characteristics and demographics

Characteristics	T2D study						Obesity study
	Placebo (n = 45)	RETA 0·5 mg (n = 47)	RETA 4·0 mg (n = 47)	RETA 8·0 mg (n = 50)	RETA 12·0 mg (n = 46)	Dulaglutide 1·5 mg (n = 46)	Placebo (n = 70)	RETA 1·0 mg (n = 69)	RETA 4·0 mg (n = 67)	RETA 8·0 mg (n = 70)	RETA 12·0 mg (n = 62)
Age, yrs	57.6 (10.8)	57.2 (10.0)	57.6 (9.0)	55.5 (8.3)	54.4 (9.7)	55.0 (10.4)	48.0 (12.5)	50.6 (13.3)	48.7 (13.1)	47.4 (12.4)	45.8 (12.2)
Sex, n (%)
Female	23 (51%)	23 (49%)	20 (43%)	31 (62%)	26 (57%)	33 (72%)	34 (49%)	33 (48%)	32 (48%)	34 (49%)	30 (48%)
Male	22 (49%)	24 (51%)	27 (57%)	19 (38%)	20 (44%)	13 (28%)	36 (51%)	36 (52%)	35 (52%)	36 (51%)	32 (52%)
Race, n (%)
American Indian or Alaska Native	0	0	0	0	2 (4%)	0	0	0	1 (3%)	0	1 (2%)
Asian	3 (7%)	0	2 (9%)	0	2 (4%)	1 (2%)	2 (3%)	0	0	1 (3%)	1 (2%)
Black or African American	5 (11%)	6 (13%)	3 (6%)	7 (14%)	3 (7%)	9 (20%)	8 (11%)	6 (9%)	6 (9%)	5 (7%)	2 (3%)
White	36 (80%)	40 (85%)	42 (89%)	43 (86%)	38 (84%)	36 (78%)	59 (84%)	61 (88%)	59 (88%)	63 (90%)	56 (90%)
Multiple	1 (2%)	1 (2%)	0	0	0	0	1 (1%)	0	1 (3%)	1 (3%)	2 (3%)
Body weight, kg	94.6 (16.6)	96.7 (18.1)	100.5 (24.4)	97.2 (20.9)	99.9 (22.7)	100.3 (23.4)	109.2 (20.9)	106.4 (19.8)	107.5 (23.7)	107.6 (21.1)	108.0 (21.7)
BMI, kg/m2	33.8 (4.9)	34.7 (5.6)	35.1 (7.0)	34.5 (6.1)	35.5 (6.9)	36.3 (6.8)	37.3 (5.9)	37.5 (5.9)	37.3 (5.2)	37.2 (5.7)	37.4 (6.0)
HbA1c, %	8.4% (1.1)	8.4% (1.2)	8.1% (1.1)	8.3% (1.2)	8.3% (1.1)	8.2% (0.9)	5.5% (0.4)	5.6% (0.4)	5.6% (0.4)	5.5% (0.4)	5.5% (0.4)
Duration of diabetes, years	8.7 (8.3)	8.8 (6.7)	9.4 (7.1)	6.6 (6.1)	7.9 (6.9)	7.2 (6.5)	-	-	-	-	-
eGFR, ml/min per 1·73 m2
Creatinine-based	90.7 (21.1)	95.1 (14.5)	91.1 (16.7)	88.1 (21.0)	91.1 (19.2)	91.1 (21.7)	89.4 (17.1)	87.9 (18.1)	87.7 (18.5)	93.8 (15.7)	93.6 (18.5)
Cystatin C–based	93.3 (20.3)	101.3 (17.8)	93.8 (22.4)	93.6 (25.0)	89.8 (24.0)	92.8 (23.4)	88.5 (19.1)	83.7 (20.0)	86.6 (22.7)	91.0 (17.0)	89.4 (19.1)
Creatinine/cystatin C–based	93.7 (21.9)	100.3 (16.3)	94.7 (20.5)	93.1 (24.6)	91.6 (22.9)	93.6 (23.7)	88.9 (16.6)	85.8 (17.8)	87.1 (19.0)	92.6 (14.5)	91.3 (16.5)
Participants with creatinine/cystatin C–based eGFR ≥60 ml/min per 1·73 m2, n (%)	41 (95%)	41 (100%)	40 (100%)	41 (91%)	39 (91%)	38 (88%)	67 (96%)	64 (93%)	61 (91%)	68 (99%)	59 (95%)
UACR, mg/g	15.4 (162)	14.0 (222)	13.0 (153)	20.7 (205)	24.6 (226)	12.5 (139)	8.7 (135)	8.7 (118)	8.1 (118)	8.3 (106)	8.3 (80)
Participants with UACR ≥ 30 mg/g, n (%)	10 (22%)	11 (23%)	11 (23%)	13 (26%)	15 (33%)	5 (11%)	8 (11%)	11 (16%)	4 (6%)	6 (9%)	4 (6%)
UACR for participants with BL UACR ≥ 30, mg/g	78.6 (108)	104.6 (159)	61.4 (64)	114.7 (184)	114.1 (170)	100.4 (402)	77.9 (109)	39.7 (51)	82.2 (252)	60.5 (62)	43.9 (32)
Blood pressure, mm Hg
Systolic	131.9 (15.0)	132.0 (11.6)	130.5 (12.3)	131.3 (11.7)	124.7 (13.7)	127.6 (12.1)	126.2 (12.6)	126.1 (14.6)	126.9 (12.8)	124.3 (12.6)	118.7 (15.5)
Diastolic	78.6 (9.8)	79.9 (8.0)	79.8 (9.0)	80.3 (8.7)	78.7 (8.4)	79.6 (8.1)	83.5 (9.5)	79.7 (9.2)	80.9 (8.5)	81.2 (9.2)	78.2 (11.2)
Participants with systolic blood pressure ≥ 140 mm Hg, n (%)	11 (24%)	11 (23%)	10 (21%)	12 (24%)	7 (15%)	7 (15%)	9 (13%)	11 (16%)	12 (18%)	7 (10%)	5 (8%)
Participants with diastolic blood pressure ≥ 90 mm Hg, n (%)	5 (11%)	3 (6%)	8 (17%)	7 (14%)	3 (7%)	4 (9%)	18 (26%)	10 (15%)	11 (16%)	12 (17%)	8 (13%)
Concomitant medication
ACE inhibitor, n (%)	14 (31%)	11 (23%)	15 (32%)	16 (32%)	13 (28%)	12 (26%)	15 (21%)	6 (9%)	10 (15%)	6 (9%)	12 (19%)
ARB, n (%)	10 (22%)	11 (23%)	11 (23%)	19 (38%)	9 (20%)	11 (24%)	12 (17%)	11 (16%)	7 (10%)	13 (19%)	6 (10%)
Diuretic, n (%)	10 (22%)	8 (17%)	10 (21%)	5 (10%)	12 (26%)	12 (26%)	14 (20%)	15 (22%)	5 (8%)	10 (14%)	8 (13%)
SGLT-2 inhibitor, n (%)	0	0	0	0	1 (2·2%)	0	0	0	0	0	0

ACE, angiotensin-converting enzyme; ARB, angiotensin 2 receptor blocker; BL, baseline; BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; RETA, retatrutide; SGLT-2, sodium-glucose co-transporter 2; T2D, type 2 diabetes mellitus; UACR, urine albumin-creatinine ratio.

Data are mean (SD) or n (%) and geometric mean (coefficient of variation [%]) for UACR for participants with BL UACR ≥ 30 mg/g.

Changes in Albuminuria

Among participants in the T2D trial, UACR remained stable during the 36-week treatment period in the placebo group (Figure 1a; Supplementary Table S1). UACR decreased in the retatrutide groups with the largest reduction observed in the retatrutide 12 mg (highest) dose group, where at week 36, UACR was changed by −37.0% from baseline (95% CI: −57.3 to −7.0) compared with placebo. At 36 weeks, UACR was not changed compared with placebo in the dulaglutide group. Retatrutide 12 mg was associated with a 32.2% (95% CI: −53.5 to −1.3) larger reduction in UACR compared with dulaglutide. In the obesity trial, UACR increased in the placebo group and was reduced in the retatrutide groups compared with placebo (Figure 1b; Supplementary Table S1). At week 48, UACR changed from baseline by −28.0% (95% CI: −46.0 to −4.1) and −31.5% (95% CI: −49.3 to −7.4) with the 8 mg and 12 mg doses of retatrutide compared with placebo, respectively. In both trials, participants with baseline UACR ≥ 30 mg/g had larger UACR reductions in the retatrutide groups than in the overall population, although the reductions did not reach statistical significance compared with placebo likely because of the small subgroups (T2D trial: n = 62; obesity trial: n = 33). In the T2D trial, retatrutide 12 mg compared with placebo was associated with changes in UACR from baseline by −48.4% (95% CI: −77.9 to 20.2; Figure 1c, Supplementary Table S1) at week 36. In the obesity trial, the UACR change at week 48 was greater with retatrutide 8 mg than with the 12 mg dose: −71.1% (95% CI: −92.8 to 15.7) and −3.7% (−80.1 to 365.0), respectively (Figure 1d, Supplementary Table S1).

Figure 1.

Changes in UACR with retatrutide versus placebo. The figure shows the percentage change from baseline in UACR. Data are least-squares means with error bars showing standard errors derived from the MMRM of the efficacy analysis set. The percentage change from baseline in UACR over time from the MMRM analysis for all participants in the (a) T2D study and (b) obesity efficacy population and among participants with baseline UACR of ≥30 mg/g in the (c) T2D and (d) obesity trials. MMRM, mixed model repeated measures. RETA, retatrutide. T2D, type 2 diabetes mellitus; UACR, urine albumin-to-creatinine ratio.

Changes in eGFR

In the T2D trial, an initial decrease in creatinine-based eGFR was observed at week 12 in the retatrutide groups, that was statistically significant compared with placebo for the 8 mg and 12 mg doses (Figure 2a; Supplementary Table S2). However, after week 12, eGFR values in the retatrutide groups increased to baseline and no eGFR differences between the retatrutide and placebo groups were observed at weeks 24 and 36. Creatinine-based eGFR in the dulaglutide group remained lower compared with placebo from week 12 until the end of treatment. As for changes in cystatin C– or creatinine/cystatin C–derived eGFR, no between-group differences were observed throughout the 36-week follow-up period (Figure 2b and c; Supplementary Table S2).

Figure 2.

Changes in eGFR with retatrutide versus placebo. The figure shows the change from baseline in Cr-, Cys–, and Cr/Cys–based eGFR. Change from baseline in Cr-, Cys–, and Cr/Cys–based eGFR over time from the MMRM analysis for participants in the T2D study efficacy population (a–c) and in the obesity study safety population (d–f). Data are least-squares means with error bars showing SEs derived from the MMRM of the safety analysis set. Cr, creatinine; Cys, cystatin C; eGFR, estimated glomerular filtration rate; MMRM, mixed model repeated measures; RETA, retatrutide; T2D, type 2 diabetes mellitus.

In the obesity trial, a reduction in creatinine-based eGFR was observed at week 12 in all retatrutide groups (Figure 2d; Supplementary Table S2) and also with placebo (in contrast to the T2D trial). After week 12, eGFR increased in a dose-associated manner in the retatrutide groups but remained stable in the placebo group. At week 48, retatrutide 4, 8, and 12 mg was associated with increased creatinine-based eGFR compared with placebo by 2.19 (95% CI: −1.31 to 5.69), 5.30 (1.86–8.74), and 8.48 (4.85–12.11) ml/min per 1.73 m², respectively. Creatinine-based eGFR decreased in the retatrutide groups during the 4-week washout period but remained higher than placebo with retatrutide 8 and 12 mg by 4.70 (1.31–8.10) and 5.94 (2.38–9.49) ml/min per 1.73 m², respectively. Cystatin C– and creatinine/cystatin C–derived eGFR increased in a dose-associated manner at week 24 and did not further change at week 48 (Figure 2e and f; Supplementary Table S2). At week 48, retatrutide 4, 8, and 12 mg were associated with increased cystatin C–derived eGFR compared with placebo by 6.10 (95% CI: 0.18–12.01), 9.22 (3.38–15.05) and 10.05 (3.92–16.17) ml/min per 1.73 m², respectively. The increases in creatinine/cystatin C–derived eGFR were similar to those observed with cystatin C–derived eGFR. Cystatin C– and creatinine/cystatin C–derived eGFR decreased toward baseline in the retatrutide groups during the 4-week washout period and were not different from placebo after the washout. Nonindexed results for eGFR based on these 3 equations are shown in Supplementary Table S3.

Changes in BP

Retatrutide treatment was associated with dose-dependent reductions in systolic and diastolic BP in the T2D and obesity trials. In the T2D trial, systolic and diastolic BP were reduced in the retatrutide 12 mg group compared with placebo by −12.2 (95% CI: −18.2 to −6.2; Figure 3a, Supplementary Table S4) and −2.7 (95% CI: −6.0 to 0.7; Figure 3b, Supplementary Table S5) mm Hg at week 36. The decrease in systolic BP at 36 weeks was more pronounced in participants with baseline values ≥ 140 mm Hg compared with the overall population (Supplementary Figure S1b and Supplementary Table S6). Systolic and diastolic BP reductions were not observed with dulaglutide in the T2D trial. In the obesity trial, retatrutide 12 mg compared with placebo, was associated with reduced systolic and diastolic BP by −10.5 mm Hg (95% CI: −15.2 to −5.8; Figure 3c, Supplementary Table S4) and −5.5 mm Hg (95% CI: −8.8 to −2.2; Figure 3d, Supplementary Table S5), respectively, at 48 weeks. The reductions in systolic and diastolic BP at 48 weeks with retatrutide were similar (although not consistently statistically significant vs. placebo) among subgroups of participants with elevated or normal BP at baseline (Supplementary Figures S1a-d and S2a-d, Supplementary Tables S6 and S7). In both the T2D and obesity trials, systolic and diastolic BP increased toward baseline at the end of the 4-week washout period (Figure 3).

Figure 3.

Changes in systolic and diastolic BP with retatrutide versus placebo. Data are presented as least-squares means with error bars showing SEs derived from the MMRM of the efficacy analysis set. Changes from baseline in BP over time from the MMRM analysis for all participants in the T2D study efficacy population (a, systolic; b, diastolic) and for all participants in the obesity study efficacy population (c, systolic; d, diastolic). BP, blood pressure; MMRM, mixed model repeated measures; RETA, retatrutide; T2D, type 2 diabetes mellitus; UACR, urine albumin-to-creatinine ratio.

Changes in Concomitant Medications

In Table 1, we report on the use of angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, diuretics and sodium-glucose co-transporter 2 inhibitors at baseline. In the obesity study, discontinuation of at least 1 antihypertensive medication occurred in 41% and 30% of participants in the 8 mg and 12 mg groups, respectively.¹⁴ In the T2D study, discontinuation of at least 1 antihypertensive medication occurred in 22% and 15% of participants in the 8 mg and 12 mg groups, respectively. Sodium-glucose co-transporter 2 inhibitors were initiated after randomization in 8 participants in the T2D study and none in the obesity study.

Correlations

In the T2D trial, there were no consistent associations between BW changes from baseline to week 36 and eGFR changes regardless of whether eGFR was derived from creatinine, cystatin C, or both (Figure 4a-c). The only exception was the retatrutide 4 mg dose group where BW change correlated with eGFR change at week 36. In the obesity trial, BW changes at week 48 in the retatrutide 4, 8, and 12 mg dose groups correlated with creatinine– and creatinine/cystatin C–derived eGFR (Figure 4d and f). There were no correlations between these parameters when eGFR was estimated from cystatin C (Figure 4e). In both the T2D and obesity trials, there were no consistent patterns of correlations between changes from baseline to end of treatment in UACR and eGFR (Supplementary Figure S3a-f) or between UACR and systolic BP (Supplementary Figure S4a and b). Similarly, changes in BW were not consistently correlated with changes in systolic BP (Supplementary Figure S5a and b).

Figure 4.

Correlation scatterplots for changes from baseline in bodyweight versus (a and d) Cr-, (b and e) Cys–, and (c and f) Cr/Cys–based Δ eGFR for participants in the (a–c) T2D (week 36) and (d–f) obesity (week 48) trials. Cr, creatinine; Cys, cystatin C; eGFR, estimated glomerular filtration rate; LY, life year; RETA, retatrutide; T2D, type 2 diabetes mellitus.

Safety

Because the main safety findings from both trials have been reported previously,^14,15 kidney-related safety parameters are summarized here. In the T2D trial, there was 1 serious adverse event (AE) of acute kidney injury in the placebo group. One participant in the retatrutide 12 mg group experienced an AE of mild kidney impairment. One participant in the retatrutide 8 mg group had an AE of moderate dehydration. Four participants (1.4%) experienced hypotension or orthostatic hypotension; all were in retatrutide groups. Four participants (1.4%) experienced fractures; 3 were in the retatrutide groups and 1 was in the dulaglutide group. In the obesity trial, there was 1 serious AE of acute kidney injury in the retatrutide 8 mg group that was considered possibly secondary to a SARS-CoV-2 infection. There were 3 other treatment-emergent AEs of CKD or renal failure as follows: 1 in the placebo group and 2 in retatrutide groups. There were 4 participants (1.2%) with AEs of dehydration as follows: 3 were in retatrutide groups and 1 was in the placebo group. Nine participants (2.7%) experienced hypotension or orthostatic hypotension of which 8 (2.4%) were in retatrutide groups and 1 (0.3%) was in the placebo group. Three participants (0.9%) had fractures; all were in the placebo group. There were no clinically significant changes in electrolyte abnormalities in either trial. Mean values of serum electrolytes at different time points in both trials are presented in Supplementary Table S8.

Discussion

Retatrutide, an agonist of the GIP, GLP-1, and glucagon receptors, improved glycemic control and reduced BW in 2 dose-ranging clinical trials in adults with T2D or obesity.^14,15 In this exploratory kidney-specific analysis, we report that albuminuria was reduced with higher doses of retatrutide, compared with placebo, in participants with T2D and in those with obesity but without T2D. The eGFR profile over time showed an acute reduction in glomerular filtration rate (GFR) upon initiation of retatrutide in both populations followed by an increase in eGFR to baseline values in participants with T2D. However, the increase in eGFR was more pronounced in participants in the obesity trial with eGFR values exceeding their baseline values after 48 weeks by 5 to 10 ml/min per 1.73 m² when estimated with creatinine and by 10 to 15 ml/min per 1.73 m² when estimated with cystatin C. This increase in eGFR was mostly reversed 4 weeks after discontinuation of retatrutide. Retatrutide was generally well-tolerated with no clinically relevant changes in electrolytes.

Retatrutide 12 mg once weekly was associated with reduced albuminuria in participants with T2D and in those with obesity. Previous clinical trials have shown an association with reduced albuminuria with incretin-based therapies. In patients with CKD and T2D, sustained reductions in albuminuria have been observed with the GLP-1 receptor agonists, semaglutide and dulaglutide.^19,20 Treatment with semaglutide 2.4 mg once weekly compared with placebo also resulted in a profound reduction in albuminuria of 52% in patients with CKD without T2D.²¹ These observations were consistent regardless of baseline sodium-glucose co-transporter 2 inhibitor use or albuminuria. Treatment with the GIP/GLP-1 receptor agonist, tirzepatide was associated with reduced albuminuria in patients with T2D or obesity, although most patients in these studies had normal albuminuria and did not have CKD.^22,23 A randomized controlled trial in patients with diabetic kidney disease and severe albuminuria demonstrated that the GLP-1/glucagon receptor agonist, cotadutide reduced UACR up to 50% after 14 weeks of treatment.¹² Our data add to a growing body of evidence that nutrient stimulated hormone-based therapies may reduce albuminuria, which may have important implications for long-term kidney function.

The 32% reduction in UACR observed with retatrutide in participants with T2D may be clinically relevant because treatments that reduce albuminuria by > 30% are associated with a high likelihood to reduce the risk of clinical kidney outcomes.²⁴ The reduced albuminuria observed with retatrutide was more pronounced among participants with T2D, which may be attributed to their higher baseline UACR compared with those in the obesity trial. It is also possible that albuminuria may have been reduced to a lesser degree in participants with obesity because of the larger increase in eGFR, which may increase albumin filtration and attenuate the potential albuminuria lowering effect. The reduced albuminuria observed with retatrutide compared with placebo seemed to be more pronounced in the subgroup of participants with UACR ≥ 30 mg/g at baseline (participants with micro- or macroalbuminuria) which may translate into higher absolute and relative risk reductions for clinically relevant kidney and cardiovascular events. However, this hypothesis requires confirmation in a dedicated kidney outcome trial.

The mechanisms for how retatrutide potentially reduces albuminuria are incompletely understood. The 2 highest retatrutide doses were associated with clinically relevant reductions in BP, which could explain the observed decreases in albuminuria and may contribute to long-term clinical benefits. However, we did not observe consistent associations between changes in BP and UACR in either trial, suggesting that the reduced albuminuria in the retatrutide treatment groups was unlikely explained by concomitant reductions in BP. Similarly, changes in BW and systolic BP were not consistently correlated. Other indirect effects, such as reductions in HbA1c and BW, may contribute to the potential albuminuria-lowering effect. The 32% larger reduction in albuminuria with retatrutide compared with dulaglutide in participants with T2D suggests that GIP and/or glucagon receptors may contribute to this potential beneficial effect. GIP receptors have been found in adipose tissue in various organs including the kidneys.²⁵ Targeting GIP receptors may have a favorable impact on inflammation that may reduce tubulo-interstitial damage and reduce albuminuria.²⁶ In addition, experimental data suggest a potential kidney protective role of targeting glucagon receptors in the kidney. In a mouse model, kidney-selective glucagon receptor deficiency led to hypertension and profound metabolic defects in the kidney including inflammation and fibrosis.¹⁶ Activating kidney-specific glucagon receptors through the administration of a GIP/GLP-1/glucagon agonist may reverse hypertension and inflammation in the kidney that then ameliorates albuminuria.

The eGFR profile changes over time with an initial decrease followed by an increase above baseline in eGFR has not been observed with any other pharmacologic interventions, to the best of our knowledge. The eGFR increase in the obesity trial was accompanied by a significant UACR decrease in the retatrutide group, suggesting that the increase in glomerular filtration was accompanied by a lower intraglomerular pressure and kidney stress. The transient eGFR decrease upon retatrutide initiation is consistent with similar transient eGFR decreases with GLP-1 and GIP/GLP-1 receptor agonists.²⁷ The underlying mechanisms of the initial reduction in eGFR with retatrutide may be attributed to transmission of a lower systemic BP in the glomeruli, or improvements in glycemic control and BW, which can attenuate neurohormonal activation and other factors associated with glomerular hypertension.²⁸ Furthermore, GLP-1 receptor activation can induce a proximal tubular natriuresis via inhibition of sodium-hydrogen exchanger 3, an effect proposed to activate tubuloglomerular feedback which may reduce glomerular hyperfiltration and GFR.²⁹ Why eGFR increased after 12 weeks of retatrutide treatment in the current studies and why the observed increase was more pronounced in participants with obesity compared with T2D is incompletely understood. Hypothetically, retatrutide may have had different pharmacodynamic effects on eGFR over time, because of the dose escalation scheme combined with activation of 3 different receptors with varying dose-responses characteristics. Mechanistic studies, such as the ongoing retatrutide iohexol-derived GFR study (NCT05936151), are required to better understand the physiological pathways underlying the effects of retatrutide on GFR over time and may help explain differences between patient populations.

An important question is whether the serum creatinine– and cystatin C–based eGFR equations reflect true changes in kidney function during treatments that reduce body mass in a population with T2D or obesity. Reductions in BW, and in particular muscle mass, may affect plasma creatinine levels without real changes in GFR, because skeletal muscle is the main source of creatinine.³⁰ In addition, reductions in body fat may affect plasma cystatin C levels without real changes in GFR because cystatin C is mainly produced in adipose tissue.³¹ In our study, we did not find correlations between BW changes and cystatin C–derived eGFR in the T2D and obesity trials. However, in the obesity study, changes in BW correlated with changes in creatinine– or creatinine/cystatin C–derived eGFR suggesting that cystatin C–based eGFR is the preferred method to monitor eGFR during treatment with retatrutide. This notion is supported by the observation that eGFR reversed toward baseline 4 weeks after retatrutide discontinuation whereas BW gains with retatrutide 8 mg and 12 mg doses were, respectively, 2.5% and 3.2% during the same washout period; suggesting that the increase in eGFR is a pharmacodynamic effect unrelated to body mass changes. Future retatrutide studies with iohexol-measured GFR may help to inform which GFR estimation equation performs best to monitor kidney function over time during retatrutide treatment.

Limitations of this study include that this was a post hoc exploratory analysis of 2 randomized controlled trials with limited data for subgroup analyses and no adjustments for multiple comparisons. The results are therefore preliminary and can only be regarded as hypothesis-generating. Second, we recognize that by design, few participants with preexisting kidney disease were included in these trials; the proportion of participants with an eGFR < 60 ml/min per 1.73 m² (creatinine/cystatin C equation) was 5.9% in the T2D trial and 5.3% in the obesity trial, which is far fewer than would be enrolled in a dedicated kidney outcome trial. In addition, only half of all participants were using renin-angiotensin-system inhibitors at baseline and UACR measurements were based on single spot urine samples. Similarly, because of the relatively short treatment period in both trials, no kidney outcomes occurred during the trials. Finally, although the magnitude of the percentage reduction in albuminuria observed with retatrutide treatment is associated with long-term kidney function preservation in previous trials, the absolute reduction in albuminuria was modest because the majority of patients had normal albuminuria. For these reasons, our results require confirmation in larger and longer clinical trials enrolling patients with established CKD. The TRIUMPH-OUTCOMES trial (NCT06383390) in people with obesity (with or without T2D) is designed to assess the potential cardiovascular and kidney protective effects of retatrutide and will provide more insight when completed.

In conclusion, in 2 dose-finding clinical trials of retatrutide, an agonist of the GIP, GLP-1, and glucagon receptors, higher doses of retatrutide were associated with reduced albuminuria and systolic BP compared with placebo in participants with T2D and/or obesity. In participants with T2D, no change in eGFR was observed after 36 weeks of treatment. However, in those with obesity but without T2D, eGFR increased in a dose-associated manner after 48 weeks of treatment. These findings warrant further investigation in clinical trials including people with CKD.

Disclosure

HJLH reports funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk (all to the University of Groningen); consulting fees from AstraZeneca, Alexion, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Novartis, Novo Nordisk, and Travere Therapeutics; payment of honoraria for lectures from AstraZeneca, Bayer, and Novo Nordisk; support for traveling to and attending the American Diabetes Association meeting and American Society of Nephrology meeting from AstraZeneca and Eli Lilly (to HJLH and the University of Groningen); and receipt of the study drug from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk. ZL, YD, KD, TC, AH, and MLH are employees and shareholders of Eli Lilly and Company.

Supplementary Material

Supplementary File (PDF)

Figure S1. Changes from baseline in systolic blood pressure among subgroups of participants with baseline systolic blood pressure < 140 versus ≥ 140 mm Hg for the (A and B) T2D study efficacy population and (C and D) the obesity study efficacy population. Figure S2. Changes from baseline in diastolic blood pressure among subgroups of participants with baseline diastolic blood pressure < 90 versus ≥ 90 mm Hg for the (A and B) T2D study efficacy population and (C and D) the obesity study efficacy population. Figure S3. Correlation scatterplots for percent changes from baseline in urine albumin-to-creatinine ratio versus (A and D) creatinine, (B and E) cystatin C–based eGFR, and (C and F) creatinine/cystatin C–based Δ eGFR for participants in (A and C) the T2D (week 36) and (D and F) obesity (week 48) trials. Figure S4. Correlation scatterplots for percent changes from baseline in urine albumin-to-creatinine ratio versus systolic blood pressure for participants in the (A) T2D (week 36) and (B) obesity (week 48) trials. Figure S5. Correlation scatterplots for changes in body weight (kg) from baseline versus systolic blood pressure for participants in the (A) T2D (week 36) and (B) obesity (week 48) trials. Table S1. Percent changes in UACR for participants in the T2D and obesity trials. Table S2. Changes in creatinine, cystatin C–based eGFR, and creatinine/cystatin C–based eGFR for participants in the T2D and obesity trials. Table S3. Nonindexed changes in creatinine–, cystatin C–, and creatinine/cystatin C–based eGFR for participants in the T2D and obesity trials. Table S4. Changes in systolic blood pressure (mm Hg) for participants in the T2D and obesity trials. Table S5. Changes in diastolic blood pressure for participants in the T2D and obesity trials. Table S6. Changes in systolic blood pressure for participants with baseline SBP < 140 mm Hg or ≥ 140 mm Hg in the T2D and obesity trials. Table S7. Changes in diastolic blood pressure for participants with baseline diastolic blood pressure ≤ 90 mm Hg and > 90 mm Hg in the T2D and obesity trials. Table S8. Analyses of circulating electrolytes for participants in the T2D and obesity trials. CONSORT Checklist.