Tirzepatide for Obesity in Adults ≥ 65 Years: A Post Hoc Analysis of the SURMOUNT and SUMMIT Clinical Trials

Nasreen Alfaris; Robert F Kushner; Jianghao Li; Kevin L Chen; Mia Fenimore; Boris Calderon; Adam Stefanski

doi:10.1111/dom.70991

. 2026 Jun 16;28(9):8072–8083. doi: 10.1111/dom.70991

Tirzepatide for Obesity in Adults ≥ 65 Years: A Post Hoc Analysis of the SURMOUNT and SUMMIT Clinical Trials

Nasreen Alfaris ^1,^✉, Robert F Kushner ², Jianghao Li ³, Kevin L Chen ³, Mia Fenimore ³, Boris Calderon ³, Adam Stefanski ³

PMCID: PMC13449079 PMID: 42303274

ABSTRACT

Aims

Tirzepatide is a once‐weekly glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist (RA) approved for weight management in adults with obesity. Data on older adults remain limited, however. This study aimed to examine tirzepatide's safety and efficacy in adults aged ≥ 65 years with obesity across Phase 3 clinical trials.

Materials and Methods

This post hoc analysis evaluated results from the SURMOUNT‐1 through ‐5 (including SURMOUNT‐1 3‐year study), SURMOUNT‐OSA and SUMMIT trials. Efficacy and safety of tirzepatide were compared between participants aged ≥ 65 years and < 65 years. Efficacy outcomes, analysed by study, were assessed at varying points depending on trial design. Safety outcomes in the pooled population were assessed throughout the treatment period.

Results

Tirzepatide treatment was associated with clinically meaningful weight reduction and favourable treatment differences in cardiometabolic risk factors and quality‐of‐life measures in adults ≥ 65 years, with broadly comparable results to those observed in adults < 65 years. No clinically meaningful differences in adverse event (AE) rates between tirzepatide and placebo were observed in older adults for gastrointestinal tolerability, falls, fractures, depression outcomes, pancreatitis, and renal, hepatic, gallbladder and biliary‐related AEs. No clinically relevant risks beyond those inherent to older age were detected in adults ≥ 65 versus < 65 years.

Conclusions

In this post hoc analysis from Phase 3 clinical trials, efficacy and safety profiles of tirzepatide in adults aged ≥ 65 years with obesity were comparable to those in adults aged < 65 years. This study supports tirzepatide's use in older adults when considering risks and benefits.

Keywords: elderly, GIP, GLP‐1, obesity therapy, weight management

1. Introduction

Obesity is a chronic progressive disease with rising prevalence across all age groups [1, 2]. In the US, approximately 30% of adults aged ≥ 65 years have obesity [3], and this proportion is increasing as the population ages [2, 4]. An estimated 1 in 3 adults older than 25 years is expected to have obesity by 2050, when a quarter of these adults will be over the age of 65 [2].

In older adults, obesity carries distinct clinical concerns. Beyond the well‐established complications, including cardiovascular disease risk, type 2 diabetes (T2D), hypertension, dyslipidemia, obstructive sleep apnea (OSA), heart failure with preserved ejection fraction (HFpEF) and osteoarthritis [1, 5], this population faces compounding risks of functional decline, disability and loss of independence that disproportionately reduce quality of life and increase healthcare utilization [4, 6]. Older adults often have diminished muscle mass and anabolic resistance, predisposing them to sarcopenia [7]. Even modest muscle loss can impair physical function and worsen frailty, concerns that may be amplified in the context of weight reduction interventions [7]. The co‐occurrence of obesity with age‐related multimorbidity creates a particularly high burden in this group [8], underscoring the urgency of effective and thoroughly monitored therapy aiming at weight reduction.

Obesity treatment in older adults requires shared decision‐making regarding the risks and benefits of weight reduction. Lifestyle intervention remains fundamental; however, its feasibility may be limited in individuals with severe obesity or functional limitations [4]. Bariatric surgery in this population has demonstrated meaningful weight reduction and metabolic benefits, but with lower efficacy and higher risk compared with younger patients [4]. Pharmacological therapy, therefore, represents a feasible, evidence‐based option for older adults, providing clinically meaningful weight reduction alongside metabolic benefits [9].

Tirzepatide, a once‐weekly injectable glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist (RA), has demonstrated substantial body weight reductions and improvements in cardiometabolic risk factors and patient‐reported outcomes (PROs) in people with obesity [10, 11]. Tirzepatide has also demonstrated beneficial effects on obesity‐related complications (ORCs), including lower risk of a composite of death from cardiovascular causes or worsening heart failure (HF) in patients with HFpEF and obesity (SUMMIT) [12], and clinically meaningful changes in sleep‐disordered breathing in patients with obesity and OSA (SURMOUNT‐OSA) [13]. In people with obesity and prediabetes, 3 years of tirzepatide treatment resulted in substantial, sustained weight reduction and lower risk of progression to T2D [14].

Given specific considerations of older patients with obesity, there is a need to understand tirzepatide when used for weight management in this population. This post hoc analysis of the SURMOUNT and SUMMIT Phase 3 trials assessed tirzepatide's safety and efficacy in participants aged ≥ 65 years with obesity or overweight compared to those aged < 65 years.

2. Materials and Methods

2.1. Study Designs

All seven Phase 3 clinical trials in this post hoc analysis are registered with clinicaltrials.gov under NCT04184622 (SURMOUNT‐1), NCT04657003 (SURMOUNT‐2), NCT04657016 (SURMOUNT‐3), NCT04660643 (SURMOUNT‐4), NCT05822830 (SURMOUNT‐5), NCT05412004 (SURMOUNT‐OSA) and NCT04847557 (SUMMIT). These trials were conducted in accordance with the principles of the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practices Guideline, as well as other applicable laws and regulations. Trial protocols were approved by appropriate independent ethics committees or institutional review boards at each site. All participants provided written informed consent.

In these multicentered, randomized trials, the safety and efficacy of tirzepatide were compared with placebo or active comparator in adults with obesity or overweight, including those with coexisting T2D (SURMOUNT‐2), HFpEF (SUMMIT) and OSA (SURMOUNT‐OSA).

Key eligibility criteria and primary results have been published [10, 11, 12, 13, 14, 15, 16, 17]. Table S1 summarizes study designs, primary endpoints and inclusion/exclusion criteria.

This post hoc analysis of the SURMOUNT‐1 to ‐5 (including SURMOUNT‐1 3‐year study), SUMMIT, and SURMOUNT‐OSA clinical trials compared tirzepatide's safety and efficacy in adults with obesity or overweight aged ≥ 65 versus < 65 years across doses up to 15 mg.

2.2. Post Hoc Analysis Assessments

Baseline characteristics for the pooled population across all trials were analysed by age subgroup (≥ 65 or < 65 years) and T2D status.

Due to study design and patient population differences, efficacy outcomes were evaluated by trial and age subgroup, including changes in body weight, cardiometabolic risk factors and health‐related quality of life (HRQoL) assessed with PROs. Additional efficacy outcomes assessed included risk reduction for new‐onset T2D in people with coexisting prediabetes (SURMOUNT‐1 3‐year study), and changes in apnea‐hypopnea index (AHI) in people with obesity and OSA (SURMOUNT‐OSA).

Body composition changes assessed in SURMOUNT‐1 were compared between age subgroups. Dual‐energy X‐ray absorptiometry (DXA) parameters were previously reported for pooled tirzepatide doses and age subgroups < 50, 50 to < 65 and ≥ 65 years [18]. The present analysis extends these findings, reporting tirzepatide dose‐specific estimates in participants aged ≥ 65 and < 65 years.

Safety endpoints were assessed in a pooled population across all trials by age subgroup, including treatment‐emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation and deaths. Other adverse events (AEs) assessed included AEs possibly due to loss of fat‐free mass (FFM), gastrointestinal (GI) AEs, major adverse cardiovascular events (MACE), Patient Health Questionnaire‐9 (PHQ‐9) depression outcomes, pancreatitis, and renal, hepatic, gallbladder and biliary AEs.

2.3. Statistical Analysis

Efficacy analyses included all randomized participants from SUMMIT and the modified intent‐to‐treat (mITT) populations of SURMOUNT‐1, ‐2, ‐3, ‐4, ‐5 and ‐OSA (all randomized participants who received at least one dose of study drug), mirroring the analysis sets of each respective parent trial. Safety analyses included all participants who received at least one dose of the study drug across all trials.

Efficacy outcomes are reported at the primary endpoint for each trial (Week 52 [SURMOUNT‐OSA, SUMMIT], Week 72 [SURMOUNT‐1, ‐2, ‐3 and ‐5], Week 88 [SURMOUNT‐4] and Week 176 [SURMOUNT‐1 3‐year study]) and were assessed using the efficacy estimand. For SURMOUNT‐3 and SURMOUNT‐4, baseline refers to the value at randomization (following the 12‐week intensive lifestyle intervention lead‐in and 36‐week open‐label tirzepatide lead‐in, respectively). Analyses of continuous endpoints were done using a mixed‐model for repeated measures (MMRM). Binary endpoints were analysed using a logistic regression model. Time‐to‐event endpoints were assessed using a Cox proportional hazards model. Covariates included as adjustment factors in each model reflect those included within each respective parent trial. See Text S1 for details of covariates and handling of missing values.

Heterogeneity tests for interactions between treatment and age subgroups were conducted using a significance threshold of p = 0.1. All other hypothesis tests were conducted at a 5% significance level without multiplicity adjustment. Analyses were performed using SAS Version 9.4 (SAS Institute) and R Version 4.4.2.

3. Results

3.1. Baseline Characteristics

A total of 6410 individuals were included in this analysis, comprising 926 adults aged ≥ 65 years and 5484 adults aged < 65 years. Of these, 1290 participants had coexisting T2D, including 351 adults aged ≥ 65 years and 939 adults aged < 65 years. This subgroup comprised the full SURMOUNT‐2 trial population and a subset of participants from the SUMMIT trial, which enrolled adults both with and without T2D. Of the 926 adults aged ≥ 65 years, 199 (21.5%) were aged ≥ 75 years and 62 (6.7%) were aged ≥ 80 years.

Baseline characteristics by age subgroup and T2D status are summarized in Table S2 and were generally comparable across age subgroups. Participants ≥ 65 years had a longer duration of obesity and a lower estimated glomerular filtration rate (eGFR) than those < 65 years. Additionally, older participants generally had a greater baseline comorbidity burden (Table S3).

3.2. Efficacy

3.2.1. Change in Body Weight

Tirzepatide treatment was associated with body weight reduction from baseline in both age subgroups across all trials (Figure 1). In adults ≥ 65 years without T2D, comprising participants of SURMOUNT‐1, SURMOUNT‐1 3‐year study, SURMOUNT‐3, SURMOUNT‐4, SURMOUNT‐5 and SURMOUNT‐OSA, the mean percent body weight change in tirzepatide‐treated participants ranged from −14.0% (SURMOUNT‐1 3‐year study, tirzepatide 5 mg) to −25.9% (SURMOUNT‐1 3‐year study, tirzepatide 15 mg). In those < 65 years without T2D, the mean percent body weight change in tirzepatide‐treated participants ranged from −15.5% to −22.7% (SURMOUNT‐1 3‐year study, tirzepatide 5 mg and tirzepatide 15 mg, respectively). In SURMOUNT‐4, after 36 weeks of open‐label tirzepatide treatment, which led to a mean 20.9% body weight reduction [16], an additional 52 weeks of tirzepatide treatment was associated with further mean percent body weight change of −7.0% and −6.6% in the older and younger subgroups, respectively.

Percent change in body weight from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years). CI, confidence interval; MBE, model‐based estimate; MMRM, mixed‐model for repeated measures; MTD, maximum tolerated dose; N, number of subjects with non‐missing baseline value and at least one non‐missing postbaseline value of the response variable; TZP, tirzepatide. Percent change in body weight derived from MMRM analysis for the efficacy estimand, completed separately for each study. ^†MBE of % change difference (95% CI) between tirzepatide and comparator from baseline; for SURMOUNT‐3 and ‐4, baseline is defined at randomization. Comparator was placebo for all studies except SURMOUNT‐5 (semaglutide MTD). All tests for treatment‐by‐age‐group interaction were not statistically significant at a significance threshold of p = 0.1.

In SURMOUNT‐2, which studied participants with obesity and coexisting T2D, mean percent body weight change in tirzepatide‐treated participants ranged from −13.9% (tirzepatide 10 mg) to −15.7% (tirzepatide 15 mg) in those ≥ 65 years and −13.3% (tirzepatide 10 mg) to −15.6% (tirzepatide 15 mg) in those < 65 years.

The SUMMIT trial studied participants with obesity and coexisting HFpEF and included participants with and without T2D. Mean percent body weight change in tirzepatide‐treated participants of the SUMMIT trial was −14.7% in those ≥ 65 years and −14.5% in those < 65 years, both with tirzepatide maximum tolerated dose (MTD).

Across trials and doses, the proportions of participants achieving ≥ 5%, ≥ 10% and ≥ 15% body weight reduction thresholds were similar in both age subgroups (Figure S1).

3.2.2. Change in PROs

Treatment differences in change from baseline in Short Form 36 Version 2 (SF‐36v2) Physical Functioning Domain score and Impact of Weight on Quality of Life‐Lite Clinical Trials (IWQOL‐Lite‐CT) Physical Function Composite score generally favoured tirzepatide versus placebo or active comparator across trials and in both age subgroups (Figure 2). Treatment differences in SF‐36v2 Mental Component Summary score change from baseline were generally small in magnitude and variable across trials (Figure S2).

Change in (A) SF‐36v2 Physical Functioning Domain score and (B) IWQOL‐Lite‐CT Physical Function Composite score from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years). CI, confidence interval; IWQOL‐Lite‐CT, Impact of Weight on Quality of Life‐Lite Clinical Trials; MBE, model‐based estimate; MMRM, mixed‐model for repeated measures; MTD, maximum tolerated dose; N, number of subjects with non‐missing baseline value and at least one non‐missing postbaseline value of the response variable; SF‐36v2, Short Form 36 Version 2; TZP, tirzepatide. Change in SF‐36v2 Physical Functioning Domain score and IWQOL‐Lite‐CT Physical Function Composite score derived from MMRM analysis for the efficacy estimand, completed separately for each study. Data are MBEs and 95% CIs of the change difference between tirzepatide and comparator, from baseline to Week 52 (SURMOUNT‐OSA), Week 72 (SURMOUNT‐1, ‐2, ‐3, ‐5), Week 88 (SURMOUNT‐4) and Week 176 (SURMOUNT‐1 3‐year study); for SURMOUNT‐3 and ‐4, baseline is defined at randomization. Comparator was placebo for all studies except SURMOUNT‐5 (semaglutide MTD). TZP doses for SURMOUNT‐1 3‐year study pooled for SF‐36v2 Physical Functioning Domain score analysis due to low sample size of the ≥ 65 years subgroup. SURMOUNT‐3 not included in SF‐36v2 Physical Functioning Domain score analysis due to insufficient sample size of the ≥ 65 years subgroup. SF‐36v2 Physical Functioning Domain score not assessed in SUMMIT. IWQOL‐Lite‐CT Physical Function Composite score not assessed in SURMOUNT‐5, SURMOUNT‐OSA or SUMMIT. All tests for treatment‐by‐age‐group interaction were not statistically significant at a significance threshold of p = 0.1, except for change in IWQOL‐Lite‐CT Physical Function Composite score in SURMOUNT‐2 (p = 0.05).

3.2.3. Change in Cardiometabolic Risk Factors

Treatment differences in change from baseline in waist circumference and systolic blood pressure (SBP), and percent change from baseline in non‐high‐density lipoprotein (non‐HDL) cholesterol, favoured tirzepatide versus placebo or active comparator in both age subgroups across trials (Figure 3). Treatment differences favouring tirzepatide versus placebo or active comparator were also generally observed in both age subgroups in change from baseline in waist‐to‐height ratio (WtHR), diastolic blood pressure (DBP) and haemoglobin A1c (HbA1c) (among those without T2D at baseline) and percent change from baseline in low‐density lipoprotein (LDL) cholesterol, high‐density lipoprotein (HDL) cholesterol, triglycerides and high‐sensitivity C‐reactive protein (hsCRP) (Figures S3–S9).

(A) Change in waist circumference (cm), (B) change in SBP (mmHg) and (C) percent change in non‐HDL from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years). CI, confidence interval; MBE, model‐based estimate; MMRM, mixed‐model for repeated measures; MTD, maximum tolerated dose; N, number of subjects with non‐missing baseline value and at least one non‐missing postbaseline value of the response variable; non‐HDL, non‐high‐density lipoprotein; SBP, systolic blood pressure; TZP, tirzepatide. Change in waist circumference, change in SBP and percent change in non‐HDL were derived from MMRM analysis for the efficacy estimand, completed separately for each study. Data are MBEs and 95% CIs of the change difference (Panel A and B) or % change difference (Panel C) between tirzepatide and comparator, from baseline to Week 52 (SURMOUNT‐OSA, SUMMIT), Week 72 (SURMOUNT‐1, ‐2, ‐3, ‐5), Week 88 (SURMOUNT‐4) and Week 176 (SURMOUNT‐1 3‐year study); for SURMOUNT‐3 and ‐4, baseline is defined at randomization. Comparator was placebo for all studies except SURMOUNT‐5 (semaglutide MTD). All tests for treatment‐by‐age‐group interaction were not statistically significant at a significance threshold of p = 0.1, except for percent change in non‐HDL in SURMOUNT‐5 (p = 0.02).

3.2.4. Glucose Control in Participants With Obesity and T2D

In participants with coexisting T2D in SURMOUNT‐2 and SUMMIT, tirzepatide treatment was associated with comparable HbA1c reductions in both age groups. In SURMOUNT‐2, HbA1c change from baseline to Week 72 in the older subgroup was −2.0% with tirzepatide 10 and 15 mg and −0.04% with placebo, versus −2.2%, −2.3% and −0.2%, respectively, in the younger subgroup. In SUMMIT, HbA1c change from baseline to Week 52 in the older subgroup was −1.1% with tirzepatide MTD and 0.04% with placebo, versus −1.1% and −0.2%, respectively, in the younger subgroup. For both trials, tests for treatment‐by‐age‐group interaction were not statistically significant at a significance threshold of p = 0.1.

3.2.5. Diabetes Risk Reduction in Participants With Obesity and Prediabetes

In the SURMOUNT‐1 3‐year study of participants with obesity and prediabetes, T2D was diagnosed in one tirzepatide‐treated participant (1.5%; 5 mg) versus 5 placebo‐treated participants (23.8%) in those ≥ 65 years (hazard ratio 0.12 for tirzepatide 5 mg; p = 0.02). In those < 65 years, T2D was diagnosed in eight tirzepatide‐treated participants (1.1%; 3 with 5 mg, 5 with 10 mg) versus 29 placebo‐treated participants (11.6%) (hazard ratios 0.09 and 0.14 for tirzepatide 5 and 10 mg, respectively; p < 0.001 for both).

3.2.6. Outcomes in Participants With Obesity and OSA

In SURMOUNT‐OSA, treatment differences in percent change from baseline in AHI favoured tirzepatide versus placebo in participants < 65 years in both trials, while confidence intervals were wide and included zero in those ≥ 65 years (Figure S10).

3.2.7. Body Composition

DXA‐assessed body composition changes at Week 72 in SURMOUNT‐1 are presented in Figure 4. Tirzepatide was associated with greater reductions in total body fat mass, lean mass, visceral fat mass and fat‐to‐lean mass ratio than placebo, with comparable results in both age subgroups.

DXA‐assessed body composition changes from baseline in SURMOUNT‐1 trial participants by age subgroups (≥ 65 and < 65 years). CI, confidence interval; DXA, dual‐energy X‐ray absorptiometry; LOCF, last observation carried forward; MBE, model‐based estimate; MTD, maximum tolerated dose; N, number of participants in the efficacy analysis set with non‐missing baseline and postbaseline value; TZP = tirzepatide. Percent changes in fat mass, lean mass, visceral fat mass and fat‐to‐lean mass ratio from baseline to LOCF endpoint calculated by analysis of covariance of the efficacy estimand. ^†MBE % change difference (95% CI) between tirzepatide and placebo. All tests for treatment‐by‐age‐group interaction were not statistically significant at a significance threshold of p = 0.1.

3.3. Safety

3.3.1. AE Overview

An overview of AEs is summarized in Table 1. TEAEs and treatment discontinuations due to AEs occurred numerically more often with tirzepatide than with placebo in both age subgroups. SAE incidence was higher in the older subgroup across treatment groups, with numerically lower rates with tirzepatide versus placebo in adults ≥ 65 years and similar rates with tirzepatide versus placebo in adults < 65 years. AEs leading to death were low across treatment groups in both age subgroups with tirzepatide versus placebo. Study discontinuations due to AEs were numerically more frequent in the older subgroup.

TABLE 1.

Summary of AEs across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years) ^a .

	< 65 years		≥ 65 years
	Placebo (N = 1511) ^b	TZP (N = 3973) ^b	Placebo (N = 340) ^b	TZP (N = 586) ^b
TEAE and SAE overview
Any TEAE	1311 (74.9%)	3230 (81.3%)	265 (77.9%)	505 (86.2%)
SAE	117 (7.7%)	279 (7.0%)	86 (25.3%)	114 (19.5%)
AE leading to death	7 (0.5%)	17 (0.4%)	13 (3.8%)	17 (2.9%)
Discontinuation from treatment due to AE	46 (3.0%)	262 (6.6%)	23 (6.8%)	76 (13.0%)
Discontinuation from study due to AE	26 (1.7%)	120 (3.0%)	22 (6.5%)	37 (6.3%)
GI AEs
Incidence after 1st dose
Nausea	146 (9.7%)	1085 (29.9%)	20 (5.9%)	146 (26.4%)
Vomiting	35 (2.3%)	482 (13.3%)	5 (1.5%)	62 (11.2%)
Diarrhoea	128 (8.5%)	842 (23.2%)	26 (7.7%)	106 (19.1%)
Constipation	82 (5.4%)	580 (16.0%)	19 (5.6%)	107 (19.3%)
Severe or serious GI events
GI disorder	0	1 (0.03%)	0	0
GI AEs as primary reason for treatment discontinuation
Any GI disorder	10 (0.7%)	144 (3.6%)	0	41 (7.0%)
Nausea	4 (0.3%)	46 (1.2%)	0	13 (2.2%)
Vomiting	0	20 (0.5%)	0	7 (1.2%)
Diarrhoea	1 (0.1%)	26 (0.7%)	0	4 (0.7%)
Constipation	0	10 (0.3%)	0	6 (1.0%)
AEs possibly due to loss of FFM
Any lean muscle TEAE	32 (2.1%)	86 (2.2%)	27 (7.9%)	41 (7.0%)
Limb fractures (any)	11 (0.7%)	34 (0.9%)	11 (3.2%)	9 (1.5%)
Spinal fractures (any)	0	2 (0.1%)	1 (0.3%)	5 (0.9%)
Thoracic cage fractures	3 (0.2%)	5 (0.1%)	4 (1.2%)	2 (0.3%)
Hip fracture	0	0	1 (0.3%)	0
Falls	6 (0.4%)	28 (0.7%)	12 (3.5%)	21 (3.6%)
Muscular weakness	2 (0.1%)	5 (0.1%)	0	2 (0.3%)

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Note: Data are from the pooled safety analysis set and are presented as n (%). N, number of subjects in analysis population; n, number of subjects with at least one event in the specific category.

Abbreviations: AEs, adverse events; FFM, fat‐free mass; GI, gastrointestinal; SAE, serious adverse event; TEAE, treatment‐emergent adverse event; TZP, tirzepatide.

^{^a}

Additional data on AEs can be found in the Supporting Information.

^{^b}

SURMOUNT‐5 excluded from pooled analysis of incidence after 1st dose of nausea, vomiting, diarrhoea and constipation (N for these rows: < 65 years, placebo: N = 1511; < 65 years, TZP: N = 3631; ≥ 65 years, placebo: N = 340; ≥ 65 years, TZP: N = 554).

3.3.2. GI AEs

GI AEs are summarized in Table 1. Nausea, vomiting, diarrhoea and constipation occurred more frequently with tirzepatide than with placebo, but at similar rates in both age subgroups. Severe or serious GI events were rare, with only one occurrence in a tirzepatide‐treated participant < 65 years. Treatment discontinuations due to GI AEs were more frequent with tirzepatide than with placebo, and numerically more common in the older subgroup, with nausea being the most common cause.

3.3.3. MACE

Clinical Endpoint Committee (CEC)‐confirmed composite MACE occurred in 2.1% versus 3.5% (≥ 65 years) and 0.7% versus 1.1% (< 65 years) of tirzepatide‐ versus placebo‐treated participants. Incidence of individual MACE components, including death due to cardiovascular causes, myocardial infarction, coronary interventions and cerebrovascular events, was low in both treatment groups and age subgroups. Hospitalization due to HF was reported in 1.2% versus 5.9% (≥ 65 years) and 0.1% versus 0.5% (< 65 years) of tirzepatide‐ versus placebo‐treated participants. All‐cause death was reported in 2.9% versus 3.8% (≥ 65 years) and 0.4% versus 0.5% (< 65 years) of tirzepatide‐ versus placebo‐treated participants.

3.3.4. PHQ‐9 Depression Outcomes

PHQ‐9 severity category shifts numerically favoured tirzepatide over placebo in both age subgroups, regardless of baseline depression status (Table S4). Among participants with no baseline depression, fewer tirzepatide‐treated participants shifted to a higher severity category than placebo. Among those with baseline depression, more tirzepatide‐treated participants shifted to a lower severity category, and fewer shifted to a higher category than placebo‐treated participants.

3.3.5. AEs Possibly due to Loss of FFM

Table 1 summarizes incidence of AEs possibly due to loss of FFM. Fractures and falls generally occurred more frequently in the older subgroup, with comparable rates between tirzepatide‐ and placebo‐treated participants. Muscular weakness was infrequent in both age subgroups and treatment groups.

3.3.6. Other AEs of Interest

Incidence of CEC‐confirmed pancreatitis was low across age subgroups (≥ 65 years: 0.7% vs. 0%; < 65 years: 0.2% vs. 0.2%, tirzepatide vs. placebo), with all cases mild or moderate in severity. Acute kidney injury occurred more frequently in the older subgroup and was comparable across treatment arms (≥ 65 years: 2.1% vs. 2.4%; < 65 years: 0.5% vs. 0.2%; tirzepatide vs. placebo). No hepatic, gallbladder or biliary‐related safety signals were observed (Tables S5–S7).

In SURMOUNT‐2, participants with coexisting T2D, no Level 3 (severe) hypoglycemia events were reported in either age subgroup. Level 2 hypoglycemia (< 54 mg/dL) occurred in 5.6% and 7.4% (tirzepatide 10 and 15 mg) versus 3.5% (placebo) of those ≥ 65 years and 3.1% and 4.3% versus 1.6%, respectively, in those < 65 years.

4. Discussion

This post hoc analysis of Phase 3 clinical trials found that tirzepatide treatment in adults aged ≥ 65 years with obesity was associated with clinically significant weight reduction, favourable treatment differences in cardiometabolic risk factors, and improvements in ORCs. Safety and efficacy results were broadly comparable to those in adults < 65 years.

Body weight reduction with tirzepatide in adults ≥ 65 years ranged from 13.9% to 25.9%, comparable to the younger subgroup. These findings are consistent with recent evidence in older adults with obesity, including results of a meta‐analysis of trials with GLP‐1 RAs [19], a pooled analysis of the STEP trials demonstrating that semaglutide‐associated weight reduction in participants ≥ 65 years was similar to the efficacy in the overall STEP 1 trial population [20], and a post hoc analysis of the ATTAIN‐1 and ‐2 trials in participants without or with T2D, respectively, showing comparable weight reductions with orforglipron in adults ≥ 65 and < 65 years [21].

As expected, in our analysis, tirzepatide was associated with greater weight reduction in individuals without coexisting T2D than in those with T2D. However, within each population, weight reduction was similar across age subgroups.

Weight reduction in older adults must be considered in the context of age‐related body composition changes. This population is more susceptible to muscle and bone mass loss with caloric restriction, potentially increasing the risk of sarcopenia, micronutrient deficiencies and fractures [4, 22]. Diminished muscle mass and anabolic resistance mean that even modest muscle loss can impair physical function, and regaining muscle after treatment discontinuation is challenging [7]. GLP‐1 RA cessation is known to lead to rapid weight regain, raising concern for progressive sarcopenic obesity with weight cycling [7]. Contemporary guidelines for older adults therefore shift the focus from lowering body mass index (BMI) to preserving functional ability and quality of life and reducing weight‐related complications [4, 23, 24, 25].

SURMOUNT‐1 was the only trial in this analysis to assess body composition using DXA. Adults ≥ 65 years in our analysis experienced predominantly fat mass loss, with fat‐to‐lean mass ratio changes comparable to younger participants. However, DXA does not capture muscle strength or functional capacity, and even proportionally preserved lean mass may represent an absolute deficit in older adults with lower baseline muscle mass. SF‐36v2 and IWQOL‐Lite‐CT were used to assess HRQoL, including physical function. Treatment differences in the SF‐36v2 Physical Functioning Domain, associated with muscle strength, lean mass and mobility‐related disability [26, 27], and IWQOL‐Lite‐CT Physical Function Composite scores both favoured tirzepatide over placebo or active comparator, irrespective of age subgroup.

AEs potentially linked to FFM loss, including fractures, falls and muscular weakness, did not differ between tirzepatide and placebo in adults ≥ 65 years. Higher rates in older adults reflected age‐related rather than treatment‐related risk. Nevertheless, it may be appropriate to monitor older adults receiving tirzepatide for changes in muscle mass and function. Clinicians may consider recommending resistance exercise and increased protein intake to help in the preservation of muscle mass for those at risk [4].

Interpretation of no imbalance in fractures between tirzepatide and placebo in this analysis is limited by the absence of bone mineral density assessments across the Phase 3 trials and a follow‐up duration that may have been insufficient to fully characterize skeletal outcomes. The broader literature on GLP‐1 RAs and fracture risk remains heterogeneous, with meta‐analyses of randomized controlled trials reporting neutral or reduced risk [28, 29, 30], whereas observational studies have suggested a modest increase in older adults [31], in patients with obesity or overweight [32], and with tirzepatide [33]. Additionally, fractures observed in people living with obesity treated with GLP‐1 RAs may reflect mechanical unloading from weight reduction rather than a direct skeletal effect [34] and could be more pronounced with higher‐efficacy agents [35], particularly in older adults with reduced bone‐restoring capacity [36]. Overall, the available evidence does not consistently support a class‐level fracture risk attributable to GLP‐1‐based therapies and further long‐term studies are warranted.

Aging is associated with increased MACE risk, driven in part by development of multimorbidity from ORCs, including hypertension, dyslipidemia, T2D, HFpEF, atrial fibrillation and atherosclerotic cardiovascular disease [5, 37]. Aging also shifts fat distribution towards visceral and other regions of ectopic adiposity [38], which is more predictive of cardiovascular risk than BMI alone [39]. In our study, treatment differences in cardiometabolic risk factors, including blood pressure, lipid profiles, waist circumference, WtHR, HbA1c and hsCRP in adults ≥ 65 years were consistent with observations in participants < 65 years.

As anticipated, MACE incidence was higher among older adults versus younger individuals, though total occurrence remained low, complicating assessment of tirzepatide's effects. The SELECT trial, powered to detect risk reduction of a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke, found similar effects across multiple age subgroups in adults with obesity and without T2D treated with 2.4 mg semaglutide [40]. The ongoing SURMOUNT‐MMO trial will provide further insights into tirzepatide's effects on cardiovascular outcomes in individuals with obesity without T2D, including effects in older adults [41].

Obesity is a causal driver of insulin resistance, prediabetes and T2D, accelerating disease onset and progression through inflammatory and β‐cell–toxic mechanisms [42]. In our study, tirzepatide was associated with consistently improved HbA1c regardless of baseline glycemic status. No attenuation of glycemic benefits among older SURMOUNT‐2 and SUMMIT participants with obesity and T2D was observed, consistent with the SURPASS‐1 to −5 post hoc analysis in older individuals with T2D and without obesity, where tirzepatide treatment was associated with reductions in HbA1c and body weight comparable to the pooled overall trial population [43].

In the SURMOUNT‐1 3‐year study, tirzepatide treatment in people with obesity and prediabetes resulted in lower risk of progression to T2D [14], but there were too few new‐onset T2D events in our age subgroup analysis to draw meaningful conclusions.

SURMOUNT‐OSA and SUMMIT demonstrated that tirzepatide treatment was associated with improvements in OSA and HFpEF, both of which predominate in older adults [12, 13, 44, 45]. In our study, treatment differences in percent change in AHI favoured tirzepatide in participants < 65 years. Results for those ≥ 65 years were inconclusive, likely reflecting small sample sizes. Previously published age subgroup analyses for SUMMIT primary outcomes suggested consistent effects of tirzepatide in those aged ≥ 65 and < 65 years on both composite of death from any cause or worsening HF event and change in Kansas City Cardiomyopathy Questionnaire clinical summary score [12].

While older adults are generally at a greater risk for AEs [46], no clinically meaningful differences were observed between tirzepatide and placebo in adults ≥ 65 years across key safety domains, including GI tolerability, falls, fractures, renal and hepatic AEs, gallbladder and biliary‐related AEs, pancreatitis and mental health outcomes. AEs more common in older participants were consistent with age‐related risk and were not attributable to tirzepatide.

GI AE rates with tirzepatide were comparable in both age subgroups. However, older individuals were more likely to discontinue tirzepatide due to GI AEs, possibly reflecting clinician caution given diminished physiological resilience, polypharmacy, decreased symptom tolerance and lower perceived benefit‐to‐risk ratio in this population [47].

As anticipated, the incidence of vomiting and diarrhoea in our study was higher with tirzepatide versus placebo, but with similar rates observed across age groups. Given older adults' elevated risk for dehydration‐related complications [48], careful monitoring is recommended. In our analysis, although acute kidney injury occurred more frequently among older adults, there was no difference between tirzepatide and placebo groups, indicating age‐ rather than treatment‐related risk. Acute pancreatitis events were rare, with very low absolute numbers and no observed age‐related difference.

Depression is prevalent among older adults, impacting HRQoL [49]. PHQ‐9 assessment in our analysis suggested no clinically significant differences in depressive symptoms between age subgroups or between tirzepatide and placebo. These findings suggest that tirzepatide treatment may not raise safety concerns regarding depression among older adults with obesity. Furthermore, no consistent treatment differences in SF‐36v2 Mental Component Summary scores were observed, with interpretation limited by small sample sizes.

This analysis included multiple Phase 3 clinical trials, providing a large dataset that enables a more informative assessment of tirzepatide in older adults than any single trial alone. A further strength is the specific focus on adults ≥ 65 years, an important yet relatively understudied population in obesity pharmacotherapy. By evaluating changes in body weight, cardiometabolic risk factors, AEs and patient‐reported or functional outcomes, this analysis offers a comprehensive picture of tirzepatide use in older adults and helps address an important gap relevant to clinical decision‐making.

Our analysis presents several limitations. Given the limited enrollment of participants aged ≥ 65 years in Phase 3 trials compared to those < 65 years, this analysis pools safety data across heterogeneous obesity populations (including those with coexisting T2D, OSA and HFpEF), which may limit interpretability. Body composition was assessed only in the 72‐week SURMOUNT‐1 trial, and the long‐term effect of tirzepatide on lean body mass beyond 72 weeks remains unknown. Because preservation of physical function may be more clinically relevant than absolute weight reduction in older adults with obesity, the lack of direct objective measures such as grip strength, gait speed and chair rise performance limits interpretation of safety with respect to muscle strength, sarcopenia and frailty. Older adults with more advanced frailty may also have been underrepresented. Finally, malnutrition‐related metrics, including micronutrient levels, were not collected systematically.

In this post hoc analysis of Phase 3 clinical trials, tirzepatide treatment in adults ≥ 65 years was associated with substantial weight reduction, favourable treatment differences in cardiometabolic risk factors and beneficial effects on ORCs, without evidence of clinically relevant risks beyond those inherent to older age. Efficacy and safety outcomes observed in this population were consistent with those reported in younger individuals.

Author Contributions

R.F.K. contributed to the design and interpretation of data for the work, as well as drafting and critical review of the work. N.A. contributed to the analysis and interpretation of data for the work, as well as drafting and critical review of the work. K.L.C. contributed to the design, acquisition of data, analysis of data and interpretation of data for the work, as well as drafting and critical review of the work. J.L. contributed to analysis of data for the work and critical review of the work. M.F. contributed to interpretation of data for the work and drafting of the work. B.C. contributed to the design, analysis and interpretation of data for the work, as well as critical review of the work. A.S. contributed to the conception, design, acquisition of data and interpretation of data for the work, as well as drafting and critical review of the work.

Funding

This work was supported by Eli Lilly and Company.

Conflicts of Interest

K.L.C., J.L., B.C., M.F. and A.S. are employees of Eli Lilly and Company. N.A. has served as an advisory board committee member for AstraZeneca and has received speaker fees from Eli Lilly and Company. R.F.K. has served as an advisor or consultant for AbbVie, Antag, AstraZeneca, Boehringer Ingelheim, Currax, Eli Lilly and Company, Novo Nordisk, Structure, Viking and Weight Watchers.

Supporting information

Text S1: Supplemental methods: analysis.

Table S1: Trial designs of the Phase 3 SURMOUNT and SUMMIT clinical trials [1–8].

Table S2: Baseline characteristics in the Phase 3 SURMOUNT and SUMMIT clinical trial populations.

Table S3: Baseline comorbidities of participants in the Phase 3 SURMOUNT and SUMMIT clinical trial populations.

Figure S1: Participants achieving body weight reduction of (A) ≥ 5%, (B) ≥ 10% and (C) ≥ 15% from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S2: Change in SF‐36v2 Mental Component Summary score from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S3: Change in WtHR from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S4: Change in DBP (mmHg) from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S5: Percent change in HDL cholesterol from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S6: Percent change in LDL cholesterol from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S7: Percent change in triglycerides from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S8: Change in HbA1c (%) from baseline in those with obesity and without T2D across Phase 3 clinical trials with tirzepatide by age subgroups (≥ 65 and < 65 years).

Figure S9: Percent change in hsCRP from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Figure S10: Percent change in AHI from baseline in those with obesity and OSA from SURMOUNT‐OSA by age subgroups (≥ 65 and < 65 years).

Table S4: PHQ‐9 score category shifts from baseline across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Table S5: Renal AEs across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Table S6: Hepatic AEs across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

Table S7: Gallbladder/biliary AEs across Phase 3 clinical trials with tirzepatide in participants with obesity or overweight by age subgroups (≥ 65 and < 65 years).

DOM-28-8072-s001.docx^{(18.3MB, docx)}

Acknowledgements

This study was funded by Eli Lilly and Company.

Alfaris N., Kushner R. F., Li J., et al., “Tirzepatide for Obesity in Adults ≥ 65 Years: A Post Hoc Analysis of the SURMOUNT and SUMMIT Clinical Trials,” Diabetes, Obesity and Metabolism 28, no. 9 (2026): 8072–8083, 10.1111/dom.70991.

Handling Editor: Richard Donnelly

Data Availability Statement

Eli Lilly and Company 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, 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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