Abstract
Introduction
Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist approved in the US for treating type 2 diabetes (T2D) and obesity, has demonstrated significant improvements in glycated hemoglobin A1c (HbA1c) and clinically meaningful weight loss in the SURPASS-1 to -5 clinical trials. This post hoc analysis examined the safety and efficacy results for tirzepatide in older participants with T2D who do not have obesity.
Methods
A post hoc analysis was conducted on a subgroup of participants aged ≥ 65 years with a body mass index (BMI) < 30 kg/m2 amongst the pooled SURPASS-1 through -5 clinical trial populations. Primary efficacy endpoints and safety were assessed for both this subgroup and overall pooled populations.
Results
Participants aged ≥ 65 years with BMI < 30 kg/m2 treated with tirzepatide experienced clinically meaningful HbA1c reduction (− 1.97 to − 2.10%) regardless of the assigned randomized maintenance dose. In contrast, a dose-proportional HbA1c decrease was observed in the overall population. Weight reduction in this subgroup was dose-proportional but numerically lower than in the overall population. Older participants without obesity were more likely to discontinue treatment due to adverse events (AEs), although the overall incidence of AEs was low in this subgroup. The incidence of hypoglycemia in this group was consistent with that of the overall cohort, regardless of concurrent insulin or sulfonylurea use.
Conclusions
Tirzepatide may be an effective treatment for older adults without obesity, and in this post hoc analysis, it was associated with clinically relevant HbA1c reduction and dose-proportional weight loss without increasing hypoglycemic risk.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13300-025-01711-0.
Keywords: Tirzepatide, GIP/GLP-1 receptor agonist, Elderly, Geriatric, Type 2 diabetes
Key Summary Points
| Why carry out this study? |
| Tirzepatide, a GIP/GLP-1 receptor agonist, demonstrated clinically meaningful reductions in HbA1c and body weight in the SURPASS-1 through -5 clinical trial program. |
| Glycemic-lowering therapeutic options for adults over 65 living with T2D should consider additional factors such as weight-loss effects, hypoglycemic risk, and safety considerations. |
| This post hoc analysis evaluated the safety and efficacy results of tirzepatide treatment in a pooled subgroup of older participants without obesity aged at least 65 years old who had a BMI of < 30 kg/m2 compared to that of the overall SURPASS 1–5 pooled participant population. |
| What was learned from the study? |
| Older participants exhibited a clinically meaningful decrease in HbA1c and dose-dependent weight reduction across all tirzepatide doses (5, 10, 15 mg). These outcomes were consistent with the results observed in the overall study population. |
| While the overall incidence of adverse events was lower in the subgroup of older participants without obesity, more participants in the subgroup discontinued due to adverse events. The incidence of hypoglycemia in older participants was consistent with that of the overall population. |
Introduction
In 2021, over 20% of individuals aged 65–95 years globally were living with diabetes, with type 2 diabetes (T2D) accounting for 96% of all cases. This high prevalence reflects a 60% increase in age-standardized T2D prevalence worldwide [1]. The affected demographic spans individuals who remain employed to those requiring supportive care with complex health needs. The demographics of this population vary and include both those who are still in employment and those requiring supportive care with complex health care needs. In addition to enhanced safety, improved cardiovascular outcomes, and improved quality of life [2], treatment considerations for adults over 65 living with T2D should also include factors such as changes in functional status, comorbidities, and estimated life expectancy [3]. Additionally, clinical profiles and treatment considerations for adults over 65 are unique with considerations for changes in body composition, insulin resistance in muscle and adipose tissues, increasing frailty, and polypharmacy [2].
Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist approved for treating T2D and obesity. Among incretin-based therapies, GLP-1 receptor agonists (GLP-1 RAs) exert both insulinotropic and glucagonostatic actions with additional cardiovascular benefits [4]. Because GLP-1 acts in a glucose-dependent manner, GLP-1 RAs are not associated with an increased risk of hypoglycemia unless they are combined with insulin secretagogues or insulin therapies [5]. Of note, the use of tirzepatide, which exerts additional action at the pancreas to lower fasting and postprandial glucagon levels in adults with T2D, was not associated with differences in the mean change in glucagon during an induced hypoglycemia compared to placebo [6]. Additionally, GLP-1 RAs exhibit weight reduction effects proportional to baseline weight. Furthermore, in participants with obesity without diabetes, tirzepatide was not associated with an excess risk of hypoglycemia [7–9].
Tirzepatide has been shown to reduce both elevated glucose levels and body weight in East Asian participants with T2D who had an average BMI of 28 kg/m2 without increasing the rate of underweight and while maintaining an adverse event (AE) profile consistent with that of the global study population [10]. A better understanding of the weight loss effects, hypoglycemic risk, and safety considerations for tirzepatide is necessary among participants who may require a more conservative treatment approach. Such participants may have greater age, lower BMI, and other treatment-related considerations.
While the World Health Organization suggests that a healthy BMI for adults ranges from 18.5 to 24.9 kg/m2 on the basis of relative risk of some diseases related to overweight or obesity [11], this may not be suitable for older adults due to multiple factors including age-related physiological changes and chronic disease [12]. A higher BMI range of 25–35 kg/m2 has been proposed based on reduced mortality risk in older adults [12–14]. A prior publication assessing the effect of baseline subgroups on the efficacy of tirzepatide in adults with T2D found that neither baseline age (< 65 years, ≥ 65 years) nor BMI (< 30, 30 to < 35, ≥ 35 kg/m2) had a significant effect on the ability of participants to achieve HbA1c ≤ 6.5%, attain a weight reduction of ≥ 10%, or increase the risk of hypoglycemia [15]. The present post hoc analysis of the SURPASS 1–5 phase 3 clinical trial program evaluated the safety and efficacy of tirzepatide in a pooled population of older participants (aged 65 years or older) without obesity (BMI of < 30 kg/m2), compared to that of the overall participant population.
Methods
SURPASS Clinical Trial Program
Study details, including concomitant medications and comparator treatment for the five SURPASS phase 3 registrational clinical trials included in this post hoc analysis, can be found at clinicaltrials.gov under NCT03954834 (SURPASS-1), NCT03987919 (SURPASS-2), NCT03882970 (SURPASS-3), NCT03730662 (SURPASS-4), NCT04039503 (SURPASS-5). Key eligibility criteria, as well as primary efficacy and safety results, have been published previously for all trials [16–20]. All trials were multicentered, randomized, parallel-group trials that compared the efficacy and safety of once-weekly tirzepatide 5, 10, and 15 mg versus placebo or active comparator in 6263 adults with T2D. Efficacy endpoints were assessed at week 40 (SURPASS-1, -2, and -5) and 52 weeks (SURPASS-3 and -4). Sites provided diabetes care consistent with local standards of care. Trials were conducted in accordance with the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines, the International Conference on Harmonization Good Clinical Practices Guideline, and other applicable laws and regulations. All protocols were approved by the appropriate local or central institutional review board. Participants provided written consent before undergoing any procedure.
The key inclusion criteria were reported with each individual study. Participants were at least 18 years of age and had T2D that was inadequately controlled while taking either no concomitant diabetes therapy or up to three oral antihyperglycemic medications or basal insulin. Eligible participants had a baseline HbA1c of 7.0% to 9.5% (SURPASS-1), 7.0% to 10.5% (SURPASS-2, -3, and -5) or 7.5% to 10.5% (SURPASS-4). Baseline BMI inclusion criteria were 23.0 kg/m2 or higher for SURPASS-1 and -5, and 25.0 kg/m2 or higher for SURPASS-2, -3, and -4.
Participants and Endpoints
This post hoc analysis of safety and efficacy results included older SURPASS-1 to -5 participants without obesity (≥ 65 years of age and BMI < 30 kg/m2 at baseline), treated with 5, 10, and 15 mg tirzepatide compared to the overall SURPASS-1 to -5 cohort previously reported elsewhere [16–20]. Efficacy endpoints were evaluated at 40 weeks (42 weeks for SURPASS-4), a timepoint common to all five SURPASS trials, for the subgroup and overall population. Safety endpoints included adverse events, treatment and study discontinuation rates, incidence of hypoglycemia, blood pressure, and pulse rates from baseline through the safety follow-up period. Severe hypoglycemia was assessed as an episode requiring the assistance of others to administer carbohydrate, glucagon, or other rescue therapies. The homeostatic model assessment (HOMA2), calculated with fasting c-peptide, was used to assess insulin resistance and β-cell function at baseline.
Statistical Analysis
Modified intent-to treat (mITT) population included all participants who received at least one dose of the study drug. The efficacy analysis set (EAS) comprised all randomly assigned participants who took at least one dose of the study drug, excluding participants who discontinued the study drug due to inadvertent enrollment and excluded data after initiation of rescue medication or premature discontinuation of the study drug. The safety analysis set (SAS) included all available data from participants in the safety population regardless of adherence to the study drug or initiation of rescue antihyperglycemic medication. Selected baseline characteristics were summarized and analyzed using descriptive statistics (mean and SD for continuous variables; counts and percentages for categorical variables).
Continuous endpoints of change from baseline at 40/42 weeks were assessed using mixed-model repeated measures (MMRM) using the EAS, adjusting for study identifier, baseline, treatment, time, and treatment-by-time interaction. No missing value imputation was conducted. Hypoglycemia rates and AEs are presented using the SAS. Statistical tests were considered significant at a two-sided alpha level of 0.05. All analyses were performed using SAS version 9.4, unless otherwise specified.
Results
Baseline Demographics
Across the SURPASS-1 to -5 studies, 4189 participants received at least one dose of tirzepatide. Of these, 540 adults were ≥ 65 years old and had a BMI in the normal-to-overweight range (23 to < 30 kg/m2) at Visit 1. These older participants without obesity were included in the post hoc subgroup analysis of the safety and efficacy of tirzepatide. The distribution of participants from each of the five SURPASS studies included in the subgroup population was consistent with that of the overall pooled population, indicating that the subgroup did not disproportionately include participants from an individual study compared with that in the overall population (Fig. 1). Both the older participants without obesity and the overall population demonstrated similar baseline characteristics in HbA1c, residual beta-cell function, insulin resistance, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate (Table 1). However, the older subgroup without obesity, compared to the overall population, had a longer duration of diabetes (13 vs. 9 years), decreased kidney function as assessed by eGFR (77.7 vs. 91 ml/min/1.73 m2), greater age (70.5 vs. 58.5 years), lower weight (74 vs. 93 kg), and smaller waist circumference (98 vs. 109 cm) at baseline.
Fig. 1.
Summary of participant distribution for post hoc analysis. Data are presented as LSM percentage of the pooled population, mITT population, and efficacy analysis set. SURPASS-1 through -5 were pooled and participants were treated with TZP. Only subjects with non-missing baseline values and at least one non-missing post-baseline value of the response variable were included in the analysis. LSM least-squares mean, mITT modified intent to treat, TZP tirzepatide
Table 1.
Baseline characteristics of enrolled participants ≥ 65 years old with BMI < 30 kg/m2 and in the overall population pooled from SURPASS-1 through -5 (overall)
| Population | TZP 5 mg | TZP 10 mg | TZP 15 mg | TZP All | ||||
|---|---|---|---|---|---|---|---|---|
| ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | |
| Part A | ||||||||
| N | 165 | 1393 | 183 | 1394 | 192 | 1402 | 540 | 4189 |
| Female, n (%) | 79 (47.9) | 674 (48.4) | 59 (32.2) | 609 (43.7) | 77 (40.1) | 668 (47.6) | 215 (39.8) | 1951 (46.6) |
| Age, years | 70.3 (4.5) | 58.3 (10.3) | 70.6 (4.6) | 58.9 (10.2) | 70.5 (4.4) | 58.3 (10.6) | 70.5 (4.5) | 58.5 (10.4) |
| Weight, kg | 73.57 (9.95) | 92.27 (20.60) | 74.95 (10.07) | 92.80 (20.81) | 74.03 (10.60) | 92.65 (20.42) | 74.20 (10.22) | 92.57 (20.61) |
| BMI, kg/m2 | 27.28 (1.62) | 33.33 (6.39) | 27.27 (1.65) | 33.44 (6.36) | 26.99 (1.67) | 33.45 (6.24) | 27.17 (1.65) | 33.41 (6.33) |
| Waist circumference, cm | 98.91 (12.37) | 109.07 (14.68) | 97.97 (7.76) | 109.53 (15.35) | 97.09 (8.21) | 108.83 (14.37) | 97.94 (9.56) | 109.15 (14.80) |
| HbA1c, % | 8.20 (0.92) | 8.30 (0.96) | 8.24 (0.93) | 8.31 (0.95) | 8.21 (0.87) | 8.27 (0.98) | 8.22 (0.90) | 8.29 (0.96) |
| HbA1c, mmol/mol | 66.11 (10.09) | 67.18 (10.45) | 66.60 (10.13) | 67.31 (10.37) | 66.24 (9.52) | 66.91 (10.76) | 66.32 (9.89) | 67.13 (10.53) |
| HOMA-IR (C-peptide) | 2.46(1.60) | 2.65 (1.67) | 2.73 (4.21) | 2.78 (2.29) | 2.46 (1.89) | 2.76 (1.97) | 2.56 (2.88) | 2.73 (1.99) |
| HOMA-B (C-peptide) | 61.05 (55.17) | 59.28 (40.24) | 54.7 (31.28) | 60.11 (36.78) | 63.09 (56.21) | 60.59 (40.45) | 59.43 (48.37) | 59.99 (39.19) |
| SBP, mmHg | 135.95 (13.60) | 131.55 (14.46) | 134.70 (14.57) | 132.48 (14.47) | 133.22 (13.86) | 131.96 (14.48) | 134.56 (14.04) | 132.00 (14.47) |
| DBP, mmHg | 74.70 (8.65) | 78.71 (9.03) | 75.17 (8.74) | 79.45 (9.31) | 75.45 (8.80) | 78.98 (9.23) | 75.13 (8.72) | 79.05 (9.19) |
| Pulse, beats/min | 71.45 (10.71) | 74.13 (10.14) | 70.63 (9.99) | 74.27 (10.31) | 72.76 (9.57) | 74.42 (10.02) | 71.64 (10.09) | 74.28 (10.16) |
| Duration of T2DM, years | 13.30 (8.07) | 9.45 (7.09) | 13.17 (8.08) | 9.29 (6.81) | 12.54 (7.76) | 9.41 (7.19) | 12.98 (7.95) | 9.38 (7.03) |
| eGFR (ml/min/1.73 m2) | 77.9 (17.7) | 91.4 (20.2) | 78.1 (14.4) | 90.7 (18.7) | 77.0 (17.9) | 91.0 (19.3) | 77.7 (16.7) | 91.0 (19.4) |
| Concomitant medication use, n (%) | 156 (94.5) | 1310 (94.0) | 167 (91.3) | 1306 (93.7) | 182 (94.8) | 1315 (93.8) | 505 (93.5) | 3931 (93.8) |
| Sulfonylurea | 34 (20.6) | 218 (15.6) | 38 (20.8) | 211 (15.1) | 39 (20.1) | 205 (14.6) | 111 (20.5) | 634 (15.1) |
| Part B | ||||||||
| N | 165 | 1394 | 183 | 1397 | 194 | 1408 | 542 | 4199 |
| Insulins and analogs, long-acting | 22 (13.3) | 132 (9.5) | 21 (11.5) | 130 (9.3) | 21 (10.8) | 135 (9.4) | 64 (11.8) | 385 (9.2) |
Data in Part A of the table are presented as mean (SD) from the mITT population, efficacy analysis set. Data in Part B of the table are presented as mean (SD) from the mITT population, safety analysis set. Note: Overall population includes all participants who received at least one dose of the study drug pooled from SURPASS-1 through -5 clinical trials
TZP tirzepatide, mITT modified intent to treat, SD standard deviation, BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, HbA1c glycated hemoglobin, T2DM type 2 diabetes mellitus, eGFR estimated glomerular filtration rate
Efficacy
At 40/42 weeks, the older subgroup without obesity showed improved mean (standard error) HbA1c levels from baseline: − 1.97% (0.08) with 5 mg, − 2.1% (0.07) with 10 mg, and − 2.08% (0.07) with 15 mg tirzepatide. Improved HbA1c levels from baseline were also observed for the overall population: − 2.08% (0.03) with 5 mg, − 2.32% (0.03) with 10 mg, and − 2.45% (0.03) with 15 mg tirzepatide (Fig. 2A). The HbA1c levels over time are shown in Fig. 2B for the subgroup and Fig. 2C for the overall cohort. The subgroup and overall cohorts had similar baseline HbA1c of 8.2% and 8.3%, respectively. The mean endpoint HbA1c levels at weeks 40/42 were 6.28% (0.08) with 5 mg, 6.15% (0.07) with 10 mg, and 6.18% (0.07) with 15 mg tirzepatide in the subgroup cohort. Mean HbA1c levels at endpoint were 6.23% (0.02) with 5 mg, 5.98% (0.02) with 10 mg, and 5.85% (0.02) with 15 mg tirzepatide for the overall cohort. In the overall population, the percent change in β-cell function assessed through HOMA-B (c-peptide) indicated a dose-proportional increase. However, the subgroup population did not display a similar dose-proportional increase (data not shown).
Fig. 2.
HbA1c change from baseline and change over time in participants ≥ 65 years old with BMI < 30 kg/m2 (subgroup) and in the overall population pooled from SURPASS-1 through -5 (overall). Association of once weekly tirzepatide and glycated hemoglobin level in an older subgroup without obesity and in the overall population. Data are presented as LSM ± SE using mITT population, efficacy analysis set. a HbA1c change from baseline to 40/42 weeks in participants ≥ 65 years old with BMI < 30 kg/m2 and in the overall population of pooled participants in SURPASS-1 through -5. b HbA1c change over time in participants ≥ 65 years old with BMI < 30 kg/m2. c HbA1c change over time in the overall population of participants pooled from SURPASS-1 through -5. BMI body mass index, HbA1c glycated hemoglobin, LSM least-squares mean, mITT modified intent to treat, S SURPASS, SE standard error
Reductions in body weight with tirzepatide were dose-dependent for both the older subgroup without obesity and the overall population (Fig. 3B and C). For the older subgroup without obesity (baseline weight: 74.20 ± 10.22 kg), the mean weights at weeks 40/42 were 68.4 kg with 5 mg, 67.1 kg with 10 mg, and 65.8 kg with 15 mg tirzepatide, representing a − 8.2%, − 9.7%, and − 11.8% weight change for the 5-, 10-, and 15-mg doses, respectively (Fig. 3A). This was comparable to the overall population (baseline weight: 92.57 ± 20.61 kg), which exhibited mean weights at weeks 40/42 of 85.9 kg with 5 mg, 83.5 kg with 10 mg, and 81.4 kg with 15 mg tirzepatide. These represented changes of − 7.9%, − 10.4%, and − 12.6% at weeks 40/42 for the 5-, 10-, and 15-mg doses, respectively.
Fig. 3.
Percent weight change from baseline and percent weight change over time in participants ≥ 65 years old with BMI < 30 kg/m2 (subgroup) and in the overall population pooled from SURPASS-1 through -5 (overall). Association of once weekly tirzepatide and weight in an older subgroup without obesity and in the overall population. Data are presented as LSM ± SE using mITT population, efficacy analysis set. a Percent weight change from baseline to week 40/42 in participants ≥ 65 years old with BMI < 30 kg/m2 and in the overall population; b Percent weight change over time in participants ≥ 65 years old with BMI < 30 kg/m2; c Percent weight change over time in the overall population of participants pooled from SURPASS-1 through -5. BMI body mass index, LSM least-squares mean, mITT modified intent to treat, S SURPASS, SE standard error, TZP tirzepatide
Safety and Other Endpoints
Adverse events are summarized in Table 2. Across all doses of tirzepatide, the proportion of participants who experienced at least one treatment-emergent adverse event (TEAE) was slightly higher in the older subgroup without obesity (72.7%) compared to the overall population (69.3%). In both populations, the most commonly reported AEs were GI in nature (nausea, diarrhea, and vomiting). The proportions of participants who experienced at least one event of nausea, diarrhea, or vomiting were similar between the two populations. Across all doses of tirzepatide, a higher number of participants in the older subgroup without obesity reported decreased appetite as an AE (14.6%) compared to the overall population (9.0%).
Table 2.
Treatment-emergent adverse events reported by participants ≥ 65 years old with BMI < 30 kg/m2 and in the overall population pooled from SURPASS-1 through -5 (overall)
| Population | TZP 5 mg | TZP 10 mg | TZP 15 mg | TZP All | ||||
|---|---|---|---|---|---|---|---|---|
| ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | |
| N | 165 | 1394 | 183 | 1397 | 194 | 1408 | 542 | 4199 |
| Participants with ≥ 1 TEAE | 113 (68.5) | 918 (65.9) | 135 (73.8) | 973 (69.6) | 146 (75.3) | 1017 (72.2) | 394 (72.7) | 2908 (69.3) |
| Nausea | 19 (11.5) | 191 (13.7) | 34 (18.6) | 261 (18.7) | 40 (20.6) | 309 (21.9) | 93 (17.2) | 761 (18.1) |
| Diarrhea | 18 (10.9) | 186 (13.3) | 31 (16.9) | 234 (16.8) | 35 (18.0) | 234 (16.6) | 84 (15.5) | 654 (15.6) |
| Decreased appetite | 16 (9.7) | 99 (7.1) | 28 (15.3) | 130 (9.3) | 35 (18.0) | 147 (10.4) | 79 (14.6) | 376 (9.0) |
| Vomiting | 11 (6.7) | 76 (5.5) | 11 (6.0) | 113 (8.1) | 21 (10.8) | 133 (9.4) | 43 (7.9) | 322 (7.7) |
| Nasopharyngitis | 5 (3.0) | 52 (3.7) | 11 (6.0) | 56 (4.0) | 9 (4.6) | 64 (4.5) | 25 (4.6) | 172 (4.1) |
| Dyspepsia | 16 (9.7) | 86 (6.2) | 12 (6.6) | 106 (7.6) | 7 (3.6) | 100 (7.1) | 35 (6.5) | 292 (7.0) |
| Weight decreased | 6 (3.6) | 21 (1.5) | 9 (4.9) | 27 (1.9) | 12 (6.2) | 31 (2.2) | 27 (5.0) | 79 (1.9) |
| Abdominal pain | 4 (2.4) | 41 (2.9) | 5 (2.7) | 54 (3.9) | 10 (5.2) | 67 (4.8) | 19 (3.5) | 162 (3.9) |
| Constipation | 8 (4.8) | 74 (5.3) | 8 (4.4) | 62 (4.4) | 8 (4.1) | 68 (4.8) | 24 (4.4) | 204 (4.9) |
| Lipase increased | 3 (1.8) | 49 (3.5) | 6 (3.3) | 50 (3.6) | 7 (3.6) | 71 (5.0) | 16 (3.0) | 170 (4.0) |
| Gallbladder-related disorders | 4 (2.4) | 16 (1.2) | 1 (0.5) | 16 (1.1) | 3 (1.5) | 11 (0.7) | 8 (1.5) | 43 (1.0) |
Data are presented as n (%) from the mITT population and safety analysis set. Subjects may be counted in more than one category. Gallbladder-related disorders include such terms as cholelithiasis, cholecystitis, cholecystitis acute, cholecystitis chronic, biliary colic, cholecystectomy, porcelain gallbladder
BMI body mass index, TEAE treatment-emergent adverse event, TZP tirzepatide
Across all doses of tirzepatide, a higher number of participants in the older subgroup without obesity (16.8%) discontinued study treatment due to an AE compared to that in the overall population (8.5%) (Table 3). There was a higher proportion of serious adverse events (SAEs) reported among the older subgroup without obesity (11.8%) compared with that of the overall population (8.1%), whereas the proportions of deaths were equivalent between the older subgroup without obesity (1.7%) and overall population (1.0%).
Table 3.
Serious adverse events and discontinuations reported by participants ≥ 65 years old with BMI < 30 kg/m2 and in the overall population pooled from SURPASS-1 through -5 (overall)
| Population | TZP 5 mg | TZP 10 mg | TZP 15 mg | TZP All | ||||
|---|---|---|---|---|---|---|---|---|
| ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | ≥ 65 years, BMI < 30 kg/m2 | Overall | |
| TEAE | 113 (68.5) | 918 (65.9) | 135 (73.8) | 973 (69.6) | 146 (75.3) | 1017 (72.2) | 394 (72.7) | 2908 (69.3) |
| SAE | 19 (11.5) | 124 (8.9) | 17 (9.3) | 114 (8.2) | 28 (14.4) | 104 (7.4) | 64 (11.8) | 342 (8.1) |
| Deaths | 3 (1.8) | 20 (1.4) | 0 (0) | 8 (0.6) | 6 (3.1) | 13 (0.9) | 9 (1.7) | 41 (1.0) |
| Discontinuations from study due to AE | 7 (4.2) | 34 (2.4) | 7 (3.8) | 26 (1.9) | 7 (3.6) | 20 (1.4) | 21 (3.9) | 80 (1.9) |
| Discontinuations from study treatment due to an AE | 20 (12.1) | 101 (7.2) | 31 (16.9) | 121 (8.7) | 40 (20.6) | 136 (9.7) | 91 (16.8) | 358 (8.5) |
Data are presented as n (%) from the mITT population and safety analysis set. Subjects may be counted in more than one category. Deaths are also included as serious adverse events and discontinuations due to adverse events.
AE adverse event, BMI body mass index, mITT modified intent to treat, SAE serious adverse event, TEAE treatment-emergent adverse event, TZP tirzepatide
While the change in weight from baseline was a key secondary outcome of the SURPASS studies, a higher proportion of episodes of potentially concerning weight loss was observed in the older subgroup without obesity compared to the overall population. Weight decrease was reported as a TEAE in 5.0% of the older subgroup without obesity versus 1.9% in the overall population. Specifically, 27 of 542 participants (5.0%) in the older subgroup without obesity reported decreased weight as a TEAE, with five discontinuing study medication due to this adverse event. All events were of mild or moderate severity. Participants who discontinued therapy due to weight loss subsequently regained weight after stopping the study drug. Within the older subgroup without obesity, a total of four participants (0.74%) reported a BMI change to ≤ 18.5 kg/m2 during the study period compared with 11 participants (0.26%) in the overall population (data not shown).
The incidence of hypoglycemia for participants treated with tirzepatide for the overall population and the older participants without obesity subgroup is summarized in Table 4. The studies were grouped according to the use of permitted concomitant antihyperglycemic medications: SURPASS-1 to -3 (0–2 orals), SURPASS-4 with or without concomitant SU (1–3 orals), and SURPASS-5 (basal insulin with or without metformin). The incidence of hypoglycemic events between the subgroup and overall population was similar within each study grouping, except in SURPASS-5. In SURPASS-5, more participants reported hypoglycemia with blood glucose ≤ 70 mg/dl or severe hypoglycemia in the lean subgroup (75.4%) compared to the overall population (61.1%).
Table 4.
Summary of hypoglycemic incidences and events for participants ≥ 65 years old by baseline insulin or sulfonylurea use and baseline BMI
| Group | SURPASS-1 through -3 pooled (no insulin or SU at baseline) | SURPASS-4 with SU at baseline | SURPASS-4 without SU at baseline | SURPASS-5 with insulin glargine at baseline | ||||
|---|---|---|---|---|---|---|---|---|
| Population | > 65 years with BMI < 30 kg/m2 | Overall | > 65 years with BMI < 30 kg/m2 |
Overall | > 65 years with BMI < 30 kg/m2 |
Overall | > 65 years with BMI < 30 kg/m2 |
Overall |
| N | 297 | 2844 | 107 | 549 | 81 | 446 | 57 | 355 |
| Hypoglycemia ≤ 70 mg/dl or severe hypoglycemia | 36 (12.1) | 283 (10.0) | 57 (53.3) | 286 (52.1) | 12 (14.8) | 60 (13.5) | 43 (75.4) | 217 (61.1) |
| Number of events | 108 | 720 | 427 | 1933 | 31 | 178 | 435 | 2393 |
| Hypoglycemia < 54 mg/dl or severe hypoglycemia | 5 (1.7) | 30 (1.1) | 12 (11.2) | 67 (12.2) | 1 (1.2) | 9 (2.0) | 8 (14.0) | 58 (16.3) |
| Number of events | 8 | 35 | 23 | 130 | 1 | 14 | 16 | 151 |
| Severe hypoglycemia | 1 (0.3) | 2 (0.1) | 0 (0.0) | – | 0 (0.0) | – | 0 (0.0) | 3 (0.8) |
Data are presented as n (%), unless stated otherwise, from the safety analysis set, including a safety follow-up period. SURPASS-1: monotherapy, no concomitant medication use. SURPASS-2: add-on to metformin. SURPASS-3: add-on to metformin with or without SGLT2i. SURPASS-4: add-on to 1–3 OAMs (metformin, SGLT2i or SU). SURPASS-5: add-on to insulin glargine with or without metformin. Severe hypoglycemia was an episode requiring the assistance of others to administer carbohydrate, glucagon, or other rescue therapies
BMI body mass index, mITT modified intent to treat, N total population, OAM oral antihyperglycemic medication, SGLT2i sodium-glucose co-transporter 2 inhibitor, SU sulfonylurea
The concomitant use of insulin or sulfonylureas (SU), known to increase the risk of hypoglycemia, was greater in the older subgroup without obesity (SU 20.5%; long-acting insulin 11.8%) compared to the overall population (SU 15.1%; long-acting insulin 9.2%) (Table 1).
The markers associated with cardiometabolic risk were also improved in the older subgroup without obesity. Improvements in HDL cholesterol and triglycerides were observed for both the subgroup and the overall population (Fig. 4). Both SBP and DBP (Fig. 5) change from baseline indicated improvement with reductions in SBP of − 6.2 mmHg for 5 mg, − 8.3 mmHg for 10 mg, and − 7.3 mmHg for 15 mg and a similar trend for DBP.
Fig. 4.
Percent change in lipids from baseline at week 40/42 in participants ≥ 65 years old with BMI < 30 kg/m2 (subgroup) and in the overall population pooled from SURPASS-1 through -5 (overall). Data are presented as LSM ± SE using mITT population, efficacy analysis set. Notes: SURPASS-1 through -5 pooled and participants treated with TZP. Only subjects with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. BMI body mass index, HDL high-density lipoprotein, LDL low-density lipoprotein, LSM least-squares mean, mITT modified intent to treat, S SURPASS, SE standard error, TZP tirzepatide
Fig. 5.
Systolic and diastolic blood pressure change from baseline at week 40/42 in participants ≥ 65 years old with BMI < 30 kg/m2 (subgroup) and in the overall population pooled from SURPASS-1 through -5 (overall). Data are presented as LSM ± SE using safety analysis set. SURPASS-1 through -5 pooled and participants treated with TZP. Only subjects with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. BMI body mass index, DBP diastolic blood pressure, LSM least-squares mean, mITT modified intent to treat, S SURPASS, SBP systolic blood pressure, SE standard error, TZP tirzepatide
Discussion
The older adult population living with T2D represents a heterogenous group with varying clinical characteristics, including diabetes duration, complications, polypharmacy and concerns such as heightened hypoglycemia risk [3]. Additionally, older adults with T2D have accelerated muscle loss as well as hypertension, chronic kidney disease, and macrovascular complications. These factors must be considered in treatment decisions, particularly as this population is projected to increase considerably by 2050 [21]. Understanding the safety and efficacy of tirzepatide in managing T2D in this demographic is thus clinically relevant.
In previous studies, treatment with tirzepatide in adults with T2D was found to be dose-dependently effective in achieving a composite endpoint of HbA1c ≤ 6.5% and weight reduction ≥ 10% without hypoglycemia in participants above/below 65 years old, and with BMI < 30 kg/m2, between 30–35 kg/m2 and over 35 kg/m2 [15]. Additionally, in a predominantly East Asian participant population, a population that tends to have lower BMI, participants receiving tirzepatide had reductions in BMI that brought them into the healthy range for BMI with few participants achieving an ‘underweight’ BMI [10].
In this post hoc analysis, the baseline clinical characteristics of the subgroup of interest and the overall population had some notable similarities and differences. Namely, HbA1c levels and β-cell function were very similar despite the differences in diabetes duration. Interestingly, insulin resistance was also similar in contrast to the greater differences in baseline BMI and weight. No clinically meaningful differences in HbA1c reduction were observed among the 5-, 10-, or 15-mg treatment groups within the older subgroup without obesity. This contrasts with the dose-dependent reductions in HbA1c observed in a comparable East Asian subgroup population (age ≥ 65 years BMI < 25 kg/m2) wherein HbA1c reductions from an overall mean baseline HbA1c of 8.16% for participants was below 6% at endpoint and ranged from − 2.2% (5 mg), − 2.6% (10 mg), and − 2.7% (15 mg) [10]. The lack of a dose-proportionate change in β-cell function in the older subgroup without obesity, similar to that observed in the overall population, could be a contributing factor to lack of dose-proportionate HbA1c reductions observed in this subgroup population. The physiological basis for this observation is unclear at this time, likely warranting further investigation. Additionally, a dose-dependent change in percent body weight loss consistent with that observed in the overall population was noted. This provides a treatment profile where absolute HbA1c reductions of 2% can be attained regardless of dose, while weight reductions remain dose-proportionate and thus individualizable. The acceptability of the observed weight change can be inferred through the number of TEAEs of weight decrease for older participants without obesity (5.0%) compared with the overall population (1.9%). Less than 1% of participants in either population reported a BMI of ≤ 18.5 kg/m2 during the study period.
The risk of metabolic abnormalities that can increase the risk of cardiovascular disease also increases with age [22]. Improvements in known cardiometabolic risk factors amongst adults with type 2 diabetes may have a beneficial effect on downstream disease burden [3]. In the current post hoc analysis, no dose-related trends in SBP or DBP were observed in contrast to that of the overall population; moderate reductions in SBP were observed, whereas the reductions in DBP were smaller than that of the overall population. A consistent improvement in lipid profile was observed in the subgroup compared to that of the overall population. However, changes in concomitant use of lipid-lowering medications were not reported. Similar improvements in these cardiometabolic outcomes, and others including HbA1C and weight, in the older subgroup without obesity were observed in the overall population, suggesting that improvement in these cardiometabolic risk factors is possible with tirzepatide treatment, regardless of the age of study participants.
Importantly, the safety profile of tirzepatide in this subgroup population was not associated with an additional risk of death. A higher percentage of SAEs was reported in the older subgroup without obesity regardless of the treatment administered (whether tirzepatide or comparator) compared to the overall population, which could indicate that the incidence of SAEs was more related to the populations studied rather than treatments administered (data not shown). Discontinuations of study medications due to AE tended to be higher for the subgroup population compared to that of the overall population. Similarly, a slightly higher proportion of participants reported at least 1 TEAE in the subgroup population. The number of study drug discontinuations of weekly GLP-1 RA for participants with BMI < 30 to 34 kg/m2 has previously been reported to be higher for participants in this BMI category compared with those who have a higher BMI at 12 months of therapy. However, these historical adherence studies with GLP-1 RAs are traditionally associated with lower weight loss compared with those recently available [22]. Of note, the number of reported AEs of weight decrease was higher for the subgroup population compared with that of the overall population, and the proportions of participants who did report this AE were lowest for the 5-mg dose. The percentage of weight loss on study medication reported by participants who did discontinue treatment was similar to those who also stayed in therapy, and weight regain occurred once participants stopped treatment. The number of participants in both the subgroup and overall populations who reported at least 1 TEAE trended towards a lower percentage for the 5-mg group and highest for the 15-mg treatment group.
Considering that participants in the subgroup population assigned to each maintenance dose of tirzepatide had similar changes from baseline in HbA1c regardless of maintenance dose with a dose-proportionate degree of weight loss consistent with that observed in the overall population, an individualized treatment approach can be assessed considering a balance of risk of AEs with the degree of weight loss that would be most beneficial considering the individual participant.
Importantly, for a population that may be more at risk of cognitive decline, the incidence of hypoglycemia is low for participants not taking either SU or insulin, regardless of baseline BMI or age. The occurrence of hypoglycemia was consistent across a variety of populations and study considerations. These participants were further broken down into those who were or were not taking SU at baseline. Moreover, the hypoglycemic events were also assessed amongst those who were taking insulin at baseline, in the case of the SURPASS-5 population, or in the pooled SURPASS-1 to -3 population, groups that were not taking insulin or insulin secretagogue. In these populations, the incidence of hypoglycemic events was consistent between the subgroup of participants over the age of 65 years with a BMI < 30 kg/m2 and the overall population, regardless of the concomitant use of hypoglycemic medication.
The analysis draws on extensive data from the SURPASS studies, which included a diverse population across various stages of T2D management, potentially enhancing generalizability. This study has several strengths and limitations. The SURPASS 1–5 studies represent a substantial accumulation of participant-level data within the context of a phase 3 clinical trial program. Encompassing a heterogeneous study population across various stages of the T2D treatment continuum, these findings may offer a degree of general applicability. A limitation of this post hoc analysis was that the number of participants in the older subgroup without obesity was considerably smaller than the overall population of the SURPASS-1 to -5 trials, suggesting caution should be exercised when interpreting data in relation to the overall population. The overall study population included all randomized participants, including those captured in the subgroup population. This methodological decision was made to ensure that safety and efficacy observations were made with respect to those captured within the primary manuscripts, however this also ensures that participants captured within the subgroup population are also captured within the overall population. Furthermore, the post hoc nature of the analysis introduces inherent limitations. Additionally, the use of an age cutoff of 65 years may not be representative of an ‘elderly’ or ‘older’ population, which would include those aged 75 years and older. For the purposes of this post hoc analysis, obesity was considered as BMI ≥ 30 kg/m2 in the absence of classification by other measurements, such as the presence of weight-related comorbidities at lower BMI ranges, adipose tissue distribution or volume. Another limitation of the study was the lack of information on frailty. Because participants would have been excluded from the study should they display impaired cognitive function or have hypoglycemia unawareness, this current assessment of safety in such a population is limited.
This post hoc analysis does, however, suggest that, in an older population without obesity, there was observed glycemic benefit with dose-proportionate weight loss without additional increase in hypoglycemic risk, regardless of the use of concomitant antihyperglycemic medication.
Conclusions
The findings of this post hoc analysis suggest that tirzepatide may offer glycemic and weight management benefits in older adults without obesity, with a safety profile supporting individualized treatment. Dose adjustments may help optimize the balance between efficacy and tolerability, particularly in patients at higher risk of adverse events. For a population at increased risk of cognitive decline and comorbidities, the low hypoglycemia risk associated with tirzepatide may be particularly noteworthy.
Further research is warranted to explore the physiological differences influencing glycemic responses across subgroups and to assess outcomes in older, frail populations.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the study participants and their families for their involvement in the studies.
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by Jack W. Daly (Eli Lilly and Company) and funded by Eli Lilly and Company.
Author Contributions
Anita Y.M. Kwan and Jennifer Peleshok contributed to the study conception. Furthermore, Anita Y.M. Kwan, Jim S. Paik, and Jennifer Peleshok contributed to the study design. Neda Rasouli and Palash Sharma were involved in the acquisition of data. Data analysis was performed by Palash Sharma and Jennifer Peleshok. Data interpretation was performed by Neda Rasouli, John P.H. Wilding, Anita Y.M. Kwan, Jim S. Paik, Palash Sharma, and Jennifer Peleshok. Jennifer Peleshok prepared the first draft of the manuscript, and all authors critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
Funding
Sponsorship for this study was funded by Eli Lilly and Company, including funding for the journal’s Rapid Service Fee.
Data Availability
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, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Declarations
Conflict of Interest
Neda Rasouli receives research funding from Eli Lilly and Company and Novo Nordisk, and is a consultant for Eli Lilly and Company, Novo Nordisk, and Sanofi. John P. H. Wilding is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Napp, Novo Nordisk, Mundipharma, Regeneron, Rhythm Pharmaceuticals, Sanofi, and Saniona, is a grant holder (University of Liverpool) for research grants for clinical trials from AstraZeneca and Novo Nordisk, and has received personal honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, and Napp. Jennifer Peleshok, Jim S. Paik, Anita Y. M. Kwan, and Palash Sharma are full-time employees of Eli Lilly and Company and are minority holders of company stock.
Ethical Approval
The SURPASS trials were conducted in accordance with consensus ethical principles, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations and were approved by the relevant ethics committee/review board at each site. All participants in all primary trials provided written informed consent. Each trial was registered with ClinicalTrials.gov: identifiers NCT03954834, NCT03987919, NCT03882970, NCT03730662, and NCT04039503.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
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, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.