Abstract
Background
Limited studies exist on incretin-based medications in older adults with obesity. Orforglipron, a novel small-molecule, non-peptide, oral glucagon-like peptide-1 receptor agonist (GLP-1 RA), led to significant weight reduction in the Phase 3, randomized, double-blind ATTAIN-1 and ATTAIN-2 trials in participants with obesity or obesity and type 2 diabetes, respectively.
Methods
This post hoc subgroup analysis evaluated once-daily orforglipron 5.5 mg, 9 mg, or 17.2 mg vs. placebo as an adjunct to healthy diet and physical activity among participants aged ≥65 years. Efficacy outcomes were analyzed separately for each trial, and safety data were pooled. The primary endpoint was percent change in body weight from baseline to Week 72.
Results
In ATTAIN-1 and ATTAIN-2, 616 randomized participants were ≥65 years of age. Of those, 613 received treatment (orforglipron 5.5 mg, n = 118; 9 mg, n = 135; 17.2 mg, n = 146; placebo, n = 214). At Week 72, the percent change in weight from baseline among participants from ATTAIN-1 was −7.9% (95% CI: −10.0, –5.9), −11.3% (−13.4, −9.3), and −13.0% (−15.7, −10.4) with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. −1.6% (−3.2, 0.1) with placebo (all p < 0.001), which was similar for those in ATTAIN-2 (orforglipron 5.5 mg: −7.5% [–9.1, −5.9]; 9 mg: −8.3% [–9.7, −6.8]; 17.2 mg: −12.2% [–13.9, −10.6]; placebo: −2.3% [–3.1, −1.4]; all p < 0.001). Comparable findings were observed in participants <65 years of age. Gastrointestinal adverse events with orforglipron were most common and generally mild to moderate in severity.
Conclusion
In this post hoc analysis of adults ≥65 years of age with obesity with or without type 2 diabetes, once-daily orforglipron was associated with significantly greater reductions in body weight vs. placebo at Week 72. The safety profile was generally consistent with other GLP-1 RAs. (ATTAIN-1: NCT05869903; ATTAIN-2: NCT05872620)
Keywords: ATTAIN-1, ATTAIN-2, Obesity, Older adults, Orforglipron, Type 2 diabetes
Graphical abstract
Highlights
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Orforglipron, a novel small-molecule, non-peptide oral GLP-1 receptor agonist, reduced body weight in ATTAIN-1 and ATTAIN-2.
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Fasting requirements for some oral therapies and needle avoidance may limit weight-management options in adults ≥65 years of age.
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This post hoc subgroup analysis evaluated safety and efficacy of orforglipron in participants ≥65 years of age from ATTAIN-1 and ATTAIN-2.
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Older participants experienced clinically meaningful reductions in body weight and HbA1c, consistent with younger participants.
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Safety findings were generally consistent across age groups and with the overall results from ATTAIN-1 and ATTAIN-2.
1. Introduction
Overweight and obesity are chronic and multifactorial diseases with an increasing global prevalence in all age groups, including the elderly [1,2]. In many countries, the lifetime risk of experiencing overweight or obesity exceeds 50%, affecting a significant proportion of the population by the age of 65–70 years [2]. Overweight and obesity are also preventable drivers of non-communicable diseases and complications, including type 2 diabetes (T2D), hypertension, sleep apnea, osteoarthritis, sarcopenia, and mental health conditions, which can reduce quality of life and elevate mortality risk [[2], [3], [4], [5]]. Additionally, obesity is a risk factor for developing cardiovascular disease (CVD) [3], the leading cause of mortality globally and within the US [6,7]. These complications are especially problematic for older adults who may be living with multiple chronic conditions [5,8].
Currently, clinical guidelines recommend the use of obesity management medications to support weight reduction in adults with overweight or obesity [[9], [10], [11]]. Glucagon-like peptide-1 receptor agonist (GLP-1 RA)–based medications, commonly provided as injectables, have demonstrated substantial weight reduction and glycemic control in people with obesity and T2D [[12], [13], [14]]. Incretin-based therapies have also demonstrated improvements in health-related quality of life (HRQoL), particularly physical functioning [15,16], and obesity-related complications, including reductions in rates of cardiovascular, renal, hepatic, osteoarthritic, and sleep disorders [17,18]. Additionally, GLP-1 RA treatment has been associated with a reduction in CVD risk in adults with obesity [19]. However, data on incretin-based therapies mostly represent efficacy in adults without a specific focus on age groups, and limited data are available on the use of incretin-based medications in older adults [[20], [21], [22], [23]] who may be more likely to have multiple chronic conditions and polypharmacy, increasing the risk of medication-related problems [24,25]. Additionally, injectable incretin-based therapies have limitations, including the need for cold storage and potential for needle-related discomfort and fear, which could negatively impact adherence and long-term persistence on treatment. Semaglutide was the first oral peptide GLP-1 RA–based medication approved to treat adults with obesity or overweight with ≥1 weight-related comorbidity [26,27]. Requirements for daily ingestion on an empty stomach with ≤4 ounces of water and a ≥30-min wait before eating or drinking may limit use [26], particularly for those older adults who have a high prevalence of multi-drug therapy [28] and may be taking medications that require food consumption. Considering these requirements, and the growing population of older adults with obesity and/or T2D, therapies that are convenient for patients are warranted.
Orforglipron is a once-daily, orally administered, small-molecule GLP-1 RA; without food or water restrictions; approved or under regulatory review across many geographies for weight management; and in clinical development for management of T2D [29,30]. The Phase 3, multinational, randomized, placebo-controlled ATTAIN-1 and ATTAIN-2 clinical trials evaluated the efficacy and safety of once-daily orforglipron 6 mg, 12 mg, and 36 mg vs. placebo as an adjunct to healthy diet and physical activity among adults with overweight or obesity, with (ATTAIN-2) or without (ATTAIN-1) T2D [31,32]. In both studies, treatment with orforglipron resulted in significant weight reduction compared with placebo. In ATTAIN-1, additional improvements from baseline in the orforglipron treatment groups were observed in waist circumference, systolic blood pressure, triglyceride levels, and non–high-density-lipoprotein (HDL) cholesterol [31]. Among participants with T2D in ATTAIN-2, clinically meaningful improvements were also observed in cardiometabolic risk factors, including hemoglobin A1c (HbA1c) [32]. The investigational capsule formulations of orforglipron (6 mg, 12 mg, and 36 mg) used in these trials are bioequivalent to the tablet doses (5.5 mg, 9 mg, and 17.2 mg) [33], which are approved in the United States [30]; accordingly, data are reported using tablet-equivalent doses. As such, comparable efficacy, safety, and tolerability profiles are expected across both formulations [33]. Here, we present the results of a post hoc subgroup analysis evaluating orforglipron vs. placebo for the treatment of older adults (≥65 years of age) from the ATTAIN-1 and ATTAIN-2 studies.
2. Methods
2.1. Study design and participants
The study designs for ATTAIN-1 (NCT05869903) and ATTAIN-2 (NCT05872620) have been described previously [31,32]. Briefly, both global, double-blind studies included participants ≥18 years of age. Participants in ATTAIN-1 had a body mass index (BMI) ≥30 kg/m2, or a BMI ≥27 kg/m2 with ≥1 obesity-related complication, and a history of ≥1 unsuccessful dietary effort to lose weight [31]. Participants in ATTAIN-2 had a BMI ≥27 kg/m2, pre-existing T2D with stable treatment for ≥90 days prior to their first visit, and a history of ≥1 unsuccessful dietary effort to lose weight [32]. Both studies were conducted in accordance with local regulations, the principles of the Declaration of Helsinki, and the International Council for Harmonisation Good Clinical Practice guidelines [31,32]. All participants provided written informed consent.
2.2. Outcomes
Efficacy endpoints were assessed at 72 weeks. The primary endpoint was the percent change in body weight from baseline. Key secondary endpoints included change from baseline in waist circumference and systolic blood pressure; percentage of participants who achieved body weight reduction thresholds of ≥5%, ≥10%, ≥15%, and ≥20%; as well as percent change in non-HDL cholesterol and triglycerides. Specific to ATTAIN-2 participants, key glycemic endpoints included percent change in HbA1c, percentage of participants reaching HbA1c target values of <7% or ≤6.5%, and fasting glucose. HRQoL was also assessed for participants in both studies using the following patient-reported outcome measures: the Impact of Weight on Quality of Life-Lite Clinical Trials version (IWQOL-Lite-CT) [34], the Short-Form Health Survey version 2 (SF-36v2) [35], and the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) [36]. Safety outcomes included occurrence of adverse events (AEs), including those possibly related to loss of muscle mass and hypoglycemic events, assessed through the safety follow-up period.
2.3. Statistical analysis
Two estimands have been previously reported: the treatment regimen estimand and the efficacy estimand, each accounting for intercurrent events in distinct ways [31,32]. The efficacy estimand was the primary estimand in this subgroup analysis and represents the treatment effect as if all the randomized participants adhered to the administration of either orforglipron or placebo as intended and did not initiate prohibited weight-management treatment (or glycemic rescue therapy or prohibited glycemic therapy for glycemic endpoints from ATTAIN-2). A maximum-likelihood-based mixed model for repeated measures (MMRM) with adjustment for baseline value, region, and other stratification factors considering a three-way or two-way interaction among treatments, visits, and baseline value (or stratification factors) was analyzed for continuous endpoints. Binary endpoints were analyzed using logistic regression. For the safety analyses, endpoints were analyzed using data from all participants who were randomly assigned to the study and received ≥1 dose of study drug. Categorical comparisons used a Mantel-Haenszel test, and risk differences with 95% CIs are reported. Prespecified continuous measures were analyzed using MMRM with relevant covariates. As an exploratory analysis, adults aged ≥65 years and those aged <65 years were compared, and a heterogeneity test was conducted to assess efficacy differences between age groups (significance threshold, p = 0.05). Efficacy outcomes were reported separately for ATTAIN-1 and ATTAIN-2. Safety outcomes were reported in the pooled safety analysis set.
3. Results
3.1. Participants
A total of 3127 and 1613 participants were randomized in ATTAIN-1 (June 2023–July 2025) and ATTAIN-2 (June 2023–August 2025), respectively. Of the 616 (13.0%) randomized participants ≥65 years of age, 613 received treatment with orforglipron 5.5 mg (ATTAIN-1: n = 40; ATTAIN-2: n = 78), 9 mg (ATTAIN-1: n = 50; ATTAIN-2: n = 85), 17.2 mg (ATTAIN-1: n = 46; ATTAIN-2: n = 100), or placebo (ATTAIN-1: n = 59; ATTAIN-2: n = 155). A total of 529 (85.9%) participants ≥65 years of age completed the studies (100 [84.7%], 116 [85.3%], 133 [90.5%], and 180 [83.7%] with orforglipron 5.5 mg, 9 mg, 17.2 mg, and placebo, respectively) and 468 (76.0%) completed 72 weeks of study treatment (95 [80.5%], 99 [72.8%], 105 [71.4%], and 169 [78.6%] with orforglipron 5.5 mg, 9 mg, 17.2 mg, and placebo, respectively; Fig. 1A and B). Comparable results were observed for participants <65 years of age. The most common reasons for treatment discontinuations were AEs and withdrawal by the participant in both the <65-year and ≥65-year subgroups. In total, 6.0% and 9.1% of participants <65 and ≥ 65 years of age, respectively, discontinued treatment due to AEs (<65 years: orforglipron 5.5 mg, 5.5%; 9 mg, 7.4%; 17.2 mg, 9.6%; placebo, 3.0%; ≥65 years: orforglipron 5.5 mg, 5.1%; 9 mg, 14.7%; 17.2 mg, 13.6%; placebo, 4.7%).
Fig. 1.
Disposition of participants <65 and ≥ 65 years of age from ATTAIN-1 and ATTAIN-2.
Disposition of participants from ATTAIN-1 (A) and ATTAIN-2 (B): Study completion was defined as completing both the 72-week treatment period and the safety follow-up period for participants without prediabetes at randomization. For participants with prediabetes at randomization, study completion was defined as completing the 72-week treatment period. If a subject discontinued the study during the treatment period, they also discontinued the study intervention, either earlier or at the same time. Data from the investigational orforglipron capsule formulations of 6 mg, 12 mg, and 36 mg have demonstrated bioequivalence with the tablet doses of 5.5 mg, 9 mg, and 17.2 mg [33], which are approved in the United States [30].
aAmong participants <65 years, 5 participants from the placebo group and 3 from the orforglipron groups (1 from each dose group) with prediabetes at randomization were included in the study intervention and discontinuation without reasons because the last dose of study intervention occurred during the primary study period, but the study intervention disposition occurred after the primary study period.
The baseline demographics and clinical characteristics for participants <65 and ≥ 65 years of age were similar between the 2 studies (Table 1). A slightly higher percentage of participants in both the <65-year and ≥ 65-year subgroups in ATTAIN-1 vs. ATTAIN-2 were female (63.9% and 68.9% vs. 46.6% and 47.9%, respectively). Participants <65 years of age were predominantly White (ATTAIN-1: n = 1608 [55.5%]; ATTAIN-2: n = 792 [66.4%]) or Asian (ATTAIN-1: n = 846 [29.2%]; ATTAIN-2: n = 250 [21.0%]), and not Hispanic or Latino (ATTAIN-1: 1765 [60.2%]; ATTAIN-2: 771 [64.6%]), as were participants ≥65 years of age (White participants from ATTAIN-1: n = 138 [70.4%], ATTAIN-2: n = 351 [83.6%]; Asian participants from ATTAIN-1: n = 38 [19.4%]; ATTAIN-2: n = 29 [6.9%]; not Hispanic or Latino participants from ATTAIN-1: 158 [80.6%], ATTAIN-2: 313 [74.5%]). Baseline mean body weight (SD) for participants <65 years of age was 103.7 kg (22.25) and 103.6 kg (23.6), mean BMI (SD) was 37.1 kg/m2 (6.5) and 36.2 kg/m2 (6.9), and mean HbA1c (SD) was 5.63% (0.34) and 8.11% (0.77) for ATTAIN-1 and -2, respectively. For participants ≥65 years of age from ATTAIN-1 and -2, baseline mean body weight (SD) was slightly lower than the younger group at 94.9 kg (17.9) and 95.2 kg (17.4), mean BMI (SD) was 35.5 kg/m2 (5.9) and 34.0 kg/m2 (5.1), and mean HbA1c (SD) was 5.77% (0.29) and 7.87% (0.64) for ATTAIN-1 and -2, respectively. Most participants ≥65 years of age had ≥1 obesity-related comorbidity; of these, 79.1% and 86.2% from ATTAIN-1 and -2 had hypertension, and 69.4% and 79.8% had dyslipidemia, respectively. Most participants <65 or ≥65 years of age (77.8% and 97.2%, respectively) were also receiving concomitant medications at baseline, with a greater percentage of participants ≥65 years of age receiving antihyperglycemic therapy compared with participants <65 years of age (Table S1).
Table 1.
Baseline characteristics of participants <65 and ≥ 65 years of age from ATTAIN-1 and ATTAIN-2.
| ATTAIN-1 |
ATTAIN-2 |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Orforglipron 5.5 mg |
Orforglipron 9 mg |
Orforglipron 17.2 mg |
Placebo |
Orforglipron 5.5 mg |
Orforglipron 9 mg |
Orforglipron 17.2 mg |
Placebo |
|||||||||
| <65 years (n = 683) | ≥65 years (n = 40) | <65 years (n = 674) | ≥65 years (n = 51) | <65 years (n = 684) | ≥65 years (n = 46) | <65 years (n = 890) | ≥65 years (n = 59) | <65 years (n = 251) | ≥65 years (n = 78) | <65 years (n = 247) | ≥65 years (n = 85) | <65 years (n = 221) | ≥65 years (n = 101) | <65 years (n = 474) | ≥65 years (n = 156) | |
| Sex (%) | ||||||||||||||||
| Female | 445 (65.2) | 24 (60.0) | 432 (64.1) | 35 (68.6) | 433 (63.3) | 32 (69.6) | 564 (63.4) | 44 (74.6) | 108 (43.0) | 42 (53.8) | 119 (48.2) | 36 (42.4) | 103 (46.6) | 51 (50.5) | 226 (47.7) | 72 (46.2) |
| Male | 238 (34.8) | 16 (40.0) | 242 (35.9) | 16 (31.4) | 251 (36.7) | 14 (30.4) | 326 (36.6) | 15 (25.4) | 143 (57.0) | 36 (46.2) | 128 (51.8) | 49 (57.6) | 118 (53.4) | 50 (49.5) | 248 (52.3) | 84 (53.8) |
| Racea(%) | ||||||||||||||||
| American Indian or Alaska Native | 2 (0.3) | 0 | 2 (0.3) | 1 (2.0) | 2 (0.3) | 0 | 4 (0.4) | 0 | 0 | 0 | 1 (0.4) | 1 (1.2) | 0 | 1 (1.0) | 1 (0.2) | 1 (0.6) |
| Asian | 196 (28.7) | 6 (15.0) | 190 (28.2) | 11 (21.6) | 208 (30.4) | 6 (13.0) | 252 (28.3) | 15 (25.4) | 54 (21.5) | 4 (5.1) | 49 (19.8) | 6 (7.1) | 48 (21.7) | 6 (5.9) | 99 (20.9) | 13 (8.3) |
| Black or African American | 67 (9.8) | 1 (2.5) | 56 (8.3) | 4 (7.8) | 66 (9.6) | 1 (2.2) | 68 (7.6) | 4 (6.8) | 17 (6.8) | 4 (5.1) | 16 (6.5) | 3 (3.5) | 19 (8.6) | 9 (8.9) | 30 (6.3) | 7 (4.5) |
| White | 376 (55.1) | 32 (80.0) | 371 (55.0) | 34 (66.7) | 358 (52.3) | 36 (78.3) | 503 (56.5) | 36 (61.0) | 169 (67.3) | 69 (89.5) | 163 (66.0) | 72 (84.7) | 146 (66.1) | 82 (81.2) | 314 (66.2) | 128 (82.1) |
| Native Hawaiian or other Pacific Islander | 0 | – | 1 (0.1) | – | 0 | – | 2 (0.2) | – | 2 (0.8) | 0 | 1 (0.4) | 0 | 0 | 0 | 2 (0.4) | 1 (0.6) |
| Multiple | 34 (5.0) | 1 (2.5) | 44 (6.5) | 1 (2.0) | 44 (6.4) | 3 (6.5) | 50 (5.6) | 4 (6.8) | 5 (2.0) | 0 | 9 (3.6) | 3 (3.5) | 5 (2.3) | 1 (1.0) | 18 (3.8) | 4 (2.6) |
| Not reported | – | – | – | – | – | – | – | – | 4 (1.6) | 1 (1.3) | 8 (3.2) | 0 | 3 (1.4) | 2 (2.0) | 10 (2.1) | 2 (1.3) |
| Missing | 8 (1.2) | 0 | 10 (1.5) | 0 | 6 (0.9) | 0 | 11 (1.2) | 0 | – | – | – | – | – | – | – | – |
| Ethnicitya(%) | ||||||||||||||||
| Hispanic or Latino | 267 (39.1) | 6 (15.0) | 267 (39.6) | 8 (15.7) | 251 (36.7) | 7 (15.2) | 352 (39.6) | 17 (28.8) | 83 (33.1) | 19 (24.4) | 77 (31.2) | 18 (21.2) | 69 (31.2) | 28 (27.7) | 159 (33.5) | 35 (22.4) |
| Not Hispanic or Latino | 409 (59.9) | 34 (85.0) | 398 (59.1) | 43 (84.3) | 428 (62.6) | 39 (84.8) | 530 (59.6) | 42 (71.2) | 162 (64.5) | 59 (75.6) | 164 (66.4) | 65 (76.5) | 146 (66.1) | 72 (71.3) | 299 (63.1) | 117 (75.0) |
| Not reported | 7 (1.0) | 0 | 9 (1.3) | 0 | 5 (0.7) | 0 | 8 (0.9) | 0 | 6 (2.4) | 0 | 6 (2.4) | 2 (2.4) | 6 (2.7) | 1 (1.0) | 16 (3.4) | 4 (2.6) |
| Geographical region (%) | ||||||||||||||||
| Asia | 189 (27.7) | 6 (15.0) | 183 (27.2) | 11 (21.6) | 194 (28.4) | 6 (13.0) | 244 (27.4) | 13 (22.0) | 48 (19.1) | 4 (5.1) | 45 (18.2) | 5 (5.9) | 46 (20.8) | 4 (4.0) | 91 (19.2) | 11 (7.1) |
| Australia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 14 (5.6) | 4 (5.1) | 15 (6.1) | 4 (4.7) | 9 (4.1) | 11 (10.9) | 22 (4.6) | 13 (8.3) |
| Central and South America | 200 (29.3) | 3 (7.5) | 200 (29.7) | 3 (5.9) | 202 (29.5) | 3 (6.5) | 265 (29.8) | 8 (13.6) | 62 (24.7) | 15 (19.2) | 67 (27.1) | 13 (15.3) | 55 (24.9) | 21 (20.8) | 128 (27.0) | 22 (14.1) |
| Europe | 114 (16.7) | 11 (27.5) | 118 (17.5) | 12 (23.5) | 116 (17.0) | 11 (23.9) | 153 (17.2) | 16 (27.1) | 66 (26.3) | 26 (33.3) | 65 (26.3) | 28 (32.9) | 57 (25.8) | 30 (29.7) | 125 (26.4) | 45 (28.8) |
| North America | 180 (26.4) | 20 (50.0) | 173 (25.7) | 25 (49.0) | 172 (25.1) | 26 (56.5) | 228 (25.6) | 22 (37.3) | 61 (24.3) | 29 (37.2) | 55 (22.3) | 35 (41.2) | 54 (24.4) | 35 (34.7) | 108 (22.8) | 65 (41.7) |
| Body weight, kg | 103.6 (22.0) | 96.3 (12.8) | 102.7 (21.7) | 95.3 (19.6) | 103.7 (23.4) | 93.7 (16.7) | 104.5 (22.0) | 94.5 (20.5) | 104.7 (23.9) | 94.4 (16.5) | 104.2 (21.9) | 98.3 (18.9) | 102.2 (24.8) | 94.5 (17.5) | 103.4 (23.8) | 94.4 (17.0) |
| BMI, kg/m2 | 37.2 (6.6) | 35.1 (4.9) | 36.8 (6.5) | 35.8 (6.4) | 37.0 (6.8) | 35.0 (5.4) | 37.2 (6.3) | 35.8 (6.5) | 36.4 (7.4) | 34.1 (5.3) | 36.6 (6.3) | 34.4 (5.7) | 35.6 (7.1) | 33.9 (5.1) | 36.1 (6.9) | 33.7 (4.7) |
| Waist circumference, cm | 112.3 (14.3) | 111.8 (10.9) | 112.0 (14.2) | 112.5 (14.6) | 112.4 (15.4) | 112.9 (12.7) | 112.8 (14.6) | 112.4 (14.2) | 117.4 (16.0) | 115.0 (11.7) | 116.4 (13.7) | 115.7 (12.6) | 114.8 (16.0) | 114.3 (13.0) | 115.8 (15.6) | 112.6 (10.8) |
| Blood pressure, mmHg | ||||||||||||||||
| Systolic | 125.1 (14.0) | 130.8 (14.9) | 124.4 (13.5) | 133.3 (13.5) | 125.4 (15.7) | 132.3 (17.7) | 125.4 (14.4) | 131.3 (14.8) | 131.0 (15.0) | 132.4 (13.9) | 131.2 (14.9) | 134.8 (15.3) | 132.2 (13.8) | 133.2 (13.4) | 129.9 (14.6) | 132.6 (12.3) |
| Diastolic | 81.2 (9.3) | 79.1 (8.4) | 81.3 (9.4) | 80.1 (9.1) | 81.2 (10.0) | 76.5 (10.4) | 82.0 (10.0) | 78.2 (8.2) | 83.1 (10.3) | 76.9 (9.1) | 83.6 (9.8) | 77.9 (9.4) | 84.2 (9.6) | 76.5 (9.2) | 82.5 (8.8) | 76.4 (8.5) |
| Lipid parameters, mg/dL | ||||||||||||||||
| Total cholesterol | 196.4 (37.2) | 191.8 (44.2) | 194.9 (38.8) | 196.4 (42.7) | 196.9 (39.2) | 187.0 (42.7) | 197.1 (39.1) | 186.9 (44.7) | 177.0 (43.3) | 160.5 (39.0) | 176.6 (46.5) | 160.9 (40.2) | 180.8 (46.6) | 157.7 (42.8) | 178.3 (46.7) | 157.4 (41.0) |
| Non-HDL cholesterol | 146.7 (35.7) | 139.9 (42.2) | 144.9 (37.5) | 140.8 (43.9) | 148.5 (38.5) | 133.7 (39.1) | 147.9 (37.4) | 132.5 (44.7) | 132.6 (43.4) | 113.1 (38.7) | 133.4 (45.7) | 114.0 (38.4) | 136.6 (45.3) | 112.3 (42.1) | 135.5 (46.1) | 111.5 (39.2) |
| HDL cholesterol | 49.5 (12.4) | 51.8 (12.8) | 49.7 (12.3) | 55.4 (12.6) | 48.2 (12.5) | 53.1 (13.1) | 48.9 (12.4) | 54.2 (12.5) | 44.2 (11.3) | 47.2 (11.5) | 43.0 (10.4) | 46.7 (9.9) | 44.0 (11.2) | 45.3 (10.4) | 42.6 (11.0) | 45.7 (10.7) |
| LDL cholesterol | 120.0 (31.7) | 111.6 (39.4) | 118.8 (33.8) | 112.1 (38.7) | 120.1 (33.4) | 109.0 (35.1) | 119.9 (33.1) | 106.7 (38.9) | 96.8 (38.0) | 78.9 (33.7) | 95.1 (36.9) | 80.1 (34.7) | 100.6 (39.7) | 80.0 (36.7) | 97.6 (41.0) | 80.2 (35.1) |
| VLDL cholesterol | 26.0 (11.7) | 28.5 (13.1) | 25.9 (11.7) | 26.7 (11.8) | 27.5 (13.4) | 24.8 (10.7) | 27.4 (13.0) | 25.9 (11.3) | 32.1 (14.3) | 30.8 (12.3) | 34.1 (14.5) | 33.2 (13.6) | 34.1 (14.8) | 32.4 (15.4) | 34.4 (14.5) | 31.2 (14.0) |
| Triglycerides | 135.0 (72.9) | 142.3 (65.8) | 132.3 (74.1) | 148.3 (95.5) | 144.1 (90.9) | 123.8 (53.7) | 143.2 (93.7) | 129.7 (56.4) | 189.2 (157.4) | 175.2 (133.2) | 195.4 (141.8) | 171.7 (86.5) | 185.0 (105.8) | 162.1 (77.3) | 199.7 (169.1) | 157.4 (73.7) |
| HbA1c, % | 5.6 (0.3) | 5.8 (0.3) | 5.6 (0.3) | 5.7 (0.3) | 5.6 (0.4) | 5.8 (0.3) | 5.6 (0.3) | 5.8 (0.3) | 8.1 (0.7) | 7.9 (0.6) | 8.1 (0.8) | 7.9 (0.6) | 8.1 (0.8) | 7.9 (0.6) | 8.1 (0.8) | 7.8 (0.7) |
| HbA1c, mmol/mol | 37.8 (3.9) | 39.7 (2.9) | 38.1 (3.7) | 39.3 (3.2) | 38.1 (3.8) | 39.4 (3.4) | 38.0 (3.6) | 39.8 (3.2) | 64.8 (8.2) | 62.5 (7.0) | 65.5 (8.8) | 62.9 (6.6) | 65.3 (8.3) | 62.7 (6.9) | 65.0 (8.5) | 62.1 (7.1) |
| Fasting serum glucose, mg/dL | 92.1 (9.8) | 99.8 (10.0) | 91.8 (9.8) | 96.7 (11.2) | 92.7 (10.5) | 98.3 (10.3) | 92.0 (9.7) | 98.0 (12.4) | 153.9 (43.4) | 149.8 (35.2) | 156.0 (43.6) | 152.3 (41.4) | 156.2 (40.7) | 151.3 (38.8) | 152.5 (38.5) | 148.4 (42.2) |
| Fasting serum glucose, mmol/L | 5.1 (0.5) | 5.5 (0.6) | 5.1 (0.5) | 5.4 (0.6) | 5.1 (0.6) | 5.5 (0.6) | 5.1 (0.5) | 5.4 (0.7) | 8.5 (2.4) | 8.3 (2.0) | 8.7 (2.4) | 8.5 (2.3) | 8.7 (2.3) | 8.4 (2.2) | 8.5 (2.1) | 8.2 (2.3) |
| Fasting insulin, mIU/L | 19.2 (14.0) | 18.0 (12.6) | 18.6 (12.3) | 16.9 (14.3) | 19.3 (12.5) | 14.7 (6.7) | 19.2 (13.9) | 16.0 (9.1) | 23.9 (20.6) | 24.7 (23.2) | 24.0 (17.2) | 23.1 (17.8) | 25.5 (26.1) | 20.6 (13.9) | 24.4 (23.0) | 17.8 (12.5) |
| hsCRP, mg/L | 5.6 (6.9) | 4.5 (7.6) | 5.7 (7.4) | 5.0 (9.8) | 5.7 (7.3) | 3.3 (2.8) | 6.0 (7.8) | 4.0 (9.0) | 5.0 (7.0) | 5.1 (11.8) | 5.6 (7.3) | 6.1 (23.5) | 5.1 (10.6) | 3.0 (2.8) | 5.6 (6.9) | 5.0 (16.3) |
Data are n (%); mean (SD) for lipid parameters, fasting insulin, and hsCRP. Data from the investigational orforglipron capsule formulations of 6 mg, 12 mg, and 36 mg have demonstrated bioequivalence with the tablet doses of 5.5 mg, 9 mg, and 17.2 mg [33], which are approved in the United States [30].
BMI = body mass index; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; SD = standard deviation; VLDL = very low-density lipoprotein.
Race and ethnicity were reported by the participants.
3.2. Efficacy
At Week 72, the mean percent change in weight from baseline among participants ≥65 years of age from ATTAIN-1 was −7.9% (95% CI –10.0 to −5.9), −11.3% (−13.4 to −9.3), and −13.0% (−15.7 to −10.4) with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. −1.6% (−3.2 to 0.1) with placebo (Fig. 2A and B; Table 2). Estimated treatment differences relative to placebo were −6.4% (95% CI –9.0 to −3.7), −9.8% (−12.4 to −7.1), and −11.4% (−14.6 to −8.3) among the respective dosing groups (p < 0.001 for all pairwise comparisons with placebo). In participants <65 years of age from ATTAIN-1, the mean percent change in weight from baseline at Week 72 was −7.7% (95% CI –8.3 to −7.1), −9.2% (−9.9 to −8.5), and −12.4% (−13.1 to −11.6) with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. −0.8% (−1.4 to −0.3) with placebo. The estimated treatment differences relative to placebo were −6.9% (95% CI –7.7 to −6.1), −8.3% (−9.2 to −7.5), and −11.5% (−12.4 to −10.6) among the respective dosing groups (p < 0.001 for all pairwise comparisons with placebo). No significant heterogeneity was observed for mean percent change in weight from baseline among age groups in ATTAIN-1 (p = 0.781). Similar results were observed among participants ≥65 years of age with T2D from ATTAIN-2 with a mean percent change from baseline in weight of −7.5% (95% CI –9.1 to −5.9), −8.3% (−9.7 to −6.8), and −12.2% (−13.9 to −10.6) with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. −2.3% (−3.1 to −1.4) with placebo (Fig. 2C and D; Table 2). The respective estimated treatment differences were −5.3% (95% CI –7.1 to −3.4), −6.0% (−7.7 to −4.3), and −10.0% (−11.8 to −8.1) vs. placebo (p < 0.001 for all pairwise comparisons with placebo). Additionally, in participants <65 years of age with T2D from ATTAIN-2, the mean percent change in weight from baseline was −5.0% (95% CI –5.7 to −4.2), −7.6% (−8.6 to −6.7), and −9.9% (−10.9 to −8.8) with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. −2.2% (−2.7 to −1.7) with placebo. The respective estimated treatment differences vs. placebo were −2.7% (95% CI –3.6 to −1.9), −5.4% (−6.5 to −4.3), and −7.7% (−8.8 to −6.5) (p < 0.001 for all pairwise comparisons with placebo). No significant heterogeneity was observed for mean percent change in weight from baseline among age groups in ATTAIN-2 (p = 0.074).
Fig. 2.
ATTAIN-1 and ATTAIN-2: Percent body weight change from baseline and proportion achieving body weight reduction thresholds by age group, and percent weight change over time in participants ≥65 years.
Data are model-based estimates using the efficacy estimand assessed at Week 72 among participants ≥65 years of age unless otherwise stated. (A, C) Percent change from baseline in body weight among participants from ATTAIN-1 (A) and ATTAIN-2 (C). (B, D) Percent change over time in body weight from baseline in participants from ATTAIN-1 (B) and ATTAIN-2 (D). The curves shown from Week 0 to Week 72 are observed mean (SE) using the efficacy estimand datapoints set, including all datapoints obtained during the treatment period and up to the earliest date of discontinuation of study treatment or initiation of prohibited weight-management treatments. (E, F) Percentage of participants <65 and ≥ 65 years of age who reached body weight reduction thresholds of ≥5%, ≥10%, ≥15%, and ≥20% in ATTAIN-1 (E) and ATTAIN-2 (F). Data from the investigational orforglipron capsule formulations of 6 mg, 12 mg, and 36 mg have demonstrated bioequivalence with the tablet doses of 5.5 mg, 9 mg, and 17.2 mg [33], which are approved in the United States [30].
*p < 0.05; **p < 0.01, ***p < 0.001. Significance values refer to risk difference comparison with placebo.
CI = confidence interval; N = number of participants with non-missing value at the specified timepoint; n = number of participants reaching threshold in observed data.
aEfficacy estimand model-based estimate (95% CI) for percent change in body weight from baseline and estimated treatment difference between orforglipron groups and placebo based on a mixed model for repeated measures analysis.
Table 2.
Change from baseline to Week 72 in the primary and secondary endpoints by treatment group among participants <65 and ≥ 65 years of age from ATTAIN-1 and ATTAIN-2—efficacy estimand datapoint set.
| ATTAIN-1 |
ATTAIN-2 |
|||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Orforglipron 5.5 mg |
Orforglipron 9 mg |
Orforglipron 17.2 mg |
Placebo |
Orforglipron 5.5 mg |
Orforglipron 9 mg |
Orforglipron 17.2 mg |
Placebo |
|||||||||
| <65 years (n = 683) | ≥65 years (n = 40) | <65 years (n = 674) | ≥65 years (n = 51) | <65 years (n = 684) | ≥65 years (n = 46) | <65 years (n = 890) | ≥65 years (n = 59) | <65 years (n = 251) | ≥65 years (n = 78) | <65 years (n = 247) | ≥65 years (n = 85) | <65 years (n = 221) | ≥65 years (n = 101) | <65 years (n = 474) | ≥65 years (n = 156) | |
| Primary endpointa | ||||||||||||||||
| Percent change in weight, % (95% CI) | −7.7 (−8.3, −7.1) |
−7.9 (−10.0, −5.9) |
−9.2 (−9.9, −8.5) |
−11.3 (−13.4, −9.3) |
−12.4 (−13.1, −11.6) |
−13.0 (−15.7, −10.4) |
−0.8 (−1.4, −0.3) |
−1.6 (−3.2, 0.1) | −5.0 (−5.7, −4.2) |
−7.5 (−9.1, −5.9) |
−7.6 (−8.6, −6.7) |
−8.3 (−9.7, −6.8) |
−9.9 (−10.9, −8.8) |
−12.2 (−13.9, −10.6) |
−2.2 (−2.7, −1.7) |
−2.3 (−3.1, −1.4) |
| Treatment comparison (95% CI); p-value | −6.9 (−7.7, −6.1); p < 0.001 |
−6.4 (−9.0, −3.7); p < 0.001 |
−8.3 (−9.2, −7.5); p < 0.001 |
−9.8 (−12.4, −7.1); p < 0.001 |
−11.5 (−12.4, −10.6); p < 0.001 |
−11.4 (−14.6, −8.3); p < 0.001 |
−2.7 (−3.6, −1.9); p < 0.001 |
−5.3 (−7.1, −3.4); p < 0.001 |
−5.4 (−6.5, −4.3); p < 0.001 |
−6.0 (−7.7, −4.3); p < 0.001 |
−7.7 (−8.8, −6.5); p < 0.001 |
−10.0 (−11.8, −8.1); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.781 | p = 0.074 | ||||||||||||||
| Key secondary endpointsa | ||||||||||||||||
| Participants with weight reduction ≥5%, % (SE)b | 63.7 (1.9) | 69.2 (7.9) | 68.7 (1.9) | 75.1 (6.4) | 76.9 (1.7) | 79.85 (7.3) | 21.5 (1.6) | 28.4 (5.9) | 47.7 (3.3) | 55.2 (6.0) | 57.5 (3.3) | 68.9 (5.3) | 71.4 (3.2) | 77.2 (4.5) | 25.0 (2.1) | 24.1 (3.8) |
| Treatment comparison (95% CI); p-value | RD 42.2 (37.4, 47.0); p < 0.001 |
RD 40.8 (21.3, 60.3); p < 0.001 |
RD 47.2 (42.4, 52.0); p < 0.001 |
RD 46.8 (29.3, 64.3); p < 0.001 |
RD 55.4 (50.8, 60.0); p < 0.001 |
RD 51.5 (33.2, 69.8); p < 0.001 |
RD 22.6 (14.9, 30.3); p < 0.001 |
RD 31.0 (17.3, 44.7); p < 0.001 |
RD 32.4 (24.7, 40.1); p < 0.001 |
RD 44.7 (32.1, 57.4); p < 0.001 |
RD 46.4 (38.7, 54.0); p < 0.001 |
RD 53.1 (41.1, 65.1); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.980 | p = 0.391 | ||||||||||||||
| Participants with weight reduction ≥10%, % (SE)b | 35.5 (1.9) | 44.4 (8.6) | 44.4 (2.0) | 55.6 (7.3) | 59.4 (2.0) | 61.4 (8.4) | 8.4 (1.0) | 9.6 (4.1) | 20.1 (2.6) | 33.9 (5.7) | 33.4 (3.2) | 41.4 (5.5) | 47.3 (3.5) | 59.6 (5.2) | 6.9 (1.3) | 7.2 (2.4) |
| Treatment comparison (95% CI); p-value | RD 27.1 (22.9, 31.3); p < 0.001 |
RD 34.9 (16.0, 53.8); p < 0.001 |
RD 36.0 (31.4, 40.5); p < 0.001 |
RD 46.0 (29.6, 62.5); p < 0.001 |
RD 51.0 (46.6, 55.3); p < 0.001 |
RD 51.8 (33.6, 70.1); p < 0.001 |
RD 13.2 (7.5, 18.9); p < 0.001 |
RD 26.6 (14.3, 38.9); p < 0.001 |
RD 26.5 (19.8, 33.2); p < 0.001 |
RD 34.2 (22.4, 45.9); p < 0.001 |
RD 40.4 (33.1, 47.6); p < 0.001 |
RD 52.4 (41.0, 63.7); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.629 | p = 0.094 | ||||||||||||||
| Participants with weight reduction ≥15%, % (SE)b | 16.2 (1.5) | 24.4 (7.4) | 23.5 (1.7) | 30.3 (7.0) | 39.6 (1.9) | 44.3 (8.3) | 3.6 (0.7) | 3.2 (2.6) | 4.4 (1.4) | 15.5 (4.3) | 18.1 (2.6) | 16.7 (4.3) | 26.5 (3.1) | 37.4 (5.1) | 2.2 (0.7) | 1.0 (1.0) |
| Treatment comparison (95% CI); p-value | RD 12.6 (9.4, 15.8); p < 0.001 |
RD 21.2 (5.9, 36.6); p < 0.007 |
RD 20.0 (16.3, 23.7); p < 0.001 |
RD 27.1 (12.3, 41.9); p < 0.001 |
RD 36.0 (32.0, 40.0); p < 0.001 |
RD 41.2 (24.0, 58.3); p < 0.001 |
RD 2.2 (−0.9, 5.4); p = 0.159 |
RD 14.5 (5.8, 23.2); p = 0.001 |
RD 15.9 (10.6, 21.2); p < 0.001 |
RD 15.7 (7.1, 24.3); p < 0.001 |
RD 24.3 (18.0, 30.6); p < 0.001 |
RD 36.4 (26.2, 46.6); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.576 | p = 0.016 | ||||||||||||||
| Participants with weight reduction ≥20%, % (SE)b | 6.9 (1.1) | 12.7 (6.1) | 11.2 (1.3) | 13.0 (5.5) | 20.0 (1.6) | 25.2 (7.2) | 1.6 (0.45) | 1.4 (1.8) | 2.1 (1.1) | 7.0 (3.2) | 7.5 (1.8) | 3.2 (2.1) | 9.7 (2.1) | 18.9 (4.1) | 0.3 (0.2) | 0.0 (0.2) |
| Treatment comparison (95% CI); p-value | RD 5.2 (2.9, 7.5); p < 0.001 |
RD 11.3 (−1.4, 23.9); p = 0.081 |
RD 9.6 (6.9, 12.2); p < 0.001 |
RD 11.6 (0.1, 23.2); p = 0.048 |
RD 18.4 (15.2, 21.6); p < 0.001 |
RD 23.8 (9.1, 38.5); p = 0.002 |
RD 1.8 (−0.3, 4.0); p = 0.096 |
RD 7.0 (0.7, 13.3); p = 0.03 |
RD 7.2 (3.6, 10.8); p < 0.001 |
RD 3.2 (−1.0, 7.3); p = 0.13 |
RD 9.4 (5.2, 13.6); p < 0.001 |
RD 18.9 (10.8, 27.0); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.722 | p = 0.033 | ||||||||||||||
| Change in waist circumference, cm (95% CI) | −7.5 (−8.2, −6.9) |
−6.9 (−8.7, −5.2) |
−8.9 (−9.6, −8.3) |
−10.3 (−12.7, −7.9) |
−11.1 (−11.7, −10.4) |
−13.0 (−15.3, −10.7) |
−2.1 (−2.6, −1.6) |
−2.4 (−4.1, −0.8) |
−5.1 (−6.0, −4.2) |
−7.7 (−9.3, −6.1) |
−7.1 (−8.0, −6.1) |
−7.3 (−8.9, −5.6) |
−8.7 (−9.7, −7.7) |
−10.0 (−11.6, −8.5) |
−2.5 (−3.1, −2.0) |
−3.0 (−3.7, −2.2) |
| Treatment comparison (95% CI); p-value | −5.4 (−6.3, −4.6); p < 0.001 |
−4.5 (−6.9, −2.1); p < 0.001 |
−6.8 (−7.7, −6.0); p < 0.001 |
−7.9 (−10.8, −5.0); p < 0.001 |
−9.0 (−9.8, −8.1); p < 0.001 |
−10.6 (−13.4, −7.8); p < 0.001 |
−2.6 (−3.6, −1.5); p < 0.001 |
−4.7 (−6.5, −2.9); p < 0.001 |
−4.5 (−5.6, −3.4); p < 0.001 |
−4.3 (−6.2, −1.5); p < 0.001 |
−6.2 (−7.3, −5.0); p < 0.001 |
−7.1 (−8.8, −5.3); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.565 | p = 0.267 | ||||||||||||||
| Change in SBP, mmHg (95% CI) | −5.8 (−6.8, −4.8) |
−5.4 (−9.8, −1.1) |
−5.7 (−6.6, −4.7) |
−9.0 (−12.6, −5.3) |
−6.5 (−7.5, −5.5) |
−10.3 (−14.3, −6.3) |
−0.7 (−1.5, 0.2) | −2.1 (−5.1, 0.9) | −4.1 (−5.5, −2.7) |
−4.8 (−7.8, −1.7 |
−5.1 (−6.7, −3.5) |
−3.8 (−6.9, −0.6) |
−6.3 (−7.9, −4.7) |
−4.9 (−8.0, −1.8) |
−1.5 (−2.6, −0.3) |
−1.5 (−3.7, 0.7) |
| Treatment comparison (95% CI); p-value | −5.2 (−6.5, −3.9); p < 0.001 |
−3.4 (−8.7, 2.0); p = 0.215 | −5.0 (−6.3, −3.7); p < 0.001 |
−6.9 (−11.6, −2.1); p = 0.005 |
−5.8 (−7.1, −4.6); p < 0.001 |
−8.2 (−13.2, −3.2); p = 0.001 |
−2.6 (−4.4, −0.8); p = 0.006 |
−3.2 (−7.0, 0.6); p = 0.094 | −3.6 (−5.6, −1.7); p < 0.001 |
−2.3 (−6.1, 1.6); p = 0.253 | −4.9 (−6.9, −2.9); p < 0.001 |
−3.4 (−7.2, 0.4); p = 0.082 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.665 | p = 0.856 | ||||||||||||||
| Percent change in triglycerides, % (95% CI) | −12.2 (−14.8, −9.4) |
−10.5 (−19.7, −0.3) |
−15.2 (−18.0, −12.3) |
−14.6 (−21.5, −7.1) |
−21.2 (−23.4, −18.9) |
−30.7 (−37.2, −23.6) |
−4.5 (−7.0, −2.0) |
−7.7 (−13.5, −1.6) |
−15.3 (−19.9, −10.5) |
−16.6 (−22.6, −10.2) |
−14.9 (−19.3, −10.3) |
−19.7 (−26.3, −12.6) |
−20.7 (−24.8, −16.3) |
−22.7 (−28.6, −16.3) |
−4.0 (−7.9, 0.0) | −6.9 (−12.4, −1.2) |
| Treatment comparison (95% CI); p-value | −8.0 (−11.7, −4.2); p < 0.001 |
−3.1 (−14.4, 9.8); p = 0.623 | −11.2 (−14.9, −7.3); p < 0.001 |
−7.5 (−16.8, 3.0); p = 0.152 | −17.5 (−20.6, −14.2); p < 0.001 |
−25.0 (−33.5, −15.3); p < 0.001 |
−11.8 (−17.7, −5.5); p < 0.001 |
−10.4 (−18.5, −1.5); p = 0.024 |
−11.3 (−17.1, −5.2); p < 0.001 |
−13.7 (−22.3, −4.3); p = 0.006 |
−17.4 (−22.8, −11.6); p < 0.001 |
−16.9 (−24.8, −8.2); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.425 | p = 0.970 | ||||||||||||||
| Percent change in non-HDL-cholesterol, % (95% CI) | −5.8 (−7.3, −4.2) |
−7.4 (−15.9, 2.1) | −8.4 (−10.0, −6.7) |
−8.3 (−13.9, −2.4) |
−8.1 (−9.6, −6.6) |
−17.0 (−22.1, −11.6) |
−1.2 (−2.6, 0.3) | −5.0 (−9.6, −0.2) |
−4.2 (−7.6, −0.6) |
−7.2 (−14.2, 0.3) | −5.2 (−8.5, −1.7) |
−10.6 (-15.7, −5.4) |
−6.9 (−10.3, −3.4) | −11.9 (−16.5, −7.0) |
−3.3 (−6.0, −0.6) |
−1.8 (−6.1, 2.6) |
| Treatment comparison (95% CI); p-value | −4.6 (−6.7, −2.5); p < 0.001 |
−2.5 (−12.5, 8.7); p = 0.648 | −7.3 (−9.4, −5.1); p < 0.001 |
−3.5 (−10.8, 4.4); p = 0.369 | −7.0 (−9.0, −5.0); p < 0.001 |
−12.7 (−19.5, −5.3); p = 0.001 |
−0.9 (−5.3, 3.8); p = 0.71 | −5.5 (−13.6, 3.4); p = 0.219 | −1.9 (−6.3, 2.7); p = 0.405 | −9.0 (−15.4, −2.1); p = 0.011 |
−3.7 (−8.1, 0.9); p = 0.113 | −10.3 (−16.4, −3.7); p = 0.003 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.395 | p = 0.370 | ||||||||||||||
| Change in HbA1c, % (95% CI) | −0.30 (−0.32, −0.28) |
−0.37 (−0.44, −0.31) |
−0.31 (−0.33, −0.29) |
−0.31 (−0.38, −0.23) |
−0.37 (−0.40, −0.35) |
−0.49 (−0.55, −0.42) |
−0.03 (−0.05, −0.01) |
−0.02 (−0.10, 0.06) | −1.25 (−1.42, −1.08) |
−1.46 (−1.61, −1.30) |
−1.60 (−1.74, −1.47) |
−1.62 (−1.79, −1.45) |
−1.83 (−1.98, −1.68) |
−1.66 (−1.81, −1.51) |
−0.16 (−0.30, −0.02) |
−0.12 (−0.30, 0.06) |
| Treatment comparison (95% CI); p-value | −0.27 (−0.30, −0.25); p < 0.001 |
−0.35 (−0.46, −0.25); p < 0.001 |
−0.28 (−0.31, −0.26); p < 0.001 |
−0.29 (−0.40, −0.18); p < 0.001 |
−0.35 (−0.38, −0.32); p < 0.001 |
−0.47 (−0.57, −0.36); p < 0.001 |
−1.09 (−1.31, −0.87); p < 0.001 |
−1.34 (−1.58, −1.10); p < 0.001 |
−1.45 (−1.65, −1.25); p < 0.001 |
−1.50 (−1.75, −1.25); p < 0.001 |
−1.67 (−1.88, −1.46); p < 0.001 |
−1.54 (−1.78, −1.30); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.250 | p = 0.420 | ||||||||||||||
| Participants with HbA1c <7%, % (SE)b | – | – | – | – | – | – | – | – | 67.2 (3.2) | 79.5 (4.8) | 76.7 (3.0) | 85.7 (4.1) | 83.0 (2.7) | 92.4 (2.7) | 23.4 (2.2) | 22.7 (3.8) |
| Treatment comparison (95% CI); p-value | – | – | – | – | – | – | – | – | RD 43.8 (36.1, 51.5); p < 0.001 |
RD 56.9 (44.8, 68.9); p < 0.001 |
RD 53.3 (45.9, 60.7); p < 0.001 |
RD 63.0 (52.3, 73.7); p < 0.001 |
RD 59.6 (52.8, 66.3); p < 0.001 |
RD 69.7 (60.6, 78.9); p < 0.001 |
||
| <65 vs. ≥65 years heterogeneity p-value | – | p = 0.213 | ||||||||||||||
| Participants with HbA1c ≤ 6.5%, % (SE)b | – | – | – | – | – | – | – | – | 52.8 (3.4) | 67.1 (5.5) | 64.0 (3.2) | 81.7 (4.4) | 73.6 (3.1) | 80.9 (4.2) | 11.5 (1.7) | 8.6 (2.4) |
| Treatment comparison (95% CI); p-value | – | – | – | – | – | – | – | – | RD 41.2 (33.9, 48.5); p < 0.001 |
RD 58.6 (46.9, 70.2); p < 0.001 |
RD 52.4 (45.3, 59.6); p < 0.001 |
RD 73.2 (63.3, 83.0); p < 0.001 |
RD 62.1 (55.1, 69.0); p < 0.001 |
RD 72.4 (63.1, 81.7); p < 0.001 |
||
| <65 vs. ≥65 years heterogeneity p-value | – | p = 0.002 | ||||||||||||||
| Participants with HbA1c <5.7%, % (SE)b | – | – | – | – | – | – | – | – | 7.6 (1.8) | 8.4 (3.1) | 16.9 (2.5) | 22.6 (5.0) | 34.0 (3.4) | 14.5 (3.8) | 0.8 (0.4) | 0.7 (0.7) |
| Treatment comparison (95% CI); p-value | – | – | – | – | – | – | – | – | RD 6.8 (3.2, 10.4); p < 0.001 |
RD 7.7 (1.5, 13.9); p = 0.015 |
RD 16.1 (11.1, 21.1), p < 0.001 |
RD 21.9 (12.0, 31.8); p < 0.001 |
RD 33.2 (26.6, 39.9); p < 0.001 |
RD 13.8 (6.1, 21.5); p < 0.001 |
||
| <65 vs. ≥65 years heterogeneity p-value | – | p = 0.001 | ||||||||||||||
| Change in fasting serum glucose, mg/dL (95% CI) | −7.4 (−8.1, −6.7) |
−12.7 (−15.4, −10.0) |
−8.3 (−9.0, −7.7) |
−13.8 (−16.7, −10.8) |
−9.0 (−9.8, −8.2) |
−12.9 (−15.4, −10.5) |
0.5 (−0.4, 1.3) | −2.7 (−5.0, −0.4) |
−30.9 (−36.3, −25.6) |
−40.3 (−44.2, −36.3) |
−39.6 (−43.9, −35.4) |
−46.4 (−49.8, −43.0) |
−44.3 (−49.2, −39.5) |
−44.7 (−49.6, −39.8) |
1.5 (−2.9, 6.0) | −3.3 (−9.3, 2.7) |
| Treatment comparison (95% CI); p-value | −7.9 (−8.9, −6.8); p < 0.001 |
−10.0 (−13.5, −6.5); p < 0.001 |
−8.8 (−9.9, −7.7); p < 0.001 |
−11.1 (−14.7, −7.4); p < 0.001 |
−9.5 (−10.6, −8.3); p < 0.001 |
−10.2 (−13.6, −6.9); p < 0.001 |
−32.4 (−39.4, −25.5); p < 0.001 |
−37.0 (−44.5, −29.5); p < 0.001 |
−41.2 (−47.4, −35.0); p < 0.001 |
−43.0 (−50.2, −35.9); p < 0.001 |
−45.9 (−52.4, −39.3); p < 0.001 |
−41.4 (−49.3, −33.4); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.686 | p = 0.662 | ||||||||||||||
| Change in fasting serum glucose, mmol/L (95% CI) | −0.41 (−0.45, −0.37) |
−0.71 (−0.86, −0.56) |
−0.46 (−0.50, −0.42) |
−0.76 (−0.93, −0.60) |
−0.50 (−0.54, −0.46) |
−0.72 (−0.85, −0.58) |
0.03 (−0.02, 0.07) | −0.15 (−0.28, −0.02) |
−1.72 (−2.01, −1.42) |
−2.24 (−2.46, −2.02) |
−2.20 (−2.44, −1.96) |
−2.57 (−2.76, −2.38) |
−2.46 (−2.73, −2.19) |
−2.48 (−2.75, −2.21) |
0.08 (−0.16, 0.33) | −0.18 (−0.52, 0.15) |
| Treatment comparison (95% CI); p-value | −0.44 (−0.50, −0.38); p < 0.001 |
−0.56 (−0.75, −0.36); p < 0.001 |
−0.49 (−0.55, −0.43); p < 0.001 |
−0.61 (−0.82, −0.41); p < 0.001 |
−0.53 (−0.59, −0.46); p < 0.001 |
−0.57 (−0.75, −0.38); p < 0.001 |
−1.80 (−2.19, −1.41); p < 0.001 |
−2.05 (−2.47, −1.64); p < 0.001 |
−2.28 (−2.63, −1.94); p < 0.001 |
−2.39 (−2.78, −1.99; p < 0.001 |
−2.55 (−2.91, −2.18); p < 0.001 |
−2.30 (−2.74, −1.85); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.686 | p = 0.662 | ||||||||||||||
| Additional secondary endpoints | ||||||||||||||||
| Percent change in total cholesterol, % (95% CI) | −3.6 (−4.7, −2.4) |
−3.5 (−10.0, 3.4) | −5.2 (−6.4, −4.0) |
−3.8 (−7.7, 0.4) | −4.7 (−5.9, −3.6) |
−10.2 (−14.6, −5.6) |
−0.9 (−2.0, −0.2) |
−4.1 (−8.0, 0.0) | −1.7 (−4.3, 1.0) | −3.1 (−8.3, 2.4) | −2.6 (−5.2, 0.1) | −4.9 (−8.7, −0.9) |
−2.9 (−5.5, −0.2) |
−5.5 (−9.1, −1.7) |
−2.1 (−4.1, 0.0) |
0.1 (−3.1, 3.4) |
| Treatment comparison (95% CI); p-value | −2.7 (−4.3, −1.1); p = 0.001 |
0.6 (−7.2, 9.1); p = 0.883 | −4.3 (−5.9, −2.7); p < 0.001 |
0.3 (−5.4, 6.4); p = 0.910 | −3.9 (−5.5, −2.3); p < 0.001 |
−6.3 (−12.4, 0.1); p = 0.053 | 0.3 (−3.0, 3.8); p = 0.843 | −3.2 (−9.2, 3.2); p = 0.318 | −0.6 (−3.9, 2.9); p = 0.744 | −5.0 (−9.8, 0.2); p = 0.058 | −0.8 (−4.2, 2.6); p = 0.626 | −5.5 (−10.3 −0.6); p = 0.029 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.410 | p = 0.453 | ||||||||||||||
| Percent change in HDL cholesterol, % (95% CI) | 2.1 (0.7, 3.5) | 7.3 (1.6, 13.4) | 3.4 (2.0, 4.8) | 7.4 (2.8, 12.1) | 5.1 (3.8, 6.5) | 6.8 (2.0, 11.9) | −0.1 (−1.3, 1.2) | 1.0 (−3.1, 5.2) | 5.1 (3.0, 7.4) | 4.3 (1.1, 7.7) | 4.7 (2.4, 7.0) | 5.5 (2.3, 8.8) | 8.7 (6.3, 11.2) | 9.5 (5.5, 13.6) | 1.4 (−0.1, 3.0) | 4.0 (1.2, 6.9) |
| Treatment comparison (95% CI); p-value | 2.2 (0.3, 4.1); p = 0.022 | 6.3 (−0.7, 13.8); p = 0.078 | 3.5 (1.6, 5.4); p < 0.001 | 6.3 (0.2, 12.9); p = 0.043 | 5.2 (3.3, 7.1); p < 0.001 | 5.8 (−0.6, 12.6); p = 0.075 | 3.7 (1.0, 6.4); p = 0.006 | 0.3 (−3.8, 4.6); p = 0.893 | 3.2 (0.5, 6.1); p = 0.022 | 1.4 (-2.7, 5.7); p = 0.507 | 7.2 (4.3, 10.2); p < 0.001 | 5.2 (0.5, 10.2); p = 0.032 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.750 | p = 0.705 | ||||||||||||||
| LDL cholesterol, % (95% CI) | −4.6 (−6.4, −2.7) |
−5.8 (−15.7, 5.2) | −6.8 (−8.6, −5.0) |
−6.4 (−12.6, 0.3) | −5.0 (−6.7, −3.3) |
−12.9 (−18.7, −6.7) |
−0.2 (−1.9, 1.5) | −4.5 (−10.1, 1.6) | 0.7 (−3.6, 5.2) | −0.4 (−9.5, 9.6) | −1.7 (−5.5, 2.3) | −6.0 (-12.3, 0.7) | −1.3 (−5.9, 3.4) | −6.5 (−11.8, −0.9) |
−3.7 (−7.1, −0.2) |
0.9 (−4.1, 6.3) |
| Treatment comparison (95% CI); p-value | −4.3 (−6.8, −1.9); p < 0.001 |
−1.4 (−13.1, 11.8); p = 0.824 | −6.6 (−9.0, −4.1); p < 0.001 |
−2.1 (−10.5, 7.2); p = 0.651 | −4.8 (−7.1, −2.4); p < 0.001 |
−8.8 (−17.0, 0.1); p = 0.053 | 4.6 (−1.1, 10.7); p = 0.117 | −1.3 (−11.5, 10.0); p = 0.813 | 2.1 (−3.2, 7.7); p = 0.445 | −6.9 (−14.6, 1.5); p = 0.106 | 2.5 (−3.4, 8.7); p = 0.418 | −7.3 (−14.3, 0.2); p = 0.057 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.606 | p = 0.253 | ||||||||||||||
| VLDL cholesterol, % (95% CI) | −12.7 (−15.2, −10.0) |
−10.7 (−20.2, −0.1) |
−15.3 (−17.9, −12.6) |
−13.3 (−20.3, −5.8) |
−21.3 (−23.5, −19.0) |
−30.3 (−36.8, −23.1) |
−4.1 (−6.5, −1.6) |
−7.4 (−13.3, −1.0) |
−14.7 (−19.1, −10.0) |
−15.9 (−22.2, −9.1) |
−14.4 (−18.8, −9.8) |
−20.5 (-27.0, −13.5) |
−18.2 (−22.2, −14.0 |
−22.3 (−28.3, −15.9) |
−4.9 (−8.4, −1.4) |
−7.5 (−12.9, −1.9) |
| Treatment comparison (95% CI); p-value | −8.9 (−12.4, −5.3); p < 0.001 |
−3.6 (−15.2, 9.7); p = 0.577 | −11.7 (−15.2, −8.0); p < 0.001 |
−6.5 (−15.9, 4.0); p = 0.216 | −18.0 (−21.1, −14.7); p < 0.001 |
−24.7 (−33.4, −15.0); p < 0.001 |
−10.2 (−15.9, −4.3; p = 0.001 |
−9.0 (−17.5, 0.3); p = 0.057 | −10.0 (−15.5, −4.0); p = 0.001 |
−14.1 (-22.5, −4.8); p = 0.004 |
−13.9 (−19.1, −8.4); p < 0.001 |
−16.0 (−24.0, −7.2); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.403 | p = 0.918 | ||||||||||||||
| Change in EQ-5D-5L Health State Index (UK) score (SE) | 0.02 (0.01) | −0.04 (0.03) | 0.01 (0.01) | 0.01 (0.01) | 0.02 (0.01) | 0.01 (0.02) | −0.01 (0.01) | −0.03 (0.02) | 0.01 (0.01) | 0.02 (0.02) | 0.00 (0.01) | 0.00 (0.02) | 0.01 (0.01) | 0.03 (0.01) | 0.00 (0.01) | −0.02 (0.01) |
| Treatment comparison (95% CI); p-value | 0.03 (0.02, 0.05); p < 0.001 | −0.02 (−0.09, 0.06); p = 0.686 | 0.02 (0.01, 0.04); p = 0.004 | 0.04 (−0.01, 0.10); p = 0.133 | 0.03 (0.01, 0.04); p < 0.001 | 0.04 (−0.02, 0.10); p = 0.192 | 0.01 (−0.01, 0.03); p = 0.497 | 0.04 (0.00, 0.09); p = 0.038 | 0.00 (−0.02, 0.02); p = 0.897 | 0.02 (-0.02, 0.06); p = 0.278 | 0.01 (−0.01, 0.03); p = 0.362 | 0.05 (0.02, 0.09); p = 0.003 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.567 | p = 0.349 | ||||||||||||||
| Change in EQ VAS score (SE) | 2.8 (0.52) | −0.6 (2.3) | 3.5 (0.5) | 1.4 (1.8) | 3.6 (0.5) | −0.7 (2.1) | 0.1 (0.6) | 1.4 (1.8) | 2.5 (0.8) | 2.6 (1.6) | 2.8 (0.7) | 2.3 (1.0) | 3.3 (0.8) | 3.1 (1.2) | 0.2 (0.6) | −0.7 (1.0) |
| Treatment comparison (95% CI); p-value | 2.7 (1.2, 4.2); p < 0.001 | −2.0 (−7.8, 3.8); p = 0.499 | 3.4 (1.9, 4.9); p < 0.001 | 0.1 (−4.9, 5.0); p = 0.976 | 3.6 (2.1, 5.0); p < 0.001 | −2.1 (−7.6, 3.4); p = 0.455 | 2.3 (0.4, 4.2); p = 0.020 | 3.3 (−0.6, 7.1); p = 0.100 | 2.6 (0.7, 4.5); p = 0.007 | 3.0 (0.2, 5.8); p = 0.038 | 3.2 (1.2, 5.1); p = 0.002 | 3.8 (0.6, 6.9); p = 0.018 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.361 | p = 0.982 | ||||||||||||||
| Change in SF-36 Scores | ||||||||||||||||
| PCS (SE) | 2.3 (0.2) | 1.2 (1.1) | 2.3 (0.2) | 1.5 (0.6) | 2.5 (0.2) | 0.9 (1.0) | 0.9 (0.2) | −0.5 (1.0) | 2.2 (0.4) | 1.4 (0.7) | 1.4 (0.5) | 0.6 (0.7) | 1.4 (0.5) | 1.1 (0.7) | 0.8 (0.3) | −0.9 (0.6) |
| Treatment comparison (95% CI); p-value | 1.4 (0.8, 2.1); p < 0.001 | 1.7 (−1.2, 4.7); p = 0.248 | 1.4 (0.7, 2.0); p < 0.001 | 2.0 (−0.3, 4.3); p = 0.091 | 1.6 (0.9, 2.2); p < 0.001 | 1.4 (−1.4, 4.3); p = 0.335 | 1.4 (0.4, 2.4); p = 0.006 | 2.4 (0.5, 4.3); p = 0.012 | 0.6 (−0.5, 1.6); p = 0.301 | 1.5 (−0.3, 3.3); p = 0.102 | 0.6 (−0.5, 1.7); p = 0.281 | 2.0 (0.2, 3.8); p = 0.03 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.976 | p = 0.696 | ||||||||||||||
| MCS (SE) | −0.7 (0.3) | −3.9 (1.3) | −0.5 (0.3) | −0.6 (0.5) | −0.5 (0.3) | −2.9 (1.1) | −1.1 (0.3) | −0.5 (0.6) | −0.7 (0.4) | 0.5 (0.7) | −0.7 (0.4) | 0.8 (0.6) | 0.3 (0.5) | 0.4 (0.6) | −0.4 (0.3) | −0.6 (0.5) |
| Treatment comparison (95% CI); p-value | 0.4 (−0.4, 1.2); p = 0.314 | −3.4 (−6.6, −0.3); p = 0.030 | 0.7 (0, 1.4); p = 0.063 | −0.1 (−1.8, 1.6); p = 0.886 | 0.7 (−0.1, 1.4); p = 0.075 | −2.4 (−5.0, 0.1); p = 0.06 | −0.3 (−1.3, 0.8); p = 0.638 | 1.1 (−0.6, 2.7); p = 0.225 | −0.2 (−1.3, 0.8); p = 0.678 | 1.3 (−0.3, 2.9); p = 0.1 | 0.8 (−0.4, 1.9); p = 0.184 | 1.0 (−0.5, 2.5); p = 0.188 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.081 | p = 0.496 | ||||||||||||||
| Physical functioning (SE) | 2.4 (0.2) | 1.5 (1.0) | 2.3 (0.2) | 2.1 (0.6) | 2.6 (0.2) | 0.5 (1.3) | 0.9 (0.2) | 0.1 (0.9) | 1.8 (0.5) | 1.1 (0.6) | 1.8 (0.4) | 0.4 (0.6) | 1.4 (0.5) | 1.2 (0.7) | 1.1 (0.3) | −0.4 (0.6) |
| Treatment comparison (95% CI); p-value | 1.5 (0.9, 2.1); p < 0.001 | 1.4 (−1.3, 4.1); p = 0.311 | 1.4 (0.7, 2.0); p < 0.001 | 2.0 (0.0, 4.1); p = 0.052 |
1.7 (1.1, 2.3); p < 0.001 | 0.4 (−2.7, 3.5); p = 0.797 | 0.7 (−0.4, 1.8); p = 0.217 | 1.5 (−0.2, 3.3); p = 0.093 | 0.7 (−0.3, 1.7); p = 0.177 | 0.8 (−0.9, 2.6); p = 0.342 | 0.3 (−0.9, 1.6); p = 0.586 | 1.6 (−0.3, 3.4); p = 0.092 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.797 | p = 0.792 | ||||||||||||||
| Role-Physical (SE) | 1.2 (0.2) | 0.7 (1.0) | 1.1 (0.2) | 0.6 (0.6) | 1.7 (0.2) | −0.6 (1.0) | 0.6 (0.2) | −0.7 (1.0) | 1.8 (0.4) | −0.1 (0.8) | 0.6 (0.4) | 0.9 (0.7) | 0.7 (0.5) | 0.7 (0.7) | 0.4 (0.3) | −0.6 (0.6) |
| Treatment comparison (95% CI); p-value | 0.6 (0.0, 1.2); p = 0.067 |
1.4 (−1.4, 4.2); p = 0.327 | 0.5 (−0.2, 1.2); p = 0.140 | 1.3 (−1.0, 3.6); p = 0.261 | 1.2 (0.5, 1.8); p < 0.001 | 0.1 (−2.7, 2.9); p = 0.963 | 1.4 (0.5, 2.4); p = 0.004 | 0.5 (−1.4, 2.4); p = 0.587 | 0.2 (−0.9, 1.3); p = 0.69 | 1.5 (−0.3, 3.3); p = 0.097 | 0.2 (−0.9, 1.3); p = 0.681 | 1.3 (−0.4, 3.1); p = 0.128 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.746 | p = 0.412 | ||||||||||||||
| Bodily pain (SE) | 0.9 (0.3) | −0.5 (1.4) | 0.8 (0.3) | 1.2 (1.0) | 0.8 (0.3) | −0.3 (1.3) | −0.3 (0.3) | 0.0 (1.2) | 0.9 (0.5) | 0.7 (0.9) | 0.2 (0.6) | −0.2 (0.9) | 0.1 (0.6) | −0.3 (0.9) | 0.2 (0.4) | −1.3 (0.7) |
| Treatment comparison (95% CI); p-value | 1.2 (0.4, 2.0); p = 0.004 | −0.5 (−4.2, 3.2); p = 0.788 | 1.2 (0.3, 2.0); p = 0.007 | 1.2 (−1.9, 4.2); p = 0.451 | 1.1 (0.2, 1.9); p = 0.012 | −0.4 (−3.9, 3.2); p = 0.847 | 0.7 (−0.5, 1.9); p = 0.24 | 2.1 (−0.3, 4.4); p = 0.083 | 0.0 (−1.3, 1.3); p = 0.967 | 1.2 (−1.1, 3.4); p = 0.313 | 0.0 (−1.4, 1.3); p = 0.947 | 1.0 (−1.3, 3.4); p = 0.395 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.840 | p = 0.798 | ||||||||||||||
| General health (SE) | 2.0 (0.3) | −1.4 (1.1) | 2.4 (0.3) | −0.2 (0.8) | 2.2 (0.3) | 0.1 (1.0) | 0.3 (0.3) | −1.1 (0.9) | 1.9 (0.4) | 3.6 (0.7) | 1.6 (0.5) | 1.4 (0.6) | 2.3 (0.5) | 2.4 (0.6) | 0.5 (0.3) | −1.2 (0.6) |
| Treatment comparison (95% CI); p-value | 1.7 (1.0, 2.4); p < 0.001 | −0.3 (−3.2, 2.5); p = 0.810 | 2.1 (1.4, 2.8); p < 0.001 | 0.9 (−1.5, 3.2); p = 0.462 | 1.9 (1.2, 2.6); p < 0.001 | 1.2 (−1.4, 3.8); p = 0.364 | 1.5 (0.3, 2.6); p = 0.01 | 4.8 (3.0, 6.7); p < 0.001 | 1.1 (−0.1, 2.2); p = 0.061 | 2.6 (0.9, 4.4); p = 0.003 | 1.8 (0.6, 2.9); p = 0.002 | 3.6 (1.9, 5.3); p < 0.001 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.697 | p = 0.084 | ||||||||||||||
| Vitality (SE) | 0.8 (0.3) | −1.6 (1.3) | 0.8 (0.3) | 0.4 (0.9) | 0.9 (0.3) | −2.5 (1.0) | −0.6 (0.3) | −1.6 (0.8) | 0.6 (0.4) | 1.4 (0.7) | −0.2 (0.5) | 1.1 (0.7) | 1.7 (0.4) | −0.1 (0.7) | −0.1 (0.4) | −0.2 (0.5) |
| Treatment comparison (95% CI); p-value | 1.4 (0.6, 2.2); p < 0.001 | 0 (−3.1, 3.1); p = 0.984 | 1.5 (0.6, 2.3); p < 0.001 | 2.0 (−0.3, 4.4); p = 0.086 | 1.5 (0.7, 2.4); p < 0.001 | −0.8 (−3.4, 1.7); p = 0.529 | 0.8 (−0.4, 1.9); p = 0.191 | 1.5 (−0.2, 3.3); p = 0.084 | −0.1 (−1.3, 1.1); p = 0.872 | 1.3 (−0.3, 3.0); p = 0.117 | 1.9 (0.7, 3.0); p = 0.001 | 0.1 (−1.6, 1.8); p = 0.886 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.387 | p = 0.156 | ||||||||||||||
| Social functioning (SE) | 0.2 (0.3) | −0.9 (1.2) | 0.6 (0.3) | −0.5 (0.7) | 0.4 (0.3) | 0.1 (0.9) | 0.0 (0.3) | −0.7 (0.7) | 0.3 (0.4) | 0.8 (0.6) | 0.0 (0.5) | 0.9 (0.4) | 0.4 (0.4) | 0.0 (0.6) | 0.0 (0.3) | −0.5 (0.5) |
| Treatment comparison (95% CI); p-value | 0.2 (−0.5, 1.0); p = 0.530 | −0.2 (−3.1, 2.6); p = 0.878 | 0.6 (−0.2, 1.3); p = 0.127 | 0.2 (−1.9, 2.2); p = 0.881 | 0.4 (−0.3, 1.2); p = 0.253 | 0.8 (−1.5, 3.0); p = 0.509 | 0.3 (−0.8, 1.4); p = 0.62 | 1.3 (−0.2, 2.9); p = 0.09 | −0.1 (−1.2, 1.1); p = 0.928 | 1.4 (0.1, 2.7); p = 0.03 | 0.4 (−0.7, 1.5); p = 0.477 | 0.4 (−1.1, 2.0); p = 0.578 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.966 | p = 0.528 | ||||||||||||||
| Role-Emotional (SE) | −0.2 (0.3) | −2.3 (1.1) | 0.3 (0.2) | 0.5 (0.5) | 0.4 (0.2) | −2.5 (1.2) | −0.4 (0.3) | 0.3 (0.6) | −0.1 (0.45) | 0.1 (0.9) | 0.2 (0.4) | 0.2 (0.7) | 0.2 (0.45) | 0.6 (0.5) | 0.0 (0.3) | −0.3 (0.5) |
| Treatment comparison (95% CI); p-value | 0.2 (−0.6, 0.9); p = 0.666 | −2.6 (−5.2, −0.1); p = 0.043 |
0.7 (0.0, 1.4); p = 0.058 |
0.2 (−1.4, 1.8); p = 0.834 | 0.8 (0.2, 1.5); p = 0.017 | −2.8 (−5.5, −0.1); p = 0.046 |
−0.2 (−1.2, 0.9); p = 0.774 | 0.4 (−1.7, 2.5); p = 0.708 | 0.1 (−0.9, 1.2); p = 0.798 | 0.5 (−1.2, 2.2); p = 0.559 | 0.2 (−0.9, 1.3); p = 0.716 | 0.9 (−0.5, 2.3); 0.209 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.088 | p = 0.933 | ||||||||||||||
| Mental health (SE) | −0.2 (0.3) | −3.3 (1.4) | −0.3 (0.3) | −0.2 (0.6) | −0.1 (0.3) | −2.8 (1.1) | −1.2 (0.2) | −0.1 (0.6) | −0.2 (0.4) | 0.6 (0.6) | −0.1 (0.4) | 0.8 (0.6) | 0.3 (0.5) | 0.8 (0.6) | −0.2 (0.3) | −1.2 (0.5) |
| Treatment comparison (95% CI); p-value | 1.1 (0.3, 1.8); p = 0.004 | −3.2 (−6.4, −0.1); p = 0.043 |
1.0 (0.2, 1.7); p = 0.008 | −0.1 (−1.9, 1.7); p = 0.918 | 1.2 (0.5, 1.9); p = 0.001 | −2.8 (−5.3, −0.2); p = 0.032 |
0 (−1.0, 1.0); p = 0.992 | 1.8 (0.2, 3.4); p = 0.025 | 0.1 (−0.9, 1.1); p = 0.854 | 1.9 (0.4, 3.5); p = 0.013 | 0.5 (−0.6, 1.6); p = 0.344 | 2.0 (0.5, 3.5); p = 0.008 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.021 | p = 0.244 | ||||||||||||||
| Change in IWQOL-Lite-CT scores Total (SE) | 11.8 (0.6) | 7.9 (3.4) | 13.2 (0.7) | 11.3 (1.6) | 14.9 (0.6) | 14.8 (2.0) | 5.0 (0.7) | 3.7 (2.2) | 8.9 (0.9) | 7.0 (1.7) | 9.0 (0.9) | 8.2 (1.3) | 10.2 (0.9) | 9.3 (1.2) | 6.1 (0.6) | 3.3 (1.1) |
| Treatment comparison (95% CI); p-value | 6.7 (4.9, 8.5); p < 0.001 | 4.2 (−4.0, 12.4); p = 0.319 | 8.2 (6.4, 10.0); p < 0.001 | 7.6 (2.1, 13.0); p = 0.006 | 9.9 (8.1, 11.7); p < 0.001 | 11.1 (5.1, 17.1); p < 0.001 | 2.8 (0.7, 5.0); p = 0.01 | 3.7 (−0.4, 7.8); p = 0.076 | 2.9 (0.8, 5.1); p = 0.008 | 4.9 (1.4, 8.4); p = 0.006 | 4.1 (2.0, 6.2); p < 0.001 | 6.0 (2.8, 9.2); p < 0.001 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.915 | p = 0.809 | ||||||||||||||
| Physical composite scores (SE) | 10.9 (0.7) | 7.9 (3.2) | 11.6 (0.7) | 7.9 (2.0) | 12.8 (0.7) | 12.9 (2.9) | 3.8 (0.7) | 0.2 (2.3) | 8.6 (1.1) | 6.5 (2.1) | 8.1 (1.1) | 6.9 (2.2) | 9.7 (1.0) | 9.4 (1.5) | 4.8 (0.8) | 1.8 (1.3) |
| Treatment comparison (95% CI); p-value | 7.0 (5.1, 8.9); p < 0.001 | 7.7 (−0.3, 15.7); p = 0.058 | 7.7 (5.8, 9.7); p < 0.001 | 7.7 (1.6, 13.8); p = 0.013 | 9.0 (7.1, 10.8); p < 0.001 | 12.8 (5.4, 20.1); p < 0.001 | 3.8 (1.1, 6.5); p = 0.005 | 4.7 (−0.3, 9.7); p = 0.064 | 3.3 (0.6. 6.0); p = 0.018 | 5.1 (0.1, 10.1); p = 0.046 | 4.9 (2.4, 7.4); p < 0.001 | 7.6 (3.6, 11.6); p < 0.001 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.862 | p = 0.821 | ||||||||||||||
| Physical function composite scores (SE) | 11.3 (0.7) | 8.6 (3.3) | 12.0 (0.7) | 7.6 (2.3) | 13.5 (0.7) | 13.5 (3.5) | 3.6 (0.7) | 0.4 (2.6) | 8.7 (1.2) | 7.1 (2.1) | 9.2 (1.2) | 8.1 (2.2) | 10.2 (1.1) | 9.5 (1.7) | 5.3 (0.8) | 1.9 (1.4) |
| Treatment comparison (95% CI); p-value | 7.7 (5.7, 9.7); p < 0.001 | 8.2 (−0.2, 16.6); p = 0.056 | 8.4 (6.4, 10.4); p < 0.001 | 7.3 (0.4, 14.1); p = 0.038 | 9.9 (8.0, 11.9); p < 0.001 | 13.1 (4.4, 21.8); p = 0.003 | 3.5 (0.6, 6.3); p = 0.018 | 5.1 (0.1, 10.2); p = 0.047 | 4.0 (1.0, 6.9); p = 0.008 | 6.2 (0.9, 11.4); p = 0.021 | 5.0 (2.2, 7.7); p < 0.001 | 7.5 (3.2, 11.8); p < 0.001 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.907 | p = 0.844 | ||||||||||||||
| Psychosocial composite scores (SE) | 12.3 (0.7) | 7.8 (3.9) | 14.1 (0.7) | 12.9 (1.9) | 16.1 (0.7) | 16.2 (2.1) | 5.7 (0.7) | 5.6 (2.4) | 9.1 (0.9) | 7.2 (1.8) | 9.6 (0.9) | 8.5 (1.2) | 10.6 (0.9) | 9.4 (1.15) | 6.9 (0.7) | 4.1 (1.2) |
| Treatment comparison (95% CI); p-value | 6.5 (4.6, 8.5); p < 0.001 | 2.2 (−6.9, 11.4); p = 0.632 | 8.4 (6.4, 10.3); p < 0.001 | 7.3 (1.3, 13.4); p = 0.018 | 10.3 (8.4, 12.3); p < 0.001 | 10.7 (4.2, 17.1); p = 0.001 | 2.2 (0.0, 4.5); p = 0.049 | 3.1 (−1.1, 7.3); p = 0.153 | 2.7 (0.5, 4.8); p = 0.015 | 4.4 (1.0, 7.8); p = 0.011 | 3.7 (1.4, 5.9); p = 0.001 | 5.3 (1.9, 8.6); p = 0.002 | ||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.867 | p = 0.884 | ||||||||||||||
| Exploratory objective (at Week 72) | ||||||||||||||||
| Percent change in hsCRP, % (95% CI) | −36.1 (−40.3, −31.7) |
−48.3 (−58.9, −35.1) |
−41.2 (−45.3, −36.8) |
−39.2 (−49.4, −27.0) |
−46.8 (−50.7, −42.6) |
−61.6 (−68.7, −52.8) |
−12.1 (−16.7, −7.2) |
−17.5 (−34.6, 4.1) | −40.9 (−47.5, −33.6) |
−32.8 (−48.3, −12.6) |
−47.8 (−53.3, −41.7) |
−39.1 (−53.1, −21.0) |
−52.1 (−58.1, −45.3) |
−48.9 (−57.2, −39.0) |
−11.1 (−17.7, −4.1) |
−6.5 (−19.3, 8.3) |
| Treatment comparison (95% CI); p-value | −27.3 (−33.4, −20.7); p < 0.001 |
−37.4 (−54.9, −13.0); p = 0.006 |
−33.1 (−38.9, −26.8); p < 0.001 |
−26.3 (−45.3, −0.7); p = 0.045 |
−39.5 (−44.9, −33.6); p < 0.001 |
−53.4 (−65.8, −36.5); p < 0.001 |
−33.5 (−42.3, −23.5); p < 0.001 |
−28.1 (−46.9, −2.6); p = 0.033 |
−41.3 (−48.7, −32.8); p < 0.001 |
−34.9 (−51.8, −12.0); p = 0.005 |
−46.1 (−53.9, −37.1); p < 0.001 |
−45.3 (−56.7, −31.0); p < 0.001 |
||||
| <65 vs. ≥65 years heterogeneity p-value | p = 0.642 | p = 0.972 | ||||||||||||||
Data are model-based estimates and 95% CIs are assessed with the use of an MMRM according to the efficacy estimand. The CIs were not adjusted for multiplicity and should not be used for hypothesis testing. Lipid parameters and hsCRP were analyzed using log-transformation. Data from the investigational orforglipron capsule formulations of 6 mg, 12 mg, and 36 mg have demonstrated bioequivalence with the tablet doses of 5.5 mg, 9 mg, and 17.2 mg [33], which are approved in the United States [30].
CI = confidence interval; EQ-5D-5L = EuroQol 5-Dimension 5-Level questionnaire; HbA1c = glycated hemoglobin, HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; IWQOL-Lite-CT=Impact of Weight on Quality of Life-Lite Clinical Trials version; LDL = low-density lipoprotein; MCS = mental component score; MMRM = mixed model for repeated measures; PCS = physical component score; SBP = systolic blood pressure; SF-36v2 = Short-Form Health Survey version 2; SE = standard error; VAS = visual analog scale; VLDL = very low-density lipoprotein.
The primary and key secondary endpoints were tested under a type 1 error control procedure using a two-sided nominal significance level of 0.05.
Data presented as model-based estimate (SE) from logistic regression according to the efficacy estimand. The percentage was calculated by combining the percentages of participants who met the target in imputed datasets with the use of Rubin's rules.
For both trials, more participants who were ≥65 years of age in the orforglipron groups reached weight reduction thresholds of ≥5%, ≥10%, ≥15%, and ≥20% from baseline than participants in the placebo group (Fig. 2E and F, Table 2). At Week 72, body weight reduction ≥10% was reached in 44.4%, 55.6%, and 61.4% of participants for orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, compared with 9.6% in the placebo group (all p < 0.001 vs. placebo) for ATTAIN-1. The respective percentages for participants in ATTAIN-2 were 33.9%, 41.4%, and 59.6% in the orforglipron treatment groups compared with 7.2% in the placebo group (all p < 0.001 vs. placebo). Lower percentages were observed in participants <65 years of age in both studies with significant heterogeneity occurring for participants in ATTAIN-2 who experienced weight reduction ≥15% (p = 0.016) and ≥20% (p = 0.033).
At Week 72, participants ≥65 years of age from ATTAIN-1 without T2D, experienced a decrease from baseline in HbA1c of 0.37%, 0.31%, and 0.49% with 5.5 mg, 9 mg, and 17.2 mg orforglipron, respectively, vs. 0.02% with placebo (Fig. 3A; Table 2). Participants <65 years of age from ATTAIN-1 experienced a decrease from baseline in HbA1c of 0.30%, 0.31%, and 0.37% with 5.5 mg, 9 mg, and 17.2 mg orforglipron, respectively, vs. 0.03% with placebo (Table 2). Among participants ≥65 years of age from ATTAIN-2 with T2D, HbA1c decreased from baseline by 1.46%, 1.62%, and 1.66% with 5.5 mg, 9 mg, and 17.2 mg orforglipron, respectively, vs. 0.12% with placebo (Fig. 3B). The proportion of participants with T2D reaching HbA1c thresholds <7%, ≤6.5%, or <5.7% at Week 72 was higher in all orforglipron groups compared with placebo for participants <65 or ≥65 years of age (Fig. 3C). The proportion of participants ≥65 years of age reaching an HbA1c level of ≤6.5% was 67.1%, 81.7%, and 80.9% with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. 8.6% with placebo. Among participants <65 years of age from ATTAIN-2 with T2D, HbA1c decreased from baseline at Week 72 by 1.25%, 1.60%, and 1.83% with 5.5 mg, 9 mg, and 17.2 mg orforglipron, respectively, vs. 0.16% with placebo. The proportion of participants <65 years of age reaching an HbA1c level ≤6.5% was 52.8%, 64.0%, and 73.6% with orforglipron 5.5 mg, 9 mg, and 17.2 mg, respectively, vs. 11.5% with placebo. Significant heterogeneity was observed between age groups for the proportion of participants to reach an HbA1c level ≤6.5% (p = 0.002), and for participants who reached an HbA1c level <5.7% (p = 0.001).
Fig. 3.
ATTAIN-1 and ATTAIN-2: Percent change from baseline in HbA1c over time in participants ≥65 years, proportion of participants achieving HbA1c thresholds by age group, change from baseline in FSG, percent change from baseline in lipid parameters by age group, change from baseline in waist circumference and SBP, and percent change from baseline in hsCRP.
Data are model-based estimates using the efficacy estimand assessed at Week 72 among participants ≥65 years of age unless otherwise stated. (A, B, D, E, H–K) The curves shown from Week 0 to Week 72 are observed mean (SE) using the efficacy estimand datapoints set, including all datapoints obtained during the treatment period and up to the earliest date of discontinuation of study treatment or initiation of prohibited weight-management treatments (or glycemic rescue therapy or prohibited glycemic therapy for glycemic endpoints only) for: percent change in HbA1c among participants from ATTAIN-1 (A) and ATTAIN-2 (B), change in FSG among participants from ATTAIN-1 (D) and ATTAIN-2 (E), change in waist circumference among participants from ATTAIN-1 (H) and ATTAIN-2 (I), change in SBP among participants from ATTAIN-1 (J) and ATTAIN-2 (K). (C) Proportion of participants with T2D reaching HbA1c targets of <7.0%, ≤6.5%, and <5.7% from ATTAIN-2. (F, G) Percent change in lipid parameters for participants in ATTAIN-1 (F) and ATTAIN-2 (G). (L, M) Percent change in hsCRP (efficacy estimand) and 95% CIs among participants from ATTAIN-1 (L) and ATTAIN-2 (M). Numbers below the graphs are the numbers of participants at the specified time point. Data from the investigational orforglipron capsule formulations of 6 mg, 12 mg, and 36 mg have demonstrated bioequivalence with the tablet doses of 5.5 mg, 9 mg, and 17.2 mg [33], which are approved in the United States [30].
CI = confidence interval; FSG = fasting serum glucose; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; SBP = systolic blood pressure; SE = standard error; T2D = type 2 diabetes; VLDL = very low-density lipoprotein.
*p < 0.05; **p < 0.01, ***p < 0.001. Significance values refer to risk difference comparison with placebo.
aEfficacy estimand model-based estimate (95% CI) for change from baseline and estimated treatment difference between orforglipron groups and placebo based on a mixed model for repeated measures analysis.
In participants <65 and ≥ 65 years of age from both ATTAIN-1 and ATTAIN-2, all doses of orforglipron were associated with significantly greater reductions from baseline in change in body weight, BMI, fasting serum glucose, waist circumference, as well as percent change in high-sensitivity C-reactive protein (hsCRP) at Week 72 compared with placebo (Tables 2 and S2; Fig. 3). Reductions from baseline to Week 72 were also observed across most treatment groups in systolic blood pressure and lipid parameters, except for HDL cholesterol, which increased as expected, for both age groups in each study. Body composition, which was only assessed in ATTAIN-1, indicated no significant difference in percent change in body lean mass among participants <65 vs. ≥65 years of age (heterogeneity p = 0.939; Table S2). Analyses of patient-reported outcomes from ATTAIN-1 and ATTAIN-2 indicated greater improvements in quality of life from baseline to Week 72 for participants receiving orforglipron vs. placebo in both age groups. Numerical improvements were observed in the IWQOL-Lite-CT (total score and composite scores), with significant differences from placebo occurring with higher doses of orforglipron (Table 2). The SF-36v2 also showed some improvements in component summary and domain scores in both age groups, but many changes were not significantly different from placebo.
3.3. Safety
Among participants <65 and ≥ 65 years of age from ATTAIN-1 and ATTAIN-2, the most frequent AEs with orforglipron were gastrointestinal (nausea, constipation, diarrhea, vomiting, and dyspepsia; Table 3), which were mostly mild to moderate in severity. Treatment discontinuation due to gastrointestinal AEs occurred in 3.5%, 5.7%, and 6.3% of participants <65 years of age and 2.6%, 9.9%, and 7.6% of participants ≥65 years of age in the pooled orforglipron 5.5-mg, 9-mg, and 17.2-mg groups, respectively, vs. 0.7% and 0.4% of participants in the placebo group. Serious adverse events (SAEs) were reported by 5.6%, 6.2%, and 5.4% of participants <65 years of age and 9.9%, 13.0%, and 11.6% of participants ≥65 years of age in the orforglipron 5.5-mg, 9-mg, and 17.2-mg groups, respectively, vs. 5.4% and 11.4% in the placebo group, with no significant pairwise differences vs. placebo (Table 3). There were 7 deaths reported among participants <65 years of age (orforglipron 5.5 mg: 1; 9 mg: 2; 17.2 mg: 2; placebo: 2) and 6 among participants ≥65 years of age (orforglipron 9 mg: 3; placebo: 3). Among participants <65 years of age, 4 deaths, including 2 in the placebo group, were due to cardiovascular events, the other 3 were undetermined, although 2 were associated with cardiovascular events. Among participants ≥65 years of age, 1 death in the orforglipron group was due to malignancy caused by metastatic ovarian cancer; the other 2 were undetermined, although 1 was associated with T2D. For participants ≥65 years of age in the placebo group, all deaths were non-cardiovascular.
Table 3.
AEs in the pooled safety population of participants <65 and ≥ 65 years of age from ATTAIN-1 and ATTAIN-2.
| Orforglipron 5.5 mg |
Orforglipron 9 mg |
Orforglipron 17.2 mg |
Placebo |
Risk Difference (95% CI) |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Orforglipron 5.5 mg vs. placebo |
Orforglipron 9 mg vs. placebo |
Orforglipron 17.2 mg vs. placebo |
||||||||||||
| <65 years (n = 933) | ≥65 years (n = 118) | <65 years (n = 920) | ≥65 years (n = 135) | <65 years (n = 903) | ≥65 years (n = 146) | <65 years (n = 1362) | ≥65 years (n = 214) | <65 years | ≥65 years | <65 years | ≥65 years | <65 years | ≥65 years | |
| Participants with ≥1 TEAE | 781 (83.7%) | 92 (78.0%) | 799 (86.9%) | 118 (87.4%) | 774 (85.8%) | 130 (89.0%) | 1129 (82.5%) | 179 (83.2%) | 1.1 (−2.0, 4.2) | −5.3 (−14.3, 3.8) | 4.3 (1.3, 7.3) | 4.3 (−3.4, 11.9) | 3.3 (0.3, 6.4) | 5.7 (−1.5, 12.8) |
| Serious AEs | 52 (5.6%) | 12 (10.0%) | 56 (6.2%) | 17 (13.0%) | 46 (5.4%) | 17 (11.6%) | 76 (5.4%) | 25 (11.4%) | 0.2 (−1.7, 2.1) | −1.5 (−8.3, 5.3) | 0.7 (−1.2, 2.7) | −1.6 (−5.5, 8.7) | −0.1 (−2.0, 1.8) | 0.2 (−6.6, 7.0) |
| AEs leading to deatha | 1 (0.1%) | 0 | 2 (0.2%) | 3 (2.2%) | 4 (0.5%) | 0 | 2 (0.1%) | 3 (1.3%) | 0.0 (−0.3, 0.2) | −1.3 (−2.8, 0.2) | 0.1 (−0.3, 0.5) | 0.9 (−2.0, 3.9) | 0.3 (−0.2, 0.8) | −1.4 (−2.9, 0.2) |
| AEs leading to discontinuation of study drug | 52 (5.6%) | 6 (5.2%) | 69 (7.5%) | 23 (17.0%) | 89 (9.9%) | 20 (13.7%) | 43 (3.1%) | 12 (5.5%) | 2.5 (0.8, 4.2) | −0.3 (−5.4, 4.8) | 4.5 (2.5, 6.4) | 11.5 (4.5, 18.6) | 6.8 (4.6, 8.9) | 8.1 (1.7, 14.4) |
| AEs leading to discontinuation of study drug in ≥1% of participants in any treatment group (preferred term) | ||||||||||||||
| Nausea | 9 (1.0%) | 0 | 19 (2.0%) | 7 (5.3%) | 20 (2.2%) | 1 (0.7%) | 1 (0.1%) | 0 | 0.9 (0.2, 1.5) | 0 | 2.0 (1.0, 2.9) | 5.3 (1.5, 9.0) | 2.2 (1.2, 3.1) | 0.6 (−0.7, 2.0) |
| Vomiting | 8 (0.9%) | 2 (1.7%) | 8 (0.9%) | 2 (1.6%) | 15 (1.6%) | 2 (1.4%) | 0 | 0 | 0.9 (0.3, 1.5) | 1.8 (−0.6, 4.1) | 0.9 (0.3, 1.5) | 1.6 (−0.5, 3.7) | 1.7 (0.8, 2.5) | 1.4 (−0.5, 3.2) |
| Diarrhea | 6 (0.6%) | 0 | 6 (0.7%) | 1 (0.8%) | 3 (0.3%) | 3 (2.0%) | 1 (0.1%) | 0 | 0.6 (0.1, 1.1) | 0 | 0.6 (0.1, 1.2) | 0.8 (−0.7, 2.3) | 0.3 (−0.1, 0.6) | 2.1 (−0.2, 4.4) |
| Decreased appetite | – | 0 | – | 3 (2.1%) | – | 0 | – | 0 | – | 0 | – | 2.1 (−0.3, 4.5) | – | 0 |
| TEAEs occurring in ≥10% of participants in any treatment group (preferred term) | ||||||||||||||
| Nausea | 249 (26.5%) | 26 (21.7%) | 322 (34.9%) | 41 (30.9%) | 315 (35.0%) | 47 (32.2%) | 138 (10.3%) | 14 (6.2%) | 16.2 (12.9, 19.5) | 15.5 (7.2, 23.7) | 24.5 (21.0, 28.0) | 24.7 (16.4, 33.1) | 24.7 (21.1, 28.2) | 26.0 (17.8, 34.2) |
| Constipation | 193 (20.6%) | 22 (18.6%) | 248 (26.7%) | 38 (27.7%) | 225 (24.9%) | 32 (22.0%) | 108 (8.1%) | 29 (13.5%) | 12.5 (9.5, 15.4) | 5.1 (−3.3, 13.5) | 18.6 (15.4, 21.8) | 14.4 (5.5, 23.2) | 16.7 (13.5, 19.9) | 8.2 (0.1, 16.3) |
| Diarrhea | 198 (21.2%) | 24 (20.3%) | 225 (24.5%) | 22 (17.2%) | 220 (24.6%) | 36 (24.6%) | 161 (11.5%) | 24 (10.8%) | 9.7 (6.6, 12.8) | 9.5 (1.1, 17.9) | 12.9 (9.7, 16.2) | 6.3 (−1.1, 13.8) | 13.1 (9.8, 16.4) | 13.8 (5.6, 21.9) |
| Vomiting | 121 (13.0%) | 15 (12.7%) | 203 (22.0%) | 19 (14.4%) | 216 (23.8%) | 33 (22.6%) | 49 (3.6%) | 8 (3.6%) | 9.4 (7.0, 11.7) | 9.1 (2.6, 15.6) | 18.5 (15.6, 21.3) | 10.7 (4.3, 17.2) | 20.3 (17.3, 23.2) | 19.0 (11.8, 26.2) |
| Dyspepsia | 111 (11.8%) | 14 (12.0%) | 144 (15.6%) | 24 (17.6%) | 122 (13.4%) | 16 (11.0%) | 64 (4.7%) | 5 (2.5%) | 7.0 (4.6, 9.3) | 9.5 (3.3, 15.8) | 10.9 (8.3, 13.5) | 15.1 (8.3, 21.9) | 8.7 (6.2, 11.2) | 8.5 (3.0, 13.9) |
| Hyperglycemia | 40 (4.6%) | 6 (5.2%) | 29 (3.4%) | 4 (3.2%) | 22 (2.8%) | 7 (4.8%) | 201 (12.3%) | 47 (20.7%) | −7.9 (−10.0, −5.9) |
−15.5 (−22.1, −8.9) |
−9.1 (−11.1, −7.2) |
−17.2 (−23.3, −11.0) |
−9.2 (−11.1, −7.3) |
−16.4 (−22.7, −10.0) |
| Decreased appetite | 58 (6.2%) | 11 (9.5%) | 80 (8.7%) | 11 (8.2%) | 85 (9.8%) | 17 (11.6%) | 44 (3.2%) | 4 (1.9%) | 3.0 (1.2, 4.8) | 7.6 (2.0, 13.2) | 5.5 (3.4, 7.5) | 6.3 (1.3, 11.3) | 6.5 (4.4, 8.7) | 9.9 (4.3, 15.4) |
| Upper respiratory tract infection | 93 (9.9%) | 7 (6.0%) | 94 (10.2%) | 13 (9.8%) | 80 (8.9%) | 17 (11.6%) | 141 (10.5%) | 17 (7.9%) | −0.6 (−3.1, 1.9) | −1.9 (−7.5, 3.7) | −0.3 (−2.8, 2.3) | 1.9 (−4.3, 8.1) | −1.6 (−4.1, 0.8) | 3.8 (−2.5, 10.2) |
| Eructation | 57 (6.1%) | 8 (6.7%) | 66 (7.3%) | 15 (11.5%) | 75 (8.5%) | 8 (5.5%) | 12 (0.9%) | 2 (0.9%) | 5.2 (3.6, 6.8) | 5.8 (1.1, 10.5) | 6.4 (4.6, 8.2) | 10.6 (5.1, 16.1) | 7.5 (5.6, 9.4) | 4.5 (0.6, 8.4) |
| Urinary tract infection | 28 (3.0%) | 7 (6.0%) | 40 (4.3%) | 15 (11.0%) | 46 (5.1%) | 7 (4.8%) | 53 (3.9%) | 8 (3.6%) | −0.9 (−2.4, 0.6) | 2.3 (−2.6, 7.3) | 0.4 (−1.2, 2.1) | 7.5 (1.6, 13.3) | 1.2 (−0.6, 3.0) | 1.2 (−3.1, 5.5) |
| AEs of special interest | ||||||||||||||
| MACEb | ||||||||||||||
| Adjudication-confirmed | 6 (0.6%) | 2 (1.7%) | 3 (0.3%) | 5 (3.7%) | 6 (0.7%) | 5 (3.4%) | 8 (0.6%) | 5 (2.3%) | 0.1 (−0.6, 0.7) | −0.6 (−3.7, 2.4) | −0.2 (−0.8, 0.4) | 1.8 (−2.0, 5.6) | 0.1 (−0.5, 0.8) | 1.2 (−2.4, 4.8) |
| Pancreatitis | ||||||||||||||
| Adjudication-confirmed | 1 (0.1%) | 0 | 3 (0.3%) | 0 | 1 (0.1%) | 1 (0.7%) | 1 (0.1%) | 1 (0.5%) | – | – | – | – | – | – |
| Hepatic events, postbaseline maximum | ||||||||||||||
| ALT ≥3 × ULN | 25 (2.7%) | 4 (3.4%) | 17 (1.9%) | 4 (3.0%) | 26 (2.9%) | 1 (0.7%) | 32 (2.4%) | 0 | 0.3 (−1.0, 1.7) | 3.2 (0.1, 6.4) | −0.5 (−1.7, 0.7) | 3.1 (0.1, 6.0) | 0.5 (−0.9, 1.9) | 0.7 (−0.7, 2.1) |
| AST ≥3 × ULN | 5 (0.5%) | 3 (2.5%) | 7 (0.8%) | 1 (0.7%) | 11 (1.2%) | 0 | 17 (1.3%) | 0 | −0.7 (−1.5, 0.0) | 2.4 (−0.2, 5.0) | −0.4 (−1.3, 0.4) | 0.8 (−0.8, 2.4) | 0 (−0.9, 0.9) | 0 |
| ALP ≥2 × ULN | 2 (0.2%) | 3 (2.5%) | 4 (0.4%) | 0 | 3 (0.3%) | 1 (0.7%) | 9 (0.7%) | 1 (0.5%) | −0.4 (−1.0, 0.1) | 1.9 (−0.8, 4.7) | −0.2 (−0.8, 0.4) | −0.4 (−1.3, 0.4) | −0.3 (−0.9, 0.2) | 0.2 (−1.4, 1.9) |
| Bilirubin ≥2 × ULN | 4 (0.4%) | 0 | 3 (0.3%) | 1 (0.7%) | 6 (0.7%) | 0 | 2 (0.1%) | 2 (0.9%) | 0.3 (−0.2, 0.8) | −0.9 (−2.1, 0.3) | 0.2 (−0.2, 0.7) | −0.1 (−2.1, 1.9) | 0.6 (0.0, 1.2) | −0.9 (−2.2, 0.4) |
| Gallbladder and biliary tract disorders | ||||||||||||||
| Any | 15 (1.6%) | 2 (1.7%) | 21 (2.3%) | 2 (1.5%) | 17 (1.9%) | 2 (1.4%) | 14 (1.0%) | 3 (1.4%) | 0.6 (−0.4, 1.6) | 0.3 (−2.6, 3.1) | 1.3 (0.1, 2.4) | 0.2 (−2.5, 2.8) | 0.8 (−0.3, 1.8) | −0.1 (−2.5, 2.4) |
| Gallbladder- related disorders | 13 (1.4%) | 1 (0.8%) | 19 (2.1%) | 2 (1.6%) | 17 (1.9%) | 1 (0.7%) | 14 (1.1%) | 3 (1.4%) | 0.3 (−0.6, 1.3) | −0.6 (−2.9, 1.6) | 1.0 (−0.1, 2.1) | 0.2 (−2.6, 2.9) | 0.8 (−0.3, 1.8) | −0.8 (−2.8, 1.3) |
| Biliary tract disorders | 5 (0.6%) | 1 (0.9%) | 8 (0.9%) | 0 | 3 (0.3%) | 1 (0.7%) | 1 (0.1%) | 0 | 0.5 (0.0, 1.0) | 0.9 (−0.8, 2.6) | 0.8 (0.2, 1.4) | 0 (0.0, 0.0) | 0.2 (−0.2, 0.6) | 0.7 (−0.7, 2.1) |
| Acute cholecystitis (weight reduction [(≥0% to <10%)] | 1/546 (0.2%) | 0 | 1/465 (0.2%) | 0 | 1/337 (0.3%) | 0 | 1/987 (0.1%) | 1/165 (0.6%) | 0.1 (−0.3, 0.5) | −0.6 (−1.8, 0.6) | 0.1 (−0.3, 0.6) | −0.6 (−1.7, 0.6) | 0.2 (−0.4, 0.8) | −0.6 (−1.7, 0.6) |
| Acute cholecystitis (weight reduction [(≥10% to <20%)] | 1/300 (0.3%) | 0 | 2/344 (0.6%) | 0 | 2/381 (0.5%) | 1/59 (1.7%) | 1/125 (0.8%) | 0 | −0.4 (−2.2, 1.4) | 0 | −0.2 (−2.0, 1.65) | 0 | −0.2 (−2.0, 1.6) | 1.8 (−1.6, 5.2) |
| Acute cholecystitis (weight reduction [(≥20%)] | 0 | 0 | 0 | 0 | 2/159 (1.3%) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1.3 (−0.5, 3.1) | 0 |
| Renal events | ||||||||||||||
| Any | 5 (0.5%) | 5 (4.3%) | 7 (0.8%) | 8 (5.9%) | 6 (0.8%) | 1 (0.7%) | 16 (1.0%) | 6 (2.6%) | −0.5 (−1.2, 0.2) | 1.6 (−2.6, 5.9) | −0.3 (−1.1, 0.5) | 3.3 (−1.2, 7.9) | −0.3 (−1.1, 0.5) | −2.1 (−4.6, 0.4) |
| Any (eGFR <60) | 2/35 (5.4%) | 2/42 (4.7%) | 1/47 (2.0%) | 4/27 (15.3%) | 1/37 (3.4%) | 0 | 5/74 (5.8%) | 5/72 (6.8%) | −0.6 (−10.1, 8.9) | −2.1 (−10.8, 6.6) | −4.1 (−11.0, 2.8) | 8.7 (−5.9, 23.2) | −2.2 (−9.8, 5.4) | −7.1 (−13.0, −1.1) |
| Any (eGFR ≥60) | 3/898 (0.4%) | 3/76 (4.2%) | 6/873 (0.7%) | 4/108 (3.6%) | 5/866 (0.7%) | 1/100 (1.0%) | 11/1287 (0.8%) | 1/142 (0.7%) | −0.5 (−1.1, 0.2) | 3.5 (−1.2, 8.2) | −0.1 (−0.8, 0.6) | 3.0 (−0.8, 6.8) | −0.1 (−0.9, 0.6) | 0.3 (−2.1, 2.6) |
| Gastrointestinal events | ||||||||||||||
| Any serious or severe events | 19 (2.1%) | 3 (2.5%) | 30 (3.3%) | 4 (3.2%) | 34 (3.8%) | 5 (3.4%) | 11 (0.8%) | 3 (1.3%) | 1.3 (0.3, 2.4) | 1.2 (−2.0, 4.5) | 2.5 (1.3, 3.8) | 1.9 (−1.5, 5.2) | 3.0 (1.7, 4.4) | 2.0 (−1.3, 5.4) |
| Lean muscle mass loss-related events | ||||||||||||||
| Any | 33 (3.6%) | 7 (6.0%) | 25 (2.7%) | 9 (6.7%) | 25 (2.8%) | 10 (6.8%) | 41 (3.1%) | 9 (4.3%) | 0.5 (−1.0, 2.0) | 1.7 (−3.4, 6.8) | −0.3 (−1.7, 1.1) | 2.4 (−2.6, 7.5) | −0.3 (−1.7, 1.1) | 2.7 (−2.2, 7.7) |
| Level 2 or Level 3 hypoglycemiac | ||||||||||||||
| Adjusted for year (postbaseline including safety follow-up) | 5 (0.5%) | 2 (1.7%) | 12 (1.3%) | 3 (2.2%) | 10 (1.1%) | 2 (1.4%) | 1 (0.1%) | 1 (0.5%) | – | – | – | – | – | – |
| Hypotension, orthostatic hypotension, and syncope | ||||||||||||||
| Hypotension | 14 (1.5%) | 4 (3.5%) | 13 (1.5%) | 3 (2.2%) | 14 (1.6%) | 5 (3.4%) | 4 (0.3%) | 2 (1.0%) | 1.2 (0.4, 2.0) | 2.5 (−1.0, 6.1) | 1.2 (0.4, 2.0) | 1.2 (−1.6, 4.1) | 1.3 (0.4, 2.2) | 2.5 (−0.7, 5.7) |
| Orthostatic hypotension | 4 (0.4%) | 1 (0.9%) | 3 (0.3%) | 0 | 6 (0.7%) | 0 | 0 | 0 | 0.4 (0.0, 0.9) | 0.9 (−0.8, 2.6) | 0.3 (0.0, 0.7) | 0 | 0.7 (0.1, 1.2) | 0 |
| Syncope | 2 (0.2%) | 2 (1.7%) | 3 (0.3%) | 0 | 5 (0.6%) | 2 (1.4%) | 8 (0.6%) | 1 (0.4%) | −0.4 (−0.9, 0.1) | 1.2 (−1.3, 3.7) | −0.3 (−0.8, 0.3) | −0.4 (−1.3, 0.5) | −0.1 (−0.7, 0.6) | 0.9 (−1.2, 3.0) |
| Hypotension by baseline antihypertensive medication use | ||||||||||||||
| Hypotension | 8/406 (1.9%) | 4/92 (4.3) | 11/380 (3.0%) | 3/112 (2.7%) | 8/368 (2.4%) | 5/117 (4.3%) | 2/606 (0.3%) | 2/181 (1.1%) | 1.5 (0.1, 2.9) | 3.3 (−1.2, 7.7) | 2.7 (0.9, 4.5) | 1.5 (−1.9, 4.9) | 2.0 (0.4, 3.6) | 3.2 (−0.8, 7.1) |
| Orthostatic hypotension | 4/406 (1.0%) | 1/92 (1.1%) | 2/380 (0.5%) | 0 | 3/368 (0.9%) | 0 | 0 | 0 | 1.0 (0.0, 2.0) | 1.1 (−1.0, 3.2) | 0.5 (−0.2, 1.2) | 0 | 0.9 (−0.1, 1.8) | 0 |
| Blood pressure decreased | 0 | 0 | 1/380 (0.3%) | 0 | 3/368 (0.8%) | 1/117 (0.8%) | 0 | 0 | 0 | 0 | 0.3 (−0.3, 0.8) | 0 | 0.8 (−0.1, 1.7) | 0.9 (−0.8, 2.5) |
Data are shown as number of participants (%) unless otherwise stated. For the blank cells, data were unavailable. Data from the investigational orforglipron capsule formulations of 6 mg, 12 mg, and 36 mg have demonstrated bioequivalence with the tablet doses of 5.5 mg, 9 mg, and 17.2 mg [33], which are approved in the United States [30].
AE = adverse event; ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; MACE = major adverse cardiovascular event; TEAE = treatment-emergent adverse event; ULN = upper limit of normal.
Deaths are also included as serious AEs and discontinuations due to AEs.
MACE includes deaths due to cardiovascular cause, myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, coronary interventions (ie, coronary artery bypass graft or percutaneous coronary intervention), and cerebrovascular events (including cerebrovascular accident [stroke] and transient ischemic attack).
Level 2: Blood glucose <54 mg/dL (3.0 mmol/L) and Level 3: Severe hypoglycemia characterized by altered mental status and/or altered physical status that the participant was unable to resolve without assistance.
There were 6 cases (orforglipron 5.5 mg: 1; 9 mg: 3; 17.2 mg: 1; placebo, 1) of adjudication-confirmed pancreatitis among participants <65 years and 2 cases (orforglipron 17.2 mg: 1; placebo: 1) among participants ≥65 years of age. Cholelithiasis was reported as a contributing factor for the 3 participants <65 years of age with pancreatitis in the orforglipron 9-mg treatment group; no contributing factors were reported for the other 3 participants <65 years with pancreatitis. Alcohol abuse was reported as a contributing factor for the participant ≥65 years of age with pancreatitis in the orforglipron 17.2-mg group. All instances of pancreatitis were of mild severity. Positively adjudicated major adverse cardiovascular events occurred in 0.5% (n = 15) of participants <65 years of age in the orforglipron treatment groups (5.5 mg: 6; 9 mg, 3; 17.2 mg, 6) vs. 0.6% (n = 8) in the placebo group and in 3.0% (n = 12) of participants ≥65 years of age in the orforglipron treatment groups (5.5 mg: 2; 9 mg: 5; 17.2 mg: 5) vs. 2.3% (n = 5) in the placebo group (all pairwise comparisons with placebo were nonsignificant). Among participants <65 years of age, a higher percentage of orforglipron-treated (1.5%–1.6%) than placebo-treated participants (0.3%) reported hypotension, which was similar to the percentage of participants ≥65 years of age who reported hypotension (orforglipron-treated: 2.2%–3.5% vs. placebo-treated: 1.0%). Among participants <65 years of age who were receiving antihypertensive medication at baseline, 1.9%, 3.0%, and 2.4% receiving orforglipron 5.5 mg, 9 mg, or 17.2 mg, respectively, experienced hypotension, vs. 0.3% of participants on placebo (pairwise p-values vs. placebo: 5.5 mg, 0.017; 9 mg, <0.001; 17.2 mg, 0.003). Among participants ≥65 years of age, 4.3%, 2.7%, and 4.3% receiving orforglipron 5.5 mg, 9 mg, or 17.2 mg, respectively, experienced hypotension, vs. 1.1% of participants on placebo (all pairwise comparisons with placebo were nonsignificant).
Among participants <65 years of age who received orforglipron, 2.5% (n = 68; orforglipron 5.5 mg: 25; 9 mg: 17; 17.2 mg: 26) had elevated postbaseline alanine aminotransferase (ALT) levels ≥3 × the upper limit of normal (ULN) and 0.8% (n = 23; orforglipron 5.5 mg: 5; 9 mg: 7; 17.2 mg: 11) had elevated postbaseline aspartate aminotransferase (AST) levels ≥3 × ULN vs. 2.4% and 1.3% in the placebo group for each outcome, respectively. Among participants ≥65 years of age who received orforglipron, 2.3% (n = 9; orforglipron 5.5 mg: 4; 9 mg: 4; 17.2 mg: 1) had elevated postbaseline ALT levels ≥3 × ULN and 1.0% (n = 4) of participants (orforglipron 5.5 mg: 3; 9 mg: 1) had elevated postbaseline AST levels ≥3 × ULN vs. 0 participants in the placebo group for either outcome. Thirteen (0.5%) orforglipron-treated participants <65 years of age had elevated postbaseline total bilirubin levels (TBIL) ≥2 × ULN vs. 2 (0.1%) participants in the placebo group. A single (0.3%) orforglipron-treated participant ≥65 years of age (in the 9-mg group) had elevated postbaseline TBIL ≥2 × ULN vs. 2 (0.9%) participants in the placebo group. A total of 3 participants (ATTAIN-1 [orforglipron 5.5 mg and 17.2 mg], 2; ATTAIN-2 [orforglipron 9 mg], 1) all <65 years of age had a combination of elevated serum aminotransferase and TBIL levels ≥3 × ULN and ≥2 × ULN, respectively. Alternative etiologies were identified for all 3 orforglipron-treated participants, including 2 cases of gallstone disease (1 with isolated bilirubin elevation that returned to normal 4 days later) and 1 case of acute hepatitis A virus infection.
Level 2 hypoglycemia (blood glucose <54 mg/dL [3.0 mmol/L]) was reported in 1.7%, 2.2%, and 1.4% of participants ≥65 years of age in the orforglipron 5.5-mg, 9-mg, and 17.2-mg treatment groups, respectively, vs. 0.5% for placebo. No participants ≥65 years of age experienced Level 3 hypoglycemia (severe hypoglycemia characterized by altered mental status and/or altered physical status that the participant was unable to resolve without assistance) and 1 participant <65 years (from ATTAIN-2) who received orforglipron 5.5 mg experienced Level 3 hypoglycemia after taking study medication and metformin and unintentionally skipping breakfast. Renal events were reported in 4.3%, 5.9%, and 0.7% of participants ≥65 years of age in the orforglipron 5.5-mg, 9-mg, and 17.2-mg treatment groups, respectively, vs. 2.6% for placebo. The respective occurrences for participants <65 years of age were 0.5%, 0.8%, and 0.8%, vs. 1.0% for placebo. Treatment-emergent adverse events (TEAEs) possibly related to loss of muscle mass occurred in 6.0%, 6.7%, and 6.8% of participants ≥65 years of age receiving orforglipron 5.5 mg, 9 mg, or 17.2 mg, respectively, vs. 4.3% for placebo (all pairwise comparisons with placebo were nonsignificant), the most common of which were limb fractures and dislocations, occurring in 1.8% of participants who received orforglipron vs. 1.0% for placebo (p = 0.424), and falls, which occurred in 3.3% of participants who received orforglipron vs. 1.8% for placebo (p = 0.252). Table 3 provides additional safety information on TEAEs and AEs of special interest.
4. Discussion
This post hoc subgroup analysis in participants <65 and ≥ 65 years of age with overweight or obesity with or without T2D from ATTAIN-1 and ATTAIN-2 evaluated 72 weeks of treatment with once-daily orforglipron as an adjunct to healthy diet and physical activity. Participants ≥65 years of age without T2D experienced mean body weight reductions up to 13.0% with orforglipron, comparable with the 12.2% reduction observed among participants ≥65 years of age with T2D. These reductions were similar to those observed in participants <65 years of age who reduced up to 12.4% and 9.9% of their body weight with orforglipron in ATTAIN-1 and -2, respectively. The differences between age groups were nonsignificant, but there was a trend indicating greater weight reduction from baseline in the older age group, which warrants further investigation. At Week 72, participants ≥65 years of age with T2D treated with orforglipron also experienced significant reductions vs. placebo in percent change in HbA1c of 1.5%, 1.6%, 1.7% vs. 0.1% for participants in the 5.5-mg, 9-mg, 17.2-mg, and placebo treatment groups respectively (p < 0.001 for all pairwise comparisons). Potential explanations for this trend suggesting greater reductions in body weight and HbA1c in older adults include age-related alterations in GLP-1 receptor sensitivity, higher protocol adherence among older trial participants, and lower baseline energy expenditure. No significant difference in percent change in muscle mass was observed among the age groups from ATTAIN-1, suggesting an improvement in the ratio of fat to lean mass.
The weight reduction observed among participants ≥65 years of age was comparable with that observed in the overall populations in both clinical trials [31,32]. The majority of safety data for orforglipron use in participants ≥65 years of age were also generally consistent with the overall populations in ATTAIN-1 and ATTAIN-2. The SAEs, major adverse cardiovascular events, renal events, and events possibly related to loss of lean muscle mass occurred at a higher rate in participants ≥65 years of age in both placebo and orforglipron groups, consistent with higher baseline risk in an older population. More orforglipron-treated participants reported TEAEs of hepatic events; however, the numbers were low, with the majority of cases related to hepatic enzyme abnormalities. Level 2 hypoglycemia occurred in 8 participants ≥65 years of age (orforglipron 5.5 mg: 2 [1.7%]; 9 mg: 3 [2.2%]; 17.2 mg: 2 [1.4%]; placebo: 1 [0.5%]), and was observed at a higher rate in orforglipron-treated participants vs. placebo.
Previous research among participants ≥65 years of age who received semaglutide or other incretin-based therapies indicated substantial weight reduction on treatment [22,37]. A real-world retrospective analysis of once-daily oral semaglutide (maximum dose: 14 mg) assessed body weight changes from baseline to 6 months among 101 patients ≥65 years of age with T2D (mean age 74.7 ± 6.1 years) [37]. Patients experienced significant decreases in body weight (−2.99 ± 3.45 kg; p < 0.001), BMI (−1.11 ± 1.27 kg/m2; p < 0.001), and waist circumference (−4.8 ± 6.2 cm; p < 0.001). A meta-analysis evaluating GLP-1 RAs (dulaglutide, semaglutide, and liraglutide) for treatment of obesity in adults ≥65 years vs. younger adults found no difference in weight reduction between age groups (pooled mean difference 0.07 [95% CI −1.8 to 1.9]; p = 0.9) [20].
Incretin-based therapies have also been shown to improve glycemic outcomes in older adults with or without T2D [20,22,37]. In the SUSTAIN 1–5 clinical trials, participants ≥65 years of age with T2D experienced HbA1c reductions of 1.3%–1.5% and 1.2%–1.8% with subcutaneous semaglutide 0.5 mg or 1.0 mg, respectively [22]. By the end of treatment, 69%–92% and 67%–86% of participants reached an HbA1c level <7%, with 90%–100% and 85%–97% reaching an HbA1c level of <8% among participants who received semaglutide 0.5 mg or 1.0 mg, respectively. The real-world retrospective analysis of daily oral semaglutide, as add-on or replacement therapy administered per guidelines for T2D management, among patients ≥65 years of age with T2D resulted in a significant mean HbA1c decrease of 0.44% (95% CI: −0.66 to −0.24; p < 0.001) after 6 months of treatment and 61.7% of patients reached an HbA1c level ≤7% after 6 months [37]. Additionally, a meta-analysis of randomized controlled trials and observational studies of GLP-1 RAs among adults ≥65 years of age with or without T2D in comparison with younger adults found a nonsignificant difference in HbA1c levels (mean: −0.202%; 95% CI: −0.742, 0.339) after adjustments for baseline differences in HbA1c levels when comparing older adults with younger adults [20].
In this post hoc analysis of older adults in ATTAIN-1 and ATTAIN-2, the safety profile of orforglipron was generally consistent with that expected for products with GLP-1 RA activity [20]. The most frequently reported AEs in this study were gastrointestinal in nature and were predominantly mild to moderate in severity. Level 2/3 hypoglycemia was rare, with no apparent differences between older and younger participants. No Level 3 hypoglycemic events were reported in the elderly population. Hepatic events were infrequent and were largely characterized by mild to moderate hepatic enzyme abnormalities. No cases of drug-induced liver injury were observed. The data presented suggest that orforglipron may be both effective and safe in individuals ≥65 years of age, regardless of T2D diagnosis, with a relative safety of orforglipron vs. placebo that remained consistent across age groups. Older adults may be more likely to have multiple chronic conditions requiring concomitant medications, increasing the risk of polypharmacy and drug-drug interactions (DDI) [24,25]. Unlike peptide-based GLP-1 RAs, which undergo enzymatic cleavage and carry minimal DDI potential, orforglipron is a small molecule metabolized primarily via CYP3A4 [30]. While the data do not demonstrate a need for concern, clinicians should carefully evaluate concomitant medications for potential CYP3A4 interactions when prescribing orforglipron, particularly in older adults who may be more sensitive to changes in drug exposure levels.
5. Limitations
Limitations of this analysis relate to the design of both ATTAIN-1 and ATTAIN-2, and the post hoc subgroup analysis performed. The sample size of participants ≥65 years of age from ATTAIN-1 and ATTAIN-2 was 616, which prevented a detailed comparison of data with other groups. Previous studies on older adults have analyzed data on additional subgroups, such as those ≥75 years of age; however, no additional subdivisions by age were included in this study. Endpoints that may be of particular interest for care of older adults, such as bone density and nutritional deficits, were not included either, and no direct comparison with other weight-management treatments was undertaken.
6. Conclusions
In adults ≥65 years of age with overweight or obesity with or without T2D, orforglipron administered once daily for 72 weeks was associated with significant body weight reduction compared with placebo and clinically meaningful improvements in BMI, HbA1c levels, fasting serum glucose, non-HDL cholesterol, triglycerides, and HRQoL. The AE profile in older adults was generally consistent with the overall population of adults from ATTAIN-1 and -2, and with other products with GLP-1 RA activity. Hepatic events were infrequent and were largely characterized by mild to moderate hepatic enzyme abnormalities.
Key takeaways
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￮
Once-daily orforglipron treatment in older adults ≥65 years of age with overweight or obesity with or without T2D was associated with significantly reduced body weight and HbA1c levels at Week 72 compared with placebo.
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￮
SAEs, major adverse cardiovascular events, renal events, and events possibly related to loss of lean muscle mass occurred at a higher rate in participants ≥65 years of age; hepatic events and Level 2 hypoglycemia were rare, with no Level 3 hypoglycemic events occurring among adults aged ≥65 years.
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￮
The findings of this post hoc analysis support orforglipron as a treatment option for adults ≥65 years of age with overweight or obesity with or without T2D.
Ethics review
This study was a post hoc subgroup analysis of data from the ATTAIN-1 (NCT05869903) and ATTAIN-2 (NCT05872620) clinical trials. Both studies were conducted in accordance with local regulations, the principles of the Declaration of Helsinki, and the International Council for Harmoniation Good Clinical Practice guidelines. All participants provided written informed consent.
Disclosures
Deborah B. Horn: Consulting fees/honorarium from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Kailera, Novo Nordisk, Roche, and Zealand Pharmaceuticals; institutional research support from Eli Lilly and Company, Kailera, KVK Tech, Novo Nordisk, and Weight Watchers. Alpana P. Shukla: Institutional research funding from Novo Nordisk, Eli Lilly and Company, and Viking Therapeutics Inc. and serves as a consultant/advisor to Eli Lilly and Company, Novo Nordisk, and Sun Pharmaceuticals. Haocheng Huang, Elvis Twum, Sheryl Elaine Allen, and Sanja Gilanovic Kis: Employees and shareholders of Eli Lilly and Company.
Data sharing 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 United States and European Union 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, 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.
Author contributions
DBH, APS, HH, ET, SEA, and SGK wrote, reviewed, and edited the draft; HH performed the data analysis. All approved the final submission and publication.
Declaration of AI use
During preparation of this work, the authors did not use any type of artificial intelligence.
Primary funding source
Eli Lilly and Company.
Financial Support
Funding for this study was provided by Eli Lilly and Company. Eli Lilly and Company was involved in the study design and conduct; collection, management, analyses, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. The sponsor did not have the right to veto publication or to control the decision of which journal the manuscript was submitted to. Final decisions resided with the authors, which included employees of the sponsor.
Acknowledgment
Medical writing assistance was provided by Heather Taft, PhD, and Thai Cao, MS, of Envision Catalyst, an Envision Medical Communications agency, a part of Envision Pharma Group, and was funded by Eli Lilly and Company. Envision Catalyst's services complied with international guidelines for Good Publication Practice.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.obpill.2026.100301.
Contributor Information
Deborah B. Horn, Email: deborah.b.horn@uth.tmc.edu.
Alpana P. Shukla, Email: aps2004@med.cornell.edu.
Haocheng Huang, Email: haocheng.huang@lilly.com.
Elvis Twum, Email: twum_elvis@lilly.com.
Sheryl Elaine Allen, Email: sheryl.allen@lilly.com.
Sanja Giljanovic Kis, Email: giljanovic_kis_sanja@lilly.com.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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