Abstract
Aims
This analysis evaluated whether gastrointestinal (GI) adverse events (AEs) including nausea, vomiting, diarrhoea (N/V/D) and dyspepsia were associated with weight reduction with tirzepatide across the SURMOUNT‐1 to ‐4 trials.
Materials and Methods
SURMOUNT‐1 to ‐4 were global Phase 3 clinical trials evaluating the safety and efficacy of tirzepatide among participants with obesity or overweight with or without type 2 diabetes (T2D). Participants were randomly assigned to receive once weekly subcutaneous tirzepatide or placebo. This post hoc analysis investigated weight change at the primary endpoint from baseline among participants who self‐reported no N/V/D, any N/V/D or nausea alone. Mediation analyses evaluated the contribution of N/V/D and dyspepsia on weight reduction. Time to first use of antidiarrheal and antiemetic usage was reported by time intervals.
Results
Baseline characteristics were similar between participants who reported N/V/D and those who did not. More participants reported GI AEs in the tirzepatide treatment arms (27.8%–72.8%) than with placebo (12.2%–32.5%). Most GI AEs were non‐serious and occurred during dose escalation. Between 1.0% and 10.5% of tirzepatide‐treated participants discontinued treatment due to GI AEs. Weight reduction with tirzepatide was similar among participants reporting no nausea, nausea alone, or any N/V/D. Mediation analyses suggested that N/V/D and dyspepsia were associated with up to 3.1% of total weight reduction. When required, first use of antidiarrheal and antiemetic medication was most commonly reported during dose escalation.
Conclusions
In this post hoc analysis, GI AEs appeared to contribute slightly to the weight reduction seen with tirzepatide in participants with obesity or overweight with or without T2D.
Keywords: gastrointestinal adverse events, GIP and GLP‐1 receptor agonist, obesity, tirzepatide, weight reduction
1. INTRODUCTION
Obesity is a major chronic disease, expected to affect nearly two billion people by 2035. 1 Obesity and its complications severely impact patients’ quality of life, 2 and greatly contribute to global mortality. 3 Clinical practice guidelines recommend the use of obesity management medications (OMMs) in addition to lifestyle modification in patients with a body mass index (BMI) of 30 kg/m2 or more (obesity), or 27 kg/m2 or more (overweight) with weight‐related comorbidities. 4 , 5
Tirzepatide is a glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 (GLP‐1) receptor agonist, 6 indicated for the treatment of obesity and type 2 diabetes (T2D). The global Phase 3 SURMOUNT‐1 to ‐4 clinical trials evaluated the efficacy and safety of tirzepatide (5, 10, 15 mg or maximum tolerated dose [MTD, 10 or 15 mg]) versus placebo, among participants with obesity or overweight with or without T2D. Tirzepatide led to substantial and clinically meaningful weight reduction across all doses in comparison with placebo in the SURMOUNT‐1 to ‐4 trials. 7 , 8 , 9 , 10
Tirzepatide and other newer incretin‐based OMMs are associated with gastrointestinal (GI) adverse events (AEs), most commonly nausea, vomiting and diarrhoea. 11 , 12 , 13 In clinical trials, GI AEs associated with tirzepatide were typically mild‐to‐moderate in severity, transient and occurred during dose escalation. 11 However, it is not known whether GI AEs contribute to the weight reduction seen with tirzepatide in people with obesity or overweight with or without T2D.
2. MATERIALS AND METHODS
2.1. Study design and participants
This post hoc analysis explored the potential relationship between GI AEs associated with tirzepatide treatment and weight reduction in the global Phase 3 SURMOUNT‐1 to ‐4 trials. Here, data were analysed at a participant‐level from each trial separately. Detailed SURMOUNT‐1 to ‐4 designs and reports have previously been published. 7 , 8 , 9 , 10 , 14 The SURMOUNT‐1, ‐3 and ‐4 trials included adult participants (aged 18 years or older) with a BMI of 30 kg/m2 or more, or with a BMI of 27 kg/m2 or more and at least one weight‐related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease) and excluded participants with T2D. 14 The SURMOUNT‐2 trial included participants with a BMI of 27 kg/m2 or more and T2D. 8 Key exclusion criteria for all trials included type 1 diabetes, the existence of a known clinically significant gastric emptying abnormality and a history of pancreatitis.
In SURMOUNT‐1, participants were randomly assigned (1:1:1:1) to tirzepatide 5 mg, 10 mg or 15 mg or placebo once weekly for 72 weeks. 7 In SURMOUNT‐2, participants were randomly assigned (1:1:1) to tirzepatide 10 or 15 mg or placebo once weekly for 72 weeks. 8 In SURMOUNT‐3 and ‐4, participants were randomly assigned (1:1) to tirzepatide MTD (10 or 15 mg) or placebo for 72 and 88 weeks, respectively. 9 , 10 Randomization occurred after a 12‐week, intensive lifestyle programme in SURMOUNT‐3, and after a 36‐week, open‐label, lead‐in period of tirzepatide treatment in SURMOUNT‐4. 9 , 10 All SURMOUT‐1–4 trials included a dose escalation period of 20 weeks. 14
In SURMOUNT‐1 to ‐4, GI AEs were self‐reported. Participants were asked to report any AE, regardless of what is expected from treatment. On visits, information on onset date, end date and severity (mild, moderate, severe) of AEs was collected using open‐ended, non‐leading verbal questions. In this post hoc analysis, a single GI AE was sufficient to categorize participants as ‘with GI AE’ as opposed to ‘without GI AE’. GI AEs were categorized based on severity and seriousness. The assessment of GI AE incidence was a component of the safety assessment of tirzepatide in the SURMOUNT‐1 to ‐4 trials. 7 , 8 , 9 , 10 , 14 All serious AEs were followed until resolution, stabilization, the event was otherwise explained or the participant was lost to follow‐up. 7 , 8 , 9 , 10 , 14 Participants who experienced intolerable GI symptoms at any time during the study were first counselled on dietary alterations to help mitigate symptoms, with recommendations including eating smaller meals, splitting three daily meals into four or more smaller ones and stopping eating when the participant felt full. If symptoms persisted, the participant could be prescribed medication at the investigator's discretion (e.g., antiemetic or antidiarrheal medication). 7 , 8 , 9 , 10 , 14 A temporary interruption of the study drug for one weekly dose was permitted, and treatment was resumed at the assigned dose, either alone or in combination with medication to treat GI symptoms. If intolerable GI symptoms persisted, the treatment dose could be de‐escalated to the next lowest dose (e.g., 15 mg reduced to 10 mg). In cases when all the above measures did not attenuate GI symptoms, participants were discontinued from the study drug. 7 , 8 , 9 , 10 , 14
The trials were conducted in accordance with the principles of the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines and Good Clinical Practice guidelines, and were approved by local institutional review board. All the participants provided written informed consent before participation.
2.2. Outcomes
The efficacy outcome was the percent change in weight from baseline to the primary endpoint. Safety outcomes included GI AEs and concomitant medications related to GI AEs.
The efficacy and safety outcomes of this post hoc analysis were assessed using data in the efficacy analysis set from all randomly assigned participants who were exposed to at least one dose of study drug (modified intention‐to‐treat population). This population subset excluded data after treatment discontinuation for all SURMOUNT‐1 to ‐4 trials, or the initiation of antihyperglycaemic rescue therapy in the SURMOUNT‐2 trial only.
2.3. Statistical analysis
Percent change from baseline (Week 0) in weight at the primary endpoint (Week 72 in SURMOUNT‐1, ‐2 and ‐3; Week 88 in SURMOUNT‐4) was assessed within each trial by GI AE subgroup (yes/no) using a mixed model for repeated measures. For these analyses, GI AEs were defined in two ways: (i) nausea, vomiting or diarrhoea (N/V/D) AEs, as the primary definition, or (ii) N/V/D or dyspepsia AEs, as the sensitivity analysis definition.
To explore the potential relationship with individual GI AEs, the percent weight reduction over time was summarized descriptively in the pooled tirzepatide‐treated participants from SURMOUNT‐1 and SURMOUNT‐2. For this analysis, weight reduction over time was summarized by self‐reported N/V/D as: no nausea, nausea alone or any N/V/D. In this analysis, the placebo‐treated participants from SURMOUNT‐1 and SURMOUNT‐2 were not evaluated due to the low incidence of GI AEs in this subpopulation. This exploration was not appropriate for other GI AEs due to their low incidence, nor for SURMOUNT‐3 and ‐4 due to their smaller sample size and study design potentially complicating the interpretation. 14 Pooled analyses were not controlled for multiplicity.
Mediation analyses were conducted in SURMOUNT‐1, ‐2 and ‐3 to evaluate the association of direct and indirect effects of tirzepatide treatment on weight change versus placebo from baseline at the primary endpoint. Mediation analyses were not conducted in SURMOUNT‐4 given the inclusion of an open‐label period and the randomized withdrawal design in this trial. Mediation analyses were not controlled for multiplicity.
The time to first report of antidiarrheal and antiemetic medication use was summarized descriptively by time intervals within each trial. Reports were summarized per 8‐week intervals from Week 0 to 48 (for instance, Weeks 0 to 8, Weeks 8 to 16), then summarized in a single time interval from Week 48 to the primary endpoint (Weeks 48 to 72 for SURMOUNT‐1, ‐2 and ‐3, and Weeks 48 to 88 for SURMOUNT‐4).
3. RESULTS
3.1. Baseline characteristics by gastrointestinal adverse events
Demographics and baseline clinical characteristics were generally similar between treatment arms within each trial. 7 , 8 , 9 , 10 , 14 Differences in baseline characteristics observed across trials reflect differences in inclusion criteria and design. SURMOUNT‐2 included participants with obesity and T2D; these participants had a longer duration of obesity and higher HbA1c level at baseline in comparison with other SURMOUNT trials. Additionally, SURMOUNT‐3 participants underwent an intensive lifestyle programme prior to treatment initiation; participants had lower BMI, weight and waist circumference at randomization in comparison with other trials. In SURMOUNT‐1, ‐3 and ‐4, there were more female participants; in SURMOUNT‐1 to ‐4, there were more White participants. 7 , 8 , 9 , 10 , 14
Within each SURMOUNT‐1 to ‐4 trial, demographics and baseline clinical characteristics were similar overall among participants between subgroups that did or did not report any N/V/D GI AE (Table 1).
TABLE 1.
Baseline characteristics.
| SURMOUNT‐1, N = 2539 | SURMOUNT‐2, N = 938 | SURMOUNT‐3, N = 579 | SURMOUNT‐4, N = 670 | |||||
|---|---|---|---|---|---|---|---|---|
| By subgroup reporting any GI AE, Yes/No, number of participants (%) | Yes, 890 (35.1) | No, 1649 (64.9) | Yes, 264 (28.1) | No, 674 (71.9) | Yes, 218 (37.7) | No, 361 (62.3) | Yes, 325 (48.5) | No, 345 (51.5) |
| Age, years, mean ± SD | 44.0 ± 12.5 | 45.4 ± 12.4 | 53.7 ± 10.9 | 54.4 ± 10.5 | 44.5 ± 12.2 | 46.2 ± 12.2 | 47.2 ± 12.9 | 48.2 ± 12.3 |
| Sex, n (%) | ||||||||
| Female | 678 (76.2) | 1036 (62.8) | 147 (55.7) | 329 (48.8) | 159 (72.9) | 205 (56.8) | 243 (74.8) | 230 (66.7) |
| Race, n (%) | ||||||||
| White | 666 (74.8) | 1126 (68.3) | 199 (75.4) | 511 (75.8) | 181 (83.0) | 317 (87.8) | 266 (81.8) | 271 (78.6) |
| Black or African American | 62 (7.0) | 139 (8.4) | 20 (7.6) | 57 (8.5) | 26 (11.9) | 37 (10.2) | 37 (11.4) | 38 (11.0) |
| Asian | 69 (7.8) | 207 (12.6) | 36 (13.6) | 89 (13.2) | 4 (1.8) | 0 (0.0) | 17 (5.2) | 31 (9.0) |
| American Indian or Alaska Native | 75 (8.4) | 156 (9.5) | 0 (0.0) | 0 (0.0) | 3 (1.4) | 3 (0.8) | 0 (0.0) | 0 (0.0) |
| Native Hawaiian or other Pacific Islander | 4 (0.4) | 5 (0.3) | 1 (0.4) | 2 (0.3) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 1 (0.3) |
| Multiple | 14 (1.6) | 16 (1.0) | 8 (3.0) | 15 (2.2) | 4 (1.8) | 4 (1.1) | 4 (1.2) | 4 (1.2) |
| Ethnicity, n (%) | ||||||||
| Hispanic or Latino | 452 (50.8) | 762 (46.2) | 155 (58.7) | 406 (60.2) | 122 (56.0) | 190 (52.6) | 140 (43.1) | 156 (45.2) |
| Not Hispanic or Latino | 381 (42.8) | 742 (45.0) | 106 (40.2) | 252 (37.4) | 93 (42.7) | 168 (46.5) | 184 (56.6) | 189 (54.8) |
| Not reported | 57 (6.4) | 145 (8.8) | 3 (1.1) | 16 (2.4) | 3 (1.4) | 3 (0.8) | 1 (0.3) | 0 (0.0) |
| Duration of obesity, years, mean ± SD | 13.9 ± 10.6 | 14.6 ± 11.0 | 18.4 ± 10.8 | 17.5 ± 11.8 | 15.6 ± 11.3 | 14.8 ± 11.1 | 15.2 ± 11.7 | 15.8 ± 11.8 |
| Body mass index, kg/m2, mean ± SD | 37.9 ± 6.6 | 38.0 ± 6.9 | 35.8 ± 6.1 | 36.2 ± 6.8 | 36.0 ± 5.9 | 35.8 ± 6.5 | 38.1 ± 5.9 | 38.8 ± 7.2 |
| Body weight, kg, mean ± SD | 103.4 ± 20.9 | 105.5 ± 22.7 | 99.6 ± 19.8 | 101.1 ± 21.6 | 100.7 ± 21.4 | 102.6 ± 21.4 | 106.1 ± 21.2 | 108.4 ± 23.3 |
| Waist circumference, cm, mean ± SD | 113.6 ± 14.9 | 114.4 ± 15.3 | 114.6 ± 13.5 | 115.1 ± 14.7 | 108.6 ± 14.5 | 110 ± 15.5 | 114.8 ± 14.1 | 115.6 ± 14.8 |
| HbA1c, %, mean ± SD | 5.6 ± 0.4 | 5.6 ± 0.4 | 8.0 ± 0.8 | 8.0 ± 0.9 | 5.3 ± 0.4 | 5.4 ± 0.4 | 5.5 ± 0.4 | 5.6 ± 0.3 |
| Prediabetes, n (%) | 359 (40.3) | 673 (40.8) | na a | na a | 67 (30.7) | 118 (32.7) | 155 (47.7) | 177 (51.3) |
Note: Data were pooled from tirzepatide‐treated participants on treatment without rescue therapy at the primary end‐point (intention‐to‐treat population).
Abbreviations: HbA1c, glycated haemoglobin; N, number of participants per study; N/V/D, nausea, vomiting or diarrhoea; na, not applicable; SD, standard deviation.
In SURMOUNT‐2, all participants had T2D.
3.2. Relationship of gastrointestinal adverse events with weight reduction
Data from the SURMOUNT‐1 to ‐4 trials indicate that nausea, diarrhoea and vomiting were the most frequent GI AEs, occurring at significantly higher frequencies in the tirzepatide treatment arms in comparison with placebo (Table S1). Dyspepsia and constipation were also frequent GI AEs. Across the SURMOUNT‐1 to ‐4 trials, 27.8% to 72.8% of participants reported at least one GI AE in the tirzepatide treatment arms, and 12.2% to 32.5% in the placebo arms. Most GI AEs were mild‐to‐moderate in severity; severe or serious GI AEs occurred in 0.3% to 5.6% of participants (Table S2). Treatment discontinuation due to GI AEs occurred in 1.0% to 10.5% of participants treated with tirzepatide (Table S3). Study discontinuation due to GI AEs occurred in 0.0% to 2.2% of participants treated with tirzepatide (Table S3). GI AEs were primarily reported during dose escalations. 7 , 8 , 9 , 10
Weight reduction was similar among participants treated with tirzepatide or placebo with or without GI AEs across the SURMOUNT‐1 to ‐4 trials (Figure 1). The mean change in weight was significantly higher (p < 0.001) in participants treated with tirzepatide compared with placebo, with or without GI AEs, for all treatment arms across the SURMOUNT‐1 to ‐4 trials. In SURMOUNT‐1, in the tirzepatide 5, 10 and 15 mg arms, the mean percentage change in weight from baseline to the primary endpoint was −17.2%, −22.2% and −22.8%, respectively, among participants who reported N/V/D; and −15.3%, −20.6% and −22.2%, respectively, among participants who did not report N/V/D. In SURMOUNT‐2, in the tirzepatide 10 and 15 mg arms, the mean percentage change in weight from baseline to the primary endpoint was −14.2% and −16.8%, respectively, among participants who reported N/V/D, and −13.1% and −15.0%, respectively, among participants who did not report N/V/D. In SURMOUNT‐3 and ‐4, in the tirzepatide MTD arm, the mean percentage change in weight from baseline (Week 0) to the primary endpoint was −22.0% and −26.3%, respectively, among participants who reported N/V/D, and −19.9% and −25.7%, respectively, among participants who did not report N/V/D.
FIGURE 1.
Percent change from baseline in weight among participants who did and did not report any N/V/D event across the SURMOUNT‐1 to ‐4 trials. Data are presented as least‐square mean (with error bars as standard error). In each trial, and for each tirzepatide dose (5, 10, 15 mg or MTD), solid left‐hand bars represent the subgroup of participants who reported any N/V/D event (N/V/D—Yes), and striped right‐hand bars represent the subgroup of participants who did not report N/V/D events (N/V/D—No). Data were pooled from the modified intention‐to‐treat population of each study that included participants who took at least one dose of treatment, excluding treatment discontinuations and participants who used antihyperglycaemic rescue therapy, were used to assess efficacy outcomes (efficacy analysis set). ***p < 0.001 versus placebo. MTD, maximum tolerated dose; N, number of participants per N/V/D (Yes/No) group; N/V/D, nausea, vomiting or diarrhoea.
When pooled across tirzepatide doses in the SURMOUNT‐1 or ‐2 trials, weight reduction over time was similar in participants with or without GI AEs (Figure 2). In SURMOUNT‐1, at 72 weeks, participants who did not report nausea lost 19.7% of weight, participants who reported nausea alone lost 22.0% of weight and participants who reported any N/V/D event lost 22.5% of weight. In SURMOUNT‐2, at 72 weeks, participants who did not report nausea lost 14.2% of weight, participants who reported nausea alone lost 16.0% of weight and participants who reported any N/V/D event lost 15.4% of weight.
FIGURE 2.
Percentage of weight reduction over time among tirzepatide‐treated participants who reported no N/V/D, nausea alone or any N/V/D event across the SURMOUNT‐1 and SURMOUNT‐2 trials. Data are presented as least‐square mean (with error bars as standard error). In each trial, for the pooled tirzepatide treatment arms, white symbols represent the subgroup of participants who did not report any N/V/D event (N/V/D = No), grey symbols represent the subgroup of participants who reported nausea alone (N/V/D = Yes, nausea alone) and black symbols represent the subgroup of participants who reported any N/V/D (N/V/D = Yes, any). Data were pooled from the modified intention‐to‐treat population of each study that included participants who took at least one dose of treatment, excluding treatment discontinuations and participants who used antihyperglycaemic rescue therapy, were used to assess efficacy outcomes (efficacy analysis set). N/V/D, nausea, vomiting or diarrhoea.
Mediation analysis showed that the estimated treatment difference for change from baseline in weight was not mediated by N/V/D, or dyspepsia GI AEs (Figure 3). N/V/D, or dyspepsia GI AEs was associated with ‐0.7% to 2.5% of total weight reduction in SURMOUNT‐1, 0.8% to 2.0% in SURMOUNT‐2 and 1.5% to 3.1% in SURMOUNT‐3.
FIGURE 3.
Mediation analyses of direct and indirect effects to the estimated treatment difference in weight change with tirzepatide versus placebo across the SURMOUNT‐1 to ‐3 trials. Mediation analyses of direct (due to treatment) and indirect effects to the estimated treatment difference (ETD) in weight change with tirzepatide versus placebo at the primary end‐point across the SURMOUNT‐1 to ‐3 trials. Indirect effects mediation analysis included N/V/D (top panel) or N/V/D and dyspepsia (bottom panel). Data were based on the modified intention‐to‐treat population of each study for each tirzepatide dose using the efficacy analysis set for N/V/D mediation analysis or using the safety efficacy set for N/V/D + dyspepsia mediation analysis. CI, confidence interval; ETD, estimated treatment difference; MTD, maximum tolerated dose; N/V/D, nausea, vomiting or diarrhoea.
3.3. Use of concomitant medication to manage gastrointestinal adverse events
Overall, 5.2% to 9.3% of tirzepatide‐treated participants reported the use of one antidiarrheal medication across the SURMOUNT‐1 to ‐3 trials versus 1.2% to 2.2% of placebo‐treated participants. Across the SURMOUNT‐1 to ‐3 trials, 13.8% to 27.5% of tirzepatide‐treated participants reported the use of one antiemetic medication, versus 5.8% to 6.7% of placebo‐treated participants The first use of these concomitant medications was most frequent during the first 24 weeks which included the dose escalation period (Figure 4). In SURMOUNT‐4, among total participants, the overall use of antidiarrheal medication was 6.6%, and use of antiemetic medication was 20.1%. The majority of concomitant medication reports included only one medication. Overall, up to 0.3% of total participants reported the use of two concomitant antidiarrheal medications, and 0.3% to 1.3% of total participants reported the use of two concomitant antiemetic medications across SURMOUNT‐1 to ‐4. No participant used more than two concomitant antidiarrheal medications across all trials. In the SURMOUNT‐1 and ‐3 trials, no participant used more than two concomitant antiemetic medications. In SURMOUNT‐2, 0.1% of participants used three concomitant antiemetic medications between Weeks 40 to 48. In SURMOUNT‐4, 0.1% and 0.2% of participants between Weeks 24 to 32, and Weeks 48 to 88, respectively, used three concomitant antiemetic medications. Overall, the use of concomitant medications was minimal and similar across the SURMOUNT‐1 to ‐4 trials, and was largely restricted to treatment initiation and dose escalation periods. A higher percentage of participants in the SURMOUNT‐4 trial reported concomitant antidiarrheal and antiemetic medication use in Weeks 0 to 24.
FIGURE 4.
Use of concomitant medication for GI AE management across the SURMOUNT‐1 to ‐4 trials. Use of antidiarrheal (top panel) or antiemetic (bottom panel) medication among participants across the modified intention‐to‐treat populations (safety analysis set) from the SURMOUNT‐1 to ‐4 trials. Data are shown as the percentage of participants who reported the use of one (green bars) or two (orange bars) concomitant medications in addition to tirzepatide treatment during study time. N, number of participants per trial.
4. DISCUSSION
This post hoc analysis provides a comprehensive assessment of the potential relationship of GI AEs to weight reduction associated with tirzepatide treatment across the SURMOUNT‐1 to ‐4 trials. Results from this study suggest that GI AEs including nausea, vomiting, diarrhoea and dyspepsia were minimally related to the weight reduction observed with tirzepatide treatment.
Data from the SURMOUNT‐1 to ‐4 trials indicated that the occurrence and frequency of GI AEs were significantly higher in participants treated with tirzepatide in comparison with placebo, with the most frequent GI AEs being nausea, vomiting and diarrhoea. 7 , 8 , 9 , 10 , 15 Across the SURMOUNT‐1 to ‐4 trials, GI AEs were mostly mild‐to‐moderate in severity, occurred during dose escalations and resulted in few treatment discontinuations. 7 , 8 , 9 , 10 These results are consistent with reports of treatment with tirzepatide in the SURPASS trials, 11 and with results observed with other OMMMs targeting GLP‐1 receptors. 13 , 16
In clinical practice, strategies can be implemented to mitigate GI side effects. These can include dietary strategies, slower dose escalation schemes or the use of temporary medication to manage GI side effects during dose escalation. In particular, dietary strategies may include eating smaller meals (splitting daily meals), stopping eating when feeling full, avoiding fatty foods and eating bland foods. 17
It has been hypothesized that GI AEs might contribute to weight reduction due to altered dietary choices and decreased food intake due to GI symptoms. 13 , 16 In this post hoc analysis, weight reduction with tirzepatide was similar in participants who did or did not report GI AEs at the primary end‐points across the SURMOUNT‐1 to ‐4 trials. Weight reduction was also similar over time between participants who did not report GI AEs, and those reporting nausea alone or any GI AE in the SURMOUNT‐1 and ‐2 trials. Of note, in this exploratory analysis, there was a trend suggesting that nausea alone, or N/V/D, may be associated with a slight increase of approximately 2% in weight reduction. Mediation analyses suggested that GI AEs including N/V/D and dyspepsia were associated with up to 3.1% of total weight reduction with tirzepatide treatment across the SURMOUNT‐1 to ‐4 trials, regardless of the treatment dose. Overall, while GI AEs did not constitute the primary mechanism of weight reduction, it appears that they may have had a slight relationship to the total effect. In particular, participants with nausea had a trend towards more body weight reduction than participants without any GI AE. As previously reported, weight reduction with tirzepatide may prominently be mediated by central nervous system signalling, impacting appetite, energy balance or other unknown factors. 8 , 18 Future studies are needed to address the underlying mechanisms of individual GI AEs on weight reduction with tirzepatide.
The present study also addressed the timing of the use of concomitant medication for GI AE management. Overall, the use of concomitant medications coincided with dose escalation in the SURMOUNT‐1 to ‐4 trials. This study identified that the use of concomitant medication mostly consisted of one product, with the use of two antidiarrheal or antiemetic products reported by less than 2% of total participants, and only three reports of three concomitant antiemetic medications use throughout the SURMOUNT‐1 to ‐4 trials. Medication use was higher in SURMOUNT‐4, during Weeks 0 to 24, than in SURMOUNT‐1 to ‐3, which may be due to all participants receiving tirzepatide during this period.
Data from the SURMOUNT‐1 to ‐4 trials were not pooled. Differences in GI AE occurrence were observed between trials which may be due to differences in design. Indeed, SURMOUNT‐2 included participants with obesity and T2D, as opposed to other SURMOUNT studies. People with obesity and T2D tend to lose less weight in response to OMMs in comparison with people with obesity without T2D. 19 In SURMOUNT‐3, placebo‐treated participants regained weight following an intensive lifestyle programme for weight reduction. 9 Of note, all participants in the SURMOUNT trials received lifestyle counselling to encourage adherence to a healthy diet and increased physical activity. Finally, in SURMOUNT‐4, participants lost more weight than in SURMOUNT‐1 to ‐3 likely due to the longer trial duration (88 weeks in SURMOUNT‐4 vs. 72 weeks in SURMOUNT‐1 to ‐3). 10 In addition, the open‐label treatment period resulted in weight reduction that was partially maintained in the eventually placebo‐treated participants by study termination, which may account for the higher weight reduction in the placebo arm of SURMOUNT‐4.
This post hoc analysis presents several limitations. GI AE analysis is based on data that were self‐reported by participants and one GI AE was sufficient to classify participants as GI AE group. Additionally, systematic scales were not used to measure GI AE severity across the SURMOUNT‐1 to ‐4 trials. GI AE reporting is subject to personal bias and may be impacted by regional differences between trials. 20 In this study, N/V/D GI AEs were pooled and evaluated together for most analyses. Other mechanisms of action that may contribute to weight reduction, particularly decreased gastric emptying, were not explored. 21 Most GI AEs occurred early during the dose escalation, while change in weight was assessed at the end of study. Also, only participants with weight data available at the primary endpoint were included. The exclusion criteria of a known clinically significant gastric emptying abnormality and differences in the use of symptomatic medications for GI tolerability issues during the trial period may have influenced the frequency or severity of GI AEs, and treatment discontinuation. The data analysed excluded participants after treatment discontinuation, which may have skewed towards individuals who were more tolerant to treatment. Mediation analyses and other pooled analyses were not controlled for multiplicity and should be considered as hypothesis‐generating rather than confirmatory. Although mediation analyses were not adjusted for potential post‐randomization confounders, the consistency in results across the SURMOUNT‐1 to 3 trials is reassuring. However, SURMOUNT‐1 to ‐4 differed in study design and populations, which may have impacted GI AE occurrence and total weight reduction. Additionally, none of the SURMOUNT‐1 to ‐4 trials included an active comparator, which does not allow for the comparison of GI tolerability of tirzepatide with other OMMs in the same populations. In the SURMOUNT‐1 to ‐4 trials, the majority of participants were White and had a BMI of 30 kg/m2 or more, and in SURMOUNT‐1, ‐3 and ‐4, the majority of participants were female; thus, findings may not accurately reflect the general population with obesity or overweight. Finally, average data from this post hoc analysis did not account for interindividual variability in drug response and GI AE occurrence. These aspects may differ between a clinical trial setting and the real‐world patient experience.
5. CONCLUSION
In conclusion, this post hoc analysis from the SURMOUNT‐1 to ‐4 trials suggests that GI AEs may have had a slight relationship to the weight reduction observed with tirzepatide in participants with obesity or overweight with or without T2D. GI AEs reported with tirzepatide across the SURMOUNT‐1 to ‐4 trials were mostly mild‐to‐moderate in severity, occurred primarily during the tirzepatide dose escalation period, diminished over time and rarely led to treatment discontinuation. Finally, the use of symptomatic medication to manage GI symptoms occurred in less than one‐third of participants.
AUTHOR CONTRIBUTIONS
All authors participated in the interpretation of the data and critical review of the manuscript and approved this manuscript to be submitted for publication. Domenica Rubino and Claire Gerber contributed to the conception of the manuscript. Dachuang Cao contributed to the planning of the analyses and conducted the statistical analysis.
FUNDING INFORMATION
This study was funded by Eli Lilly and Company.
CONFLICT OF INTEREST STATEMENT
DMR is currently a clinical investigator for Astra Zeneca, Novo Nordisk, Boehringer Ingelheim and Kallyope; received consultant/advisor fees from Novo Nordisk, Regeneron, Boehringer Ingelheim, Shionogi, Cytoki Pharma and Eli Lilly and Company; payment or honoraria for participating as a speaker from Novo Nordisk; CME honoraria from Prime Therapeutics, Peer View, Medscape, Endocrine Society and ADA; travel support for speaking/presenting from Novo Nordisk, Boehringer Ingelheim, Eli Lilly and Company, Prime Inc., Peer View, Medscape, Endocrine Society and ADA; support for meeting registration from Endocrine Society, ADA, and The Obesity Society; medical writing support from Novo Nordisk and Boehringer Ingelheim; and is a shareholder at Eli Lilly and Company. SDP declares personal fees for advisory board membership and speaking from Abbott, AstraZeneca, Bayer, Bausch, Boehringer Ingelheim, Dexcom, Eli Lilly and Company, GSK, HLS Therapeutics, Janssen, Merck, Novo Nordisk, Pfizer, Regenron and Sanofi; consulting fees from Abbott, AstraZeneca, Dexcom, HLS Therapeutics, Janssen and Novo Nordisk; fees or grants for clinical trials from AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pfizer, Prometic and Sanofi; grants from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company and Sanofi; and non‐financial support for travel to meetings from AstraZeneca, Bausch Health, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Novo Nordisk and Sanofi. LC declares clinical investigator activity for Eli Lilly and Company. DC, FC, AS, JFB, RG and CG are employees and shareholders of Eli Lilly and Company.
PEER REVIEW
The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16176.
Supporting information
Data S1: Supporting Information.
ACKNOWLEDGEMENTS
The authors would like to thank Gaston L. Cluzel, PhD, from Eli Lilly and Company, for writing and editorial contributions. Partial data from this analysis were presented at the Obesity Week, held on 14–17 October 2023, in Dallas, Texas, USA.
Rubino DM, Pedersen SD, Connery L, et al. Gastrointestinal tolerability and weight reduction associated with tirzepatide in adults with obesity or overweight with and without type 2 diabetes in the SURMOUNT‐1 to ‐4 trials. Diabetes Obes Metab. 2025;27(4):1826‐1835. doi: 10.1111/dom.16176
DATA AVAILABILITY STATEMENT
Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for 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 have been made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data‐sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data‐sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1: Supporting Information.
Data Availability Statement
Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, except for 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 have been made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data‐sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data‐sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.