Abstract
Background
Nutritional deficiencies are common among people with obesity, before and during treatment, such as with very-low-calorie diets and metabolic/bariatric surgery. Obesity management medications (OMMs) can reduce appetite and dietary intake, potentially affecting nutritional status. The impact of OMMs on nutritional outcomes in people with obesity warrants further study.
Methods
We conducted a post hoc analysis of available nutritional status-related data from the randomized, placebo-controlled, phase 3 SURMOUNT-1-4 trials of tirzepatide (N = 4726). Descriptive statistics were utilized to explore available nutritional status-related data from clinical trial reports, including investigator-reported treatment-emergent adverse events (TEAEs) based on 14 MedDRA preferred terms, chosen to identify cases of macronutrient malnutrition; investigator-reported vitamin deficiency-related TEAEs; biomarkers assessed systematically during the trials (albumin; total lymphocyte count [TLC]); reasons for early treatment discontinuation; and participants reaching body mass index (BMI) < 18.5 and < 22 kg/m2.
Results
Investigators reported 3 of 14 TEAEs potentially related to macronutrient malnutrition. TEAE incidence of Abnormal loss of weight, Underweight, and Hypoalbuminemia was 0.03 %, 0.06 %, and 0.03 % with tirzepatide and 0 %, 0 %, and 0.06 % with placebo, respectively. Vitamin deficiency-related TEAEs were reported for 0.99 % and 1.07 % of tirzepatide- and placebo-treated participants, respectively. Albumin <3.3 g/dL occurred in 0.06 % and 0.13 % of tirzepatide- and placebo-treated participants, respectively, while TLC <910/μL occurred in 2.90 % and 1.77 %. Treatment discontinuations potentially related to nutritional status (primarily achievement of desired weight and perceived excessive weight loss) occurred in 0.53 % of participants. Overall, 0.38 % and 0.06 % of tirzepatide- and placebo-treated participants reached BMI <18.5 kg/m2.
Conclusions
TEAEs and treatment discontinuations due to macronutrient malnutrition were uncommon in the SURMOUNT-1-4 trials of tirzepatide for obesity. Lack of routinely collected vitamin and mineral levels during the trials limited assessment of the impact of tirzepatide treatment on micronutrient status. Systematic assessment of nutritional status before and during OMM treatment would enhance future trials.
Clinicaltrials.gov identifiers
NCT04184622 (SURMOUNT-1); NCT04657003 (SURMOUNT-2); NCT04657016 (SURMOUNT-3); and NCT04660643 (SURMOUNT-4).
Keywords: Nutritional status, Obesity management medication, SURMOUNT-1-4 trials, Tirzepatide, Treatment-emergent adverse events
Graphical abstract
1. Introduction
Nutritional deficiencies are common in individuals with obesity and may occur before or during treatment with very-low-calorie diets and metabolic/bariatric surgery [1]. Data are limited regarding the nutritional impact of incretin-based obesity management medications (OMMs), including tirzepatide and semaglutide. Preexisting nutritional deficiencies, malnutrition risk factors, significantly reduced appetite, or gastrointestinal adverse events (AEs) may increase malnutrition risk during OMM treatment [1]. Emerging evidence from healthcare claims of glucagon-like peptide-1 (GLP-1) receptor agonist treatment, primarily in individuals with type 2 diabetes (80.5 %) and/or obesity (44.9 %), suggests micronutrient deficiencies are common in that population and may increase during treatment with a GLP-1 receptor agonist as well as with metformin [2]. Currently, there are no reports leveraging data from randomized controlled trials examining the nutritional impact of incretin-based OMMs in the treatment of obesity. Clinical studies measuring ad libitum food intake with OMM treatment have demonstrated significant reductions in energy intake at single meals [1]. Additionally, model-estimated mean reductions in daily energy intake as large as 1200 kcal/day from baseline intake have been reported based on clinical trial data for semaglutide and tirzepatide [3]. In the setting of reduced energy intake, dietary quality and balanced dietary intake are increasingly important to ensure nutritional adequacy.
Tirzepatide, a glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist, demonstrated up to a 25.8 % mean weight reduction in people with obesity or overweight in the global, phase 3 SURMOUNT-1-4 trials [[4], [5], [6], [7]]. Although these trials did not include systematic assessment of micronutrient levels at predetermined time points, clinical trial reports from the studies included some data potentially related to nutrition.
This post hoc analysis assessed available nutritional status–related data from the SURMOUNT-1-4 clinical trial reports, including data on treatment-emergent AEs (TEAEs), biomarkers potentially related to nutrition, reasons for early treatment discontinuation, and participants who reached prespecified body mass index (BMI) thresholds.
2. Methods
This study was a post hoc analysis of the phase 3 randomized, placebo-controlled, SURMOUNT-1-4 trials of tirzepatide in participants (N = 4726) with BMI ≥30 or ≥27 kg/m2 with ≥1 obesity-related complication without diabetes (SURMOUNT-1), with type 2 diabetes (SURMOUNT-2), without diabetes after intensive lifestyle intervention (SURMOUNT-3), or after a lead-in period with open-label tirzepatide (SURMOUNT-4) [[4], [5], [6], [7]]. Study designs for these trials, conducted from 2019 to 2024, are described in previous reports (Supplement, Table S1) [[4], [5], [6], [7]]. In all 4 trials, participants received regular lifestyle counseling sessions, delivered by a registered dietitian or health professional with similar qualifications. During the treatment periods of all 4 trials, counseling emphasized a healthy dietary pattern with an energy deficit of approximately 500 kcal/day and a macronutrient composition of approximately 50 % carbohydrates, approximately 20 % protein, and <30 % fat. During the 12-week intensive lifestyle intervention lead-in phase before the treatment period in SURMOUNT-3, the recommended energy intake was 1200 kcal/day for women and 1500 kcal/day for men, and participants could consume up to 2 liquid meal replacements per day. Trials followed ethical guidelines (Declaration of Helsinki, Good Clinical Practice, institutional review board approval); participants provided written informed consent before participation. The post hoc analysis followed CONSORT 2025 reporting guidelines.
Trial site investigators were responsible for participant monitoring as well as assessment, determination, and reporting of all TEAEs, including clinically significant laboratory abnormalities and any AEs identified by clinicians outside of the trial (e.g., during an annual visit with a primary care physician). In accordance with the SURMOUNT-1-4 protocols, routine study assessments were conducted at regularly defined intervals and included both efficacy assessments (such as body weight, fasting glucose, HbA1c, and lipid panel) and safety assessments (including vital sign measurements, physical examinations, review of concomitant medications, and laboratory tests such as a comprehensive chemistry panel and complete blood cell count). Beyond the routine assessments specified in the protocols, site investigators could order any laboratory or imaging assessments they deemed clinically necessary to assess signs or symptoms of concern. In addition, site investigators were responsible for reporting any early treatment discontinuations, including reasons for discontinuation. All individual study participant data collected during the trial were anonymized, collected, and stored in a sponsor-provided electronic data capture system.
For this post hoc analysis, clinical trial reports from the modified intention-to-treat populations of SURMOUNT-1-4 were searched to determine the incidence of 14 TEAEs potentially related to nutritional status based on Medical Dictionary for Regulatory Activities preferred terms, which were chosen to identify macronutrient (energy/protein) malnutrition cases and were selected following a literature review [[8], [9], [10]]. These included Abnormal loss of weight, Adult failure to thrive, Cachexia, Hypoalbuminemia, Kwashiorkor, Lymphopenia, Malnutrition, Marasmus, Protein deficiency, Sarcopenia, Sarcopenic obesity, Starvation, Starvation ketoacidosis, and Underweight. The incidence of vitamin deficiency TEAEs was assessed separately, as micronutrient-related biomarkers were not systematically measured per the protocols, and subclinical micronutrient deficiencies commonly occur in people with obesity [1].
Per the SURMOUNT-1-4 protocols, 2 biomarkers potentially related to nutritional risk—albumin and total lymphocyte count (TLC)—were systematically assessed before and during treatment in all participants. Participants with laboratory values below the reference range (albumin, <3.3 g/dL; TLC, <910/μL) at randomization were not included in analyses of the incidence of laboratory abnormalities after randomization.
Investigator-reported reasons for early treatment discontinuation and AE reports were reviewed to identify the occurrence of early treatment discontinuation potentially related to nutritional status. Proportions of participants reaching BMI <18.5 and < 22 kg/m2 were quantified. These BMI thresholds were chosen because BMI <18.5 kg/m2 is an established underweight threshold [[11], [12], [13]] and was a protocol-specified threshold for treatment discontinuation, and <22 kg/m2 was a protocol-specified threshold for modifying energy intake guidance. Incidences of potential nutrition-related events were summarized for participants who reported AEs of nausea, vomiting, or diarrhea. Incidences of severe/serious gastrointestinal AEs among participants with nutrition-related events were also assessed. Descriptive statistics (along with confidence intervals where applicable) are presented throughout, as data are limited and insufficient for drawing safety conclusions, precluding the use of other analysis techniques including statistical comparison. No imputation was performed for missing data.
3. Results
Baseline characteristics and participant disposition are described in prior reports [[4], [5], [6], [7]].
No TEAEs were reported for 11 of 14 terms potentially related to macronutrient malnutrition. Abnormal weight loss and Underweight were reported for 1/3141 (0.03 % [95 % confidence interval, −0.03 %–0.09 %]) and 2/3141 (0.06 % [−0.02 %–0.15 %]) tirzepatide-treated participants, respectively, with no reports among placebo-treated participants (Table 1). TEAEs of Hypoalbuminemia were reported for 1/3141 (0.03 % [−0.03 %–0.09 %]) tirzepatide-treated participants and 1/1585 (0.06 % [−0.06 %–0.19 %]) placebo-treated participants. Overall, TEAEs potentially related to macronutrient malnutrition were reported in 4/3141 (0.12 %) tirzepatide-treated participants.
Table 1.
Incidence of TEAEs potentially related to macronutrient malnutrition.
| No. (%) | SURMOUNT-1 |
SURMOUNT-2 |
SURMOUNT-3 |
SURMOUNT-4 |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| PBO (n = 643) | TZP 5 mg (n = 630) |
TZP 10 mg (n = 636) |
TZP 15 mg (n = 630) |
PBO (n = 315) | TZP 10 mg (n = 312) |
TZP 15 mg (n = 311) |
PBO (n = 292) | TZP MTD (n = 287) | PBO (n = 335) | TZP MTD (n = 335) | |
| Abnormal loss of weight | 1 (0.2) | ||||||||||
| Adult failure to thrive | |||||||||||
| Cachexia | |||||||||||
| Hypoalbuminemia | 1 (0.3) | 1 (0.3) | |||||||||
| Kwashiorkor | |||||||||||
| Lymphopenia | |||||||||||
| Malnutrition | |||||||||||
| Marasmus | |||||||||||
| Protein deficiency | |||||||||||
| Sarcopenia | |||||||||||
| Sarcopenic obesity | |||||||||||
| Starvation | |||||||||||
| Starvation ketoacidosis | |||||||||||
| Underweight | 1 (0.3) | 1 (0.3) | |||||||||
Abbreviations: MTD, maximum tolerated dose; n, number of participants in the population; no., number of participants meeting criteria; PBO, placebo; TEAE, treatment-emergent adverse event; TZP, tirzepatide.
Empty table cells indicate that no events were reported. Data on investigator-reported TEAEs were collected in all studies.
In SURMOUNT-4, all participants were treated with TZP during a 36-week, open-label, lead-in period. The hypoalbuminemia event for the participant in the SURMOUNT-4 PBO arm had an onset date of 631 days (90.1 weeks) from the date of the first dose in the lead-in period.
TEAEs potentially related to macronutrient malnutrition were searched based on the following Medical Dictionary for Regulatory Activities preferred terms: Abnormal loss of weight, Adult failure to thrive, Cachexia, Hypoalbuminemia, Kwashiorkor, Lymphopenia, Malnutrition, Marasmus, Protein deficiency, Sarcopenia, Sarcopenic obesity, Starvation, Starvation ketoacidosis, and Underweight. TEAEs were reported for abnormal loss of weight, hypoalbuminemia, and underweight but not for the other 11 terms. TEAEs related to vitamin deficiency/hypovitaminosis were assessed separately due to the lack of systematic assessment.
Vitamin deficiency–related TEAEs (namely vitamin D, vitamin B12, and folate) were reported for 31/3141 (0.99 % [0.64 %–1.33 %]) tirzepatide-treated participants and 17/1585 (1.07 % [0.57 %–1.58 %]) placebo arm participants (Table 2).
Table 2.
Vitamin deficiency–related treatment-emergent adverse events.
| Preferred Term, No. (%) | SURMOUNT-1 |
SURMOUNT-2 |
SURMOUNT-3 |
SURMOUNT-4 |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| PBO (n = 643) | TZP 5 mg (n = 630) |
TZP 10 mg (n = 636) |
TZP 15 mg (n = 630) |
PBO (n = 315) | TZP 10 mg (n = 312) |
TZP 15 mg (n = 311) |
PBO (n = 292) | TZP MTD (n = 287) | PBO (n = 335) | TZP MTD (n = 335) | |
| Vitamin deficiencya | 3 (0.5) | 8 (1.3) | 5 (0.8) | 6 (1.0) | 8 (2.5) | 3 (1.0) | 4 (1.3) | 4 (1.4) | 1 (0.3) | 2 (0.6) | 4 (1.2) |
| Anaemia folate deficiency | |||||||||||
| Anaemia vitamin B12 deficiency | |||||||||||
| Anaemia vitamin B6 deficiency | |||||||||||
| Biotin deficiency | |||||||||||
| Folate deficiency | 1 (0.3) | ||||||||||
| Hypovitaminosis | |||||||||||
| Multi-vitamin deficiency | |||||||||||
| Vitamin A deficiency | |||||||||||
| Vitamin B complex deficiency | |||||||||||
| Vitamin B1 deficiency | |||||||||||
| Vitamin B12 deficiency | 3 (0.5) | 1 (0.2) | 1 (0.2) | 5 (1.6) | 1 (0.3) | 1 (0.3) | 1 (0.3) | 3 (0.9) | |||
| Vitamin B2 deficiency | |||||||||||
| Vitamin B6 deficiency | |||||||||||
| Vitamin C deficiency | |||||||||||
| Vitamin D deficiency | 3 (0.5) | 5 (0.8) | 5 (0.8) | 5 (0.8) | 5 (1.6) | 2 (0.6) | 4 (1.3) | 3 (1.0) | 1 (0.3) | 2 (0.6) | 3 (0.9) |
| Vitamin E deficiency | |||||||||||
| Vitamin K deficiency | |||||||||||
Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; MTD, maximum tolerated dose; n, number of participants in the population; no., number of participants meeting criteria; PBO, placebo; TZP, tirzepatide.
Empty table cells indicate that no events were reported. Data on investigator-reported treatment-emergent adverse events were collected in all studies.
In SURMOUNT-4, all participants were treated with TZP during a 36-week, open-label, lead-in period. The vitamin B12 deficiency event for the participant in the SURMOUNT-4 PBO arm had an onset date of 439 days (62.7 weeks) from the date of the first dose in the lead-in period. The 2 vitamin D deficiency events for the participants in the SURMOUNT-4 PBO arm had onset dates of 527 days (75.3 weeks) and 439 days (62.7 weeks) from the date of the first dose in the lead-in period.
“Vitamin deficiency” is not a MedDRA preferred term but represents ≥1 specific vitamin deficiency from the list of MedDRA preferred terms in the table (“Anaemia folate deficiency” through “Vitamin K deficiency”).
“Vitamin deficiency” is not a MedDRA preferred term but represents ≥1 specific vitamin deficiency from the list of MedDRA preferred terms in the table (“Anaemia folate deficiency” through “Vitamin K deficiency”).
At randomization, no participants had an albumin level <3.3 g/dL and 24 participants had a TLC <910/μL (Supplement, Table S2). After randomization, albumin <3.3 g/dL occurred in 2/3141 (0.06 % [−0.02 %–0.15 %]) tirzepatide-treated participants and 2/1585 (0.13 % [−0.05 %–0.30 %]) placebo-treated participants. TLC <910/μL occurred in 91/3141 (2.90 % [2.31 %–3.48 %]) tirzepatide-treated participants and 28/1585 (1.77 % [1.12 %–2.42 %]) placebo-treated participants, not counting those participants with a low value at randomization (Table 3).
Table 3.
Laboratory marker values and abnormalities potentially related to nutritional risk.
| SURMOUNT-1 |
SURMOUNT-2 |
SURMOUNT-3 |
SURMOUNT-4 |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| PBO (n = 643) | TZP 5 mg (n = 630) |
TZP 10 mg (n = 636) |
TZP 15 mg (n = 630) |
PBO (n = 315) | TZP 10 mg (n = 312) |
TZP 15 mg (n = 311) |
PBO (n = 292) | TZP MTD (n = 287) | PBO (n = 335) | TZP MTD (n = 335) | |
| Albumin <3.3 g/dLa, no. (%) | 2 (0.3) | 1 (0.2) | 1 (0.3) | ||||||||
| TLC <910/μLa, no. (%) | 9 (1.4) | 21 (3.3) | 15 (2.4) | 20 (3.2) | 5 (1.6) | 12 (3.8) | 8 (2.6) | 6 (2.1) | 10 (3.5) | 8 (2.4) | 5 (1.5) |
| Albumin (g/dL), mean | |||||||||||
| Baseline | 4.47 | 4.47 | 4.46 | 4.47 | 4.55 | 4.55 | 4.54 | 4.58 | 4.57 | 4.5 | 4.6 |
| Change from baseline | −0.02 | 0 | 0 | −0.01 | 0.03 | 0.03 | 0.04 | −0.07 | −0.04 | −0.03 | −0.01 |
| TLC (109/L), mean | |||||||||||
| Baseline | 2.18 | 2.13 | 2.16 | 2.13 | 2.15 | 2.27 | 2.26 | 1.95 | 1.95 | 1.82 | 1.79 |
| Change from baseline | −0.25 | −0.27 | −0.29 | −0.29 | −0.13 | −0.25 | −0.20 | −0.03 | −0.10 | 0.14 | −0.01 |
Abbreviations: MTD, maximum tolerated dose; n, number of participants in the population; no., number of participants meeting criteria; PBO, placebo; TLC, total lymphocyte count; TZP, tirzepatide.
Empty table cells indicate that no events were reported. Data were collected in all studies.
In SURMOUNT-4, all participants were treated with TZP during a 36-week, open-label, lead-in period.
Participants with a laboratory value below the reference range (albumin <3.3 g/dL or TLC <910/μL) at randomization were not counted. Counts include incidences of post-randomization readings below the reference range for participants with values within or above the reference range at randomization.
Overall, 25/4726 (0.53 % [0.32 %–0.74 %]) participants discontinued treatment for reasons potentially related to nutritional status, with the most common reasons being achievement of desired weight and perceived excessive weight loss (Table 4).
Table 4.
Incidence of treatment discontinuation reasons potentially related to nutritional status.
| No. (%) | SURMOUNT-1 |
SURMOUNT-2 |
SURMOUNT-3 |
SURMOUNT-4 |
Total |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PBO | TZP 5 mg |
TZP 10 mg |
TZP 15 mg |
PBO | TZP 10 mg |
TZP 15 mg |
PBO | TZP MTD |
PBO | TZP MTD |
PBO | TZP | Total | |
| n | 643 | 630 | 636 | 630 | 315 | 312 | 311 | 292 | 287 | 335 | 335 | 1585 | 3141 | 4726 |
| BMI <18.5 kg/m2 | 2 (0.3) | 2 (0.06) | 2 (0.04) | |||||||||||
| Decreased appetite | 1 (0.2) | 1 (0.2) | 2 (0.06) | 2 (0.04) | ||||||||||
| Lowest BMI <18.5 kg/m2 | ||||||||||||||
| Lowest BMI ≥18.5-<22 kg/m2 | 1 (0.2) | |||||||||||||
| Lowest BMI ≥22 kg/m2 | 1 (0.2) | |||||||||||||
| Achieved desired weight | 3 (0.5) | 2 (0.3) | 4 (0.6) | 1 (0.3) | 1 (0.3) | 11 (0.4) | 11 (0.2) | |||||||
| Lowest BMI <18.5 kg/m2 | ||||||||||||||
| Lowest BMI ≥18.5-<22 kg/m2 | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.3) | ||||||||||
| Lowest BMI ≥22 kg/m2 | 2 (0.3) | 1 (0.2) | 3 (0.5) | 1 (0.3) | ||||||||||
| Perceived excessive weight loss | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.3) | 3 (1.0) | 1 (0.3) | 2 (0.6) | 1 (0.1) | 9 (0.3) | 10 (0.2) | ||||
| Lowest BMI <18.5 kg/m2 | ||||||||||||||
| Lowest BMI ≥18.5-<22 kg/m2 | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.3) | 1 (0.3) | |||||||||
| Lowest BMI ≥22 kg/m2 | 1 (0.3) | 2 (0.7) | 1 (0.3) | 1 (0.3) | ||||||||||
| All nutrient-related discontinuation reasons | 4 (0.6) | 6 (0.9) | 6 (1.0) | 1 (0.3) | 1 (0.3) | 4 (1.4) | 1 (0.3) | 2 (0.6) | 1 (0.1) | 24 (0.8) | 25 (0.5) | |||
Abbreviations: BMI, body mass index; MTD, maximum tolerated dose; n, number of participants in the population; no., number of participants meeting criteria; PBO, placebo; TZP, tirzepatide.
Investigator-reported reasons for treatment discontinuation potentially related to nutritional status are included.
Empty table cells indicate that no events were reported. Data were collected in all studies.
BMI thresholds of 18.5 kg/m2 and 22 kg/m2 were chosen as endpoints because 18.5 kg/m2 is an established threshold defining underweight and was a protocol-specified threshold for treatment discontinuation, and 22 kg/m2 was prespecified in study protocols as the point when study staff were instructed to modify dietary recommendations to promote weight stability rather than ongoing weight loss.
In SURMOUNT-4, all participants were treated with TZP during a 36-week, open-label, lead-in period.
BMI <18.5 kg/m2 was reached in 12/3141 (0.38 % [0.17 %–0.60 %]) tirzepatide-treated participants and 1/1585 (0.06 % [−0.06 %–0.19 %]) placebo-treated participants as early as week 36 (Supplement, Table S3). BMI <22 kg/m2 was reached in 228/3141 (7.26 % [6.35 %–8.17 %]) tirzepatide-treated participants and 16/1585 (1.01 % [0.52 %–1.50 %]) placebo-treated participants as early as week 12. Among participants who reached BMI <22 kg/m2 (n = 244), baseline BMI averaged 31.5 kg/m2 (standard deviation: 3.02) and weight reduction averaged −31.9 % (standard deviation: 8.91).
Given that gastrointestinal AEs could potentially impact dietary intake and nutritional status, the incidence of potential nutrition-related events was explored in the subpopulation of study participants who reported AEs of nausea, vomiting, or diarrhea (Supplement, Table S4). These results were consistent with the findings observed in the overall population. Furthermore, no severe/serious gastrointestinal AEs were reported for participants who discontinued treatment due to BMI <18.5 kg/m2, decreased appetite, or perceived excessive weight loss (data not shown). In the tirzepatide arms, severe/serious gastrointestinal AEs were reported in 6 participants who reached BMI <22 kg/m2 and in 1 participant who discontinued treatment after achieving desired weight. No events were reported with placebo.
4. Discussion
In this post hoc analysis of SURMOUNT-1-4, investigator-reported AEs were compiled to explore the possible association of tirzepatide for treatment of obesity with nutritional outcomes, given its potential for appetite suppression and gastrointestinal AEs, as well as significant weight reduction. TEAEs potentially related to macronutrient malnutrition were uncommon, as were treatment discontinuations potentially related to nutritional status. Despite the significant mean weight reductions observed with tirzepatide in these trials, relatively few participants reached BMI thresholds of <18.5 or <22 kg/m2, suggesting that excessive weight reduction was not common in these trials that included regular dietary counseling with a registered dietitian or health professional with similar qualifications. Reports of clinically significant vitamin deficiency TEAEs were uncommon, although micronutrient levels were not routinely assessed per the protocols. Because micronutrient deficiencies are known to be common in individuals with obesity [1], systematic collection of micronutrient levels both before and during treatment may lead to increased identification of vitamin deficiencies, including subclinical deficiencies, in this population.
5. Limitations
Study limitations include the lack of systematic assessment of nutritional status and the lack of data on body composition, dietary intake, and additional biomarkers such as micronutrient levels and total protein, potentially underestimating the prevalence of nutritional deficiencies in the study population. Furthermore, in the setting of intentional weight loss, nutrition-related TEAEs might not be recognized by trial site investigators or other clinicians involved in study participants' care (e.g., registered dietitians providing lifestyle counseling or participants’ primary care physicians), potentially leading to underestimation of the occurrence of nutritional deficiencies in the study population. In addition, despite historical use, biomarkers such as albumin and TLC are no longer recommended as surrogate markers of nutritional status per se [14]. Instead, it is now recognized that such biomarkers may reflect underlying acute or chronic disease processes that impact nutritional risk [15].
6. Conclusions
In this post hoc analysis of data from the SURMOUNT-1-4 trials, investigator-reported TEAEs related to macronutrient malnutrition and vitamin deficiency were uncommon during treatment with tirzepatide for obesity. However, a lack of standardized nutritional assessments during the trials limits safety-related conclusions. Future trials could benefit from systematic assessment of nutritional status to better evaluate the nutritional impact of OMMs and to help clinicians identify individuals at increased risk of malnutrition with OMM treatment. In clinical practice, nutritional assessment before and during OMM treatment can help identify individuals at increased malnutrition risk, and dietary counseling with a registered dietitian is recommended to optimize nutritional and health outcomes with OMM therapy.
Key takeaway clinical messages
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•
Nutrient deficiencies are common among people with obesity even prior to treatment, and limited information is available to understand whether treatment with incretin-based OMMs impacts nutritional outcomes.
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•
The current post hoc analysis found that investigator-reported TEAEs related to macronutrient and vitamin deficiencies were uncommon during the phase 3 SURMOUNT-1-4 trial program of tirzepatide.
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•
The SURMOUNT trials were not designed to specifically study the impact of tirzepatide on dietary intake and nutritional status, and additional data from future clinical trials could help inform the management of patients treated with OMMs. Dietary counseling with a registered dietitian is recommended to optimize obesity management, regardless of treatment approach.
Author contributions
LMN was involved in the conception, funding acquisition, and supervision of the work. DC and QM were involved in data curation and formal analysis of the data for the work. AS was involved in the investigation of the work. LMN, DC, QM, SGB, and GKD were involved in the development and design of methodology. AS and LMN were involved in drafting the manuscript. All authors provided critical revision of the manuscript for important intellectual content and approved the final submission and publication.
Ethical review
The phase 3 randomized, placebo-controlled, SURMOUNT-1-4 trials [[4], [5], [6], [7]] were conducted in accordance with the principles of the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines. The protocols were reviewed and approved by independent institutional review boards or ethics committees before initiation. All participants provided written informed consent before any study-related procedures were performed. The investigators ensured that participant confidentiality was maintained throughout the study. This post hoc analysis followed CONSORT 2025 reporting guidelines. The ClinicalTrials.gov identifiers for the studies reported here are as follows: NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3), and NCT04660643 (SURMOUNT-4).
Data sharing statement
Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Declaration of artificial intelligence (AI) and AI-assisted technologies
No AI was used in the drafting and submission of this disclosure.
Source of funding
This work was funded by Eli Lilly and Company, whose employees were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Conflicts of interest
JPA has received advisory or consulting fees from AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Nestle, and Novo Nordisk; received honoraria for lectures from Clinical Care Options, the Institute for Medical and Nursing Education, and PeerView; and served in a leadership or fiduciary role with The Obesity Society Governing Board. OPB has received consulting fees from Novo Nordisk, and honoraria for CME lectures and travel support from INME. CT has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Academy of Nutrition and Dietetics and the Commission on Dietetic Registration, Abbott Nutrition, Eli Lilly and TD Cowen; received support for attending meetings and/or travel from the Academy of Nutrition and Dietetics; served in a leadership or fiduciary role with the Academy of Nutrition and Dietetics Weight Management Dietetic Practice Group Executive Committee and Commission on Dietetic Registration; and served as a spokesperson for the Academy of Nutrition and Dietetics. AS, GKD, ALM, DC, and QM are employees and stockholders of Eli Lilly and Company. SGB is an employee and stockholder of Eli Lilly and Company; Black Physician's Healthcare Network Outreach and Education Partner Grantee, made to Embrace You Weight and Wellness, LLC; received consulting fees from Black Health, Black Physicians Healthcare Network, and Novo Nordisk; received honoraria and was a Board Member with the Obesity Medicine Association; participated in a Data Safety Monitoring Board or Advisory Board with Eli Lilly and Novo Nordisk; and served in a leadership role with the Black Physicians Healthcare Network, Parent Teacher Association, National Wellness Institute, and Obesity Medicine Association. LMN is an employee and stockholder of Eli Lilly and Company; has received grants or contracts from Aegerion Pharmaceuticals; and has served in a leadership or fiduciary role with Current Developments in Nutrition (journal) and the National Board of Physician Nutrition Specialists.
Acknowledgements
Kadie Vanderman, MS, PhD, Syneos Health provided writing assistance and Adrienne Schreiber, BA, and Alyssa Luck, BSPH, provided editorial assistance, funded by Eli Lilly and Company. The medical writer/editors adhered to Good Publication Practice (GPP3) guidelines and International Committee of Medical Journal Editors recommendations.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.obpill.2026.100248.
Contributor Information
Jaime P. Almandoz, Email: Jaime.Almandoz@UTSouthwestern.edu.
Octavia Pickett-Blakely, Email: Octavia.Pickett-Blakely@pennmedicine.upenn.edu.
Colleen Tewksbury, Email: Colleen.Tewksbury@pennmedicine.upenn.edu.
Adam Stefanski, Email: stefanski_adam@lilly.com.
Sylvia Gonsahn-Bollie, Email: Sylvia.gonsahnbollie@lilly.com.
Georgios K. Dimitriadis, Email: georgios.dimitriadis@lilly.com.
Ada Leticia Murro, Email: Murro_ada_leticia@lilly.com.
Dachuang Cao, Email: cao_dachuang@lilly.com.
Qier Meng, Email: qiermeng919@outlook.com.
Lisa M. Neff, Email: neff_lisa@lilly.com.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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