BACKGROUND:A knowledge gap remains in how the rate of body weight reduction impacts efficacy and safety of obesity management medications. This SURMOUNT-5 post hoc analysis aimed to define rapid responders and evaluated efficacy and safety of tirzepatide versus. semaglutide in rapid responders versus non-rapid responders. METHODS:Rapid responders and non-rapid responders were defined as participants that obtained ≥ 15% and < 15% body weight reduction by Week 24, respectively. Baseline characteristics, and proportion of participants achieving body weight reduction thresholds by Week 72 were assessed. End-of-study safety and gastrointestinal adverse events measures were summarized. RESULTS:Overall, 32.3% were rapid responders (tirzepatide: 44%, semaglutide: 21%). The proportions of participants achieving body weight reduction thresholds by Week 72 were higher for rapid responders versus non-rapid responders. Safety trends for tirzepatide and semaglutide were similar between responder groups. A numerically higher number of gastrointestinal/hepatobiliary adverse events were reported in rapid responders. Study treatment completion was similar among rapid responders and non-rapid responders for both treatments. CONCLUSIONS:In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants in both responder groups achieved all body weight reduction thresholds versus semaglutide. Although rapid responders experienced more gastrointestinal/hepatobiliary adverse events in both treatments, this did not affect rates of study treatment completion relative to non-rapid responders. TRIAL REGISTRATION:clinicaltrials.gov identifier NCT05822830.

Prevention of progression into type 2 diabetes (T2D) in patients with prediabetes is a key goal of obesity management. In SURMOUNT-5, once weekly tirzepatide at the maximum tolerated dose (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) resulted in significantly greater body weight reduction in adults living with obesity without T2D. Assess changes in glycemia outcomes with tirzepatide (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) in participants with obesity and prediabetes from SURMOUNT-5. Participants (N = 425) with baseline prediabetes, defined as having ≥ 1 fasting lab-based value of either FSG 100–125 mg/dL or HbA1c 5.7–6.4

RATIONALE: In the SURMOUNT-OSA clinical studies, tirzepatide improved measures of obstructive sleep apnea (OSA) and cardiometabolic parameters in participants with moderate-to-severe OSA and obesity, including apnea hypopnea index (AHI), sleep apnea specific hypoxic burden (SASHB), systolic blood pressure (SBP), C-reactive protein (CRP), and body weight (BW). Here we evaluate the associations between tirzepatide treatment and changes in these parameters versus placebo by baseline OSA severity. METHODS: SURMOUNT-OSA (NCT05412004) comprised two Phase 3 studies comparing the effects of tirzepatide maximum tolerated dose (10 mg or 15 mg once weekly) versus placebo in adults with moderate-to-severe OSA and obesity over 52 weeks. Study 1 participants were not on positive airway pressure (PAP) therapy; Study 2 participants were on PAP. These post-hoc analyses classified on-treatment participants with non-missing baseline AHI measurements into approximately evenly weighted OSA severity subgroups by baseline AHI (moderate, AHI ≥15 to <30; severe, AHI ≥30 to <70; very severe, AHI ≥70). Measures related to OSA were analyzed by logistic regression for binary outcomes and mixed-model repeated measures for continuous variables. RESULTS: In our analyses, we did not observe consistent associations between baseline OSA severity and changes in measures of OSA or cardiometabolic parameters across both studies. Significant differences between severity subgroups were observed for change difference in AHI (p=0.032) and percent body weight reductions (p=0.042) among participants not on PAP in Study 1 (Table 1). In Study 1 and 2, tirzepatide was associated with significant reductions versus placebo in AHI, SASHB, SBP, and BW across all severity subgroups. In both studies, the odds of achieving ≥50% AHI reduction with tirzepatide were significantly higher than with placebo in all severity groups. The odds of achieving AHI <5 or AHI 5-14 with Epworth Sleepiness Scale ≤10 were also significantly higher with tirzepatide than placebo in all subgroups except the Study 1 very severe subgroup. Greater reductions were observed in high-sensitivity CRP with tirzepatide than placebo across all severity groups, though significant differences were only associated with the severe subgroup in both studies. CONCLUSION: In these post-hoc analyses of the SURMOUNT-OSA studies, tirzepatide was associated with significant improvements versus placebo in measures of OSA and cardiometabolic parameters irrespective of participants’ OSA severity at baseline or PAP therapy use.

BACKGROUND:Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown. METHODS:In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. RESULTS:A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13.0 cm (95% CI, -14.3 to -11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation. CONCLUSIONS:Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.).

Introduction and Objective: A knowledge gap remains in how rate of weight reduction (WR) with new obesity management medications impacts efficacy and safety. This SURMOUNT-5 post hoc aimed to define rapid responders [RR] and to evaluate efficacy and safety in RR vs non-rapid responders (NRR). Methods: Defining RR was informed by tertile analysis of all participants’ WR by week (wk) 24. Proportion of participants achieving WR targets by wk72, and time to ≥15% WR from efficacy analysis set, and safety / GI tolerability measures were summarized by treatment and responder (RR vs NRR) group. Results: RR was defined as ≥15% WR by wk24 (32.3% of all participants). RR included 44% of tirzepatide (TZP) and 21% of semaglutide (Sema) participants. Median time to ≥15% WR was 36 and 52 wk for TZP and Sema, respectively. The proportions of participants achieving WR targets by wk72 were higher for RR vs NRR (Table). Safety trends for TZP and Sema were similar for RR vs NRR. Numerically higher number of GI and hepatobiliary AE were reported in RR. For RR vs NRR, treatment completion was nominally higher for TZP and similar for Sema. Conclusion: In this post hoc, the TZP group had greater proportions of participants that achieved all WR targets in both RR and NRR compared to Sema. With both treatments, RR had nominally more GI and hepatobiliary AE, yet these trends were not associated with ability to complete treatment compared to NRR. L.J. Aronne: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Lilly USA LLC. Research Support; Lilly USA LLC. D. Horn: Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Amgen Inc. Advisory Panel; Novo Nordisk. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Novo Nordisk. B. Falcon: Employee; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H.T. Hoffmann: Employee; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Introduction and Objective: Time to treatment target is a consideration in clinical decision making. Additionally, greater magnitudes of sustained body weight (BW) reduction are shown to provide added health benefits. In SURMOUNT-5, once weekly tirzepatide (TZP) at the maximum tolerated dose (MTD) (10/15mg) resulted in significantly greater BW reduction vs semaglutide (SEMA) MTD (1.7/2.4mg) in adults living with obesity. This post hoc analysis assessed time to reach BW reduction thresholds and continuous time spent in BW control with TZP vs SEMA in SURMOUNT-5. Methods: Participants randomized (1:1) to receive TZP MTD (N=374) or SEMA MTD (N=376) and with an on-treatment BW measurement at week 72 were included in analysis. Among participants achieving BW reduction thresholds (≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%) at week 72, time to first reaching thresholds and continuous time spent at each threshold was descriptively analyzed. Sustained BW reduction was defined as achieving BW reduction threshold at a postbaseline visit and at all subsequent visits (±3%) up to week 72. Results: At week 72, time to reach thresholds was shorter with TZP vs SEMA except ≥25%, which was similar (median weeks: 8 vs 12 for ≥5%, 16 vs 20 for ≥10%, 24 vs 36 for ≥15%, 36 vs 48 for ≥20%, 48 vs 48 for ≥25%, and 48 vs 52 for ≥30%). Of the participants who achieved and sustained the defined thresholds during the 72-week trial, median duration in weeks of sustained BW reduction was longer with TZP vs SEMA: 64 vs 60 for ≥5%, 56 vs 52 for ≥10%, 48 vs 36 for ≥15%, 36 vs 25 for ≥20%, 25 vs 24 for ≥25%, and 24 vs 21 for ≥30%. Conclusion: In this post hoc analysis, participants in the TZP arm reached clinically meaningful BW reduction sooner vs SEMA in adults living with obesity. For participants who achieved BW reduction thresholds during the 72-week trial, both treatment groups had sustained BW reduction. ​Additional studies are needed to further assess sustainability of BW reduction and its clinical impact​. D.B. Horn: Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Amgen Inc. Advisory Panel; Novo Nordisk. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Novo Nordisk. L.J. Aronne: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Lilly USA LLC. Research Support; Lilly USA LLC. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H.T. Hoffmann: Employee; Eli Lilly and Company. B.L. Falcon: Employee; Eli Lilly and Company. D. Cao: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Eli Lilly and Company

Rationale: Obstructive sleep apnea (OSA) is associated with obesity and cardiometabolic risk. In the SURMOUNT-OSA studies, tirzepatide demonstrated clinically meaningful improvements in apnea-hypopnea index (AHI) (-27.4 to -30.4 events/hour) and body weight reduction (-18.1% to -20.1%) in participants with moderate-to-severe OSA and obesity. This post-hoc analysis investigated the hypothesis that improvements in cardiometabolic biomarkers are concordant with degree of OSA improvement from SURMOUNT-OSA. Methods: SURMOUNT-OSA was comprised of two 52-week, Phase 3 studies comparing maximum tolerated dose (MTD) of tirzepatide (10 mg or 15 mg) versus placebo in participants with moderate-to-severe OSA and obesity. Study 1 included participants not on PAP therapy, and study 2 included participants on PAP therapy. The current post-hoc analysis investigated the association of tirzepatide MTD and placebo with cardiometabolic parameters in participants achieving <25% (Low), 25%-<50% (Medium), or ≥50% (High) reduction in AHI from both SURMOUNT-OSA studies. An ANCOVA model was used to assess change from baseline at 52 weeks within treatment groups based on efficacy estimand, including participants with non-missing baseline and final AHI values. Results: The current analysis comprised 178 participants in study 1 (tirzepatide n=96, placebo n=82) and 188 participants in study 2 (tirzepatide n=105, placebo n=83). Following tirzepatide treatment, participants with greater improvements in AHI observed greater reduction in triglycerides in study 1 (Low, -25.1%; Medium, -32.2%; High, -35.8%) and study 2 (Low, -24.8%; Medium, -33.8%; High, -37.5%) (Figure 1A). Participants with greater improvements in AHI following tirzepatide displayed greater improvements in HDL-C in study 1 (Low, 6.3%; Medium, 10.7%; High, 13%) and non-HDL-C in study 2 (Low, -11.5%; Medium, -13.7%; High, -18.1%) (Figure 1B&C). In the tirzepatide group, participants with greater improvements in AHI observed greater reductions in fasting glucose in study 1 (Low, -12.2 mg/dL; Medium, -14.6 mg/dL; High, -15.5 mg/dL) and study 2 (Low, -3.1 mg/dL; Medium, -13.8 mg/dL; High, -15.6 mg/dL) and greater reductions in fasting insulin in study 2 (Low, -23.4%; Medium, -32.2%; High, -51.8%) (Figure 1D&E). Additional cardiometabolic parameters (blood pressure, LDL-C) demonstrated improvements with tirzepatide but no trend was observed with AHI improvement. In general, greater improvements in cardiometabolic parameters were observed with tirzepatide versus placebo across categories of AHI reduction. Conclusions: In this post-hoc analysis of the SURMOUNT-OSA studies, participants with moderate-to-severe OSA and obesity with greater reductions in AHI following tirzepatide treatment displayed greater improvements in some cardiometabolic parameters. In general, greater improvements in cardiometabolic parameters were observed with tirzepatide versus placebo.

Introduction and Objective: While highly effective obesity medications have been shown to lead to substantial weight reduction, few data exist on achieving normal BMI. SURMOUNT(SM)-1 3-year study is a phase 3 trial of dual GIP/GLP-1 receptor agonist tirzepatide (TZP). This study aimed to assess baseline characteristics of participants on TZP with prediabetes who reached normal BMI (< 25 kg/m2). Methods: SM-1 participants with obesity and prediabetes, randomized to TZP (5, 10 or 15mg) or placebo who received ≥75% doses were included and baseline characteristics compared between those who reached normal BMI vs not. Results: Out of 714 TZP-treated participants, 17.6% (N=128) reached normal BMI by the study end. Compared to those who did not reach normal BMI, these participants were: more likely to be female, slightly older, on higher TZP doses (10 or 15mg), with lower baseline weight, waist circumference, BMI, HbA1c, insulin, systolic blood pressure, eGFR and ALT (Table 1). Sensitivity analysis (normal BMI cutoff for Asian < 23) is consistent with main results. Conclusion: In this post-hoc analysis, nearly 1 in 5 reached normal BMI by 176 weeks TZP treatment. Compared to participants who did not reach normal BMI, those who reached normal BMI had higher proportion of females, older age, on higher TZP doses, and lower baseline BMI. These findings may help tailor obesity treatment to individual health goals. R. Srinath: Research Support; Dexcom, Inc. N. Sattar: Other Relationship; Abbott, AbbVie Inc, Amgen Inc, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company. Advisory Panel; Hanmi Pharm. Co., Ltd. Consultant; Carmot Therapeutics, Inc, Menarini. Other Relationship; Novartis AG, Novo Nordisk, Pfizer Inc, Roche Diagnostics. Consultant; GlaxoSmithKline plc, Metsera. Other Relationship; American Diabetes Association, Medscape. H. Wang: None. B. Falcon: Employee; Eli Lilly and Company. L. Garcia-Perez: Employee; Eli Lilly and Company. A. Stefanski: Employee; Eli Lilly and Company. A.W. Plat: Employee; Lilly USA LLC. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Tirzepatide, a once weekly GIP/GLP-1 receptor agonist, demonstrated robust weight reduction efficacy, with body weight reductions of 13-23% in people with obesity or overweight in the SURMOUNT-1 (SM-1; participants without type 2 diabetes [T2D]) and SURMOUNT-2 (SM-2; participants with T2D) trials. In this post-hoc analysis, we aimed to describe week 24 weight loss by categorical weight reduction at the end of study (week 72), to provide insights to weight loss trajectories when considering individualized weight reduction targets. Data from tirzepatide-treated participants who received ≥75% doses in SM-1 (N=1596) and SM-2 (N=532) were included in the analysis. Data were pooled for all doses in each study and summarized descriptively for week 72 categorical weight reductions of ≥5% to < 10%, ≥10% to < 15%, ≥15% to < 20%, ≥20% to < 25%, or ≥25%. At baseline, mean age was 45 years, weight 104.8 kg, and BMI 38.0 kg/m2 in SM-1, and 54 years, 101.1 kg, and 36.1 kg/m2 in SM-2. 68% and 50% of participants were female in SM-1 and -2, respectively. SM-1 participants with weight reduction of ≥5% to < 10%, ≥10% to < 15%, ≥15% to < 20%, ≥20% to < 25%, or ≥25% at week 72 had mean weight change at week 24 (95% confidence interval [CI]) of -7.8% ( -8.3, -7.2), -10.1% (-10.6, -9.6), -12.7% (-13.1, -12.2), -14.8% (-15.3, -14.4), and -18.9% (-19.3, -18.4), respectively. The corresponding weight change for SM-2 participants was -7.5% (-8.2, -6.7), -9.8% (-10.5, -9.1), -12.2% (-12.9, -11.5), -14.5% (-15.4, -13.7), and -18.6% (-19.7, -17.4) at week 24, respectively. When assessing body weight change in females and males, in SM-1, mean weight change at week 24 was -7.6% (95% CI -8.5, -6.8), -9.9% (-10.6, -9.3), -12.6% (-13.2, -12.0), -14.5% (-15.0, -14.0), and -19.0% (-19.5, -18.5) in females, and -7.9% (-8.7, -7.1), -10.3% (-11.1, -9.5), -12.8% (-13.6, -12.0), -15.7% (-16.6, -14.8), and -18.4% (-19.4, -17.4) in males, for each of the week 72 weight reduction categories, respectively. In SM-2, mean weight change at week 24 was -7.2% (95% CI -8.5, -5.9), -10.3% (-11.5, -9.1), -12.1% (-13.0, -11.2), -14.3% (-15.3, -13.3), and -17.9% (-19.1, -16.8) in females, and -7.7% (-8.6, -6.7), -9.4% (-10.2, -8.6), -12.2% (-13.2, -11.2), -15.0% (-16.9, -13.1), and -19.9% (-22.5, -17.2) in males, respectively. In SM-1 and -2, participants reached at least 70% of their week 72 weight reduction by week 24. Within week 72 weight reduction categories, males tended to have more weight reduction by week 24 than females, suggesting sex-specific trajectories. These data may be useful in clinical decision making when considering dose adjustments to achieve individualized weight reduction targets.

Introduction and Objective: In SURPASS-1-4 (SP), baseline factors associated with higher likelihood of achieving body weight (BW) reduction ≥15% at WK 40/42 with tirzepatide (TZP) in participants with T2D were: higher TZP dose, female sex, White or Asian race, metformin use, better glycemic status and lower non-HDL-C. We assessed performance of these predictors in BW reduction ≥15% at WK 48 in SURMOUNT-2 (SM-2), a study of TZP in chronic weight management in adults with T2D with obesity or overweight. Methods: The multivariate model from SP was run in SM-2 participants who were on TZP at WK 48, ≥75% compliance and no rescue medication during the study treatment period. The AUC (area under curve) of the SM-2 model was calculated to determine its accuracy. Results: BW reduction ≥15% was achieved in 41.8% (n = 230) participants on TZP at WK 48 and 91.3% (n = 210) sustained BW reduction ≥15% at WK 72. Factors identified in SP that were replicated with respect to the estimated effect size in SM-2: higher TZP dose, female, and lower HbA1c, FSG and non-HDL-C (Table 1). In SM-2, unlike in SP, Asian race and metformin use were not positively associated with BW reduction ≥15%. The AUC was 65.6%. Conclusion: In the current study there are some consistencies in SM- 2 when applying the SP model. However, the overall performance of the predictors of the model demonstrates a need for refinement. Disclosure I. Lingvay: Consultant; Altimmune, Astra Zeneca, Bayer, Biomea, Boehringer-Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Sanofi. Research Support; NovoNordisk, Sanofi, Mylan, Boehringer-Ingelheim. Consultant; TERNS Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. M. Malecki: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott, Dexcom, Inc., Boehringer-Ingelheim. Speaker's Bureau; AstraZeneca, Merck & Co., Inc. Advisory Panel; Krka. Speaker's Bureau; Servier Laboratories. I. Benabbad: Employee; Eli Lilly and Company. B. Falcon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company, Sangamo Therapeutics. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Wang: None. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Abstract Introduction Obesity has been estimated to be prevalent in 70% of patients with obstructive sleep apnea (OSA). In SURMOUNT-1, phase 3, 72-week, randomized, double-blind clinical trial in participants with obesity or overweight, those treated with tirzepatide achieved significantly greater weight reduction than placebo. Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. The current post-hoc analysis assessed efficacy of tirzepatide versus placebo on weight reduction in participants with OSA and obesity or overweight. Methods MMRM analysis was conducted in SURMOUNT-1 participants reporting a baseline medical history of “apnoea”, “positive airway pressure therapy” or “sleep apnoea syndrome”. Weight loss measures were assessed in participants on treatment (efficacy estimand) using the modified intention-to-treat analysis set (participants who received at least one dose of study drug (tirzepatide 5mg, 10mg, 15mg, or placebo)). Results There were 197 participants with OSA included in this analysis (tirzepatide 5mg n=41, 10mg n=51, 15mg n=46, and placebo n=59), with baseline age of 48-53 years, body weight 110-122 kg, BMI 39-43kg/m2, presence of hypertension 48-73%, and proportion of females 42-53%. At week 72, estimated treatment difference between tirzepatide and placebo in mean percent weight change was -11.2% (5mg), -18.2% (10mg), and -20.7% (15mg), all P< 0.001. Significantly more participants treated with tirzepatide achieved ≥5% body weight reduction (83-98% treated with tirzepatide, 25% with placebo) and ≥10% body weight reduction (46-93% treated with tirzepatide, 15% with placebo) than those treated with placebo (all P< 0.001). 27-62% of participants treated with tirzepatide achieved ≥20% body weight reduction compared to 0% in the placebo group (tirzepatide 5mg P=0.006, 10mg and 15mg P< 0.001). All doses of tirzepatide significantly reduced waist circumference from baseline to week 72 (-10.6cm, -18.2cm, -18.9cm, all P< 0.001). Placebo did not significantly reduce waist circumference at week 72 compared to baseline (-3.5cm, P=0.053). Conclusion Participants with OSA and obesity or overweight treated with tirzepatide had significantly greater weight reduction than those treated with placebo in the SURMOUNT-1 trial. This degree of weight loss would be expected to have a clinically meaningful impact on OSA severity and is being investigated in the SURMOUNT-OSA trial. Support (if any) Eli Lilly and Company.

Introduction: Tirzepatide is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes and under investigation for chronic weight management. In SURMOUNT-1, tirzepatide treatment resulted in substantial body weight reductions in people with obesity (body mass index (BMI) ≥30 kg/m 2 ) or overweight (BMI ≥27 kg/m 2 ). Hypothesis: This post hoc analysis assessed the baseline characteristics of tirzepatide-treated participants who reached normal BMI, defined by <25 kg/m 2 . Methods: Participants (N=1834) from SURMOUNT-1 with at least one post-baseline BMI measurements and adherent to tirzepatide (≥75% of doses received) were included in this analysis. The proportion of participants who shifted to a normal BMI was assessed during the study period. Baseline demographics and clinical characteristics were compared between participants who shifted to a normal BMI vs those who did not reach a normal BMI by week 72. Results: A total of 380 participants shifted to a normal BMI during the study period. Participants who shifted to a normal BMI were slightly older, more likely to be female, with shorter duration of obesity and lower baseline BMI (in particular a BMI ≥27 to <30 kg/m 2 or ≥30 to <35 kg/m 2 ), HbA1c, fasting glucose, fasting insulin, systolic blood pressure, ALT and eGFR vs those who did not reach a normal BMI (Table). Additionally, fewer had prediabetes and hypertension, and a greater proportion of participants had dyslipidemia in those who reached the normal BMI vs those who did not. Conclusions: In this post hoc analysis from SURMOUNT-1, approximately one in five participants with overweight or obesity receiving tirzepatide treatment reached the normal BMI (<25 kg/m 2 ) by week 72. Participants who reached the normal BMI were older, more likely to be female and had several favorable characteristics at baseline including lower baseline BMI, HbA1c, blood pressure, ALT and eGFR compared to those who did not reach the normal BMI.

Supplemental Table 1. Cell culture conditions. Supplemental Table 2. Antibody details. Supplemental Table 3. Catalog information for Dharmacon RNAi constructs. Supplemental Table 4. EC50 values of prexasertib in pediatric cell lines included in the cancer cell line sensitivity panel. Supplemental Table 5. Quantification of percent positive cells for each immunostain following prexasertib treatment. Supplemental Figure 1. Prexasertib induces caspase activation in NB cell lines. Supplemental Figure 2. Prexasertib promotes neuroblastoma cell death by inducing DNA damage. Supplemental Figure 3. Inhibition of CHK1 promotes phosphorylation of RPA32/2. Supplemental Figure 4. Assessment of siRNA-mediated knockdown of CHK1 on total protein and phosphorylation status. Supplemental Figure 5. No significant weight loss was observed during prexasertib treatment. Supplemental Figure 6. Combination with doxorubicin does not enhance prexasertib efficacy in vivo. Supplemental Figure 7. Vasculature markers are more prevalent in prexasertib-treated neuroblastoma xenografts. Supplemental Figure 8. Prexasertib reduces VEGF endothelial cell cord formation in vitro, but does not affect established cords. Supplemental Figure 9. Neuroblastoma cell lines drive endothelial cord formation in vitro.

Supplementary Table 1 from VEGF and c-Met Blockade Amplify Angiogenesis Inhibition in Pancreatic Islet Cancer

This file contains details too lengthy to put in the primary manuscript file as well as methods for supplemental data

These figures contain extensions of data that would not fit in the primary manuscript but are important for a complete understanding of the work. These include analysis of other data sets, correlations between genomic profiling our stromal subtyping and information on bioinformatics and animal models.

Figure S2: Co-targeting S1P1 and VEGFR2 pathways induced reduction in permeability of retinal vessels. Ter 119 staining (panels A) visualize red blood cells and show that the combination of DC101 and the S1P1 antagonist in the retina led to reduction of the areas of hemorrhage within the vascular plexus and restricted only to the angiogenic front indicating that the remaining vessels in the remodeled area are less permeable.