https://orcid.org/0000-0002-1604-2593
Figures
Abstract
Background
Modest body weight reduction can greatly improve many health-related outcomes. In the SURMOUNT clinical trial program, once-weekly tirzepatide resulted in substantial body weight reductions in people with obesity, without and with type 2 diabetes.
Objective
This post-hoc analysis assessed the proportion of participants achieving body weight reduction thresholds (≥5%, ≥10%, ≥15%), systolic blood pressure reduction ≥5 mmHg, and non-high-density lipoprotein cholesterol (non-HDL-C) <130 mg/dL with tirzepatide.
Methods
Participants from SURMOUNT 1–4 randomized to tirzepatide or placebo with valid baseline and ≥1 non-missing post-baseline body weight, systolic blood pressure and non-HDL-C measurements were included in this analysis. The proportion of participants achieving the triple endpoints was assessed at the primary endpoint of each study (Week 72 for SURMOUNT-1, SURMOUNT-2 and SURMOUNT-3 and Week 88 for SURMOUNT-4).
Results
Across the trials, 32–38% vs 2–8% of tirzepatide-treated vs placebo-treated participants achieved ≥5% body weight reduction, systolic blood pressure reduction ≥5 mmHg, and non-HDL-C <130 mg/dL, 28–37% vs 1–5%, respectively, achieved the triple endpoint with the ≥10% body weight reduction threshold, and 22–34% vs 1–3%, respectively, achieved the triple endpoint with the ≥15% body weight reduction threshold. The between-treatment odds ratios for these proportions across the trials, were statistically significant (all p<0.001).
Conclusion
In this post hoc analysis of SURMOUNT, more participants achieved the triple endpoint of body weight reduction thresholds, systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL with tirzepatide vs placebo. Studies evaluating the potential cardiovascular benefits of tirzepatide are ongoing.
Citation: Sattar N, Srinath R, García-Pérez L-E, Lee CJ, Karanikas CA, Chen X, et al. (2026) Achieving the triple endpoint of body weight reduction thresholds, systolic blood pressure reduction ≥5 mmHg and non-HDL cholesterol <130 mg/dL with tirzepatide in people with obesity: A post hoc analysis from the SURMOUNT trials. PLoS One 21(8): e0345032. https://doi.org/10.1371/journal.pone.0345032
Editor: Surya Prakash Bhatt, All India Institute of Medical Sciences, INDIA
Received: February 17, 2026; Accepted: July 28, 2026; Published: August 13, 2026
Copyright: © 2026 Sattar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: Supported by Eli Lilly and Company.
Competing interests: Naveed Sattar reports consulting and/or speaker fees from Abbott Laboratories, Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his institution from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Reshmi Srinath declares no competing interests. Luis-Emilio Garcia-Perez, Clare J. Lee, Chrisanthi A. Karanikas, Xinyue Chen and Arian Plat are employees and shareholders at Eli Lilly and Company.
Introduction
Obesity is a complex condition associated with many chronic diseases [1–4]. Obesity has also been associated with a reduction in disease-free life (ranging from 3–8 years) [5] and with an estimated 1.3-fold higher risk of early death compared to individuals with healthy body weight [6–8].
Modest body weight reductions of 5% may lessen or resolve certain obesity-related complications [9]. In the Look AHEAD study, body weight reductions of 5% to <10% significantly improved glycemic control, lipid levels, and blood pressure in participants with obesity and without type 2 diabetes, and even greater odds of improving cardiovascular risk factors were observed in individuals who achieved 10–15% body weight reduction [10]. As the prevalence of obesity continues to rise, targeted pharmacotherapy in addition to lifestyle modification has become more pertinent to the management of chronic, excess body weight.
Tirzepatide is a once weekly glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for type 2 diabetes and obesity, among other indications. In the SURMOUNT clinical trial program, tirzepatide treatment at all doses studied (5 mg, 10 mg, or 15 mg or the maximum tolerated dose [MTD] of 10 mg or 15 mg) resulted in robust and clinically meaningful reductions in body weight ranging from 13–26%, with 82–99% of participants achieving body weight reduction thresholds of ≥5% over a period of 72 or 88 weeks in the respective studies [11–14]. Furthermore, significant reductions in systolic blood pressure of up to 11 mmHg and non-high-density lipoprotein cholesterol (non-HDL-C) of up to 13% were observed with tirzepatide compared with placebo [11–14], suggesting improved cardiometabolic health beyond the observed body weight reduction.
Many individuals do not meet the recommended thresholds for these biomarkers [15], which may increase cardiovascular risk. Hence, a broader evaluation of the cardiometabolic changes associated with tirzepatide may offer further evidence of its potential clinically relevant benefits for people living with obesity, with and without type 2 diabetes. Although prespecified cardiovascular outcomes trials for treatment with this dual agonist in people with obesity without type 2 diabetes are ongoing, GLP-1 receptor agonists have been shown to have cardioprotective effects and reduce the risk of major adverse cardiovascular events that may lead to death [16].
Combining multiple endpoints into a single composite can offer a broader perspective on the potential of additional benefits of obesity treatment on related cardiovascular comorbidities. In this post hoc analysis of SURMOUNT, we assessed the proportion of participants who achieved the triple composite endpoint of body weight reduction thresholds (≥5%, ≥10%, ≥15%), with reductions in systolic blood pressure ≥5 mmHg [17] and non-HDL-C <130 mg/dL [18] following treatment with tirzepatide compared with placebo.
Materials and methods
Participants and study design
The study designs and primary results of the SURMOUNT-1 through SURMOUNT-4 trials are published [11–14]. Briefly, the SURMOUNT clinical program consisted of Phase 3 randomized controlled trials, ranging from 72 to 88 weeks in duration and designed to assess tirzepatide 5 mg, 10 mg, and 15 mg or MTD of 10 mg and 15 mg in adults, obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2 with at least one weight-related comorbid condition), without and with type 2 diabetes [11–14]. SURMOUNT-4 included a 36-week, open-label lead-in period with tirzepatide treatment followed by a 52-week, double-blind, placebo-controlled period [14]. In all trials, the primary endpoint was the percentage change in body weight from randomization to end of treatment, with superiority of tirzepatide vs placebo. Due to the design differences of these SURMOUNT trials, they were analyzed separately in this study. Given that participants in the placebo arm of SURMOUNT-4 received tirzepatide in the 36-week lead-in period prior to being randomized, this placebo arm was expected to outperform the placebo arm of the other SURMOUNT trials.
The SURMOUNT clinical trials included in this analysis are registered in clinicaltrials.gov (NCT04184622 [SURMOUNT-1], NCT04657003 [SURMOUNT-2], NCT04657016 [SURMOUNT-3], and NCT04660643 [SURMOUNT-4]) and were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. All participants provided signed informed consent, and protocols were approved by local ethical review boards. Eli Lilly and Company (Indianapolis, IN, USA) sponsored the program.
Endpoints
The triple composite endpoints consisted of participants achieving a body weight reduction ≥5% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL, a body weight reduction ≥10% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL, and a body weight reduction ≥15% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL. End of treatment body weight, absolute and percent changes from baseline in body weight, systolic blood pressure, and non-HDL-C (overall population and by baseline non-HDL-C <130 mg/dL and ≥130 mg/dL) were evaluated at the primary endpoint of each respective trial (Week 72 for SURMOUNT-1, SURMOUNT-2 and SURMOUNT-3 and Week 88 for SURMOUNT-4).
Statistical analyses
Only participants with valid baseline body weight and at least one non-missing post-baseline body weight, with valid baseline systolic blood pressure and at least one non-missing post-baseline systolic blood pressure, and with valid baseline non-HDL-C and at least one non-missing post-baseline non-HDL-C were included in this analysis. The proportion of participants achieving the triple composite endpoints was compared between the tirzepatide (SURMOUNT-1: 5 mg, 10 mg or 15 mg, SURMOUNT-2: 10 mg or 15 mg, SURMOUNT-3 and SURMOUNT-4: MTD of 10 mg or 15 mg) and placebo groups (including participants from SURMOUNT-4 who underwent a 36-week lead-in with tirzepatide prior to switching to placebo) using the efficacy analysis dataset. The efficacy analysis dataset included on-treatment data from randomly assigned participants who were exposed to at least one dose of the study drug. Participants who discontinued the study drug because of inadvertent enrolment were excluded from the analysis. Missing endpoint measures for body weight, systolic blood pressure, and non-HDL-C were imputed separately using a mixed-model repeated measures analysis. The imputed values were used to determine whether each component threshold was met, and the resulting composite endpoint status was analyzed using the logistic regression adjusted for relevant baseline values and stratification factors. In SURMOUNT-1, a logistic regression model was fitted with treatment group (placebo, tirzepatide 5 mg, 10 mg, 15 mg) as a factor, consistent with the fixed-dose parallel-group design. Similarly, in SURMOUNT-2, a logistic regression model was fitted with treatment group (placebo, tirzepatide 10 mg, and 15 mg) as a factor. In SURMOUNT-3 and SURMOUNT-4, tirzepatide was administered as a maximum tolerated dose (MTD) and therefore a single comparison of MTD versus placebo was conducted. Safety data were descriptively assessed.
All analyses presented herein were exploratory in nature, thus p-values were nominal, and multiplicity adjustment was not performed. The statistical significance threshold of a p-value <0.05 was applied to assist data interpretation and functioned as hypothesis-generating. Analyses were performed using SAS version 9.4 (Copyright © 2017 SAS Institute Inc., Cary, NC, USA). Additional statistical analysis methods are provided in the S1 Appendix. The data sets used in this analysis are provided in the S2 Appendix.
Results
Participants
The numbers of participants included in this analysis were N = 2345, N = 879, N = 515, and N = 570 in SURMOUNT-1 through SURMOUNT-4, respectively. Overall, baseline demographics and clinical characteristics were similar between treatment groups within trials (Table 1). Baseline demographics and clinical characteristics in participants by achievement of each composite endpoint (yes, no) are presented in S1, S2 and S3 Tables.
Triple composite endpoints
Baseline, change from baseline and percent change from baseline for individual parameters are presented in S4 Table. Across SURMOUNT-1 through SURMOUNT-4, a significantly greater proportion of participants treated with tirzepatide at all doses studied achieved all composite endpoints compared with placebo at the primary endpoint of Week 72/88 (all p<0.001). The proportion of participants who achieved body weight reduction ≥5% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL with tirzepatide ranged from 32–38% vs 2–8% with placebo (Fig 1A, S5 Table). The odds ratios (95% confidence intervals) were 6.87 (4.75, 9.93), 8.05 (5.56, 11.65), and 9.43 (6.53, 13.62), for tirzepatide 5 mg, 10 mg, and 15 mg vs placebo, respectively, in SURMOUNT-1, 6.52 (3.94, 10.79) and 5.79 (3.50, 9.59) for tirzepatide 10 mg and 15 mg vs placebo, respectively, in SURMOUNT-2, and 24.35 (10.53, 56.29) for tirzepatide MTD vs placebo in SURMOUNT-3 (all p<0.001). The proportion of participants who achieved body weight reduction ≥10% ranged from 28–37% with tirzepatide vs 1–5% with placebo (Fig 1B, S5 Table). The odds ratios (95% confidence intervals) were 8.93 (5.86, 13.61), 10.46 (6.86, 15.97), and 13.45 (8.84, 20.47) for tirzepatide 5 mg, 10 mg, and 15 mg vs placebo, respectively, in SURMOUNT-1, 13.47 (6.54, 27.76) and 14.42 (7.00, 29.71) for tirzepatide 10 mg and 15 mg vs placebo, respectively, in SURMOUNT-2, and 45.07 (15.15, 134.06) for tirzepatide MTD vs placebo in SURMOUNT-3 (all p<0.001). The proportion of participants who achieved body weight reduction ≥15% ranged from 22–34% with tirzepatide vs 1–3% with placebo (Fig 1C, S5 Table). Odds ratios (95% confidence intervals) were 10.15 (5.97, 17.26), 16.87 (9.96, 28.58), and 20.70 (12.25, 34.97) for tirzepatide 5 mg, 10 mg, and 15 mg vs placebo, respectively, in SURMOUNT-1, 23.57 (8.11, 68.48) and 27.50 (9.48, 79.77) for tirzepatide 10 mg and 15 mg vs placebo, respectively, in SURMOUNT-2, and 45.64 (12.94, 160.92) for tirzepatide MTD vs placebo in SURMOUNT-3 (all p<0.001). In SURMOUNT-4, in participants who switched to placebo following a 36-week lead-in with tirzepatide, 14%, 10% and 8% achieved the composite endpoints with a body weight reduction ≥5%, ≥10%, ≥15%, respectively (Fig 1A-1C, S5 Table). The odds ratios (95% confidence intervals) for achieving each composite endpoint in SURMOUNT-4 were 4.58 (2.91, 7.20), 6.05 (3.69, 9.94), and 7.29 (4.24, 12.53), respectively, for tirzepatide MTD vs placebo (all p<0.001).
Data included observed values. Missing endpoint measures were imputed by predictions using observed data in the efficacy analysis set from the same treatment group through an MMRM analysis model for post-baseline measures. (A) Proportions of participants achieving the triple composite endpoints of body weight reduction threshold ≥5% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL. (B) body weight reduction threshold ≥10% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL. (C) body weight reduction threshold ≥15% with systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL. **p<0.001 for tirzepatide versus placebo within each study, based on logistic regression. All pairwise comparisons across all trials and body weight reduction thresholds were statistically significant (all p<0.001). See S5 Table for trial-specific odds ratios, 95% confidence intervals, and p-values. aSURMOUNT-4 study design included a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period [14].
Safety
Across the population analyzed, at least one treatment-emergent adverse event was reported by 58–82% of participants treated with tirzepatide or placebo (Table 2). Other than coronavirus disease of 2019, the most frequently reported treatment-emergent adverse events were gastrointestinal-related, including nausea, diarrhea, and constipation.
Discussion
In this post hoc analysis of the SURMOUNT trials, triple composite endpoints—weight loss, lower systolic blood pressure, and reduced non-HDL-C—were assessed in participants with obesity or overweight, without and with type 2 diabetes. At weeks 72/88, 22–37% of participants treated with tirzepatide achieved body weight reduction thresholds ≥10% or ≥15%, systolic blood pressure reduction ≥5 mmHg and non-HDL-C <130 mg/dL compared with placebo.
Current guidelines suggest modest weight loss to reduce or prevent some obesity-related complications, while a reduction of body weight of 10% or more may resolve additional comorbidities [9,19]. This analysis higher body weight reduction thresholds to offer additional insight on participants who achieved these more intensive composite endpoints with tirzepatide. Because participants in the placebo group from SURMOUNT-4 received tirzepatide during the 36-week lead-in period before randomization, it was anticipated that this placebo group would perform better than the placebo groups in other SURMOUNT trials [14]. In the SURMOUNT trials, 41–87% of tirzepatide-treated participants achieved at least a 15% reduction in body weight, compared to 2–24% with placebo [11–14].
Obesity causally contributes to other cardiovascular risk factors, including dyslipidemia, type 2 diabetes, hypertension, and sleep disorders [20] and is strongly related to heart failure and kidney disease, regardless of diabetes status [21]. Thus, intentional reductions in body weight may offer the additional benefit of lowering multimorbidity progression and all-cause mortality [22,23]. Recently, the SURPASS-CVOT confirmed our observations in participants with T2D and atherosclerotic cardiovascular disease, which showed that tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke [24,25], providing further evidence of the potential cardioprotective effects of tirzepatide.
Herein, we report that up to 38% of participants with obesity or overweight, without and with type 2 diabetes, achieved the triple composite endpoint of body weight reduction thresholds (≥5%, ≥10%, ≥15%), systolic blood pressure reduction ≥5 mmHg, and non-HDL-C <130 mg/dL with tirzepatide. In the population reported herein, cardiometabolic parameters were relatively within normal range at baseline and comparable between those who did vs did not achieve each composite endpoint. This may, in part, influence the achievability of each composite endpoint. Therefore, understanding the baseline parameters and their impact on the individual components of the composite endpoint is key for accurate interpretation and analysis of the composite endpoint.
The association between excess adiposity and elevated blood pressure is widely recognized, with estimates indicating that obesity is responsible for approximately 65–78% of hypertension cases [26,27]. Results from a recent meta-analysis suggest that a reduction of 5 mmHg in systolic blood pressure may lower the risk of major cardiovascular events by ~10%, even in individuals who are within a normal range [17]. Similarly, abnormalities in lipid metabolism were observed in up to 70% of the adults living with obesity [28].
Non-HDL-C appears to be a more accurate indicator of cardiovascular death risk than low-density lipoprotein cholesterol (LDL-C) [29,30]. The optimal non-HDL-C level is 30 mg/dL higher than the desired LDL-C level [31]. For individuals with moderate-to-high risk for atherosclerotic cardiovascular disease (ASCVD), this translates to a non-HDL-C <130 mg/dL [31]. Among individuals with low 10-year ASCVD risk, non-HDL-C ≥160 mg/dL was significantly associated with cardiovascular disease and death due to coronary heart disease [32]. In this group, non-HDL-C levels between 130 and 160 mg/dL were linked to higher cardiovascular disease and coronary heart disease mortality, regardless of other risk factors [32]. Results of the current composite endpoint suggest a clinically meaningful response to therapy beyond the observed body weight reduction with tirzepatide.
Overall, the safety profile of the participants included in this analysis was similar to what was observed in the primary SURMOUNT studies [11–14]. Aside from coronavirus disease of 2019, the most frequently reported adverse events were gastrointestinal-related (nausea, diarrhea, constipation).
A limitation of this analysis was its post hoc nature, therefore not adjusted for multiplicity and is intended to be interpreted solely as exploratory and hypothesis-generating. Furthermore, as a composite endpoint assessing risk factors and absolute values together, caution is recommended in interpreting these results. Additional limitations of this analysis are the different trial designs and durations, including the 36-week open-labeled tirzepatide lead-in in SURMOUNT-4, and trial populations, including individuals without and with prediabetes or type 2 diabetes. However, results from the 72-week studies were generally consistent those observed at Week 88 in SURMOUNT-4. Systolic blood pressure and non-HDL-C in the study population were already relatively normal at baseline, which may have attenuated the observed improvement in these parameters and potentially limiting the generalizability of the results to a higher-risk population.
In conclusion, in this post hoc analysis of the SURMOUNT trials, a greater proportion of participants with obesity or overweight, without and with type 2 diabetes, treated with tirzepatide achieved clinically meaningful composite endpoints, including body thresholds ≥5%, ≥10%, and ≥15% with reductions in systolic blood pressure ≥5 mmHg and non-HDL-C <130 mg/dL than those treated with placebo. These findings may suggest an improvement in cardiometabolic risk factors along with clinically meaningful weight reductions associated with tirzepatide treatment. As current guidelines from major international societies evolve, there is greater focus on taking a complication-centric approach to weight management, where those with more severe/advanced comorbidities may warrant more aggressive care. Early intervention with obesity medications like tirzepatide, which can provide meaningful weight loss and potential improvement in cardiometabolic parameters may be considered for individuals living with obesity to mitigate cardiovascular risk. However, whether the improvements in cardiometabolic risk factors observed with tirzepatide treatment in the current analysis can impact morbidity and mortality in adults with obesity who are at risk of cardiovascular disease is currently being investigated in participants with obesity in the SURMOUNT-MMO trial (NCT05556512).
Supporting information
S1 Appendix. Additional statistical analysis methods.
https://doi.org/10.1371/journal.pone.0345032.s001
(DOCX)
S1 Table. Baseline demographics and clinical characteristics in participants who achieved the triple composite endpoint with body weight reduction ≥5% (Yes, No).
https://doi.org/10.1371/journal.pone.0345032.s003
(DOCX)
S2 Table. Baseline demographics and clinical characteristics in participants who achieved the triple composite endpoint with body weight reduction ≥10% (Yes, No).
https://doi.org/10.1371/journal.pone.0345032.s004
(DOCX)
S3 Table. Baseline demographics and clinical characteristics in participants who achieved the triple composite endpoint achieved with body weight reduction ≥15% (Yes, No).
https://doi.org/10.1371/journal.pone.0345032.s005
(DOCX)
S4 Table. Change from baseline in body weight, systolic blood pressure, and non-HDL-C at the primary endpoint in the SURMOUNT program.
https://doi.org/10.1371/journal.pone.0345032.s006
(DOCX)
S5 Table. Proportion of participants achieving the triple composite endpoint across the SURMOUNT program.
https://doi.org/10.1371/journal.pone.0345032.s007
(DOCX)
Acknowledgments
We thank Armen Zakharyan (TechData Service Company) for his contributions to data preparation and analysis.
References
- 1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet. 2024;403(10431):1027–50. pmid:38432237
- 2. Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15(5):288–98. pmid:30814686
- 3. Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376(3):254–66. pmid:28099824
- 4. Muscogiuri G, Pugliese G, Laudisio D, Castellucci B, Barrea L, Savastano S, et al. The impact of obesity on immune response to infection: plausible mechanisms and outcomes. Obes Rev. 2021;22(6):e13216. pmid:33719175
- 5. Nyberg ST, Batty GD, Pentti J, Virtanen M, Alfredsson L, Fransson EI, et al. Obesity and loss of disease-free years owing to major non-communicable diseases: a multicohort study. Lancet Public Health. 2018;3(10):e490–7. pmid:30177479
- 6. Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju S, Wormser D, Gao P, Kaptoge S, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;388(10046):776–86. pmid:27423262
- 7. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13–27. pmid:28604169
- 8. Kivimäki M, Strandberg T, Pentti J, Nyberg ST, Frank P, Jokela M, et al. Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. Lancet Diabetes Endocrinol. 2022;10(4):253–63. pmid:35248171
- 9. Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocrine Practice. 2016;22(Suppl 3):1–203. pmid:27219496
- 10. Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34(7):1481–6. pmid:21593294
- 11. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–16. pmid:35658024
- 12. Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613–26. pmid:37385275
- 13. Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023;29(11):2909–18. pmid:37840095
- 14. Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin W-Y, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38–48. pmid:38078870
- 15. Hu G, Ding J, Ryan DH. Trends in obesity prevalence and cardiometabolic risk factor control in US adults with diabetes, 1999-2020. Obesity. 2023;31(3):841–51. pmid:36697975
- 16. Lee MMY, Sattar N, Pop-Busui R, Deanfield J, Emerson SS, Inzucchi SE, et al. Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized trials. Diabetes Care. 2025;48(5):846–59. pmid:40156846
- 17. Blood Pressure Lowering Treatment Trialists’ Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet. 2021;397(10285):1625–36. pmid:33933205
- 18. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88. pmid:31504418
- 19. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985–3023. pmid:24239920
- 20. Powell-Wiley TM, Poirier P, Burke LE, Després J-P, Gordon-Larsen P, Lavie CJ, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143(21):e984–1010. pmid:33882682
- 21. Sattar N, Presslie C, Rutter MK, McGuire DK. Cardiovascular and kidney risks in individuals with type 2 diabetes: contemporary understanding with greater emphasis on excess adiposity. Diabetes Care. 2024;47(4):531–43. pmid:38412040
- 22. Sattar N, Lee MMY, McGuire DK. What the SELECT trial of semaglutide means for clinicians. Nat Med. 2024;30(7):1830–1. pmid:38796654
- 23. Kritchevsky SB, Beavers KM, Miller ME, Shea MK, Houston DK, Kitzman DW, et al. Intentional weight loss and all-cause mortality: a meta-analysis of randomized clinical trials. PLoS One. 2015;10(3):e0121993. pmid:25794148
- 24. Nicholls SJ, Pavo I, Bhatt DL, Buse JB, Del Prato S, Kahn SE, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med. 2025;393(24):2409–20. pmid:41406444
- 25. Sattar N, Gerstein HC, D’Alessio D, Bhatt DL, Buse JB, Del Prato S, et al. Estimating the true MACE benefits from tirzepatide in SURPASS-CVOT using an imputed placebo analysis of REWIND. Diabetes Care. 2026:dc260298. pmid:41940793
- 26. Garrison RJ, Kannel WB, Stokes J 3rd, Castelli WP. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med. 1987;16(2):235–51. pmid:3588564
- 27. Shariq OA, McKenzie TJ. Obesity-related hypertension: a review of pathophysiology, management, and the role of metabolic surgery. Gland Surg. 2020;9(1):80–93. pmid:32206601
- 28. Vekic J, Stefanovic A, Zeljkovic A. Obesity and dyslipidemia: a review of current evidence. Curr Obes Rep. 2023;12(3):207–22. pmid:37410248
- 29. Raja V, Aguiar C, Alsayed N, Chibber YS, ElBadawi H, Ezhov M, et al. Non-HDL-cholesterol in dyslipidemia: review of the state-of-the-art literature and outlook. Atherosclerosis. 2023;383:117312. pmid:37826864
- 30. Welsh C, Celis-Morales CA, Brown R, Mackay DF, Lewsey J, Mark PB, et al. Comparison of conventional lipoprotein tests and apolipoproteins in the prediction of cardiovascular disease. Circulation. 2019;140(7):542–52. pmid:31216866
- 31. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(Suppl 2):1–87. pmid:28437620
- 32. Abdullah SM, Defina LF, Leonard D, Barlow CE, Radford NB, Willis BL, et al. Long-term association of low-density lipoprotein cholesterol with cardiovascular mortality in individuals at low 10-year risk of atherosclerotic cardiovascular disease. Circulation. 2018;138(21):2315–25. pmid:30571575