PMID: 41284285 Obesityisachronicdiseaseassociatedwithelevatedrisk for cardiometabolic complications. The aims of obesity treatmentfocusnotonlyonreducingweightbut alsoonmitigatingweight-relatedcomplications.Currentguidelines recommend obesity management medications in combination with lifestyle intervention to achieve and maintain weightreductionandimprovecardiometabolicparametersin people living with obesity.1-4 Weight regain is typically observed after withdrawal ofpharmacotherapy,evenwithcontinuedlifestyleintervention,asshowninwithdrawalrandomized clinical trials of obesity management medications.5-7 Therefore, long-term treatment with obesity management medicationsmayberequiredtomaintainweightreductionand associated cardiometabolic benefits. Tirzepatide is a once-weeklyglucose-dependentinsulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for long-term treatment of obesity, obstructive sleepapnea,andtype2diabetes.8,9IntheSURMOUNT-4withdrawaltrial,tirzepatidetreatmentfor36weekswasassociated with improvementinanthropometricparameters(eg,weight, body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], and waist circumference [WC]) and in cardiometabolic parameters (eg, blood pressure [BP], lipid profile, hemoglobin A1c [HbA1c], fasting serum glucose [FSG], and fasting insulin) in adults with obesity or overweight with weight-related complications.7 Most participants randomizedtotheplaceboarmafter36weeksoftreatmentexperienced weight regain.7 In addition, tirzepatide withdrawal was associated with reversal of most of the initial improvementsinHbA1c,FSG,fastinginsulin,cholesterol,triglycerides, and BP achieved with tirzepatide treatment, despite continuedlifestyle intervention.7 The aim of this analysis was to evaluate the degree of weightregainexperiencedacrossSURMOUNT-4participants randomizedtowithdrawaloftirzepatideafter36weeksoftreatment and to assess associated changes in cardiometabolic parametersontirzepatidewithdrawalbythedegreeofweight regain. Methods StudyDesignandParticipants This is a post hoc analysis of the SURMOUNT-4 trial (ClinicalTrials.gov identifier: NCT04660643). The study design, participant eligibility criteria, and protocol have been published,7 and the trial protocol can be found in Supplement 1. Briefly, the SURMOUNT-4 trial was a phase 3 withdrawal randomized clinical trial with a 36-week, open-label tirzepatide lead-in period (week 0 to week 36), after which participants who achieved the maximum tolerated dose of tirzepatide (10 or 15 mg) were randomized 1:1 to either continue tirzepatide or switch to placebo for an additional 52-week, double-blind period (week 36 to week 88). This analysis focused on participants who were randomized to placebo and, therefore, stopped tirzepatide. Throughout the study, treatment was an adjunct to a reduced calorie diet (healthy 500 kcal per day deficit) and increased physical activity (at least 150 minutes E2 JAMAInternalMedicine PublishedonlineNovember 24,2025 (Reprinted) KeyPoints Question Doesthedegreeofweightregainfollowingtirzepatide withdrawal affect long-term cardiometabolic benefits in individuals with obesity or overweight? Findings Inthis post hocanalysis of theSURMOUNT-4 randomizedclinical trial including 308 participants, participants experienced weight reduction andimprovementin cardiometabolic parameters after a 36-week tirzepatide treatment. Oneyearafter tirzepatide withdrawal, a higher degree of weightregain wasassociated withagreaterreversal of initial improvementsinwaistcircumference, blood pressure, non–high-density lipoprotein cholesterol, glycemic parameters, andinsulin resistance. Meaning Inthisposthocanalysis,ontirzepatide withdrawal, greater reversal of initial cardiometabolic benefits was observed in participants who regained 25%ormoreoftheirinitial weight reduction vs those whodidnot. perweek).Eligibleparticipants wereadultswithaBMIof30or greater or of 27 or greater with at least 1 weight-related complication. Key exclusion criteria included diabetes, prior or planned surgical treatment for obesity, and treatment with a medicationthatpromotesweightreductionwithin3months prior to enrollment. Race and ethnicity were self-reported by participants using fixed selection categories (race: Asian, BlackorAfricanAmerican,NativeHawaiianorOtherPacificIslander, or White; ethnicity: Hispanic/Latino or non-Hispanic). However, the study was not designed to represent the racial diversity of the participating countries. Thestudy protocol was approved by local ethical review boards. Written informed consent wasobtainedfromallparticipants. This study was conducted according to local regulations and the International Conference on Harmonization GuidelinesforGoodClinicalPracticeandtheDeclarationofHelsinki. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. Procedures Participants were categorized by degree of weight regain from week 36 to week 88 after tirzepatide withdrawal. The degree of weight regain was assessed as a percentage of weight reduction from week 0 to week 36. The percentage of weight regain from week 36 to week 88 relative to weight reduction at week 36 was grouped into the following categories: less than 25%, 25% to less than 50%, 50% to less than 75%, and 75%ormore. Outcomes Outcomes included changes from week 36 to week 88 in weight, BMI, and cardiometabolic parameters by categories of weight regain from week 36 to week 88 relative to weight reduction at week 36. Cardiometabolic parameters included WC,systolic BP (SBP), diastolic BP (DBP), triglycerides, nonhigh-density lipoprotein (HDL) cholesterol, HDL cholesterol, HbA1c,FSG,fastinginsulin,andindexesofhomeostaticmodel assessmentofinsulinresistance(HOMA2-IR)andβ-cellfunction(HOMA2-B).Changesfromweek0toweek36andchanges jamainternalmedicine.com Downloaded from jamanetwork.com by guest on 11/25/2025Cardiometabolic Parameter ChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity over week 0 to week 88 in weight, BMI, and cardiometabolic parameters were also reported by categories of weight regain from week 36 to week88relative to weight reduction at week 36. Statistical Analysis This post hoc analysis was performed on the modified intentto-treat population, comprising all randomly assigned participants who were exposed to at least 1 dose of the study drug. The analysis only included tirzepatide-treated participants randomized to placebo who achieved 10% or more weight reduction at week 36 with the maximum tolerated dose of tirzepatide. The 10% cutoff was chosen to build an analysis population of clinically meaningful weight reduction. Most participants met this cutoff (308 of 335 participants). Only participants with a nonmissing week 36 weight measurement value and at least 1 nonmissing weight measurement value after week 36 were included in the analysis. Original Investigation Research (eFigure 1 in Supplement 2). Among the 308 participants assignedtoplacebo,266(86.4%)completedthestudyvisitatweek 88withanobservedweightmeasurement(eTable1inSupplement2).Of308includedparticipants,219(71.1%)werefemale, 89 (28.9%) were male, and the mean (SD) age was 47.1 (12.2) years. Baseline (week 0) demographic and clinical characteristics were similar across categories of weight regain from week 36 to week88(Table 1;eTable2inSupplement 2). There were nostatisticallysignificantdifferencesamongweightregaincategories for any of the variables at week 0. SummaryofWeightRegainatWeek88Relative to WeightReductionatWeek36 For the calculation of percentage of weight regain from week36toweek88relativetoweek36,missingweightmeasures at week 88 were imputed by predictions using observeddatathroughamixedmodelforrepeatedmeasuresadjusted for week 0 value, week 36 value, country, sex, and maximum tolerated dose of tirzepatide at week 36. All outcomeswereevaluatedwithineachcategoryofweightregain. Baseline demographic and clinical characteristics (at week0)andchangesfromweek0toweek36inclinicalcharacteristics were assessed using descriptive summary statistics. Continuous variables were presented as means and SDs and categorical variables were presented as counts and percentages. Pvaluesforcomparisonamongcategoriesofweightregain fromweek36toweek88werecomputedusinganalysis of variance incontinuousdataandχ2testincategoricaldata. Changesfromweek36toweek88andovertheentirestudy (week 0 to week 88) in clinical characteristics were assessed usingamixedmodelforrepeatedmeasuresadjustedforweek 0value,week36value,country,sex,andmaximumtolerated dose of tirzepatide at week 36. Fasting lipids, fasting insulin, HOMA2-IR,andHOMA2-Bwereanalyzedonlog-transformed dataduetotheirskeweddistributionsandthenconvertedback onthescale of percentage change. All results were presented asleast-squaresmeansandSEsor2-sided95%CIswithcorresponding P values. Statistical significance was defined as P <.05,andall Pvalues were 2-tailed. All analyses presented areexploratoryinnature.Statisticalanalyseswereperformed usingSASversion9.4(SASInstitute).Datawereanalyzedfrom February 2024toMarch2025. Results Participants Among the 335 participants from the modified intent-to-treat population who were randomized to the placebo arm in the SURMOUNT-4 study, 308 participants (with any weight measurementafterweek36)achievedatleast10%reductioninimputed weightbytheendofthe36-weekopen-labellead-inperiodwithtirzepatidetreatmentandwereincludedinthisanalysis jamainternalmedicine.com Awaterfallplotofthepercentageweightregainfromweek36 toweek88ontirzepatidewithdrawalisshownineFigure2in Supplement2.Ofthe308participantsincludedinthisanalysis, there were54participantsinthelessthan25%weightregain group, 77 in the 25% to less than 50% group, 103 in the 50%tolessthan75%group,and74inthe75%ormoregroup. Therefore, atweek88,254participants(82.5%)whostopped tirzepatide regained 25% or more of the initial weight reductionachievedatweek36and54(17.5%)regainedlessthan25%. ChangesinCardiometabolicParametersDuring theLead-InPeriod(Week0toWeek36) Thesummaryofchangesincardiometabolicparametersfrom week0toweek36duringthetirzepatidelead-intreatmentperiod bycategories of weightregainatweek88ispresentedin Table 2 and eTable 2 in Supplement 2. There was a decrease in weight,BMI,WC,SBP,DBP,triglycerides,non-HDLcholesterol, HDL cholesterol, HbA1c, FSG, fasting insulin, HOMA2IR, and HOMA2-B. There were statistically significant differences among categories of weight regain at week 88 for the changes from week 0 to week 36 in weight, BMI, and WC. Namely, greater weight regain at week 88, after 52 weeks of tirzepatide withdrawal, was associated with smaller initial reductions in weight, BMI, and WCatweek36aftercompletingthetirzepatide treatment period. There were no statistically significant differences among weight regain categories for the decreases from week0toweek36inBP,fastinglipids, HbA1c, FSG, fasting insulin, and HOMA2-IR. ChangesinCardiometabolicParametersDuring theRandomizedPeriod(Week36toWeek88) Thesummaryofchangesincardiometabolicparametersfrom week 36 to week 88 after tirzepatide withdrawal by categories of weight regain at week 88 is presented in Table 2 and eTable2inSupplement2.Changesovertimearedisplayedin Figure 1, Figure 2, and Figure 3. On tirzepatide withdrawal, greater weight regain at week 88wasassociatedwithgreater reversal of improvements in weight, BMI, WC, BP, triglycerides, non-HDL cholesterol, HbA1c, FSG, fasting insulin, and HOMA2-IR.Afterwithdrawal oftirzepatide, from week 36 to week88,themeanchangeinweightincreased by weight regaincategory(<25%weightregain,3.2%[95%CI,1.8-4.6];25% to <50%,11.7%[95%CI,10.5-12.9];50%to<75%,18.5%[95% CI, 17.1-19.9]; ≥75%, 22.9% [95% CI, 20.9-24.9]; P < .001), as (Reprinted) JAMAInternalMedicine PublishedonlineNovember 24,2025 E3 Downloaded from jamanetwork.com by guest on 11/25/2025didBMI(0.9[95%CI,0.5-1.3],3.3[95%CI,2.9-3.7],5.1[95% CI,4.7-5.5],and6.9[95%CI,6.3-7.5],respectively;P<.001), WC(0.8cm[95%CI,−1.0to2.6],5.4cm[95%CI,4.0-6.8],10.1 cm[95%CI,8.9-11.3],and14.7cm[95%CI,12.7-16.7],respecTable1.Baseline(Week0)DemographicandClinicalCharacteristicsbyCategoriesofWeightRegain inParticipantsRandomizedtoTirzepatideWithdrawala Characteristic Participants,No.(%) Pvalue Weightregainatweek88 Overall(N=308) <25%(n=54) ≥25to<50% (n=77) ≥50to<75% (n=103) ≥75%(n=74) Age,mean(SD),y 46.3(12.6) 46.4(14.3) 48.0(10.8) 47.1(11.5) 47.1(12.2) .80 Sex Female 36(66.7) 60(77.9) 74(71.8) 49(66.2) 219(71.1) .37 Male 18(33.3) 17(22.1) 29(28.2) 25(33.8) 89(28.9) Self-reportedrace Asian 5(9.3) 3(3.9) 10(9.7) 3(4.1) 21(6.8) .45 BlackorAfricanAmerican 4(7.4) 9(11.7) 11(10.7) 6(8.1) 30(9.7) NativeHawaiianorOtherPacificIslander 1(1.9) 0 0 0 1(0.3) White 44(81.5) 65(84.4) 80(77.7) 64(86.5) 253(82.1) Self-reportedethnicity HispanicorLatino 27(50.0) 38(49.4) 48(46.6) 29(39.2) 142(46.1) .55 Non-Hispanic 27(50.0) 39(50.6) 55(53.4) 45(60.8) 166(53.9) Maximumtolerateddoseoftirzepatideat week36beforewithdrawal,mg 10 2(3.7) 6(7.8) 5(4.9) 3(4.1) 16(5.2) .68 15 52(96.3) 71(92.2) 98(95.1) 71(95.9) 292(94.8) Durationofobesity,mean(SD),y 15.9(10.0) 14.4(12.5) 14.7(11.4) 14.4(9.5) 14.8(11.0) .86 Weight-relatedcomplications 0 18(33.3) 27(35.1) 29(28.2) 26(35.1) 100(32.5) .42 1-2 23(42.6) 33(42.9) 49(47.6) 31(41.9) 136(44.2) >2 13(24.1) 17(22.1) 25(24.3) 17(23.0) 72(23.4) Weight,mean(SD),kg 111.2(22.5) 107.5(26.9) 103.1(22.0) 107.7(20.2) 106.7(23.1) .19 BMI,mean(SD)b 39.2(6.6) 38.8(8.7) 37.4(6.1) 38.7(6.1) 38.4(7.0) .35 BMIcategory ≥25to<30 0 2(2.6) 3(2.9) 1(1.4) 6(1.9) .58 ≥30to<35 17(31.5) 25(32.5) 40(38.8) 23(31.1) 105(34.1) ≥35to<40 13(24.1) 25(32.5) 33(32.0) 24(32.4) 95(30.8) ≥40 24(44.4) 25(32.5) 27(26.2) 26(35.1) 102(33.1) Waistcircumference,mean(SD),cm 116.6(14.3) 114.2(14.5) 113.0(15.5) 117.0(13.9) 114.9(14.7) .27 Bloodpressure,mean(SD),mmHg Systolic 124.3(12.1) 126.1(13.6) 125.3(12.4) 124.3(12.8) 125.1(12.7) .78 Diastolic 79.2(7.9) 81.6(7.6) 82.0(8.5) 80.9(7.7) 81.1(8.0) .21 Pulserate,mean(SD),beats/min 72.4(9.6) 74.7(9.1) 73.0(9.2) 71.6(8.4) 73.0(9.1) .20 Triglycerides,mean(SD),mg/dL 125.5(60.6) 126.8(66.4) 142.0(123.1) 127.2(77.2) 131.8(90.7) .58 Non–HDL-C,mean(SD),mg/dL 139.6(38.4) 139.2(32.0) 147.4(40.2) 135.8(34.2) 141.2(36.7) .18 HDL-C,mean(SD),mg/dL 51.1(11.1) 52.4(12.9) 50.1(13.6) 53.6(14.4) 51.7(13.2) .34 HemoglobinA1c,mean(SD),% 5.6(0.4) 5.5(0.4) 5.5(0.4) 5.5(0.4) 5.5(0.4) .23 HemoglobinA1ccategory <5.7% 28(51.9) 51(66.2) 69(67.0) 50(67.6) 198(64.3) .22 ≥5.7% 26(48.1) 26(33.8) 34(33.0) 24(32.4) 110(35.7) Fastingglucose,mean(SD),mg/dL 93.1(11.5) 94.6(11.7) 93.9(10.0) 94.4(10.2) 94.0(10.7) .87 Fastinginsulin,mean(SD),μIU/mL 13.6(11.1) 13.5(10.7) 13.8(9.8) 13.0(11.6) 13.5(10.6) .96 Abbreviations:BMI,bodymassindex;HDL-C,high-densitylipoprotein cholesterol. SIconversions:Toconverttriglyceridestommol/L,multiplyby0.0113; HDL-Ctommol/L,multiplyby0.0259;hemoglobinA1ctoproportionoftotal hemoglobin,multiplyby0.01;glucosetommol/L,multiplyby0.055;insulinto pmol/L,multiplyby6.945. aDatainparticipantswith 10%weightreductionatweek36(randomization). bCalculatedasweightinkilogramsdividedbyheightinmeterssquared. Research OriginalInvestigation CardiometabolicParameterChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity E4 JAMAInternalMedicine PublishedonlineNovember24,2025 (Reprinted) jamainternalmedicine.com Downloaded from jamanetwork.com by guest on 11/25/2025Table2.ClinicalCharacteristicsatWeek36(Randomization)andWeek88byCategoriesofWeightRegain inParticipantsRandomizedtoTirzepatideWithdrawala Outcome Weightregainatweek88 Overall(N=308) Pvalue <25%(n=54) ≥25to<50% (n=77) ≥50to<75% (n=103) ≥75%(n=74) Weight,kg Week36,mean(SD) 85.1(19.8) 82.7(22.8) 80.2(19.5) 88.1(18.8) 83.6(20.4) .07 Percentagechangefromweek0to week36,mean(SD) −23.6(7.2) −23.4(6.3) −22.6(6.1) −18.3(5.7) −21.9(6.6) <.001 Week88,LSM(95%CI) 87.2(86.0to88.4) 91.5(90.7to92.3) 94.5(93.5to95.5) 107.0(105.6to 108.4) 95.5(94.5to96.5) NA Percentagechangefromweek36to week88,LSM(95%CI) 3.2(1.8to4.6)b 11.7(10.5to 12.9)b 18.5(17.1to 19.9)b 22.9(20.9to 24.9)b 15.1(13.9to 16.3)b <.001 BMIc Week36,mean(SD) 29.9(5.9) 29.8(7.3) 29.0(5.8) 31.6(5.9) 30.0(6.3) .05 Changefromweek0toweek36,mean (SD) −9.2(3.1) −9.0(3.1) −8.3(2.3) −7.0(2.3) −8.3(2.8) <.001 Week88,LSM(95%CI) 30.6(30.2to31.0) 33.1(32.7to33.5) 34.1(33.7to34.5) 38.6(38.0to39.2) 34.3(33.9to34.7) NA Changefromweek36toweek88,LSM (95%CI) 0.9(0.5to1.3)b 3.3(2.9to3.7)b 5.1(4.7to5.5)b 6.9(6.3to7.5)b 4.4(4.0to4.8)b <.001 Waistcircumference,cm Week36,mean(SD) 97.0(14.6) 94.2(15.4) 95.2(14.8) 100.8(14.3) 96.6(15.0) .03 Changefromweek0toweek36,mean (SD) −19.6(9.1) −20.0(7.4) −17.9(7.9) −16.2(8.5) −18.3(8.2) .02 Week88,LSM(95%CI) 97.6(95.8to99.4) 99.4(98.0to 100.8) 105.3(104.1to 106.5) 115.0(113.0to 117.0) 104.8(103.8to 105.8) NA Changefromweek36toweek88,LSM (95%CI) 0.8(−1.0to2.6) 5.4(4.0to6.8)b 10.1(8.9to11.3)b 14.7(12.7to 16.7)b 8.4(7.4to9.4)b <.001 Systolicbloodpressure,mmHg Week36,mean(SD) 113.7(12.8) 113.8(11.8) 114.9(12.6) 114.4(10.7) 114.3(12.0) .92 Changefromweek0toweek36,mean (SD) −10.6(12.4) −12.3(13.0) −10.5(12.7) −9.9(12.5) −10.8(12.6) .67 Week88,LSM(95%CI) 120.4(117.5to 123.3) 121.3(118.8to 123.8) 124.6(122.1to 127.1) 124.5(122.1to 126.9) 123.0(121.6to 124.4) NA Changefromweek36toweek88,LSM (95%CI) 6.8(3.9to9.7)b 7.3(4.8to9.8)b 9.6(7.1to12.1)b 10.4(8.0to12.8)b 8.7(7.3to10.1)b .002 Diastolicbloodpressure,mmHg Week36,mean(SD) 73.9(8.8) 76.0(8.7) 77.3(8.2) 76.5(8.9) 76.2(8.6) .13 Changefromweek0toweek36,mean (SD) −5.3(7.5) −5.6(8.5) −4.7(10.1) −4.3(9.0) −5.0(9.0) .83 Week88,LSM(95%CI) 76.8(74.6to79.0) 77.7(75.9to79.5) 81.2(79.4to83.0) 80.4(78.6to82.2) 79.3(78.3to80.3) NA Changefromweek36toweek88,LSM (95%CI) 2.8(0.6to5.0)d 1.6(−0.2to3.4) 3.9(2.1to5.7)b 4.3(2.5to6.1)b 3.2(2.2to4.2)b <.001 Pulserate,beats/min Week36,mean(SD) 77.7(9.0) 78.0(7.6) 77.9(9.7) 78.1(9.2) 77.9(9.0) 1.00 Changefromweek0toweek36,mean (SD) 5.4(9.7) 3.3(8.3) 4.9(9.1) 6.5(8.4) 5.0(8.9) .18 Week88,LSM(95%CI) 72.5(70.2to74.8) 71.2(69.5to72.9) 71.9(70.2to73.6) 73.7(71.9to75.5) 72.3(71.3to73.2) NA Changefromweek36toweek88,LSM (95%CI) −5.4(−7.7to −3.1)b −6.7(−8.4to −5.0)b −5.7(−7.4to −4.0)b −4.2(−6.0to −2.4)b −5.5(−6.5to −4.6)b .50 Triglycerides,mg/dLe Week36,mean(SD) 85.7(31.0) 89.7(38.9) 88.6(40.7) 102.0(58.2) 91.6(43.9) .12 Changefromweek0toweek36,mean (SD) −39.8(45.0) −37.2(51.6) −53.4(93.4) −25.2(58.2) −40.2(69.5) .06 Week88,LSM(95%CI) 84.7(74.9to94.5) 87.6(80.9to94.3) 104.6(97.0to 112.2) 109.2(99.8to 118.6) 97.4(93.1to 101.7) NA Percentagechangefromweek36to week88,LSM(95%CI) 5.5(−6.7to17.7) 5.3(−2.7to13.3) 29.6(20.2to 39.0)b 18.9(8.7to29.1)b 16.1(11.0to 21.2)b NA Non–HDL-C,mg/dLe Week36,mean(SD) 129.4(41.7) 129.4(31.4) 133.9(37.9) 130.5(31.4) 131.2(35.5) .81 Changefromweek0toweek36,mean (SD) −10.2(32.6) −9.8(29.0) −13.4(30.0) −5.3(23.7) −10.0(28.9) .33 Week88,LSM(95%CI) 124.9(116.3to 133.5) 128.3(123.2to 133.4) 138.4(132.5to 144.3) 139.2(132.3to 146.1) 133.6(130.3to 136.9) NA Percentagechangefromweek36to week88,LSM(95%CI) −0.4(−7.3to6.5) 1.6(−2.3to5.5) 8.4(3.9to12.9)b 10.8(5.3to16.3)b 5.6(3.1to8.1)b NA (continued) CardiometabolicParameterChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity OriginalInvestigation Research jamainternalmedicine.com (Reprinted) JAMAInternalMedicine PublishedonlineNovember24,2025 E5 Downloaded from jamanetwork.com by guest on 11/25/2025tively;P<.001),SBP(6.8mmHg[95%CI,3.9-9.7],7.3mmHg [95%CI,4.8-9.8],9.6mmHg[95%CI,7.1-12.1],and10.4mm Hg[95%CI,8.0-12.8],respectively;P=.002),DBP(2.8mmHg [95%CI,0.6-5.0],1.6mmHg[95%CI,−0.2to3.4],3.9mmHg [95%CI,2.1-5.7],and4.3mmHg[95%CI,2.5-6.1],respectively;P<.001),triglycerides(5.5%[95%CI,−6.7to17.7],5.3% [95%CI,−2.7to13.3],29.6%[95%CI,20.2to39.0],and18.9% [95%CI,8.7to29.1],respectively),non-HDLcholesterol(−0.4% [95%CI,−7.3to6.5],1.6%[95%CI,−2.3to5.5],8.4%[95%CI, 3.9-12.9],and10.8%[95%CI,5.3-16.3],respectively),HbA1c (0.14%[95%CI,0.06-0.22],0.15%[95%CI,0.09-0.21],0.27% [95%CI,0.21-0.33],and0.35%[95%CI,0.29-0.41],respectively;P<.001),FSG(3.8mg/dL[95%CI,1.6-6.0],6.9mg/dL [95%CI,5.1-8.7],9.2mg/dL[95%CI,7.0-11.4],and9.0mg/dL [95%CI,7.0-11.0],respectively;P<.001),fastinginsulin(−4.0% [95%CI,−20.7to12.7],15.4%[95%CI,2.3-28.5],46.2%[95% CI,29.5-62.9],and26.3%[95%CI,9.6-43.0],respectively),and HOMA2-IR(0.6%[SE,5.07],12.6%[SE,4.39],39.5%[SE,5.44], and27.0%[SE,5.49],respectively).Changesatweek88in WC,triglycerides,non-HDLcholesterol,fastinginsulin,and HOMA2-IRinparticipantswithlessthan25%weightregain werenotsignificantlydifferentcomparedwithweek36. Ofnote,astatisticallysignificantmeanincreasefromweek 36toweek88inHDLcholesterolwasobservedacrossallcategoriesofweightregain(<25%weightregain,19.7%[95%CI, 13.8-25.6];25%to<50%,16.7%[95%CI,12.6-20.8];50%to <75%,13.6%[95%CI,9.7-17.5];≥75%,13.4%[95%CI,9.317.5];P≤.001)(Table2).Ontheotherhand,astatisticallysignificantdecreasefromweek36toweek88inHOMA2-Bwas observedforthelessthan25%andthe25%tolessthan50% weightregaincategories(eTable2inSupplement2). ChangesinCardiometabolicParametersOver theEntireStudy(Week0toWeek88) Changesincardiometabolicparametersovertheentirestudy (week0toweek88)bycategoriesofweightregainatweek88 areshownineFigures3to6inSupplement2.Overall,atweek 88,participantswith75%ormoreweightregainaftertirzepatidewithdrawalreversedcardiometabolicparameterstobaseline(week0)values.Participantswithlessthan25%and25% Table2.ClinicalCharacteristicsatWeek36(Randomization)andWeek88byCategoriesofWeightRegain inParticipantsRandomizedtoTirzepatideWithdrawala(continued) Outcome Weightregainatweek88 Overall(N=308) Pvalue <25%(n=54) ≥25to<50% (n=77) ≥50to<75% (n=103) ≥75%(n=74) HDL-C,mg/dLe Week36,mean(SD) 47.2(11.8) 50.3(11.5) 48.0(11.6) 49.5(11.7) 48.8(11.7) .39 Changefromweek0toweek36,mean (SD) −3.9(8.9) −2.1(8.0) −2.1(8.0) −4.1(7.9) −2.9(8.1) .24 Week88,LSM(95%CI) 55.9(53.2to58.6) 57.7(55.5to59.9) 53.8(52.0to55.6) 54.0(52.0to56.0) 55.2(54.2to56.2) NA Percentagechangefromweek36to week88,LSM(95%CI) 19.7(13.8to 25.6)b 16.7(12.6to 20.8)b 13.6(9.7to17.5)b 13.4(9.3to17.5)b 15.4(13.2to 17.6)b NA HemoglobinA1c,% Week36,mean(SD) 5.1(0.3) 5.0(0.3) 5.0(0.3) 5.0(0.4) 5.0(0.3) .54 Changefromweek0toweek36,mean (SD) −0.51(0.25) −0.41(0.28) −0.51(0.27) −0.46(0.23) −0.47(0.26) .07 Week88,LSM(95%CI) 5.2(5.1to5.3) 5.2(5.1to5.3) 5.3(5.2to5.4) 5.4(5.3to5.5) 5.3(5.26to5.34) NA Changefromweek36toweek88,LSM (95%CI) 0.14(0.06to 0.22)b 0.15(0.09to 0.21)b 0.27(0.21to 0.33)b 0.35(0.29to 0.41)b 0.24(0.20to 0.28)b <.001 Fastingglucose,mg/dL Week36,mean(SD) 85.6(7.7) 84.6(7.8) 83.6(7.3) 85.5(7.1) 84.7(7.5) .29 Changefromweek0toweek36,mean (SD) −7.5(9.8) −10.0(10.5) −10.3(9.1) −9.0(9.6) −9.4(9.7) .36 Week88,LSM(95%CI) 89.2(87.0to91.4) 92.1(90.3to93.9) 92.8(90.6to95.0) 94.3(92.3to96.3) 92.3(91.3to93.3) NA Changefromweek36toweek88,LSM (95%CI) 3.8(1.6to6.0)b 6.9(5.1to8.7)b 9.2(7.0to11.4)b 9.0(7.0to11.0)b 7.6(6.6to8.6)b <.001 Fastinginsulin,μIU/mLe Week36,mean(SD) 7.5(6.3) 7.1(5.6) 6.9(5.3) 8.8(4.9) 7.5(5.5) .13 Changefromweek0toweek36,mean (SD) −6.5(7.6) −6.4(8.3) −6.8(9.0) −4.2(9.6) −6.0(8.8) .24 Week88,LSM(95%CI) 5.6(4.6to6.6) 6.2(5.4to7.0) 8.0(7.0to9.0) 9.6(8.4to10.8) 7.4(6.8to8.0) NA Percentagechangefromweek36to week88,LSM(95%CI) −4.0(−20.7to 12.7) 15.4(2.3to28.5)d 46.2(29.5to 62.9)b 26.3(9.6to43.0)b 23.3(15.1to 31.5)b NA Abbreviations:BMI,bodymassindex;HDL-C,high-densitylipoprotein cholesterol;LSM,least-squaresmean;NA,notapplicable. SIconversions:Toconverttriglyceridestommol/L,multiplyby0.0113; HDL-Ctommol/L,multiplyby0.0259;hemoglobinA1ctoproportionoftotal hemoglobin,multiplyby0.01;glucosetommol/L,multiplyby0.055;insulinto pmol/L,multiplyby6.945. aDatainparticipantswith10%ormoreweightreductionatweek36. bP .001vsweek36. cCalculatedasweightinkilogramsdividedbyheightinmeterssquared. dP<.05vsweek36. eFastinglipidsandinsulinatweek88andpercentagechangefromweek36to week88wereanalyzedonlog-transformeddataandthenconvertedbackon thescaleofpercentagechange.Nostatisticalcomparisonamongweight regaincategoriesavailableforfastinglipidsandinsulinatweek88and percentagechangefromweek36toweek88. Research OriginalInvestigation CardiometabolicParameterChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity E6 JAMAInternalMedicine PublishedonlineNovember24,2025 (Reprinted) jamainternalmedicine.com Downloaded from jamanetwork.com by guest on 11/25/2025tolessthan50%weightregainhadsignificantlylowervalues thanbaselineatweek88inWC,SBP,DBP,triglycerides,nonHDLcholesterol,HbA1c,FSG,andfastinginsulin. Ofnote,asignificantincreasefrombaselinetoweek88in HDLcholesterolwasobservedacrossallcategoriesofweight regain(eFigure5CinSupplement2). Figure1.ChangeinWeight,BodyMassIndex(BMI),andWaistCircumferencebyCategories ofWeightRegainonTirzepatideWithdrawal 0 0 0 Percentage change in weight (week 36-88) A Participants, No. 36 54 77 103 74 40 53 77 103 74 52 54 72 98 70 52 70 91 67 64 49 67 88 65 76 46 68 86 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in weight, % 30 20 10 22.9a 18.5a 11.7a 3.2a Time, wk Change in BMI (week 36-88) B Participants, No. 36 54 77 103 74 40 53 77 103 74 52 54 72 98 70 52 70 91 67 64 49 67 88 65 76 46 68 86 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in BMI 8 4 6 2 6.9a 5.1a 3.3a 0.9a Time, wk Change in waist circumference (week 36-88) C Participants, No. 36 54 77 103 74 40 53 76 103 73 52 54 72 98 71 52 70 91 67 64 49 67 88 65 76 46 68 86 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in waist circumference, cm 20 10 5 15–5 14.7a 10.1a 5.4a 0.8 Time, wk Overall mean (SD) weight at week 36, 83.6 (20.4) kg Overall mean (SD) BMI at week 36, 30.0 (6.3) Overall mean (SD) waist circumference at week 36, 96.6 (15.0) cm <25% Weight regain ≥25%-<50% Weight regain ≥50%-<75% Weight regain ≥75% Weight regain Datainparticipantsrandomizedto tirzepatidewithdrawalwith10%or moreweightreductionatweek36. Week0toweek36wasthe tirzepatidelead-inperiod.Week36to week88wasthetirzepatide withdrawalperiod.Dataare least-squaresmeans;errorbars indicateSEs.Statisticalsignificance wasobservedamongweightregain categoriesforweight,BMI(calculated asweightinkilogramsdividedby heightinmeterssquared),andwaist circumference. aP .001vsweek36. CardiometabolicParameterChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity OriginalInvestigation Research jamainternalmedicine.com (Reprinted) JAMAInternalMedicine PublishedonlineNovember24,2025 E7 Downloaded from jamanetwork.com by guest on 11/25/2025Discussion Thisposthocanalysisevaluatedtheassociationbetweenthe degreeofweightregainandcardiometabolicparameterson withdrawaloftirzepatideinparticipantswhoachievedclinicallymeaningful(≥10%)weightreductionduringthe36-week tirzepatidelead-intreatmentintheSURMOUNT-4trial.As expectedandinlinewithsimilarresearchwithobesitymanagementmedications,5-7withdrawaloftirzepatideledtomost participantsregainingweightdespitecontinuedlifestyle intervention.Interestingly,themagnitudeofweightregain following1yearoftirzepatidewithdrawalvariedwidely.For example,wefoundthatmostparticipants(254[82.5%])had regained25%ormoreoftheinitialweightreductionachieved duringthe36-weektirzepatidelead-intreatment.Weight regainof25%ormoreofinitialweightreductionhasclinical relevancegiventheevidencetodatesuggestingthelossof cardiometabolicbenefitatorbeyondthislevelofweight regain.10,11Furthermore,approximately1in2participants haveregained50%ormoreoftheweightreductionand1in4 regainedmost(≥75%)oftheweightreduction,withalmost 9%ofparticipantsexperiencingmorethan100%weight regain.Ontheotherhand,asmallfractionoftheparticipants (54[17.5%])experiencedlimitedweightregain(<25%)on withdrawaloftirzepatideandwithcontinuedlifestylemodification.Approximately4%ofparticipantscontinuedtolose weightonwithdrawaloftirzepatideandcontinuedlifestyle intervention.Therewerenoapparentdifferencesinbaseline demographicandclinicalcharacteristicsofparticipantsacross thedifferentcategoriesofweightregain.Combined,most participantsregainedweightonwithdrawaloftirzepatide, andtherewasaheterogeneityinthedifferentmagnitudesof weightregainobservedacrosstheparticipants,likelyrelated todifferentfactorsunderlyingthepathophysiologyofobesity andtreatmentresponse. Overall,greaterweightregainontirzepatidewithdrawal wasassociatedwithagreaterreversalofimprovementsincardiometabolicparameters,includingWC,BP,lipids,andHbA1c withtirzepatidetreatment.Thisobservationisconsistentwith thefindingsobservedwithlifestyleinterventionintheLook AHEADtrial10andwiththewithdrawalofglucagon-likepepFigure2.ChangeinBloodPressurebyCategoriesofWeightRegainonTirzepatideWithdrawal–4 0 Change in systolic blood pressure (week 36-88) A Participants, No. 52 54 72 98 72 40 53 77 103 73 36 54 77 103 74 52 70 91 67 64 49 68 88 64 76 46 68 85 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in systolic blood pressure, mm Hg 15 10 5 10.4a 9.6a 7.3a 6.8a 4.3a 3.9a 2.8b 1.6 Time, wk Change in diastolic blood pressure (week 36-88) B Participants, No. 36 54 77 103 74 40 53 77 103 73 52 54 72 98 72 52 70 91 67 64 49 68 88 64 76 46 68 85 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in diastolic blood pressure, mm Hg 8 0 2 4 6–2 Time, wk Overall mean (SD) systolic blood pressure at week 36, 114.3 (12.0) mm Hg Overall mean (SD) diastolic blood pressure at week 36, 76.2 (8.6) mm Hg <25% Weight regain ≥25%-<50% Weight regain ≥50%-<75% Weight regain ≥75% Weight regain Datainparticipantsrandomizedto tirzepatidewithdrawalwith10%or moreweightreductionatweek36. Week0toweek36wasthe tirzepatidelead-inperiod.Week36to week88wasthetirzepatide withdrawalperiod.Dataare least-squaresmeans;errorbars indicateSEs.Statisticalsignificance wasobservedamongweightregain categoriesforsystolicbloodpressure anddiastolicbloodpressure. aP .001vsweek36. bP<.05vsweek36. Research OriginalInvestigation CardiometabolicParameterChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity E8 JAMAInternalMedicine PublishedonlineNovember24,2025 (Reprinted) jamainternalmedicine.com Downloaded from jamanetwork.com by guest on 11/25/2025tide-1receptoragonistsemaglutide,2.4mg,intheSTEP1trial extension.11IntheSURMOUNT-4trial,participantswhomaintainedtheweightreduction(<25%weightregain)atweek88 alsomaintainedonaveragethebenefitsgainedincentraladiposity,triglycerides,non-HDLcholesterol,fastinginsulin,and insulinresistance.Inanotherstudy,repeatedcyclesofweight reductionandweightregainmaybedetrimentaltohealth,as theregainedweightafterintentionalweightreductionmaybe Figure3.ChangeinGlycemicParametersbyCategoriesofWeightRegainonTirzepatideWithdrawal 0 0 0 Change in HbA1c (week 36-88) A Participants, No. 36 53 72 99 72 52 53 70 98 71 52 69 91 63 64 49 67 84 64 76 46 67 85 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in HbA1c, % 0.5 0.4 0.3 0.2 0.1 0.35a 0.27a 0.15a 0.14a Time, wk Change in FSG (week 36-88) B Participants, No. 36 53 71 99 72 52 53 70 98 69 50 68 88 60 64 49 67 84 63 76 46 68 85 66 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in FSG, mg/dL 15 10 5 9.0a 9.2a 6.9a 3.8a Time, wk Percentage change in fasting insulin (week 36-88) C Participants, No. 36 53 72 99 72 52 52 70 98 70 52 68 89 65 64 47 68 85 63 76 46 66 84 65 88 <25% ≥25%-<50% ≥50%-<75% ≥75% Change from week 36 in fasting insulin, % 60 20 40–20 46.2a 26.3a 15.4b–4.0 Time, wk Overall mean (SD) HbA1c at week 36, 5.0% (0.3%) Overall mean (SD) FSG at week 36, 84.7 (7.5) mg/dL Overall mean (SD) fasting insulin at week 36, 7.5 (5.5) mIU/L <25% Weight regain ≥25%-<50% Weight regain ≥50%-<75% Weight regain ≥75% Weight regain Datainparticipantsrandomizedto tirzepatidewithdrawalwith10%or moreweightreductionatweek36. Week0toweek36wasthe tirzepatidelead-inperiod.Week36to week88wasthetirzepatide withdrawalperiod.Dataare least-squaresmeansforhemoglobin A1c(HbA1c)andfastingserumglucose (FSG)andestimatesforfasting insulin;errorbarsindicateSEs. Fastinginsulinwasanalyzedon log-transformeddataandthen convertedbackonthescaleof percentagechange.Statistical significancewasobservedamong weightregaincategoriesforHbA1c andFSG.Nostatisticalcomparison amongweightregaincategorieswas availableforfastinginsulin.To convertHbA1ctoproportionoftotal hemoglobin,multiplyby0.01; glucosetommol/L,multiplyby 0.055;insulintopmol/L,multiplyby 6.945. aP .001vsweek36. bP<.05vsweek36. CardiometabolicParameterChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity OriginalInvestigation Research jamainternalmedicine.com (Reprinted) JAMAInternalMedicine PublishedonlineNovember24,2025 E9 Downloaded from jamanetwork.com by guest on 11/25/2025Research OriginalInvestigation Cardiometabolic Parameter ChangebyWeightRegainonTirzepatideWithdrawalinAdultsWithObesity proportionally higher in fat mass, thus potentially impacting thebodycompositioninanunhealthyway.12Combined,these observations support the health benefits of sustained, longterm treatment of obesity. Theimpactonlipidparameters,includingtriglyceridesand non-HDL,withtirzepatidewithdrawalwasasexpected.Forexample,thereversalofimprovementintriglyceridesandnonHDLontirzepatidewithdrawalwassignificantlygreaterinparticipants who regained a substantial amount (≥50%) of their initial weight reduction. On the other hand, a mean reduction in HDL cholesterol was observed with tirzepatide treatmentfollowedbyastatisticallysignificantincreaseinHDLcholesterol ontirzepatidewithdrawal.Thetransitorydecreasein HDL cholesterol with weight reduction and subsequent increase reverting the initial effect has previously been observed in people reducing weight through diet.13 Further insights ontheeffectoftirzepatide-inducedweightchangeson HDLcholesterol changes are currently being investigated. Additionally, SBP significantly increased on withdrawal of tirzepatideacrossallcategoriesofweightregain,withhigherincreaseobservedwithgreatermagnitudesofweightregain.Previous analyses of the SURPASS clinical trials and the SURMOUNT-1 ambulatory BP monitoring substudy reported a decreaseinSBPwithtirzepatidetreatmentinparticipantswith type2diabetesand/orobesity.14,15TheimprovementinBPwith tirzepatide treatment and subsequent deterioration on withdrawaloftirzepatideislikelyrelatedtobothweight-dependent andweight-independentmechanisms.14Theproposedweightindependent mechanisms for the effect of incretins on BP include reduction in sympathetic activity, a natriuretic effect throughtheinhibitionofreninangiotensinaldosteronesystem andsubsequentinhibitionofthesodiumreabsorptionatthelevel of the kidneys, and a beneficial effect on vascular remodeling and on endothelial function.16 However, further studies are neededtounderstandthesemechanisms. Notably,thereversalinglycemicbenefitsinHbA1candFSG were observed early on within 16 weeksofwithdrawingtirzepatide likely due to the known direct glucose-lowering effect of tirzepatide, and as expected, the magnitude of reversal in HbA1c improvementwasgreaterwithhigherdegreesof weight regain.17,18 Similarly, there was a trend for greater reversalintheimprovementinmarkersofinsulinresistance,such as fasting insulin and HOMA2-IR, with higher magnitudes of weight regain on tirzepatide withdrawal. On the other hand, a marker of β-cell function, HOMA2-B, decreased with tirzepatide treatment and decreased further with withdrawal of tirzepatide. This observation is in contrast to previously reportedposthocstudiesoftirzepatideinadultswithtype2diabetes and obesity, where a significant increase in HOMA2-B withtirzepatide treatmentwasobserved.19,20Therefore,further studies are warranted to confirm the observations with regard to insulin resistance and pancreatic β-cell function in adults with obesity. Finally, although some improvement from baseline was still observed in all assessed cardiometabolic parameters despite partial weight regain of up to 50% after 1 year of tirzepatide withdrawal, these findings support the importance of long-term maintenance of weight reduction through lifestyle intervention and obesity management medications to sustain cardiometabolic benefits and improved health-related quality of life.6,11,21,22 Together, these results may inform patientclinician conversations and shared decision-making on longterm weight management focused on sustained health benefits and help counsel patients on the implications of treatment discontinuation. Future studies are warranted to evaluate and optimize strategies for maintenance of weight reduction. Strengths andLimitations Strengths of this analysis included the randomized withdrawal design of the SURMOUNT-4 trial with continued lifestyle intervention in the placebo arm,highstudycompletion rate, a widerangeofweightregainobservedaftertirzepatide withdrawal(whichallowedforcategoricalevaluationofweight regain), and long-term follow-up data over 52 weeks to observechangesinanthropometricsandcardiometabolicparameters. Limitations included the post hoc nature of the analysis, lack of data on the impact on body composition, and objective measures on physical activity and diet to correlate withthisanalysis.Inaddition,longertimeisneededtodetermineif thepreserved benefits seen with lower weight regain would eventually be lost, and the categorical evaluation of weight regain may nothaveallowedfor amoredetailed look at theweightregaincutoffassociatedwithreversalofcardiometabolic benefits from weight reduction. Conclusions In this post hoc analysis of the SURMOUNT-4trial, mostparticipants (82%) among those who achieved clinically meaningful weight reduction with tirzepatide treatment regained 25%ormoreoftheirinitial weight reduction within 1 year of withdrawing tirzepatide. Higher weight regain on withdrawaloftirzepatidewasassociatedwithagreaterreversalof improvements in cardiometabolic parameters achieved with tirzepatidetreatment.Thesefindingssupporttheneedforcontinued obesity treatment in adults living with obesity.