Evidence reference only. Not medical advice, not a dosing guide, and not a recommendation to use any drug.
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Maintenance and regain

13 findings across 7 drug records. Domain pages are descriptive indexes, not advice.

Most represented records

GLP-1 RA class (3)

Weight-loss Physiology (drug-agnostic) (2)

Retatrutide (2)

Semaglutide (2)

Tirzepatide (2)

Evidence spread

High evidence 0 Moderate evidence 6 Low evidence 5 Very low evidence 2

Weight-loss Physiology (drug-agnostic) MARKETED
Maintenance and regain Increase
Moderate evidence

MECHANISM (set-point / why regain happens): one year after diet-induced weight loss, circulating appetite-regulating hormones remained shifted in a direction that...

Sumithran P, Prendergast LA, Delbridge E et al., N Engl J Med, 2011 Source
Full findingMECHANISM (set-point / why regain happens): one year after diet-induced weight loss, circulating appetite-regulating hormones remained shifted in a direction that favours regain (ghrelin up; leptin/PYY/CCK/insulin down) and had NOT reverted, with persistently increased hunger. The foundational human evidence that the body defends a higher weight via a durable orexigenic state.
PopulationSumithran/Proietto (NCT00870259): N=50 overweight/obese adults without diabetes; 10-week very-low-energy diet; hormones at baseline, 10 wk, 62 wk.
Fundingacademic/government - Australian NHMRC and others (not industry)
Scope limitssmall sample (N~50)
Comparatorswithin-subject baseline
Weight-loss Physiology (drug-agnostic) MARKETED
Maintenance and regain Decrease
Low evidence

MECHANISM (adaptive thermogenesis / set-point): six years after large weight loss, resting metabolic rate remained suppressed below baseline and metabolic adaptation...

Fothergill E, Guo J, Howard L et al., Obesity (Silver Spring), 2016 Source
Full findingMECHANISM (adaptive thermogenesis / set-point): six years after large weight loss, resting metabolic rate remained suppressed below baseline and metabolic adaptation persisted DESPITE substantial regain - direct human DXA-plus-calorimetry evidence that adaptive thermogenesis is durable and proportional to ongoing weight suppression.
PopulationFothergill/Hall ('Biggest Loser'): N=14 of 16 competitors; DXA + indirect calorimetry at baseline, 30 wk, 6 yr.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsanimal data; human relevance uncertain; small sample (N~14)
Comparatorswithin-subject baseline
GLP-1 RA class MARKETED
Maintenance and regain Increase
Low evidence

Class-level synthesis: a narrative review of randomised-withdrawal trials, meta-analyses and real-world cohorts (>289,000 patients) concludes that GLP-1RA...

Shah E, AlShiab R, Abdo A et al., Diabetes Obes Metab, 2026 Source
Full findingClass-level synthesis: a narrative review of randomised-withdrawal trials, meta-analyses and real-world cohorts (>289,000 patients) concludes that GLP-1RA discontinuation is followed by substantial weight regain (60-90% within a year) and parallel reversal of cardiometabolic benefits, attributed to reactivation of orexigenic pathways and adaptive thermogenesis. It also notes the absence of validated tapering strategies.
PopulationNarrative review of randomised-withdrawal trials, systematic reviews/meta-analyses and observational cohorts (>289,000 patients).
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitspossible confounding by indication
Comparatorscontinued therapy
GLP-1 RA class MARKETED
Maintenance and regain Not directional
Low evidence

EMERGING CONCERN / GAP: no published study measured body composition (DXA/MRI fat vs lean) across a complete loss-then-regain cycle ON a GLP-1/incretin drug, so...

Gap synthesis across the confirmed D4 withdrawal records (no single source reports drug-s...
Full findingEMERGING CONCERN / GAP: no published study measured body composition (DXA/MRI fat vs lean) across a complete loss-then-regain cycle ON a GLP-1/incretin drug, so whether regained weight is disproportionately FAT with lean mass incompletely restored is untested. The withdrawal trials report TOTAL weight regain only; the human composition-across-cycle evidence (Biggest Loser) is diet/exercise, not drug. The worry is biologically plausible and reinforced by documented incretin-class lean-mass loss during the loss phase (D2), but direct drug-specific data are absent.
PopulationCross-study gap assessment across STEP-1 extension, STEP-4, SURMOUNT-4 (total weight only) and the metabolic-adaptation cohort.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsDELIBERATE GAP-FLAG. Captures the 'a weight cycle worsens fat:lean ratio' concern as EMERGING with thin/absent direct human drug data. Anchors the open question; cross-ref D2 lean-mass loss (loss phase documented; regain-phase composition NOT). NOT a positive finding - records an absence. COUNCIL: rule whether a sourceless gap row belongs or should be an OQ only.
GLP-1 RA class MARKETED
Maintenance and regain Not directional
Very low evidence

EVIDENCE GAP: no randomised trial of a LOWER maintenance dose or an INTERMITTENT / reduced-frequency incretin dosing schedule for sustaining weight loss was located....

Gap synthesis; corroborated by Shah E et al., Diabetes Obes Metab, 2026 (no validated tap...
Full findingEVIDENCE GAP: no randomised trial of a LOWER maintenance dose or an INTERMITTENT / reduced-frequency incretin dosing schedule for sustaining weight loss was located. The maintenance trials prove FULL-dose continuation works but say nothing about whether a reduced or intermittent dose can hold weight off; the class discontinuation review explicitly notes no validated tapering strategies exist.
PopulationGap assessment across STEP-4, SURMOUNT-4 and the GLP-1RA discontinuation review.
Fundingnot-stated
Scope limitsno outcome data yet (ongoing)
Multiple (review) MARKETED
Maintenance and regain Not directional
Low evidence

INTERPRETIVE NOTE (neutral framing): authoritative bodies frame obesity as a chronic, relapsing, progressive disease (World Obesity Federation; joint World Heart...

Bray GA, Kim KK, Wilding JPH (WOF), Obes Rev, 2017; companion WHF/WOF paper, Eur J Prev C... Source
Full findingINTERPRETIVE NOTE (neutral framing): authoritative bodies frame obesity as a chronic, relapsing, progressive disease (World Obesity Federation; joint World Heart Federation / World Obesity Federation). This is the backdrop the withdrawal trials are read against: if obesity is chronic and relapsing, regain on stopping is the expected disease course and indefinite MAINTENANCE of some kind is implied (which could be pharmacological, surgical or intensive behavioural). The trials evidence only that DRUG continuation maintains DRUG-induced loss - NOT that lifelong drug therapy specifically is required or net-beneficial over a decade scale. Recorded as framing context, NOT a verdict on whether any individual should be on lifelong therapy.
PopulationWorld Obesity Federation position statement (2017) and joint WHF/WOF position paper (2022).
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsNeutral interpretive note. The 'chronic relapsing disease' framing reframes regain-on-stopping as expected disease relapse rather than treatment failure. Graded low (position/consensus, not primary data). COI / INDEPENDENCE (Council Evidence-grader + Red-team): the WOF (2017) and WHF/WOF (2022) are obesity-medicine field bodies with substantial pharmaceutical-industry funding ties, and the position-statement authors OVERLAP with the sponsored withdrawal-trial author lists (e.g. Wilding, also lead author of STEP-1 / C-SEMAGLUTIDE-MAINT-02). The 'chronic disease -> continued therapy' framing is CONCORDANT with the manufacturers' commercial interest in continued treatment; treat as an interpretive stance, NOT independent evidence. Validation: PMID 28489290 + 36007112 confirmed.
Liraglutide MARKETED
Maintenance and regain Decrease
Moderate evidence

SCALE Maintenance: adults who first lost >=5% on a low-calorie-diet run-in were randomised to liraglutide 3.0 mg or placebo to test MAINTENANCE of diet-induced loss....

Wadden TA, Hollander P, Klein S et al., Int J Obes (Lond), 2013 (SCALE Maintenance) Source
Full findingSCALE Maintenance: adults who first lost >=5% on a low-calorie-diet run-in were randomised to liraglutide 3.0 mg or placebo to test MAINTENANCE of diet-induced loss. Liraglutide held and added to the loss while placebo did not. SCOPE CAVEAT: this tests maintenance-vs-placebo on a background of diet-induced loss, NOT withdrawal of established drug responders, so it is mechanistically maintenance-vs-placebo, not active-drug-discontinuation regain.
PopulationSCALE Maintenance (NCT00781937): N=422; obese/overweight adults without diabetes who lost >=5% on a low-calorie diet; double-blind RCT, 56 weeks.
Fundingindustry - Novo Nordisk
Scope limitsThe closest liraglutide analogue to STEP-4, but indirect: its placebo arm is diet-maintenance (near-flat -0.2%) on continued lifestyle support, NOT drug discontinuation, so it is not directly comparable to the +6.9/+14.0% regain seen when established sema/tirz responders switch to placebo. Direction tagged 'decrease' (continued loss on active drug). Graded moderate. VALIDATOR: confirm PMID 23812094 + the design (maintenance-of-diet-loss, not drug withdrawal).
Comparatorsplacebo
Retatrutide INVESTIGATIONAL
Maintenance and regain Not directional
Moderate evidence

RETATRUTIDE GAP: no maintenance, withdrawal/regain or intermittent-dosing data specific to retatrutide exist. The phase-2 obesity trial reported continuous...

Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526 Source
Full findingRETATRUTIDE GAP: no maintenance, withdrawal/regain or intermittent-dosing data specific to retatrutide exist. The phase-2 obesity trial reported continuous on-treatment loss to 48 weeks (up to -24.2%) with weight still declining at trial end, but contained NO withdrawal or off-treatment arm. Reta's regain kinetics are UNKNOWN and must be inferred from the GLP-1/GIP class - a CLASS-TRANSFER expectation (reta would be expected to regain like the class), NOT a reta result. The steep, non-plateauing curve concerns the CEILING of loss, NOT regain kinetics; the proportion and absolute magnitude of any reta regain are UNQUANTIFIED and untested. Reta's glucagon arm (an energy-expenditure component absent from the GLP-1/GIP class) makes the class-transfer NON-AUTOMATIC in mechanism as well as magnitude - its off-treatment behaviour cannot be assumed to track a pure incretin in either direction. If regain is disproportionately fat (the C-CLASS-MAINT-04 gap), the agent that loses the most is the one whose loss-regain cycle could most degrade the lean:fat ratio (cross-ref D2) - the highest-stakes, untested instance of that gap.
PopulationReta phase-2 obesity (Jastreboff, NEJM 2023, NCT04881760): N=338; 48 weeks on-treatment; no withdrawal arm.
Fundingindustry-Eli Lilly
Scope limitsconference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint
Comparatorsplacebo
Retatrutide INVESTIGATIONAL
Maintenance and regain Not directional
Very low evidence

REGISTRY (no results): TRIUMPH-6 (NCT06859268) is the registered phase-3b retatrutide weight-MAINTENANCE trial with a continued-vs-withdrawal (re-randomisation) design...

Eli Lilly. TRIUMPH-6: maintenance of weight reduction with retatrutide. ClinicalTrials.go... Source
Full findingREGISTRY (no results): TRIUMPH-6 (NCT06859268) is the registered phase-3b retatrutide weight-MAINTENANCE trial with a continued-vs-withdrawal (re-randomisation) design - the first reta trial designed to measure maintenance vs withdrawal of weight reduction, i.e. the trial whose future readout would fill the reta regain gap.
PopulationTRIUMPH-6 (NCT06859268): adults with obesity and a history of unsuccessful dietary weight loss, without diabetes; retatrutide lead-in then re-randomise (continue dose 1 / escalate dose 2 / placebo); phase-3b double-blind.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsRegistered per the D4 remit; confirmed on clinicaltrials.gov as the reta maintenance / continued-vs-withdrawal trial, primary completion April 2028. Promissory note (very-low). VALIDATOR: confirm NCT06859268 design + completion date.
Comparatorsplacebo; retatrutide (continued); retatrutide (escalated)
Semaglutide MARKETED
Maintenance and regain Increase
Moderate evidence

STEP-4 randomised-withdrawal RCT: adults who had lost a mean 10.6% during a 20-week semaglutide run-in were re-randomised (2:1) at week 20 to continue semaglutide 2.4...

Rubino D, Abrahamsson N, Davies M et al., JAMA, 2021 (STEP 4) Source
Full findingSTEP-4 randomised-withdrawal RCT: adults who had lost a mean 10.6% during a 20-week semaglutide run-in were re-randomised (2:1) at week 20 to continue semaglutide 2.4 mg or switch to placebo. Those switched to placebo REGAINED weight (+6.9%) while those continuing kept losing (-7.9%); waist/BP gains were preserved only with continued treatment. The headline is regain-on-withdrawal; the continued arm is the maintenance counterpart.
PopulationSTEP-4 (NCT03548987): N=803 randomised; adults BMI >=30 (or >=27 + comorbidity) without diabetes; double-blind phase-3a withdrawal at week 20; 48 weeks post-randomisation.
Fundingindustry - Novo Nordisk
Scope limitsCanonical randomised-withdrawal regain figure for semaglutide (+6.9% over 48 wk). Counterpart to the on-treatment weight-loss rows: loss is maintained only while treatment continues. Authors frame as supporting continued treatment for maintenance. Pairs with the STEP-1 extension (longer off-treatment arc + cardiometabolic reversal). VALIDATOR: confirm PMID 33755728 + the +6.9/-7.9 figures.
Comparatorsplacebo (switch from semaglutide)
Semaglutide MARKETED
Maintenance and regain Increase
Low evidence

STEP-1 off-treatment extension: after BOTH semaglutide and lifestyle were stopped at week 68, participants regained ~two-thirds of lost weight (11.6 of 17.3 pp) by...

Wilding JPH et al., Diabetes Obes Metab 2022 Source
Full findingSTEP-1 off-treatment extension: after BOTH semaglutide and lifestyle were stopped at week 68, participants regained ~two-thirds of lost weight (11.6 of 17.3 pp) by week 120, and on-treatment cardiometabolic improvements reverted towards baseline. The clearest class documentation of cardiometabolic REVERSAL on regain.
PopulationSTEP-1 extension (NCT03548935): exploratory subset N=327; adults with obesity without diabetes; off-treatment observational follow-up after the 68-week RCT.
Fundingindustry-Novo Nordisk
Scope limitsSource of the widely-cited 'regained ~two-thirds' figure + the explicit cardiometabolic-reversal statement. Graded MODERATE not high: exploratory, non-randomly-selected off-treatment extension where lifestyle was ALSO withdrawn (so regain reflects total withdrawal, not drug alone). Reports TOTAL weight only - no fat-vs-lean composition (see C-CLASS-MAINT-04 gap). VALIDATOR: confirm PMID 35441470 + the 11.6/17.3 figures.
Comparatorsplacebo (also withdrawn)
Tirzepatide MARKETED
Maintenance and regain Increase
Moderate evidence

SURMOUNT-4 randomised-withdrawal RCT: after a 36-week open-label lead-in (mean loss 20.9%), participants were randomised at week 36 to continue tirzepatide or switch...

Aronne LJ et al., JAMA 2024 (SURMOUNT-4) Source
Full findingSURMOUNT-4 randomised-withdrawal RCT: after a 36-week open-label lead-in (mean loss 20.9%), participants were randomised at week 36 to continue tirzepatide or switch to placebo. Withdrawal led to substantial regain (+14.0%) whereas continued treatment maintained and augmented loss (-5.5%). Same architecture as STEP-4, larger magnitudes off a deeper lead-in loss.
PopulationSURMOUNT-4 (NCT04660643): N=670 randomised; adults BMI >=30 (or >=27 + complication) without diabetes; 36-week open lead-in then 52-week double-blind withdrawal.
Fundingindustry-Eli Lilly
Scope limitsopen-label (unblinded)
Comparatorsplacebo (switch from tirzepatide)
Tirzepatide MARKETED
Maintenance and regain Increase
Moderate evidence

SURMOUNT-4 post-hoc: cardiometabolic markers tracked WITH the magnitude of weight regain after tirzepatide withdrawal - greater regain was associated with larger...

Horn DB, Linetzky B, Davies MJ et al., JAMA Intern Med, 2026 Source
Full findingSURMOUNT-4 post-hoc: cardiometabolic markers tracked WITH the magnitude of weight regain after tirzepatide withdrawal - greater regain was associated with larger increases in waist, SBP, non-HDL cholesterol, HbA1c and fasting insulin. ASSOCIATIONAL only: post-hoc, non-randomised regain strata (stratified on a post-randomisation outcome), confounded by regainer phenotype; all endpoints are surrogates, no events.
PopulationPost-hoc of SURMOUNT-4 (NCT04660643): N=308 tirzepatide-treated with >=10% loss randomised to placebo, stratified by week-88 regain.
Fundingindustry-Eli Lilly
Scope limitsdisproportionality: reporting != incidence/causality; possible confounding by indication; post-hoc (not prespecified)
Comparatorswithin-arm regain strata