11 findings across 7 drug records. Domain pages are descriptive indexes, not advice.
The grade rates how strong the evidence is, not how good or safe the drug is. A low or very-low grade means the evidence is thin, not that an effect is harmful or ruled out.
Most represented records
GLP-1-based therapies, multi-agent (2)
Semaglutide (2)
Tirzepatide (2)
Weight-loss physiology, drug-agnostic (2)
Liraglutide (1)
Multi-agent review synthesis (1)
Retatrutide (1)
Evidence spread
High evidence 0Moderate evidence 6Low evidence 5Very low evidence 0
MECHANISM (set-point / why regain happens): one year after diet-induced weight loss, circulating appetite-regulating hormones remained shifted in a direction that...
SourceSumithran P, Prendergast LA, Delbridge E et al., N Engl J Med, 2011Source
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)
MECHANISM (adaptive thermogenesis / set-point): six years after large weight loss, resting metabolic rate remained suppressed below baseline and metabolic adaptation...
SourceFothergill E, Guo J, Howard L et al., Obesity (Silver Spring), 2016Source
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)
Comparatorswithin-subject baseline
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
weight-maintenance-regainIncrease
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...
SourceShah E, AlShiab R, Abdo A et al., Diabetes Obes Metab, 2026Source
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)
Comparatorscontinued therapy
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
weight-maintenance-regainNot 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...
SourceGap 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)
Multi-agent review synthesisSTATUS UNKNOWN
weight-maintenance-regainNot directional
Low evidence
INTERPRETIVE NOTE (neutral framing): authoritative bodies frame obesity as a chronic, relapsing, progressive disease (World Obesity Federation; joint World Heart...
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)
LiraglutideMARKETED
weight-maintenance-regainDecrease
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....
SourceWadden 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
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
weight-maintenance-regainNot directional
Moderate evidence
RETATRUTIDE GAP: no maintenance, withdrawal/regain or intermittent-dosing data specific to retatrutide exist. The phase-2 obesity trial reported continuous...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
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.
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...
SourceRubino 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.
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...
SourceWilding JPH et al., Diabetes Obes Metab 2022Source
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
Comparatorsplacebo (also withdrawn)
TirzepatideMARKETED
weight-maintenance-regainIncrease
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...
SourceAronne 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
Comparatorsplacebo (switch from tirzepatide)
TirzepatideMARKETED
weight-maintenance-regainIncrease
Moderate evidence
SURMOUNT-4 post-hoc: cardiometabolic markers tracked WITH the magnitude of weight regain after tirzepatide withdrawal - greater regain was associated with larger...
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.
The Echo Compendium