---
type: source
title: "Metabolic Rebound After GLP-1 Discontinuation: Systematic Review and Meta-Analysis (eClinicalMedicine/Lancet, 2025)"
author: "eClinicalMedicine (The Lancet)"
url: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00614-5/fulltext
date: 2025-01-01
domain: health
secondary_domains: []
format: peer-reviewed meta-analysis
status: processed
processed_by: vida
processed_date: 2026-04-27
priority: high
tags: [glp-1, weight-regain, discontinuation, metabolic-rebound, semaglutide, tirzepatide, chronic-disease, adherence]
extraction_model: "anthropic/claude-sonnet-4.5"
---

## Content

Published in *eClinicalMedicine* (The Lancet Group). Systematic review and meta-analysis of weight regain following GLP-1 receptor agonist discontinuation (PMC12535773).

**Core findings:**

- Weight regain after discontinuation is **proportional to original weight loss**
- Liraglutide patients: regained **2.20 kg** after stopping
- Semaglutide/tirzepatide patients: regained **9.69 kg** after stopping (dramatically higher because the initial weight loss was larger)
- Most patients regain **two-thirds of their prior weight loss within 6 months** of stopping

**Metabolic rebound mechanism:**
- GLP-1 suppression of appetite is pharmacological, not behavioral modification
- When drug withdrawn, underlying neurobiological hunger signals return to baseline
- Cardiometabolic benefits (reduced blood pressure, improved lipids, lower CVD risk) reverse along with weight regain

**Clinical implications:**
- GLP-1 agonists function as "chronic maintenance therapy" — not a course of treatment but a permanent biological support
- The drug does not "treat" obesity in the remission sense; it manages it while present
- This is the biological mechanism underlying the economic "chronic use model" KB claim

## Agent Notes

**Why this matters:** This meta-analysis provides the mechanistic underpinning for WHY GLP-1s require chronic use: the neurobiological hunger signal is not modified permanently, only suppressed pharmacologically. When you stop, you go back to baseline within months. This is the biological grounding for the "chronic use model inflationary through 2035" KB claim — but combined with the JAMA Open adherence data (65% annual dropout), the implication is: most patients will discontinue and regain weight, creating a clinical/economic revolving door.

**What surprised me:** The magnitude of semaglutide/tirzepatide regain (9.69 kg) vs. liraglutide (2.20 kg). The newer, more effective drugs produce faster, more dramatic weight regain when stopped — the benefit is proportional to the drug's efficacy. The better the drug, the more it matters when you stop.

**What I expected but didn't find:** Data on whether the cardiometabolic benefits have a "durable" component after discontinuation even if weight rebounds. The available evidence suggests they don't — benefits reverse with weight regain. There may be exceptions for patients who maintain some behavioral change, but the meta-analysis doesn't segment this.

**KB connections:**
- Directly supports the "chronic use model" framing in the existing GLP-1 claim — biological mechanism confirmed
- CONFLICTS with the JAMA Open adherence data: if 65% discontinue AND most regain 2/3 of weight → then the net population health benefit is much smaller than projected from trial data
- Combined finding (JAMA Open + this meta-analysis): ~65% of obesity patients discontinue within 1 year AND within 6 months regain 2/3 of weight lost → effective population-level obesity treatment rate is dramatically lower than trial efficacy suggests
- The "chronic use model" is simultaneously: (1) biologically necessary for maintained benefit, AND (2) empirically not achieved by most real-world patients — this is the central tension in GLP-1 economics

**Extraction hints:**
- Use WITH JAMA Open adherence data to enrich the existing GLP-1 claim: "chronic use model inflationary through 2035" needs two qualifications: (a) chronic use is biologically necessary (this paper), AND (b) chronic use is not achieved by majority of patients (JAMA Open). Net cost impact is lower than the "inflationary" framing suggests.
- Could support a new divergence: "GLP-1s chronic use model: inflationary (if adherence scales) vs. moderate impact (if real-world adherence persists)"
- The proportional regain finding is independently extractable: "the most effective GLP-1 drugs (semaglutide, tirzepatide) produce the largest weight regain upon discontinuation"

**Context:** eClinicalMedicine is The Lancet Group's open-access journal, top-tier. Systematic review and meta-analysis is the highest evidence level for this type of question. High confidence in the directional finding.

## Curator Notes (structured handoff for extractor)
PRIMARY CONNECTION: Existing GLP-1 KB claim ("chronic use model inflationary through 2035") — provides biological mechanism AND creates the tension with adherence data
WHY ARCHIVED: High-quality meta-analysis confirming that GLP-1 benefits require ongoing pharmacological suppression — not a one-time course. Important for understanding the structural economics of GLP-1 adoption.
EXTRACTION HINT: Use in combination with JAMA Open adherence source (same archive queue, dated 2025-glp1-discontinuation-reinitiation-jama-open.md) to qualify the inflationary claim. The right claim is about the tension: biological necessity of chronic use vs. empirical failure of chronic use at population scale.
