Stopping Peptides: What Studies Report After Discontinuation and How Long Trials Ran

Two related questions come up whenever a peptide drug is discussed: what the published literature observed after treatment was withdrawn, and how long the compounds were actually administered in the trials that generated the data. Both questions have partial answers, and both answers come almost entirely from one family of peptides — the glucagon-like peptide-1 (GLP-1) receptor agonists, particularly semaglutide, which has been studied in withdrawal extensions, continuation-versus-placebo designs and multi-year outcome trials.

This page is for educational purposes only and is not medical advice; consult a licensed physician about any medical decision. Nothing below describes what any individual should do, and trial durations described here were protocol parameters set by investigators, not recommendations.

What "stopping" meant inside the published trials

In clinical research, discontinuation is usually a planned design feature rather than a personal decision. Trials handled it in three broad ways. Some ran a fixed treatment period and then followed participants off-treatment, as in the STEP 1 trial extension, where researchers monitored participants for 52 weeks after the 68-week treatment period ended (PMID 35441470). Others randomised participants who had already responded to either continue the peptide or switch to placebo, as in the STEP 4 trial, which used a 20-week run-in followed by 48 weeks of randomised treatment (PMID 33755728). A third group simply ran long, as in SELECT, where the study followed participants for a mean of about 40 months (PMID 37952131).

How long the studies ran

The table below lists the treatment or follow-up durations reported in the trials summarised on this page. These are descriptions of study design; they are not durations suggested for any individual.

A pattern is visible across that set: 68 weeks became the conventional phase 3 duration for weight-related endpoints, seen in the 68-week STEP 1 trial (PMID 33567185), the 68-week OASIS 1 trial of oral semaglutide 50 mg once daily (PMID 37385278) and the 68-week trial in adults with obesity and knee osteoarthritis (PMID 39476339). Longer exposure was examined separately, with 104 weeks in STEP 5 (PMID 36216945).

Weight change after withdrawal: what studies report

The clearest discontinuation data in this citation set come from the STEP 1 trial extension, where participants who had completed 68 weeks of semaglutide 2.4 mg plus lifestyle intervention were followed for a further year off treatment; the study reported that participants regained roughly two-thirds of the weight they had lost, with cardiometabolic variables moving back toward pre-treatment values (PMID 35441470). Researchers framed that result as evidence that the changes observed during treatment were largely treatment-dependent rather than persistent after withdrawal (PMID 35441470).

STEP 4 approached the same question prospectively. After a 20-week run-in on semaglutide, participants randomised to continue lost a further 7.9% of body weight from week 20 to week 68, whereas those switched to placebo gained 6.9%, a between-group difference of 14.8 percentage points, as the study reported (PMID 33755728). In other words, within a single randomised comparison, continuation and withdrawal diverged in opposite directions over 48 weeks (PMID 33755728).

What continued treatment looked like over time

For context on the trajectory that withdrawal interrupts, STEP 1 reported a mean body weight change of −14.9% with once-weekly semaglutide 2.4 mg versus −2.4% with placebo at week 68 (PMID 33567185), and STEP 5 reported −15.2% versus −2.6% at week 104 (PMID 36216945). In the four-year SELECT weight analysis, researchers reported that weight reduction continued for roughly the first year and was then broadly sustained while treatment continued (PMID 38740993). A systematic review and meta-analysis of semaglutide in obesity without diabetes similarly reported significant weight reduction versus placebo across the pooled trials (PMID 36578889).

Do non-weight outcomes behave the same way after stopping?

The STEP 1 extension reported that improvements in cardiometabolic variables observed during treatment also reverted toward baseline once semaglutide and the lifestyle intervention were withdrawn (PMID 35441470). For outcomes measured only during continuous treatment, no withdrawal data exist in this citation set: SELECT reported a lower rate of major adverse cardiovascular events with semaglutide 2.4 mg than placebo over a mean of about 40 months of on-treatment follow-up, but did not report what happened after discontinuation (PMID 37952131). The knee osteoarthritis trial likewise reported pain and weight outcomes at week 68 rather than after withdrawal (PMID 39476339).

Discontinuation outside of trials

Randomised trials measure planned stopping; observational work measures unplanned stopping. A 2025 review of real-world evidence examined utilisation, clinical and comparative effectiveness, and adverse effects of newer GLP-1 receptor agonist–based weight-loss therapies, noting that real-world use patterns differ from the controlled conditions of registration trials (PMID 40196933). A retrospective cohort study of adults with overweight or obesity dispensed semaglutide or tirzepatide reported greater on-treatment weight reduction with tirzepatide at 3, 6 and 12 months, and the study also characterised treatment discontinuation within the cohort (PMID 38976257). Those analyses describe how long people remained on therapy in practice; they were not designed to identify a point at which stopping would be appropriate (PMID 38976257).

Adverse Events Around Discontinuation: What Studies Report

Tolerability is one of the reasons treatment ends before a protocol does. A systematic review of randomised controlled trials of GLP-1 receptor agonists for weight loss in adults without diabetes reported that gastrointestinal adverse events were the most frequently reported category (PMID 39761578). A meta-analysis of semaglutide in obesity without diabetes reported the same pattern, with gastrointestinal events more common on semaglutide than placebo (PMID 36578889). In OASIS 1, the study reported that adverse events with oral semaglutide 50 mg were mostly gastrointestinal and typically mild to moderate (PMID 37385278), and STEP 1 reported that gastrointestinal events were the most common reason for discontinuation of the trial drug (PMID 33567185). The real-world review also summarised adverse effects reported outside trial settings (PMID 40196933).

How durations and quantities are expressed in this literature

Reading discontinuation research accurately depends on a few measurement conventions rather than on any handling instruction:

• Weeks, not cycles. Endpoints were anchored to protocol weeks — week 68 in STEP 1 (PMID 33567185) and week 104 in STEP 5 (PMID 36216945) — so "how long" in the literature means how long the protocol ran.
• Percentage of baseline body weight. Weight outcomes were reported as percentage change from baseline, such as −14.9% versus −2.4% at week 68 in STEP 1 (PMID 33567185).
• Milligrams and route. Quantities were tied to a route and schedule, such as once-weekly subcutaneous semaglutide 2.4 mg in SELECT (PMID 37952131) versus oral semaglutide 50 mg once daily in OASIS 1 (PMID 37385278), which are not interchangeable numbers.
• Run-in versus randomised phases. STEP 4 reported weight change from week 20 rather than from week 0 because its randomisation began after a run-in (PMID 33755728).

Storage, reconstitution and handling belong to the same measurement literacy: published trials used manufactured, quality-controlled investigational product administered on a fixed schedule, and the durations reported above describe that product under those conditions (PMID 33567185). Materials labelled research-use-only are not the same articles and carry no equivalent stability or outcome data.

What this body of evidence does not settle

None of the studies cited here tested when treatment ought to end, compared different planned stopping points, or evaluated tapering schedules. The withdrawal data describe what happened after protocol-defined endpoints: two-thirds of lost weight regained one year after semaglutide was stopped in the STEP 1 extension (PMID 35441470), and divergence between continuation and placebo in STEP 4 (PMID 33755728). The systematic review of GLP-1 receptor agonist trials in adults without diabetes likewise summarised efficacy and safety within trial periods rather than after them (PMID 39761578). Beyond this drug class, most peptides discussed in consumer settings have no published withdrawal follow-up at all, so statements about what happens after stopping them are not supported by the trial literature summarised here.

References

• Once-Weekly Semaglutide in Adults with Overweight or Obesity (The New England Journal of Medicine, 2021)
• Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial (JAMA, 2021)
• Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension (Diabetes, Obesity & Metabolism, 2022)
• Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial (Nature Medicine, 2022)
• Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis (Journal of the ASEAN Federation of Endocrine Societies, 2022)
• Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial (Lancet, 2023)
• Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (The New England Journal of Medicine, 2023)
• Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial (Nature Medicine, 2024)
• Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity (JAMA Internal Medicine, 2024)
• Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis (The New England Journal of Medicine, 2024)
• Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials (Annals of Internal Medicine, 2025)
• Real-world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP-1RA-based weight-loss therapies (Diabetes, Obesity & Metabolism, 2025)