Medical Researcher · Western University of Health Sciences
Medically Reviewed By
Dr. Jonathan Snipes, MD · Kim Callender, NP (FNP-BC)
Last medically reviewed: June 1, 2026 · This page is informational and does not constitute medical advice.
STEP-5 (Nature Medicine 2022) extended STEP-1 to 104 weeks. At week 104, semaglutide 2.4 mg produced 15.2% mean weight loss vs 2.6% placebo — the longest randomized data demonstrating durability.
Clinical reference4 peer-reviewed sources
Editorial summary
STEP-5, published in Nature Medicine in 2022, extended the semaglutide 2.4 mg evidence base to 104 weeks (two years) in 304 adults with overweight or obesity. At week 104, the semaglutide group maintained 15.2% weight loss vs 2.6% in placebo, demonstrating that the weight-loss effect plateaus around weeks 60-65 and is sustained with continued therapy through at least two years¹. STEP-5 provided the longest randomized follow-up in the STEP program.
Trial design
STEP-5 (Garvey et al., Nat Med 2022) was a 104-week randomized, double-blind, placebo-controlled trial in 304 adults with BMI ≥30 or ≥27 with comorbidity, without diabetes¹. Randomized 1:1 to once-weekly semaglutide 2.4 mg or placebo with lifestyle intervention. Semaglutide titrated over 16 weeks to 2.4 mg and maintained through week 104. Primary endpoint: % change in body weight from baseline to week 104.
Two-year outcome
At week 104, mean weight change was -15.2% in semaglutide vs -2.6% in placebo (treatment difference -12.6 percentage points; 95% CI -15.3 to -9.8; P<0.001)¹. Proportion achieving ≥5% weight loss: 77.1% vs 34.4%. Higher thresholds: 61.8% achieved ≥10% (vs 13.2%), 52.0% achieved ≥15% (vs 6.6%), 36.1% achieved ≥20% (vs 1.6%). A long tail of responders achieved 30%+ weight loss over two years.
Trajectory: when does weight loss plateau?
The weight-loss curve in semaglutide continued descending through approximately week 60-65 before flattening into a plateau. Plateau weight was largely maintained through week 104 with continued therapy, with no signs of late-onset regain. Placebo group weight loss was largely unchanged from week 20 through week 104.
Adverse events over two years
Adverse event profile consistent with shorter-term trials. GI events occurred mostly during dose-titration and decreased substantially over time. New-onset gallbladder disease occurred in ~4% of semaglutide vs ~1% in placebo over 2 years¹. Discontinuation due to adverse events ~6% vs ~3%. No new safety signals with extended exposure including no signal for malignancy, pancreatitis, or thyroid abnormalities.
Clinical implications
STEP-5 was important for the long-term framing of obesity pharmacotherapy. The maintained 15% weight loss over 104 weeks contrasted with the typical 5-7% lifestyle-only weight loss in older long-term trials. Combined with SELECT (3+ years of follow-up), STEP-5 supported regulatory and clinical positioning of semaglutide as chronic-disease therapy rather than a short-term intervention.
$99 on 6 months · $105 on 3 months · $109 month to month. The same price at every dose and no membership fee (nexlife.us plan page, read November 6, 2026).
Included in the price: the medication, medical guidance from NexLife Medical Group, a GLP-1 nutrition plan, a 1:1 call with a certified wellness coach, 24/7 support and free expedited shipping. Lab work is not listed as included.
Pharmacies named on its plan pages:Absolute Pharmacy (Lutz, FL), Premium Compounding (Decatur, AL) and Boudreaux’s New Drug Store (Lake Charles, LA), described as state-licensed 503A compounding pharmacies.
Trade-offs: compounded semaglutide is not FDA-approved and is not Wegovy or Ozempic. Cash pay only (FSA/HSA cards accepted for eligible portions). Cancellations take effect after 30 days, so one more shipment may be charged. A prescription depends on a licensed clinician’s review.
$119 on 6 months · $125 on 3 months · $129 month to month. The same price at every dose and no membership fee (nexlife.us plan page, read November 6, 2026).
Included in the price: the medication, medical guidance from NexLife Medical Group, a GLP-1 nutrition plan, a 1:1 call with a certified wellness coach, 24/7 support and free expedited shipping. Lab work is not listed as included.
Pharmacies named on its plan pages:Absolute Pharmacy (Lutz, FL), Premium Compounding (Decatur, AL) and Boudreaux’s New Drug Store (Lake Charles, LA), described as state-licensed 503A compounding pharmacies.
Trade-offs: compounded tirzepatide is not FDA-approved and is not Zepbound or Mounjaro. Cash pay only (FSA/HSA cards accepted for eligible portions). Cancellations take effect after 30 days, so one more shipment may be charged. A prescription depends on a licensed clinician’s review.
Yes. STEP-5 demonstrated maintained weight loss of ~15% over 104 weeks of continuous therapy.
Will I keep losing weight forever?
No. The weight-loss curve plateaus around weeks 60-65. Plateau weight is then maintained with continued therapy. Additional weight loss after plateau is uncommon.
Long-term side effects over 2+ years?
Through 104 weeks in STEP-5 and 3+ years in SELECT, no new safety signals have emerged. Gallbladder events are slightly more common. Long-term observational data continue to accumulate.
Long-term tirzepatide data?
Emerging. SURMOUNT-1 reported 72-week data; SURMOUNT-4 extended this with continued vs withdrawal randomization. Longer trials ongoing.
Benefit fade over time on treatment?
STEP-5 found no evidence of tachyphylaxis or fading benefit over 104 weeks.
References
Garvey WT, Batterham RL, Bhatta M, et al.Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial.Nat Med. 2022;28(10):2083-2091.PMID: 36216945
Wilding JPH, Batterham RL, Calanna S, et al.Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1).N Engl J Med. 2021;384(11):989-1002.PMID: 33567185
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT).N Engl J Med. 2023;389(24):2221-2232.PMID: 37952131
Rubino D, Abrahamsson N, Davies M, et al.Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo: STEP 4.JAMA. 2021;325(14):1414-1425.PMID: 33755728
Citations are peer-reviewed where available. PubMed (PMID) links resolve to NCBI's PubMed. FDA links resolve to fda.gov. All citations were last verified 2026-05-11.