STEP 5 Trial: Two-Year Semaglutide Data Proves Long-Term Weight Loss Durability

Medically reviewed by Dr. James Whitfield, DO, FACOI

The STEP 5 trial answered the critical question: does semaglutide maintain its weight loss effect over the long term? Published in Nature Medicine in 2022, this 104-week study showed that semaglutide 2.4mg sustained approximately 15% weight loss for two full years, with continued cardiometabolic benefits.

STEP 5: The Longest STEP Trial

One of the most important questions in obesity pharmacotherapy is whether weight loss medications maintain their effectiveness over time. The STEP 5 trial, published in Nature Medicine in October 2022 by Garvey et al., provided the most comprehensive long-term data for semaglutide 2.4 mg, demonstrating sustained efficacy over a full two-year treatment period [1].

Study Design

STEP 5 was a 104-week (2-year), randomized, double-blind, placebo-controlled trial conducted at 41 sites across the United States. The study enrolled 304 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity, without type 2 diabetes.

Participants were randomized 1:1 to receive either semaglutide 2.4 mg or matching placebo via once-weekly subcutaneous injection, alongside lifestyle intervention. The dose was escalated over 16 weeks to the target dose of 2.4 mg weekly.

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Weight Loss Results Over Two Years

The primary endpoint — percentage change in body weight from baseline to week 104 — demonstrated remarkable durability:

Mean Body Weight Change at Week 104:

Semaglutide: -15.2% (approximately -15.9 kg)

Placebo: -2.6%

Treatment difference: -12.6 percentage points (95% CI, -15.3 to -9.8; P<0.001)

Weight Loss Trajectory:

The weight loss pattern revealed important insights about semaglutide's long-term pharmacology:

Weeks 0-60: Progressive weight loss, with the nadir (maximum weight loss) occurring around week 60

Weeks 60-104: Weight stabilized with a slight plateau, maintaining the vast majority of lost weight

The mean weight loss at week 68 was -15.8%, and at week 104 was -15.2%, indicating minimal weight regain while on treatment [1].

Categorical Weight Loss at Week 104:

≥5% weight loss: 77.1% semaglutide vs. 34.4% placebo

≥10% weight loss: 61.8% vs. 13.3%

≥15% weight loss: 52.1% vs. 7.0%

≥20% weight loss: 36.1% vs. 3.9%

Sustained Cardiometabolic Benefits

STEP 5 demonstrated that the cardiometabolic improvements seen in shorter trials were maintained over two years:

Waist circumference: -14.4 cm vs. -5.2 cm at week 104

Systolic blood pressure: Sustained reductions of approximately 5 mmHg

HbA1c: Maintained improvement, with fewer participants progressing to prediabetes or diabetes

Lipid profile: Sustained improvements in triglycerides, VLDL, and free fatty acids

C-reactive protein: Persistent reduction indicating ongoing anti-inflammatory effects

These sustained improvements suggest that continued semaglutide treatment provides ongoing cardiometabolic protection, not just weight loss [1].

Safety Over Two Years

The extended treatment period provided valuable long-term safety data:

Gastrointestinal events remained the most common adverse effects but were predominantly mild-to-moderate and decreased over time

Serious adverse events: 15.3% semaglutide vs. 9.3% placebo

Discontinuation due to adverse events: 5.9% semaglutide vs. 4.6% placebo

Gallbladder disorders: 3.6% semaglutide vs. 0.7% placebo

No new safety signals emerged during the extended treatment period

The safety profile over 104 weeks was consistent with the known GLP-1 receptor agonist class effects, with no evidence of increased risk over time [1].

Comparison with Other STEP Trials

STEP 5 results were consistent with, and complementary to, other trials in the STEP program:

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The consistency of ~15% weight loss across STEP 1, 3, and 5 (all in non-diabetic populations) reinforced the reliability of semaglutide's efficacy [2].

Clinical Significance

STEP 5 addressed several critical questions for clinical practice:

Durability confirmed: Weight loss with semaglutide is maintained for at least two years with continued treatment, countering concerns about tolerance or tachyphylaxis.

No dose escalation needed: The 2.4 mg dose remained effective throughout the study without requiring dose increases.

Ongoing treatment paradigm: The results support treating obesity as a chronic disease requiring ongoing pharmacotherapy, similar to hypertension or hyperlipidemia.

Quality of life: Patient-reported outcomes showed sustained improvements in physical functioning and weight-related quality of life over the full two years [1].

Limitations

The study was limited by its relatively small sample size (304 participants) compared to STEP 1 (1,961 participants). The study population was predominantly White (75%) and female (78%), which may limit generalizability. Additionally, the trial did not include patients with type 2 diabetes [1].

> Related Comparison: Ozempic vs Mounjaro: Complete Comparison

References

Garvey WT, Batterham RL, Bhatta M, et al. "Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial." Nature Medicine. 2022;28(10):2083-2091. PubMed: 36216945

Bergmann NC, Davies MJ, Lingvay I, Knop FK. "Semaglutide for the treatment of overweight and obesity: A review." Diabetes, Obesity and Metabolism. 2023;25(1):18-35. PMC: 10092086

Kushner RF, Calanna S, Davies M, et al. "Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5." Obesity. 2020;28(6):1050-1061. PubMed: 32441473

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