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Semaglutide is a game changer for overweight and obesity

Once-Weekly Semaglutide in Adults with Overweight or Obesity

STEP trials

N Engl J Med 2021; 384:989-1002

STEP Trials

(Semaglutide Treatment Effect in People with obesity)

What is semaglutide

  • Semaglutide is a glucagon-like peptide (GLP-1) analogue which works by slowing gastric emptying, increasing production of insulin by enhancing the growth of beta cells in the pancreas that make insulin. Moreover, semaglutide decreases glucagon that would normally increase secretion of glucose into the bloodstream.

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant, 14.9% reduction in body weight.


  • 1961 participants

  • BMI > 30 or BMI > 27 with 1 weight-related coexisting condition (not diabetes)

  • 68 weeks of treatment with semaglutide (slowly ramped up to 2.4 mg) and lifestyle interventions

    • Lifestyle interventions - Counseling and decrease in 500 kcal daily and 150 minutes exercise weekly (encouraged)

  • Primary endpoints - Percent weigh lost or weight loss of at least 5% of body weight

  • Intention to treat model - meaning that all patients that were enrolled were included in the analysis

  • Most participants were white females, average BMI 37.9, mean body weight 231 kg, 43.7% with prediabetes


  • 94% participants completed the trial

  • Mean weight loss was 14.9% on semaglutide compared to 2.4% on placebo (95% CI)

  • 86% in semaglutide group lost at least 5% of their body weight versus 69% on placebo

  • Other trends noted

    • Decreased average sugar, blood pressure, waist circumference, lipids, inflammatory markers

    • Semaglutide lead to decreased visceral fat mass with an increase in lean body mass

  • Most common side effect is nausea

What does all this mean?

  • Semaglutide will be continued to be studied.

  • Semaglutide joins liraglutide (Victoza) as another GLP-1 agonist option for weight loss.

  • The problem - It is very expensive.

Follow up study

  • STEP 2: Compared three doses of semaglutide and subsequent weight loss over 68 weeks

    • 2.4 mg - 9.64% weight loss

    • 1.0 mg - 6.99% weight loss

    • placebo - 3.42% weight loss

  • STEP 3: semaglutide 2.4 mg and intensive lifestyle behavioral therapy

    • 2.4 mg - 16.4% weight loss with 86.6% losing at least 5% bodyweight

    • placebo - 5.7% with 47.6% losing at least 5% of bodyweight

  • STEP 4: semaglutide 2.4 mg for 20 weeks then randomized to continue or switch to placebo

    • 2.4 mg - 17.4% weight loss

    • switched to placebo - regained average of 6.9% leading to average weight loss of 5%

What does this all mean?

  • Semaglutide is an amazing medication for weight loss in the setting of overweight and obesity with our without diabetes.

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