SEMAGLUTIDE (WEGOVY®)





Acronyms



DRUGS IN CLASS



MECHANISM OF ACTION



FDA-APPROVED INDICATIONS



WEIGHT LOSS


RCT
STEP 1 Study - Wegovy vs Placebo for Weight Loss in Adults Without Diabetes, NEJM (2021) [PubMed abstract]
  • The STEP 1 study enrolled 1961 overweight or obese adults without diabetes
Main inclusion criteria
  • Age ≥ 18 years
  • ≥ 1 failed attempt at dieting
  • BMI ≥ 30 or ≥ 27 with one weight-related condition (e.g. OSA, hyperlipidemia, CVD)
Main exclusion criteria
  • Diabetes
  • HgA1C ≥ 6.5%
  • Previous obesity surgery
  • History of chronic pancreatitis
  • Acute pancreatitis within 180 days
Baseline characteristics
  • Average age 46 years
  • Female sex - 74%
  • Average weight - 231 lbs (105 kg)
  • Average BMI - 38
Randomized treatment groups
  • Group 1 (1306 patients): Wegovy 2.4 mg subcutaneously once weekly
  • Group 2 (655 patients): Placebo
  • Wegovy was started at a dose of 0.25 mg once weekly and increased every 4 weeks over a period of 16 weeks to a target dose of 2.4 mg once weekly
  • All patients also received diet and exercise counseling
Primary outcome: Coprimary endpoints were the percentage change in body weight from baseline to week 68 and achievement of a reduction in body weight of 5% or more from baseline to week 68
Results

Duration: 68 weeks
Outcome Wegovy Placebo Comparisons
Percent weight loss 14.9% 2.4% p<0.001
Weight loss 33.6 lbs (15.3 kg) 5.7 lbs (2.6 kg) Diff -28, 95%CI (-30 to -25.7)
≥ 5% weight loss 86.4% 31.5% p<0.001
≥ 10% weight loss 69.1% 12% p<0.001
≥ 15% weight loss 50.5% 4.9% p<0.001
Change in fasting glucose -8.35 mg/dl -0.48 mg/dl Diff –7.87, 95%CI (–9.04 to –6.70)
Nausea 44.2% 17.4% N/A
Diarrhea 31.5% 15.9% N/A
Vomiting 24.8% 6.6% N/A
Constipation 23.4% 9.5% N/A
Hypoglycemia 0.6% 0.8% N/A
Drug discontinuation due to side effect 7% 3.1% N/A

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




RCT
STEP 8 trial - Wegovy vs Saxenda for Weight Loss in Overweight Adults, JAMA (2022) [PubMed abstract]
  • The STEP 8 trial enrolled 338 adults with BMI ≥ 30 or ≥ 27 and 1 or more weight-related comorbidities
Main inclusion criteria
  • Adults ≥ 18 years
  • BMI ≥ 30 or ≥ 27 with one weight-related condition (OSA, hyperlipidemia, CVD, hypertension)
  • ≥ 1 self-reported unsuccessful dietary weight loss effort
Main exclusion criteria
  • Diabetes
  • HgA1C ≥ 6.5%
  • Weight change ≥ 5 kg in last 90 days
Baseline characteristics
  • Average age 49 years
  • Female sex - 78.4%
  • Average BMI - 38
  • Average weight - 231 lbs (105 kg)
Randomized treatment groups
  • Group 1 (126 patients): Wegovy (semaglutide) 2.4 mg once weekly
  • Group 2 (127 patients): Saxenda (liraglutide) 3 mg once daily
  • Group 3 (85 patients): Placebo
  • Patients were randomized 3:1 to Wegovy or matching placebo or 3:1 to Saxenda or matching placebo. Wegovy and Saxenda treatment group assignments were not blinded.
  • Wegovy was titrated to 2.4 mg over 16 weeks. A 1.7 mg maintenance dose was permitted if 2.4 mg could not be tolerated
  • Saxenda was titrated over 4 weeks. If 3.0 mg dose was not tolerated, treatment could be restarted, with reescalation over 4 weeks.
Primary outcome: Percentage change from baseline in body weight at week 68
Results

Duration: 68 weeks
Outcome Wegovy Saxenda Comparisons
Primary outcome (% weight loss) 15.8% 6.4% p<0.001
People with ≥ 10% weight loss 71% 26% p<0.001
People with ≥ 20% weight loss 39% 6% p<0.001
Actual weight loss 34 lbs (15.3 kg) 15 lbs (6.8 kg) diff 8.5, 95%CI[11.2 to 5.7]
Discontinued treatment 13.5% 27.6% N/A
Nausea 61% 59% N/A
Constipation 39% 32% N/A
Diarrhea 28% 18% N/A
Vomiting 25% 21% N/A
  • Weight loss for the pooled placebo groups was 1.9%
  • Among subjects who did not stop treatment, 86.2% received the 2.4-mg dose of semaglutide and 95.7% received the 3.0-mg dose of liraglutide

Findings: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.



WEIGHT LOSS IN ADOLESCENTS


RCT
STEP TEENS Study - Wegovy vs Placebo for Weight Loss in Obese Adolescents, NEJM (2022) [PubMed abstract]
  • The STEP TEENS study enrolled 201 obese adolescents aged 12 - 17 years
Main inclusion criteria
  • Age 12 to <18 years
  • BMI ≥ 95th percentile OR ≥ 85th with ≥ 1 of the following:
    • Hypertension
    • Dyslipidemia
    • OSA
    • Type 2 diabetes
Main exclusion criteria
  • Diet med within 90 days
  • Secondary obesity
  • Severe psychiatric disorder
  • HgA1C > 10%
Baseline characteristics
  • Average age 15.4 years
  • Female sex - 62%
  • Average weight - 238 lbs (108 kg)
  • Average BMI - 37
Randomized treatment groups
  • Group 1 (134 patients): Wegovy 2.4 mg once weekly
  • Group 2 (67 patients): Placebo
  • Before treatment, all patients underwent a 12-week run-in phase where they received lifestyle interventions
  • Wegovy was started at 0.25 mg once weekly and titrated to 2.4 mg over 16 weeks
Primary outcome: Percentage change in BMI from baseline to week 68
Results

Duration: 68 weeks
Outcome Wegovy Placebo Comparisons
Primary outcome -16.1% +0.6% p<0.001
Change in body weight -34 lbs (15 kg) +5.3 lbs (2.4 kg) diff 17.7 kg, 95%CI [-21.8 to -13.7]
% change in body weight -14.7% +2.7% diff 17.4%, 95%CI [-21.1 to -13.7]
Nausea 42% 18% N/A
Vomiting 36% 10% N/A
Diarrhea 22% 19% N/A
Abdominal pain 15% 6% N/A
Cholelithiasis 4% 0% N/A
  • 90% of participants in both groups completed 68 weeks of treatment. Of the participants who completed treatment with Wegovy, 87% completed the trial at the 2.4-mg dose.

Findings: Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone



HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)


RCT
STEP-HFpEF trial - Semaglutide vs Placebo in Obese Nondiabetics with HFpEF, NEJM (2023) [PubMed abstract]
  • STEP-HFpEF enrolled 529 patients with HFpEF (EF ≥ 45%) and a BMI ≥ 30
Main inclusion criteria
  • BMI ≥ 30
  • EF ≥ 45%
  • NYHA class II, III, or IV symtpoms
  • ≥ 1 of the following:
    • Elevated LV filling pressure
    • Elevated natriuretic peptide + ECHO abnormalities
    • Hospitalization for HF within 12 months + diuretic use or ECHO abnormalities
Main exclusion criteria
  • Diabetes
  • SBP > 160 mmHg
  • History of bariatric surgery
  • ≥ 11 lb change in body weight within 90 days
Baseline characteristics
  • Median age 69 years
  • Median BMI - 37
  • Median body weight - 231 lbs (105 kg)
  • LVEF ≥ 50% - 84%
  • Atrial fibrillation - 52%
  • Median NT-proBNP - 451 pg/ml
  • Median C-reactive protein - 3.8 mg/L
  • Median KCCQ-CSS - 58.9
  • Median 6-minute walk distance - 320 m
  • NYHA class: II - 66% | III or IV - 34%
Randomized treatment groups
  • Group 1 (263 patients): Semaglutide with a target dose of 2.4 mg once weekly
  • Group 2 (266 patients): Placebo
  • Semaglutide was started at 0.25 mg once weekly and titrated over 16 weeks
Primary outcome: Dual primary endpoints were the change in the KCCQ-CSS (scale 0 - 100 with higher scores reflecting better health) and the percentage change in body weight from baseline to week 52
Results

Duration: 52 weeks
Outcome Semaglutide Placebo Comparisons
Change in KCCQ-CSS +16.6 +8.7 p<0.001
Change in body weight -13.3% -2.6% p <0.001
Change in 6-min walk distance +21.5 m +1.2 m p <0.001
Change in C-reactive protein -43.5% -7.3% p <0.001
Change in NT-proBNP -21% -5.3% N/A
GI side effects leading to discontinuation 9.5% 2.6% N/A
Cardiac disorder (e.g. A fib, heart failure) 2.7% 11.3% p <0.001
  • At week 52, 84% of active participants in the semaglutide group were receiving the 2.4 mg dose
  • 16% of semaglutide-treated patients discontinued therapy prematurely compared to 15.8% in the placebo group
  • A secondary analysis that pooled data from STEP-HFpEF and STEP-HFpEF DM found that women had similar improvements in heart failure symptoms as men and lost more weight. [PMID 38913003]

Findings: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo.





CARDIOVASCULAR DISEASE


RCT
SELECT trial - Semaglutide vs Placebo for Secondary Prevention of CVD Events in Obese Nondiabetics, NEJM (2023) [PubMed abstract]
  • The SELECT trial enrolled 17,604 nondiabetics with a history of CVD and a BMI ≥ 27
Main inclusion criteria
  • Age 45 years and older
  • BMI ≥ 27
  • One or more of the following:
    • Previous MI
    • Stroke
    • Symptomatic PAD
Main exclusion criteria
  • Diabetes or diabetes drug within 90 days
  • NYHA class IV heart failure
  • End-stage kidney disease
  • CVD event within 60 days
Baseline characteristics
  • Average age 62 years
  • Average BMI - 33
  • Average weight - 213 lbs (96.7 kg)
  • Prediabetes - 66.4%
  • CVD qualifier: MI - 76% | Stroke - 23% | PAD - 9%
Randomized treatment groups
  • Group 1 (8803 patients): Semaglutide with a target dose of 2.4 mg once weekly
  • Group 2 (8801 patients): Placebo
  • Semaglutide was titrated over 4 months (0.25, 0.5, 1, 1.7, 2.4 mg). Patients who did not tolerate dose increases could stay at lower doses.
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-first-event analysis
Results

Duration: 40 months
Outcome Semaglutide Placebo Comparisons
Primary outcome 6.5% 8% p<0.001
Death from CVD 2.5% 3% p=0.07
Overall mortality 4.3% 5.2% HR 0.81 95%CI [0.71 - 0.93]
Nonfatal MI 2.7% 3.7% HR 0.72 95%CI [0.61 - 0.85]
Nonfatal Stroke 1.7% 1.9% HR 0.93 95%CI [0.74 - 1.15]
% weight loss at 104 weeks 9.39% 0.88% Diff -8.51 95%CI [(-8.75 to -8.27]
  • At week 104, 77% of semaglutide-treated patients were taking the 2.4 mg dose
  • Permanent drug discontinuation due to side effects occurred in 16.6% of semaglutide-treated patients and 8.2% of placebo-treated patients
  • A subgroup analysis of patients with HFpEF or HFrEF at baseline found that semaglutide significantly reduced CVD and heart failure endpoints compared to placebo in both groups. [PMID 39181597]

Findings: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months.




KNEE OSTEOARTHRITIS (OA)


RCT
STEP 9 - Semaglutide vs Placebo for Knee Osteoarthritis in Patients with Obesity, NEJM (2024)  [PubMed abstract]
  • The STEP 9 study enrolled 407 patients with BMI ≥ 30 and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain
Main inclusion criteria
  • Age 18 years or older
  • BMI ≥ 30
  • ACR diagnostic criteria for knee OA
  • Moderate X-ray changes (Kellgren-Lawrence grade 2 or 3) in target knee
  • Knee OA WOMAC pain score of ≥ 40
Main exclusion criteria
  • Use of opioid medications
  • Use of obesity medication within 90 days
  • Knee injection within 90 days
Baseline characteristics
  • Average age - 56 years
  • Average weight - 239 lbs (108.6 kg)
  • Average BMI - 40.3
  • Female sex - 82%
  • Average WOMAC pain score - 70.9
Randomized treatment groups
  • Group 1 (271 patients): Semaglutide 2.4 mg once weekly
  • Group 2 (136 patients): Placebo
  • Semaglutide was started at 0.24 mg once weekly and titrated over 16 weeks to 2.4 mg
Primary outcome: The percentage change in body weight and the change in the WOMAC pain score (scale 0 - 100, with higher scores meaning worse outcomes) from baseline to week 68
Results

Duration: 68 weeks
Outcome Semaglutide Placebo Comparisons
% change in body weight -13.7% -3.2% p<0.001
Change in WOMAC pain score -41.7 points -27.5 points p<0.001
≥ 10% body weight loss 70.4% 9.2% p<0.001
Change in SF-36 physical-function score 12.0 points 6.5 points p<0.001
Drug discontinuation due to adverse event 6.7% 3.0% RR 2.26, 95%CI[0.82 to 6.30]
GI event leading to discontinuation 2.2% 0% RR 2.2 95%CI[-0.8 - 4.8]
  • The incidence of serious adverse events was similar between groups (semaglutide - 10.0%, placebo - 8.1%)

Findings: Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo.



SIDE EFFECTS


  • Reference [1]
Side effect Wegovy
(N=1261)
Placebo
(N=2116)
Nausea 44% 16%
Diarrhea 30% 16%
Vomiting 24% 6%
Constipation 24% 11%
Abdominal pain 20% 10%
Dyspepsia 9% 3%
Abdominal distension 7% 5%
Belching 7% < 1%
Flatulence 6% 4%

















CONTRAINDICATIONS



PRECAUTIONS






DRUG INTERACTIONS





DOSING



Weeks Weekly Dose
1 through 4 0.25 mg
5 through 8 0.5 mg
9 through 12 1 mg
13 through 16 1.7 mg
Week 17 and onward 1.7 mg or 2.4 mg



LONG-TERM SAFETY



BIBLIOGRAPHY