Acronyms
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- AHA - American Heart Association
- CAD - Coronary artery disease
- CrCl - Creatinine clearance
- CVD - Cardiovascular disease
- DM - Diabetes mellitus
- FBS - Fasting blood sugar
- GFR - Glomerular filtration rate
- GI - Gastrointestinal
- GLP-1 - Glucagon-like peptide-1
- HFpEF - Heart failure with preserved ejection fraction
- NAION - Nonarteritic anterior ischemic optic neuropathy
- OSA - Obstructive sleep apnea
- PAD - Peripheral artery disease
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- Thyroid C-cell tumor = Thyroid medullary tumor
- WOMAC - Western Ontario and McMaster Universities Osteoarthritis Index
DRUGS IN CLASS
- GLP-1 analogs
- Semaglutide (Wegovy®) is a GLP-1 analog, a drug class originally developed to treat type 2 diabetes. Patients receiving GLP-1 analogs sometimes saw significant weight loss, creating interest in using them as an obesity treatment. Another GLP-1 analog, liraglutide (Saxenda®), was FDA-approved for weight loss in 2014.
- Semaglutide is available in three medications: Wegovy®, Ozempic®, and Rybelsus®. Ozempic® (injection) and Rybelsus® (tablet) are FDA-approved to treat type 2 diabetes, and Wegovy® is approved for weight loss.
MECHANISM OF ACTION
- GLP-1 analogs
- Glucagon-like peptide-1 (GLP-1) is a hormone secreted into the bloodstream by special cells in the intestine in response to food consumption. GLP-1 has the following actions: (1) slows gastric emptying; (2) stimulates insulin release and suppresses glucagon secretion in the pancreas; (3) suppresses appetite in the brain. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1, rendering it inactive.
- GLP-1 analogs have a similar structure to endogenous GLP-1, mimicking its actions in the pancreas, stomach, and brain. They have also been modified so that DPP-4 cannot metabolize them.
FDA-APPROVED INDICATIONS
- Weight loss (adults)
- As an adjunct to diet and exercise for weight loss in adults with a BMI ≥ 30 or ≥ 27 in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes, dyslipidemia) [STEP 1 study]
- Adult BMI calculator
- Weight loss (children ≥ 12 years old)
- As an adjunct to a reduced-calorie diet and increased physical activity in pediatric patients aged 12 years and older with an initial BMI at the 95th percentile or greater for age and sex. [STEP TEENS study]
- Child and teen BMI calculator
- Secondary prevention of CVD (adults)
- To reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with established cardiovascular disease and either obesity or overweight. [SELECT trial]
WEIGHT LOSS
- Overview
- The effects of Wegovy on weight loss were studied in the five trials detailed below. In the first two trials, Wegovy was compared to placebo in adults without diabetes. In the third trial, all patients were given Wegovy for 20 weeks and then randomized to continue it or switch to placebo for 48 additional weeks. In the fourth trial, it was compared to Ozempic and placebo in adults with diabetes, and in the fifth trial, it went head-to-head with Saxenda, another GLP-1 agonist approved for 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.
- RCTSTEP 3 Trial - Wegovy vs Placebo for Weight Loss in Overweight Adults Without DM, JAMA (2021) [PubMed abstract]
- Design: Randomized, placebo-controlled trial (N=611 | length = 68 weeks) in overweight or obese adults (average weight 233 lbs | average BMI 38) without diabetes
- Treatment: Wegovy 2.4 mg sub-q once weekly vs Placebo. All patients received diet counseling and behavioral therapy.
- Primary outcome: Percentage change in body weight and the proportion of participants who lost at least 5% of baseline weight by week 68
- Results:
- Primary outcome (% weight loss): Wegovy - 16%, Placebo - 5.7% (p<0.001)
- Primary outcome (≥ 5% weight loss): Wegovy - 86.6%, Placebo - 47.6% (p<0.001)
- Average weight loss: Wegovy - 37 lbs (16.8 kg) , Placebo - 13.6 lbs (6.2 kg) (p<0.001)
- Adverse gastrointestinal events: Wegovy - 83%, Placebo - 63%
- Adverse events leading to drug discontinuation: Wegovy - 5.9%, Placebo - 2.9%
- Findings: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.
- RCTSTEP 4 study - Continue vs Stop Wegovy after 20 Weeks in Overweight Adults, JAMA (2021) [PubMed abstract]
- Design: Randomized, placebo-controlled trial (N=902 | length = 68 weeks) in overweight or obese adults (average weight 235 lbs | average BMI 38) without diabetes
- Treatment: All patients received Wegovy for 20 weeks. Those who were receiving Wegovy 2.4 mg at week 20 were randomized to continue Wegovy 2.4 mg or placebo for 48 more weeks.
- Primary outcome: Percent change in body weight from randomization (week 20) to week 68
- Results:
- At week 20, average weight loss was 10.6%
- Primary outcome: Continue Wegovy -7.9%, Placebo +6.9% (p <0.001)
- Findings: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks
- RCTSTEP 2 Trial - Wegovy 2.4 mg vs Ozempic 1 mg vs Placebo for Weight Loss in Overweight Diabetics, Lancet (2021) [PubMed abstract]
- Design: Randomized, placebo-controlled trial (N=1210 | length = 68 weeks) in overweight diabetics with BMI ≥ 27 (average weight 220 lbs | average BMI 35.7) and an A1C of 7 - 10% (average 8.1%)
- Treatment: Wegovy 2.4 mg sub-q once weekly vs Ozempic 1 mg sub-q once weekly vs Placebo
- Primary outcome: Percentage change in body weight from baseline to week 68 and loss of at least 5% of baseline weight at week 68 for semaglutide 2.4 mg vs placebo
- Results:
- Primary outcome (% weight loss): Wegovy 2.4 mg - 9.64%, Ozempic 1 mg - 6.99%, Placebo - 3.42% (Semaglutide 2.4 vs placebo, p<0.0001)
- Primary outcome (≥ 5% weight loss): Wegovy 2.4 mg - 68.8%, Ozempic 1 mg - 57.1%, Placebo - 28.5% (Semaglutide 2.4 vs placebo, p<0.0001)
- Average weight loss: Wegovy 2.4 mg - 21.3 lbs (9.7 kg), Ozempic 1 mg - 15.2 lbs (6.9 kg), Placebo - 7.7 lbs (2.2 kg)
- Decrease in A1C: Wegovy 2.4 mg - 1.6%, Ozempic 1 mg - 1.5%, Placebo - 0.4%
- Adverse gastrointestinal events: Wegovy 2.4 mg - 63.5%, Ozempic 1 mg - 57.5%, Placebo - 34.3%
- Adverse events leading to drug discontinuation: Wegovy 2.4 mg - 6.2%, Ozempic 1 mg - 5%, Placebo - 3.5%
- Findings: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in body weight compared with placebo.
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 |
|
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.
- Summary
- Wegovy achieved impressive weight loss in the trials detailed above, and it was decisively better than Saxenda in the STEP 8 trial.
- In the STEP 2 trial that only enrolled overweight diabetics, Wegovy caused more weight loss than Ozempic 1 mg, but the difference was not overwhelming (9.6% vs 7%). A1C reductions were also similar between the groups (1.6% vs 1.5%).
- In the STEP 4 trial, patients lost 10.6% of their body weight after 20 weeks of Wegovy, and those who continued it lost an additional 7.9% over 48 weeks. Patients who were switched to placebo gained back 6.9%.
- Gastrointestinal side effects were common in all the trials but did not lead to a large number of discontinuations
WEIGHT LOSS IN ADOLESCENTS
- Overview
- The STEP TEENS study detailed below evaluated the effects of Wegovy on weight loss in obese adolescents aged 12 - 17 years
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 |
|
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
- Summary
- Wegovy caused impressive weight loss in the STEP TEENS study, and its effects were greater than other drugs approved for adolescent obesity (see Qsymia and Saxenda). As expected, gastrointestinal side effects were common, and 4% of Wegovy-treated patients experienced cholelithiasis, a known adverse effect of rapid weight loss. In 2022, Wegovy received FDA approval to treat adolescent obesity based on the STEP TEENS study.
HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)
- Overview
- HFpEF is a syndrome characterized by symptoms of heart failure (e.g., dyspnea, fluid retention, fatigue) in patients with an ejection fraction of 45% or greater. It is believed to arise secondary to impaired left ventricular relaxation during diastole, with obesity being a significant risk factor. HFpEF is notoriously difficult to treat, and currently, only two drugs, the SGLT2 inhibitors dapagliflozin and empagliflozin, are FDA approved to treat it. The two trials below evaluated the effects of semaglutide on HFpEF in patients without (STEP-HFpEF) and with diabetes (STEP-HFpEF DM).
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 |
|
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.
- RCTSTEP-HFpEF DM trial - Semaglutide vs Placebo in Obese Diabetics with HFpEF, NEJM (2024) [PubMed abstract]
- Design: Randomized, placebo-controlled trial (N=616 | length = 52 weeks) in obese type 2 diabetics (BMI ≥ 30) with HFpEF
- Treatment: Semaglutide titrated to 2.4 mg once weekly vs Placebo
- Primary outcome: Change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight
- Results:
- Primary outcome (change in KCCQ-CSS score): Semaglutide +13.7, Placebo +6.4 (p<0.001)
- Primary outcome (% weight change): Semaglutide -9.8%, Placebo -3.4% (p<0.001)
- Findings: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure–related symptoms and physical limitations and greater weight loss than placebo at 1 year.
- AHA recommendations
- Summary
- Semaglutide improved HFpEF symptoms in the STEP-HF trials, which is unsurprising given that significant weight loss improves almost any cardiac outcome. In their discussion, the STEP-HF authors note that the difference in KCCQ-CSS improvement between semaglutide and placebo (8 points) was much greater than that seen in trials with other agents, including SGLT2 inhibitors, Entresto, and spironolactone (typically 0.5 - 2.3 points). SGLT2 inhibitor trials were longer and primarily focused on cardiovascular outcomes (e.g., heart failure hospitalization, cardiovascular death), whereas the STEP-HF trials evaluated symptoms and weight loss.
CARDIOVASCULAR DISEASE
- Overview
- The SELECT trial below evaluated the effects of semaglutide on the secondary prevention of cardiovascular disease in nondiabetics
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] |
|
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.
- AHA recommendations
- Summary
- The SELECT trial found that semaglutide improved cardiovascular outcomes among patients with established CVD, which is unsurprising given the positive effects weight loss has on a person's health. The absolute risk reductions were small, only 1.5% (6.5% vs 8%) for the composite outcome and 0.9% (4.3% vs 5.2%) for overall mortality, but the enormous size of the trial (N=17,604) caused them to come back significant. The number needed to treat to prevent one composite event is 67, and one death is 111. Semaglutide-treated patients lost an average of 9.4% of their body weight over two years, while 17% discontinued the drug because of side effects.
KNEE OSTEOARTHRITIS (OA)
- Overview
- Knee osteoarthritis (OA) is caused and worsened by obesity, as both mechanical stress and obesity-induced inflammation accelerate joint destruction. Weight loss improves knee OA, with studies showing a 2% improvement in the WOMAC pain, function, and stiffness scores for every 1% reduction in body weight. The STEP-9 study, detailed below, compared semaglutide to placebo in patients with moderate knee osteoarthritis and at least moderate pain.
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] |
|
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.
- Summary
- As expected, semaglutide-induced weight loss improved knee pain and function in a predominantly female population (82%) with moderate knee OA. A missed opportunity in the study was the absence of follow-up imaging to assess for changes in joint pathology.
SIDE EFFECTS
- Gastrointestinal (GI) side effects
- Gastrointestinal complaints are the most common side effects of Wegovy. To help prevent these issues, Wegovy is started at a low dose and titrated gradually. Incidences of GI complaints from Wegovy trials are presented in the table below.
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% |
- Hypoglycemia
- Wegovy by itself does not pose a significant risk of hypoglycemia. When it is taken with diabetes medications, particularly insulin and insulin secretagogues, the risk of hypoglycemia is increased. In the STEP 1 Study that only enrolled nondiabetics, Wegovy did not increase the risk of hypoglycemia. In trials involving diabetics, the incidence of hypoglycemia was 6.2% in Wegovy-treated patients and 2.5% in placebo-treated patients.
- Patients who are taking concomitant diabetes medications should monitor their blood sugars closely and be prepared to treat hypoglycemia (see hypoglycemia for more)
- Injection site reactions
- Injection site reactions, including pruritus, erythema, inflammation, induration, and irritation, may occur. In studies, reactions were reported in 1.4% of Wegovy-treated patients and 1.0% of placebo-treated patients.
- Severe GI adverse reactions
- Severe GI adverse reactions have been reported in patients receiving Wegovy. In placebo-controlled trials, severe GI reactions were reported in 4.1% of Wegovy-treated patients compared to 0.9% of placebo-treated patients. Wegovy is not recommended in patients with severe gastroparesis.
- Hypersensitivity reactions
- Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with semaglutide
- Avoid use in patients with known hypersensitivity to semaglutide and use caution in patients with a history of reactions to other GLP-1 analogs
- Semaglutide antibodies
- Semaglutide can induce an immune response that leads to the production of anti-semaglutide antibodies, and in some cases, these antibodies cross-react with endogenous GLP-1
- In trials, 2.9% of Wegovy-treated patients developed anti-semaglutide antibodies, and of these patients, 56% had antibodies that cross-reacted with endogenous GLP-1. The effects of these antibodies on efficacy and hypersensitivity reactions are unknown.
- Pancreatitis
- Acute pancreatitis has been reported in patients receiving GLP-1 analogs, including semaglutide. In trials, acute pancreatitis occurred in 4 Wegovy-treated patients (0.2 cases per 100 patient-years) and 1 placebo-treated patient (< 0.1 cases per 100 patient-years). There is limited data on the use of Wegovy in patients with a history of pancreatitis, and it is unknown if these patients are at increased risk of Wegovy-induced pancreatitis. If symptoms of pancreatitis occur (e.g., abdominal pain, nausea, vomiting), discontinue Wegovy and initiate appropriate care. If pancreatitis is confirmed, Wegovy should not be restarted.
- Decreased kidney function
- There have been case reports of decreased kidney function in patients receiving semaglutide. In most cases, patients were experiencing GI side effects of semaglutide (e.g. nausea, vomiting, and/or diarrhea) that can lead to dehydration and worsening kidney function.
- Use caution in patients with renal impairment, and monitor renal function in patients experiencing significant GI reactions
- Hypotension and syncope
- GI side effects from Wegovy can lead to dehydration and low blood pressure. In trials, hypotensive events were reported in 1.3% of Wegovy-treated patients and 0.4% of placebo-treated patients, and syncope occurred in 0.8% and 0.2%, respectively. Patients taking antihypertensives are at greater risk. Monitor blood pressure closely in susceptible patients.
- Gallbladder disease
- In adult trials, cholelithiasis was more common in Wegovy-treated patients than placebo-treated patients (1.6% vs 0.7%), as was cholecystitis (0.6% vs 0.2%). In adolescent trials, Wegovy-treated patients were also more likely to experience cholelithiasis (3.8% vs 0%) and cholecystitis (0.8% vs 0%). Substantial or rapid weight loss can increase the risk of cholelithiasis; however, even after accounting for the degree of weight loss, Wegovy-treated patients still had a higher incidence of acute gallbladder disease.
- Patients who report symptoms of gallbladder disease (e.g. abdominal pain, nausea, vomiting) should have a prompt workup
- Thyroid cancer
- In toxicology studies, a dose-dependent and treatment-duration-dependent increase in the incidence of malignant and benign thyroid medullary tumors (C-cell tumors) was observed in rats and mice receiving clinically relevant doses of GLP-1 analogs. This prompted the FDA to place a boxed warning about medullary thyroid cancer on some GLP-1 analogs, including semaglutide. It is unknown if GLP-1 analogs increase the risk of tumors in humans as the incidence of these events is too low to establish causality.
- Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, a condition that increases the risk for medullary thyroid cancer. Patients should be aware of the potential risk and report any thyroid symptoms if they occur. Medullary thyroid cancer usually causes elevations in calcitonin levels above 50 ng/L.
- Diabetic retinopathy
- In adult type 2 diabetic trials, diabetic retinopathy was reported in 4% of Wegovy-treated patients and 2.7% of placebo-treated patients. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with baseline diabetic retinopathy may be at greater risk for worsening and should be monitored appropriately. The long-term effects of semaglutide on diabetic retinopathy have not been studied.
- Pancreatic enzyme elevations
- In trials, patients treated with Wegovy had an average increase from baseline in amylase of 16% and lipase of 39%. No increase was observed in placebo-treated patients. The significance of these effects is unknown.
- Heart rate increase
- In adult trials, Wegovy-treated patients had an average increase in heart rate of 1 - 4 bpm compared to placebo. Maximum increases of 10 - 19 bpm from baseline at any visit were observed in more Wegovy-treated patients than placebo-treated patients (41% vs 34%), as were increases of ≥ 20 bpm (26% vs 16%). In adolescent trials, changes in heart rate of 20 bpm or more were more common in Wegovy-treated patients than placebo-treated patients (54% vs 39%).
- Monitor heart rates in Wegovy-treated patients and discontinue therapy if sustained increases occur
- Suicide behavior and ideation
- Suicidal behavior and ideation have been reported in clinical trials with other weight management products. Monitor patients for depression, suicidal thoughts, or other unusual changes in mood. Avoid use in patients with a history of suicidal behavior, and discontinue therapy in patients who develop suicidal ideation. On 1/11/2024, the FDA issued a communication stating that after a review of clinical trial data, they have not found an association between GLP drugs and suicidal behavior or thoughts. Their review is ongoing. FDA Safety Communication
- Nonarteritic anterior ischemic optic neuropathy
- A single-institution cohort study published in 2024 found an association between semaglutide and nonarteritic anterior ischemic optic neuropathy (NAION), a condition marked by anterior optic nerve ischemia without arteritis. [PMID 38958939]
- Semaglutide may increase the risk of NAION; however, further evaluation is needed to prove causality
CONTRAINDICATIONS
- A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in Wegovy
PRECAUTIONS
- Kidney disease
- No dose adjustment is necessary for any degree of renal impairment
- Liver disease
- No dose adjustment is necessary for any degree of hepatic impairment
- Stomach disorders
- Wegovy slows gastric emptying and is not recommended in patients with significant stomach disorders, including diabetic gastroparesis
- General anesthesia or deep sedation
- GLP-1 therapies, like Wegovy, slow gastric emptying, possibly increasing the risk of residual gastric contents and pulmonary aspiration in patients receiving anesthesia or deep sedation for procedures. Rare postmarketing cases of pulmonary aspiration from retained stomach contents have been reported in GLP-1-treated patients, even after following the recommended preoperative fast. Recommendations from the American Society of Anesthesiologists for managing GLP-1 therapies perioperatively are available here - GLP-1 therapy perioperative management recommendations.
DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Semaglutide (Wegovy®)
- Insulin and insulin secretagogues - when combined with insulin or insulin secretagogues (e.g. sulfonylureas, meglitinides), semaglutide increases the risk of hypoglycemia. Monitor blood sugars closely and adjust medications as needed.
- Drugs affected by decreased gastric emptying - see gastric emptying below
- Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of GLP-1 analogs
- Drugs affected by gastric emptying
- Medications are partially digested in the stomach before being emptied into the small intestine, where most drug absorption occurs. GLP-1 analogs slow the process of gastric emptying, potentially altering the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
- Antibiotics
- Antibiotics require rapid absorption to achieve their desired therapeutic effect
- Drugs with a narrow therapeutic index
- Drugs with narrow therapeutic index may have their steady-state altered by delayed gastric emptying
- Examples of drugs with a narrow therapeutic index:
- Carbamazepine (Tegretol®)
- Cyclosporine (Neoral®)
- Digoxin
- Levothyroxine (Synthroid®)
- Lithium
- Phenytoin (Dilantin®)
- Tacrolimus (Prograf®)
- Theophylline (Theo-24®)
- Warfarin (Coumadin®) [2]
- Metabolism and clearance
- Semaglutide is metabolized by proteolytic cleavage and beta-oxidation. The remnants of these processes are eliminated via the urine and feces.
DOSING
- Dosage forms (single-dose pen-injector)
- 0.25 mg/0.5 ml
- 0.5 mg/0.5 ml
- 1 mg/0.5 ml
- 1.7 mg/0.75 ml
- 2.4 mg/0.75 ml
- Comes in carton with 4 pens
- Store in refrigerator. May be kept at room temperature for up to 28 days.
- No generic. Cost > $150/month.
- Dosing (adults and children ≥ 12 years)
- The recommended titration schedule for Wegovy is provided in the table below
- Wegovy is given once weekly, on the same day each week, at any time of day, with or without meals
- Administer subcutaneously in the abdomen, thigh, or upper arm
- Missed doses:
- If one dose is missed and the next scheduled dose is more than 2 days away (48 hours), administer Wegovy as soon as possible. If one dose is missed and the next scheduled dose is less than 2 days away (48 hours), do not administer the dose. Resume dosing on the regularly scheduled day of the week.
- If 2 or more consecutive doses are missed, resume dosing as scheduled or, if needed, reinitiate Wegovy and follow the dose escalation schedule, which may reduce the occurrence of gastrointestinal symptoms associated with reinitiation of treatment.
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 |
- Storage
- Keep pens refrigerated. Do not freeze.
- Prior to cap removal, pens may be kept at room temperature for up to 28 days.
LONG-TERM SAFETY
- The first GLP-1 analog (exenatide) was FDA-approved in 2005. When used appropriately, GLP-1 analogs have a good safety record.
BIBLIOGRAPHY
- 1 - Wegovy PI
- 2 - North Carolina Pharmacy Practice Act. Article 4A. 90-85.28(b1).