# Once-Weekly Semaglutide for Weight Loss and Knee Pain Relief in People with Obesity and Knee Osteoarthritis

In a 68-week randomized trial of 407 adults with obesity and painful knee osteoarthritis, once-weekly semaglutide 2.4 mg produced a 13.7% average weight loss versus 3.2% with placebo, and a 41.7-point improvement on a 100-point knee pain scale versus 27.5 points with placebo. Both differences were statistically significant (P<0.001). Physical function improved more with semaglutide (12.0 vs. 6.5 points on the SF-36 scale), and serious adverse events were similar between groups, though more participants stopped treatment because of side effects with semaglutide than with placebo (6.7% vs. 3.0%), most often due to gastrointestinal problems.

# Once-Weekly Semaglutide for Weight Loss and Knee Pain Relief in People with Obesity and Knee Osteoarthritis

## Table of Contents

- Key Points
- Background: Why This Research Matters
- How the Study Was Conducted
- Who Participated in the Study
- Key Findings: Weight Loss and Pain Relief
- Additional Findings: Function, Waist Size, and More
- Safety and Side Effects
- What This Means for Patients
- Limitations of the Study
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information

## Key Points

- In a 68-week trial of 407 adults with obesity and knee osteoarthritis, once-weekly semaglutide 2.4 mg led to 13.7% average weight loss versus 3.2% with placebo.
- Knee pain on a 100-point scale improved by 41.7 points with semaglutide versus 27.5 points with placebo; the extra benefit was 14.1 points.
- Physical function and waist circumference improved more with semaglutide than placebo in the trial.
- Serious adverse events were similar, but 6.7% on semaglutide stopped treatment due to side effects, most commonly gastrointestinal problems, versus 3.0% on placebo.
- The trial was limited to 407 mostly women and White participants, and longer studies are needed to confirm durability and structural effects.

## Background: Why This Research Matters

Knee osteoarthritis (the wear-and-tear form of arthritis) is the most common type of arthritis. It causes chronic pain, reduced mobility, disability, and a lower quality of life. Obesity is a major risk factor for developing knee osteoarthritis and for the condition getting worse.

Obesity-related knee osteoarthritis arises from several combined factors. These include increased mechanical stress on weight-bearing joints, metabolic dysfunction (problems with how the body processes energy and nutrients), and obesity-induced inflammation. Each of these factors contributes to joint damage and pain.

Weight reduction is known to help. Research has shown that for every 1% reduction in body weight, patients experience about a 2% improvement in WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain, function, and stiffness scores. Weight loss may also reduce the risk of structural progression of the disease.

Treatment guidelines recommend weight reduction and physical activity as the first-line management for obesity-related knee osteoarthritis. However, achieving clinically important weight reduction requires a combination of a reduced-calorie diet and patient-centered physical-activity interventions. These lifestyle changes can be challenging for patients to maintain over the long term.

Bariatric surgery (weight-loss surgery) may reduce knee pain in people with obesity, but data from randomized controlled trials are lacking. There remains an unmet need for weight-management medications that can help patients achieve nonsurgical, sustained weight reduction and reduce pain related to obesity and knee osteoarthritis.

Semaglutide is a GLP-1 (glucagon-like peptide-1) receptor agonist. It is given as a once-weekly injection under the skin. This medication is approved in several countries for weight management in people with a body-mass index (BMI) of 30 or greater. This medication is also approved for people with a BMI of 27 or greater who have at least one weight-related coexisting condition. In the United States, semaglutide is also approved for reducing the risk of major adverse cardiovascular events in adults with established cardiovascular disease and overweight or obesity.

The effect of GLP-1 receptor agonists on knee osteoarthritis outcomes in people with obesity had not been well studied before this trial. The STEP 9 trial was designed to assess whether a 2.4-mg dose of semaglutide would be superior to placebo as an add-on to lifestyle modifications. The trial assessed whether semaglutide would reduce body weight and pain related to knee osteoarthritis.

## How the Study Was Conducted

The STEP 9 trial was a multicenter, double-blind, randomized, placebo-controlled trial. This means that neither the participants nor the researchers knew who was receiving the active medication versus the placebo (an inactive injection). The trial was conducted at 61 sites across 11 countries.

The trial followed the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. An independent ethics committee or institutional review board at each participating institution approved the protocol.

The sponsor (Novo Nordisk) designed the trial, prepared the protocol and statistical analysis plan, and performed the statistical analyses. The investigators were responsible for trial-related medical decisions and data collection. The authors interpreted the aggregated data and made the decision to submit the manuscript for publication.

**Study design details:**

- Participants were randomly assigned in a 2:1 ratio to receive semaglutide or placebo. This means that for every 2 people receiving semaglutide, 1 person received placebo.
- Treatment lasted 68 weeks, followed by a 7-week follow-up period during which participants did not receive semaglutide or placebo.
- Block randomization was used with a block size of six, with no stratification factors.
- Throughout the trial, participants in both groups received counseling on a reduced-calorie diet and physical activity.

**Dosing schedule:**

- Semaglutide was started at a dose of 0.24 mg.
- The dose was increased over time, with the goal of reaching the 2.4-mg target dose by week 16.
- Participants who had unacceptable side effects at 2.4 mg could continue at a lower dose of 1.7 mg, provided the investigator considered the treatment safe.
- The protocol recommended that participants make at least one additional attempt to escalate to the target dose of 2.4 mg, at the investigator's discretion.

Treatment with other antiobesity medications was not permitted during the trial. However, the use of other interventions for knee osteoarthritis was permitted. Pain medication could be used throughout the trial, but opioid use was an exclusion criterion at baseline, and use was discouraged during the trial.

During washout periods (24 to 72 hours before visits), acetaminophen could be used for pain management at a maximum of 4 grams per day. No pain medication could be used within the 24 hours before a visit. Participants kept an electronic diary to record pain and pain-medication use. The worst daily knee pain was recorded using a numerical rating scale ranging from 0 to 10, with higher scores indicating worse pain.

**How outcomes were measured:**

The primary end points (main outcomes measured) were the percentage change in body weight and the change in the WOMAC pain score from baseline to week 68. The WOMAC pain score is measured on a scale of 0 to 100, with higher scores reflecting worse outcomes.

Confirmatory secondary end points included:

- The percentage of participants with a body-weight reduction of at least 5% or at least 10%
- The change in the WOMAC physical-function score
- The change in physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2.0 (on a scale of 0 to 100, with higher scores indicating greater well-being)

Supportive secondary end points included changes in waist circumference, WOMAC stiffness score, WOMAC total score, pain intensity (as reported in the pain diary), and pain-medication use. Exploratory end points included the change in the 6-minute walk distance.

**Statistical analysis:**

The two primary end points were tested at a significance level of 5%. The alpha was split between the two end points: 1% for the percentage change in body weight and 4% for the change in WOMAC pain score. If superiority was confirmed for both primary end points, the confirmatory secondary end points could be tested at a 5% significance level in a prespecified hierarchical manner.

The full analysis population included all participants who underwent randomization (according to the intention-to-treat principle). The safety analysis population included all participants who underwent randomization and received at least one dose of semaglutide or placebo.

The incidence of mild and moderate adverse events with a 2.4-mg dose of semaglutide has been characterized in previous trials. Because of this, a targeted approach to collection of safety data was used. Investigators recorded only serious adverse events, adverse events leading to discontinuation, adverse events warranting invasive knee procedures, medication errors, acute pancreatitis, coronavirus disease 2019, and pregnancy or pregnancy-related adverse events. Blood pressure was measured as part of the safety assessments.

## Who Participated in the Study

From October 2021 through March 2022, a total of 407 participants underwent randomization. Of these, 271 were assigned to receive semaglutide, and 136 were assigned to receive placebo.

Most participants completed the treatment period: 86.7% in the semaglutide group and 77.9% in the placebo group. Most also completed the trial: 90.8% in the semaglutide group and 89.7% in the placebo group.

Among the 235 participants in the semaglutide group who completed the treatment period, at the last treatment visit, 211 (89.8%) were receiving the full 2.4-mg dose. At the last treatment visit, 9 (3.8%) were receiving 1.7 mg to less than 2.4 mg, and 11 (4.7%) were receiving less than 1.7 mg. Four participants (1.7%) did not report the dose.

**Baseline characteristics of participants:**

- Mean age: 56 years
- Women: 81.6%
- White: 60.9%
- Mean body weight: 108.6 kg (about 239 pounds)
- Mean BMI: 40.3
- Mean waist circumference: 118.7 cm
- Mean WOMAC pain score: 70.9 (on a scale of 0 to 100, with higher scores reflecting worse outcomes)

The distribution of BMI categories was as follows:

- BMI 30 to less than 35: 24.3% of participants
- BMI 35 to less than 40: 34.4% of participants
- BMI 40 or greater (severe obesity): 41.0% of participants
- BMI less than 30: 0.2% of participants

Coexisting conditions were common among participants:

- Hypertension (high blood pressure): 48.2%
- Dyslipidemia (abnormal cholesterol levels): 30.5%
- Gastroesophageal reflux disease (GERD): 11.3%
- Asthma: 9.3%
- Cardiovascular disease: 5.2%

The characteristics of participants at baseline were balanced between the two groups.

## Key Findings: Weight Loss and Pain Relief

Semaglutide produced significantly greater weight loss and pain relief than placebo over the 68-week treatment period. Both primary end points were met with high statistical significance (P<0.001).

**Body weight change:**

The mean change in body weight from baseline to week 68 was −13.7% in the semaglutide group and −3.2% in the placebo group. The estimated difference between groups was −10.5 percentage points (95% confidence interval [CI], −12.3 to −8.6; P<0.001).

In plain language, the 95% confidence interval means that researchers are 95% confident the true difference between semaglutide and placebo falls between 8.6 and 12.3 percentage points of weight loss. The P value of less than 0.001 means there is less than a 0.1% probability that this result occurred by chance alone.

Researchers analyzed the data using the trial product estimand. This estimand assesses efficacy if the treatment regimen was followed as intended, without discontinuations or use of other interventions. The results were similar. The estimated difference was −12.1 percentage points (95% CI, −13.8 to −10.5).

**WOMAC pain score change:**

The mean change in the WOMAC pain score from baseline to week 68 was −41.7 points in the semaglutide group and −27.5 points in the placebo group. The estimated difference between groups was −14.1 points (95% CI, −20.0 to −8.3; P<0.001).

This means that patients receiving semaglutide experienced a 41.7-point improvement on a 100-point pain scale, compared with a 27.5-point improvement for those receiving placebo. The additional benefit attributable to semaglutide was 14.1 points on this scale.

The results of the trial product estimand were similar for pain. The estimated difference was −14.8 points (95% CI, −20.1 to −9.4).

**Percentage of participants achieving weight loss thresholds:**

At week 68, the percentages of participants who had body-weight reductions from baseline of at least 5% and at least 10% were significantly higher in the semaglutide group than in the placebo group:

- At least 5% weight loss: 87.0% with semaglutide vs. 29.2% with placebo
- At least 10% weight loss: 70.4% with semaglutide vs. 9.2% with placebo
- At least 15% weight loss: 47.8% with semaglutide vs. 2.5% with placebo
- At least 20% weight loss: 23.3% with semaglutide vs. 0% with placebo

These findings show that nearly 9 in 10 participants receiving semaglutide achieved at least 5% weight loss, and more than 7 in 10 achieved at least 10% weight loss. Nearly half achieved at least 15% weight loss, and nearly one-quarter achieved at least 20% weight loss. In contrast, no participants in the placebo group achieved 20% weight loss.

## Additional Findings: Function, Waist Size, and More

Beyond the primary end points, semaglutide also produced greater improvements in physical function, waist circumference, and other measures of knee osteoarthritis.

**WOMAC physical-function score:**

Over the 68-week period, participants in the semaglutide group had a greater decrease (improvement) from baseline in WOMAC physical-function score than participants in the placebo group. The mean change was −41.5 points with semaglutide versus −26.7 points with placebo. The estimated difference was −14.9 points (95% CI, −20.4 to −9.3; P<0.001).

**SF-36 physical-function score:**

At week 68, participants in the semaglutide group also had a greater increase (improvement) in SF-36 physical-function score from baseline than those in the placebo group. The mean change was 12.0 points with semaglutide versus 6.5 points with placebo. The estimated difference was 5.6 points (95% CI, 3.1 to 8.0; P<0.001).

The SF-36 is a widely used survey that measures health-related quality of life. Higher scores indicate greater well-being and physical function.

**Waist circumference:**

Treatment with semaglutide resulted in a greater reduction in waist circumference over the 68-week period than placebo. The difference between groups was −6.9 cm (95% CI, −9.1 to −4.7).

**WOMAC pain score responders:**

A greater percentage of participants in the semaglutide group had a reduction in the WOMAC pain score of at least 30% and at least 50% compared with the placebo group.

**Subgroup analyses:**

The results of subgroup analyses indicated greater improvements in WOMAC pain scores with semaglutide than with placebo across all BMI subgroups. These subgroups were BMI less than 35, BMI 35 to less than 40, and BMI 40 or greater. This means that the pain-relieving benefits of semaglutide were consistent regardless of participants' starting BMI category.

## Safety and Side Effects

The incidence of serious adverse events was similar in the two groups. This means that the rate of serious adverse events was similar between the semaglutide and placebo groups.

However, adverse events that led to permanent discontinuation of the trial regimen occurred more frequently in the semaglutide group. Specifically:

- 6.7% of participants in the semaglutide group discontinued treatment due to adverse events
- 3.0% of participants in the placebo group discontinued treatment due to adverse events

Gastrointestinal disorders (such as nausea, vomiting, or diarrhea) were the most common reason for discontinuation in the semaglutide group. This is consistent with the known side-effect profile of GLP-1 receptor agonists.

The trial used a targeted approach to collecting safety data. This approach was used because the incidence of mild and moderate adverse events with a 2.4-mg dose of semaglutide has been characterized in previous trials. Investigators recorded only serious adverse events, adverse events leading to discontinuation, adverse events warranting invasive knee procedures, medication errors, acute pancreatitis, coronavirus disease 2019, and pregnancy or pregnancy-related adverse events.

Blood pressure was measured as part of the safety assessments.

## What This Means for Patients

This trial demonstrates that once-weekly semaglutide 2.4 mg, combined with counseling on a reduced-calorie diet and physical activity, produces clinically meaningful weight loss and pain relief. This applies to people with obesity and knee osteoarthritis.

The weight loss achieved with semaglutide was substantial. Participants receiving semaglutide lost an average of 13.7% of their body weight over 68 weeks, compared with 3.2% for those receiving placebo. This difference of more than 10 percentage points is clinically important.

The pain relief was also substantial. Participants receiving semaglutide experienced a 41.7-point improvement on the WOMAC pain scale, compared with 27.5 points for placebo. While both groups improved (likely due to the lifestyle counseling and placebo effect), the semaglutide group experienced significantly greater pain relief.

Physical function improved more with semaglutide as well. Participants receiving semaglutide had greater improvements in both the WOMAC physical-function score and the SF-36 physical-function score. This means that patients were not only experiencing less pain but also functioning better in their daily lives.

The finding that nearly half of participants receiving semaglutide achieved at least 15% weight loss, and nearly one-quarter achieved at least 20% weight loss, is notable. These levels of weight loss are associated with significant health benefits, including improvements in knee osteoarthritis symptoms.

The safety profile was generally consistent with previous studies of semaglutide. Serious adverse events were similar between groups, but gastrointestinal side effects led to more discontinuations in the semaglutide group. Patients considering semaglutide should be aware of the potential for gastrointestinal side effects and discuss strategies for managing them with their healthcare provider.

The subgroup analyses showed that the pain-relieving benefits of semaglutide were consistent across all BMI categories. This suggests that semaglutide may be beneficial for patients with obesity and knee osteoarthritis regardless of their starting BMI.

## Limitations of the Study

Several limitations of this trial should be considered when interpreting the results.

First, the trial included only 407 participants, which is a relatively modest sample size. Larger trials would provide more precise estimates of treatment effects and allow for more detailed subgroup analyses.

Second, the trial duration was 68 weeks, with a 7-week follow-up period. Longer-term studies are needed to determine whether the benefits of semaglutide persist over time and whether the medication affects the structural progression of knee osteoarthritis.

Third, the trial population was predominantly women (81.6%) and White (60.9%). The results may not be fully generalizable to other populations.

Fourth, all participants received counseling on a reduced-calorie diet and physical activity. The effects of semaglutide observed in this trial may not be the same in patients who do not receive such counseling.

Fifth, the trial used a targeted approach to collecting safety data, recording only specific types of adverse events. This means that the full spectrum of side effects may not be captured in this report.

Sixth, supportive secondary and exploratory end-point analyses were not controlled for multiplicity and should not be used to infer definitive treatment effects. This means that some of the secondary findings could be due to chance.

Finally, the trial was funded by Novo Nordisk, the manufacturer of semaglutide. While the authors vouch for the accuracy and completeness of the data, potential conflicts of interest should be considered.

## Recommendations and Next Steps

Based on the results of this trial, patients with obesity and knee osteoarthritis who are considering treatment options should discuss semaglutide with their healthcare provider. The medication may be appropriate for those who have not achieved adequate weight loss or pain relief with lifestyle modifications alone.

Patients considering semaglutide should be aware of the following:

1. Semaglutide is given as a once-weekly injection under the skin.
1. The dose is gradually increased over 16 weeks to reach the target dose of 2.4 mg.
1. Gastrointestinal side effects are common and may lead to discontinuation in some patients.
1. The medication should be used in combination with a reduced-calorie diet and physical activity.
1. Regular follow-up with a healthcare provider is important to monitor for side effects and assess treatment response.

Future research should focus on:

- Longer-term studies to assess the durability of weight loss and pain relief
- Studies to determine whether semaglutide affects the structural progression of knee osteoarthritis
- Studies in more diverse patient populations
- Studies comparing semaglutide with other weight-management medications and interventions
- Studies to identify which patients are most likely to benefit from semaglutide treatment

The STEP 9 trial represents an important step forward in the management of obesity-related knee osteoarthritis. The findings suggest that semaglutide, combined with lifestyle modifications, can produce clinically meaningful weight loss and pain relief in this patient population.

## Frequently Asked Questions

### What did the trial find about semaglutide for weight loss in people with obesity and knee osteoarthritis?

In a 68-week trial of 407 adults with obesity and painful knee osteoarthritis, once-weekly semaglutide 2.4 mg produced an average weight loss of 13.7%, compared with 3.2% with placebo. The difference was statistically significant. Nearly 9 in 10 participants on semaglutide lost at least 5% of body weight, and more than 7 in 10 lost at least 10%.

### How much did knee pain improve with semaglutide compared with placebo?

On a 100-point knee pain scale (WOMAC), semaglutide improved scores by 41.7 points on average, versus 27.5 points with placebo. The extra benefit from semaglutide was 14.1 points. Both groups improved, likely due to lifestyle counseling and placebo effect, but the semaglutide group had significantly greater pain relief.

### Who was included in this trial of semaglutide for knee osteoarthritis?

The trial enrolled 407 adults with obesity and painful knee osteoarthritis. Their average age was 56 years, 81.6% were women, and 60.9% were White. Average body weight was 108.6 kg (about 239 pounds) and average BMI was 40.3. Many had other conditions such as high blood pressure or abnormal cholesterol.

### What are the side effects and risks of semaglutide 2.4 mg for this use?

Serious adverse events were similar between semaglutide and placebo groups. However, 6.7% of participants on semaglutide stopped treatment due to side effects, compared with 3.0% on placebo. Gastrointestinal problems like nausea, vomiting, or diarrhea were the most common reason for stopping. Discuss managing these side effects with your healthcare provider.

### How is semaglutide given and what is the dosing schedule?

Semaglutide is given as a once-weekly injection under the skin. In the trial, it started at 0.24 mg and the dose was increased over 16 weeks to reach the target dose of 2.4 mg. Some participants who had unacceptable side effects at 2.4 mg continued at a lower dose of 1.7 mg if their investigator considered it safe.

### Did physical function and waist size improve with semaglutide?

Yes. In the trial, semaglutide led to greater improvements in physical function than placebo on two scales: WOMAC physical-function score improved by 41.5 points versus 26.7 points, and SF-36 physical-function score improved by 12.0 points versus 6.5 points. Waist circumference also decreased more with semaglutide, by an average of 6.9 cm more than placebo.

### What are the limitations of this trial that patients should know?

The trial included only 407 participants, lasted 68 weeks, and was mostly women (81.6%) and White (60.9%), so results may not apply to everyone. All participants received diet and activity counseling. Safety data collection was targeted, so not all side effects may be captured. The trial was funded by the manufacturer of semaglutide.

### I have obesity and painful knee osteoarthritis — when should I seek a second opinion about whether semaglutide is right for me?

A second opinion can help when lifestyle changes alone have not produced adequate weight loss or knee pain relief, since semaglutide 2.4 mg is given as a once-weekly injection and the dose is raised over 16 weeks to reach the target. It may also be useful if you have gastrointestinal conditions, because nausea, vomiting, or diarrhea were the most common reasons participants stopped treatment. Reviewing whether semaglutide suits your situation, alongside a reduced-calorie diet and physical activity, is a reasonable step. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis NEJM 2024

**Authors:** H. Bliddal, H. Bays, S. Czernichow, J. Uddén Hemmingsson, J. Hjelmesæth, T. Hoffmann Morville, A. Koroleva, J. Skov Neergaard, P. Vélez Sánchez, S. Wharton, A. Wizert, and L.E. Kristensen, for the STEP 9 Study Group

**Publication:** New England Journal of Medicine, October 31, 2024, Volume 391, Number 17, pages 1573-1583

**DOI:** 10.1056/NEJMoa2403664

**ClinicalTrials.gov number:** NCT05064735

**Funding:** Novo Nordisk

*This patient-friendly article is based on peer-reviewed research.*


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