Now, with all that being said, there are some important points to make that have come out since Wegovy’s popularity has increased.

For starters, a secondary analysis of a small subset of participants found that those who were receiving semaglutide were losing higher levels of lean body mass compared to those who received placebo. Specifically, about 38% of the mass they lost was lean mass.[3]

Novo Nordisk’s STEP 4 trial comparing continuous semaglutide 2.4mg for 68 weeks vs switching to placebo after week 20 also had some noteworthy results. That study found that participants who switched to placebo at week 20 experienced less reduction in bodyweight percentage, waist circumference, and actual bodyweight (p<0.001). And of the 268 who were switched to placebo, 206 (82.4%) gained weight again. [4]

And the STEP 1 Trial Extension found similar results, with the conclusion stating, “One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables.”[5]

How did the authors interpret this?

“These results emphasize the chronicity of obesity and the need for treatments that can maintain and maximize weight loss”4 In other words “these results justify the long-term use of our drug, substantial profits for our company, in order for patients to have sustained results.”

Another way to interpret the results is that while semaglutide obviously helps with weight reduction, a lot of it possibly lean mass, the results don’t seem to be sustained unless patients stay on the drug for an indefinite period of time. This doesn’t only equal sustained weight loss, it also represents a sustained cost for patients, a new lifelong drug, and increased risk of adverse effects secondary to extended drug us.

Specifically, patients who use semaglutide are at 3.5 times higher risk of experiencing nausea, 2.6 times higher risk of experiencing diarrhea, 5.2 times higher risk of experiencing vomiting, 2.3 times higher risk of experiencing constipation, 1.8 times higher risk of experiencing abdominal pain, and 3 times higher risk of experiencing indigestion than those who take a placebo. [6]

There’s also evidence that, at least compared to bupropion-naltrexone (another weight loss drug on the market), drugs like semaglutide place patients at increased risk of pancreatitis, bowel obstruction, gastroparesis, and biliary disease. [7]

Thus, while it cannot be denied that semaglutide is an effective weight loss drug, it also can’t be denied that use of the drug is not without risk. If there are safer and cheaper alternatives for patients, wouldn’t we medical practitioners want to know about it and want to offer it for our patients’ consideration? Absolutely!

One thing you’ll notice about medical research is that it is limited in the number of studies that directly compare exercise and diet modifications against a drug or other intervention. The vast majority, the semaglutide studies included, will study exercise and diet coupled with the drug or procedure against the placebo, but almost never pit exercise and diet directly against a drug.

In 2002, the Diabetes Prevention Program Research Group was one of a few exceptions which published an article in the New England Journal of Medicine that did just that. [8] The authors randomly assigned participants to 3 groups, a metformin (850mg twice daily) group, a placebo group, and lifestyle-intervention group. They wanted to see which would result in reduced incident of new diagnosis of type 2 diabetes as well as measure the percent of weight loss in the groups. Before I tell you what they found, I want you to take a look at how the lifestyle-intervention group was supposed to achieve their weight loss goal:

“through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. A 16-lesson curriculum covering diet, exercise, and behavior modification was designed to help the participants achieve these goals. The curriculum, taught by case managers on a one-to-one basis during the first 24 weeks after enrollment, was flexible, culturally sensitive, and individualized. Subsequent individual sessions (usually monthly) and group sessions with the case managers were designed to reinforce the behavioral changes.”

Now, here are the results of the study:

The average weight loss in the three groups was .22lbs for placebo, 4.63lbs for metformin, and 12.35lbs for the lifestyle-modification group (P<0.001). Now, by no means are these results nearly as dramatic as the semaglutide ones. But they’re real and they show that lifestyle-modifications such as greater activity levels and diet modifications do result in measurable reduction in weight. Additionally, the lifestyle-intervention group also had a much lower rate of new diagnosis of type 2 diabetes than either of the other two groups. And that’s important!

Briefly though, I also want to highlight that the lifestyle-intervention was fairly comprehensive. That’s important to recognize because that implies, at least according to this particular study, that in order to see a reduction in weight, and to prevent the occurrence of type 2 diabetes, patients had to make significant changes to their lifestyle. That’s often easier said than done.

Looking at exercise specifically, a 2019 meta-analysis published in Nutrients reported that exercise did certainly result in bodyweight reduction (average difference = −4.3 kg, 95% CI: −7.61, −0.99, p = 0.01; I2 = 0%), reduction of body fat mass (average difference = −2.99 kg, 95% CI: −4.39, −1.59, p < 0.0001, I2 = 0%), and reduction in percent body fat (average difference= −2.31%, 95% CI: −3.26, −1.36, p = 0.00001, I2 = 0%). The “95% CI,” “p=”, and “I2=” in essence mean that we can be at least 95% sure that the values that are being reported fall somewhere in the ranges reported, that the results are unlikely to be a coincidence, and that the data used for this analysis was not super varied.

Converted to pounds, that’s an average difference of 9.48lbs of reduction in bodyweight and 6.59lbs of body fat reduction. Again, not earth-shattering, but very real results.

Lastly, a 2015 systematic review and meta-analysis titled “Effects of Lifestyle Interventions That Include a Physical Activity Component in Class II and Class III Obese Individuals” reported that in general, lifestyle interventions such as a diet and exercise resulted in reduced bodyweight, waist circumference, total cholesterol, diastolic blood pressure and fasting glucose levels.[9] Importantly, the authors pointed out that there was a lot variance in the kind of studies that were reviewed and that the reported improvements were better, the longer the studies lasted.

What I’m getting at here is that diet and exercise work. They not only work to reduce bodyweight, but they impact other components of our health as well. And while I concede that by no means do the effects of lifestyle interventions seem to match up with the powerful effect that semaglutide has on weight reduction, for many patients, making changes to their diet and activity level represent safer and cheaper alternatives to pharmacotherapy.