The Ozempic Era: The Promise, The Risks & The Long Game

The authors of the STEP 1 Extension trial concluded that, “after a substantial reduction in body weight during 68 weeks of treatment with once‐weekly s.c. semaglutide plus lifestyle intervention, subsequent treatment withdrawal led to most of the weight loss being regained within 1 year, and a similar change in some cardiometabolic variables back to baseline, reinforcing the need for continued treatment to maintain weight loss and cardiometabolic benefits.”

One of the arguments against regular melatonin use is the claim that it may lead to melatonin dependency and stop our body’s own endogenous melatonin production. After reviewing the literature, I could not find any strong evidence showing individuals can become dependent on melatonin. I suspect much of these concerns come from categorizing melatonin as a hormone or from early animal and in-vitro studies. And although it is a hormone, it’s mechanism in the body is unlike other hormones.

We have entered a new era in medicine—the Ozempic era.

GLP-1 drugs have brought about a tectonic shift in how we approach medicine. There is no scientist or clinician who should or could deny the life- and health-changing effects of these medications, even beyond their directed use for diabetes and weight loss. GLP-1 receptor agonists (semaglutide, branded as Ozempic) and/or dual GLP-1 + GIP receptor agonists (tirzepatide, branded as Mounjaro) are very powerful drugs that are here to stay.

Now is the time to begin thinking about the long-term impact of GLP-1 and GIP drugs.

In other words, what happens to individuals who are on these medications long-term, and what happens when they eventually stop?

Two large trials have already begun answering these questions for us, including the Semaglutide Treatment Effect in People with Obesity (STEP 1) extension trial and STEP 4 trials. These were two well-designed trials, with the STEP 1 trial consisting of almost 2,000 obese individuals without diabetes and the STEP 4 trial consisting of about 900 obese individuals without diabetes. The intention of both studies was to assess the long-term outcomes and impact on individuals after they discontinued semaglutide (Ozempic/Wegovy). To understand the importance of these studies and their clinical relevance, we first need to break down how they were designed and conducted.

Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725

STEP 1 Extension Trial

Study Objective:

In the STEP 1 extension trial, researchers investigated the impact of long-term semaglutide use and, as part of the extension, a subset of the participants were taken off Ozempic to assess how their health changed after stopping a GLP-1 RA. Researchers monitored weight loss—a major focus and benefit of these medications—along with other metabolic markers, including blood pressure, C-reactive protein (CRP), HbA1c%, and lipids (total cholesterol, LDL-C, and triglycerides).

Of course, we know that medications like Ozempic, Wegovy, and Mounjaro help with weight loss, and we assume that other metabolic markers that improve with weight loss also improve while on these drugs. Essentially, if semaglutide reduces weight, it should also improve metabolic markers like blood pressure and blood sugar levels.

But what happens when these medications are stopped? The STEP 1 extension trial was able to assess this compared to a placebo group.

The Intervention:

For the first 16 weeks of the trial, the participants (n=1,962) were slowly titrated up to 2.4 mg of semaglutide (Wegovy). Once they reached the 2.4 mg dose, they remained on it for 68 weeks. At week 68, the trial was extended, and a subset of semaglutide users (n=333) were split into two groups:

Group 1: Individuals who were originally on the placebo from day 1 continued on the placebo. This was an important part of the study design, allowing researchers to track a placebo group throughout the trial.

Group 2: This group had been taking 2.4 mg of semaglutide from day 1 but was then transitioned to the placebo group, where they were taken off semaglutide and received placebo injections for 52 weeks after being on semaglutide for 68 weeks.

During this time, researchers measured weight, blood pressure, CRP (an inflammatory marker), triglycerides, LDL-C, and HbA1c% (a marker of diabetes or prediabetes).

This was a well-designed study that provided critical insight into what happens when semaglutide is discontinued after a year or more of use—especially since it measured cardiometabolic health a full year after stopping the drug, which mirrors real-world clinical scenarios. Weight loss is great, but weight regain is the real concern.

Outcomes at 68 Weeks:

At 68 weeks, as expected, individuals in the semaglutide group (Group 2) lost about 40 lbs. or 17.3% of their body weight, while weight in the placebo group remained essentially unchanged. Group 2 also saw impressive reductions in:

Blood pressure: From borderline stage 1 hypertension (130/80 mmHg) to normal (121/78 mmHg)
HbA1c%: From prediabetic (5.7%) to normal (<5.7%)
CRP (inflammatory marker): Dropped by 56%
Triglycerides: Dropped from 131 mg/dL to 95.7 mg/dL

Notably, triglyceride reduction was one of the most clinically relevant lipid improvements. Although the normal range for triglycerides is <150 mg/dL, research suggests that once triglycerides exceed 100 mg/dL, coronary heart disease risk significantly increases.

Extension Outcomes at 120 Weeks (After Stopping Semaglutide):

The most clinically relevant part of this trial was when Group 2 stopped semaglutide and switched to placebo. At the end of the trial:

Those who were on semaglutide lost about 40 lbs. in 68 weeks.
They then regained about 26 lbs. after stopping the drug.
Total weight loss after 2.5 years (30 months): 15 lbs.

This means that, over 2.5 years, the net weight loss was about 0.5 lbs. per month. Not terrible, but when broken down further:

During semaglutide use: 2.3 lbs. lost per month.
After stopping semaglutide: 2 lbs. regained per month.

What Does This Mean for Precision Medicine?

Let’s compare two hypothetical individuals:

Person A steadily loses 15 lbs. over 2.5 years (~0.5 lbs./month).
Person B loses 40 lbs. in 17 months (~2.3 lbs./month) but then regains 26 lbs. over the next year (~2 lbs./month).

Although Person B is still 15 lbs. lighter than where they started, are they actually healthier? Possibly not—especially if metabolic markers revert back to baseline.

The Most Concerning Finding: Diabetes Progression

After 68 weeks on semaglutide, pre-diabetes was essentially reversed. However, after discontinuing treatment:

Most participants reverted back to prediabetes.
Two participants progressed from prediabetes to full-blown diabetes (HbA1c >6.5%).

This suggests that while weight loss and metabolic improvements occur on semaglutide, they may not lead to long-term metabolic health improvements unless lifestyle changes (like strength training) are made.

A major issue? Loss of lean mass.

DEXA scans from a subset of participants showed that, after 68 weeks of semaglutide use, 39% of the weight lost was lean mass. Lean mass is not only muscle but also bone. This is concerning because muscle is critical for metabolic health, insulin sensitivity, and long-term disease prevention and loss of bone mass is incredible concerning and difficult to correct once it is lost.

Final Thoughts: The Good & The Bad

I want to be clear - I am not opposed to GLP-1 drugs like semaglutide or tirzepatide—when used correctly. In fact, I see many patient’s lives changed when these medications are used appropriately. However, obesity is a chronic condition, and these drugs may be necessary long-term. That is what concerns me.

The yo-yo weight loss effect of stopping these drugs could create long-term metabolic damage, and we still don’t have clear answers on:

Should GLP-1 drugs be cycled instead of taken continuously?
Can they serve as short-term tools to redirect people into a healthier lifestyle?
What are the long-term risks for insulin resistance, metabolic disease, and muscle mass?
Are we artificially creating a yo-yo diet effect?

While these medications show promise, clinicians must incorporate lifestyle interventions to prevent rebound weight gain and metabolic decline.

Next Up:

We’ll dive deeper into set-point theory, metabolic adaptation, and the yo-yo diet effect in future posts.

References

Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553. doi:10.1111/DOM.14725

Ahmad I, Zhan M, Miller M. High prevalence of C-reactive protein elevation with normal triglycerides (100-149 mg/dL): Are triglyceride levels below 100 mg/ dL more optimal in coronary heart disease risk assessment? American Journal of the Medical Sciences. 2005;329(4). doi:10.1097/00000441-200504000-00002

Fontbonne A, Eschwege E, Cambien F, et al. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Diabetologia. 1989;32(5). doi:10.1007/bf00265546

Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2021;384(11):989-1002. doi:10.1056/NEJMOA2032183/SUPPL_FILE/NEJMOA2032183_DATA-SHARING.PDF

Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1. doi:10.1001/JAMA.2021.3224

Jensterle M, Ferjan S, Janez A. The maintenance of long-term weight loss after semaglutide withdrawal in obese women with PCOS treated with metformin: a 2-year observational study. Front Endocrinol (Lausanne). 2024;15:1366940. doi:10.3389/FENDO.2024.1366940