GLP-1 Agonists: What They Do - and Don’t Do - for Fat Loss

In recent years, GLP-1 receptor agonists have reshaped the landscape of obesity treatment. Drugs like semaglutide (sold under brand names Wegovy and Ozempic) and liraglutide (Saxenda, Victoza) are no longer just for diabetes—they are now increasingly prescribed for weight loss, backed by a growing body of clinical evidence.

Originally developed to manage blood glucose in people with type 2 diabetes, these medications have demonstrated significant weight-reducing effects. But despite the enthusiasm, GLP-1 agonists are frequently misunderstood. They are not metabolic miracle drugs, nor are they meant for short-term use. Understanding how they work—and where their limitations lie—is essential for patients and practitioners alike.

This is an exploration of the science behind GLP-1 agonists, their real-world effectiveness, and the critical distinctions between what they can and cannot do when it comes to fat loss.

First, we must understand what a GLP-1 is and the role of receptor agonists. GLP-1 (glucagon-like peptide-1) is a hormone released in the gut after food intake. It plays a central role in regulating postprandial glucose levels, appetite, and digestive motility. It does this through several mechanisms: it increases insulin secretion when blood sugar is high, inhibits the release of glucagon (a hormone that raises blood sugar), delays gastric emptying, and acts directly on appetite centers in the brain to promote satiety.

GLP-1 receptor agonists are synthetic compounds that mimic the effects of this natural hormone, but in a more potent and longer-acting form. When administered via injection (daily or weekly, depending on the drug), these medications suppress appetite, delay stomach emptying, and modulate signals in the hypothalamus and brainstem involved in hunger regulation. The result is a sustained decrease in caloric intake over time, which leads to fat loss.

It’s important to note that these drugs do not directly increase energy expenditure. Clinical trials have confirmed that GLP-1 agonists have minimal to no impact on basal metabolic rate. They do not enhance fat oxidation or “melt” fat away. Rather, the weight loss they facilitate occurs indirectly, by reducing food intake and thereby creating a calorie deficit.

"It’s important to note that these drugs do not directly increase energy expenditure."

So what does the research show? The most robust data for weight loss come from trials involving semaglutide and liraglutide, both of which have been studied in large, randomized, placebo-controlled trials.

Liraglutide was first to market in the obesity space. At a dose of 3.0 mg daily (branded as Saxenda), it was evaluated in the SCALE Obesity and Prediabetes trial. Over 3,700 adults with BMI ≥30 or ≥27 with comorbidities were followed for 56 weeks. Participants taking liraglutide lost, on average, 8.4% of their body weight, compared to 2.8% in the placebo group. Additionally, 63% of liraglutide-treated individuals achieved at least 5% weight loss, and 33% lost over 10% of their body weight.

Semaglutide, a more potent molecule, demonstrated even greater weight reduction. In the STEP 1 trial, adults with obesity (without diabetes) were randomized to receive either 2.4 mg semaglutide weekly or placebo, alongside lifestyle counseling. At 68 weeks, the semaglutide group lost an average of 14.9% of their baseline weight, compared to just 2.4% in the placebo group. Half of participants on semaglutide lost at least 15% of their weight, and one-third lost 20% or more.

In people with type 2 diabetes, GLP-1 agonists are somewhat less potent for weight loss, though still clinically meaningful. In the SUSTAIN and PIONEER trials, semaglutide at doses of 0.5–1.0 mg (Ozempic) produced average weight losses of 3–6 kg. These results reflect the complex interplay between diabetes, insulin resistance, and concurrent medications. Nevertheless, semaglutide and liraglutide remain among the few diabetes medications associated with weight loss rather than gain.

As excitement around these medications grows, so does misinformation. It’s critical to dispel a few key myths as there are some things GLP-1 agonists simply cannot do.

First, GLP-1 agonists do not increase resting metabolism. They are not thermogenic agents. Their mechanism is driven entirely by reduced food intake, not increased energy output. While some patients report feeling “energized” or less preoccupied with food, there is no direct fat-burning effect from the drug itself.

Second, these medications are not a permanent fix. In most trials, discontinuation leads to weight regain. The STEP 1 extension study found that participants who stopped semaglutide regained about two-thirds of the lost weight within 12 months. This rebound reflects the fact that GLP-1 agonists are managing a chronic, relapsing condition—obesity—not curing it.

Third, these drugs do not work in isolation. All pivotal trials paired the medication with structured lifestyle counseling, including dietary changes and physical activity. While the medication amplifies the effect, behavioral change remains a central component of long-term success.

Lastly, it is important to be aware of the risks and side effects. GLP-1 receptor agonists are generally safe, but they are not without side effects. The most common adverse events are gastrointestinal, especially during dose titration. These include nausea, constipation, diarrhea, bloating, and early satiety. In most cases, these symptoms are temporary and subside with time.

More serious—but rare—risks include acute pancreatitis, gallbladder disease, and a possible increased risk of thyroid C-cell tumors (observed in rodents, not confirmed in humans). For this reason, these drugs are contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2).

Additionally, rapid improvements in blood glucose may worsen diabetic retinopathy in susceptible individuals, as seen in the SUSTAIN-6 trial.

From a practical standpoint, access remains a challenge. Monthly costs for Wegovy or Saxenda typically exceed $1,200 without insurance coverage, and reimbursement for obesity treatment is inconsistent across insurers. These medications are approved for adults with a BMI ≥30, or ≥27 with at least one weight-related comorbidity such as hypertension or type 2 diabetes.

GLP-1 receptor agonists represent one of the most significant pharmacologic advances in obesity treatment in recent decades. Through their effects on appetite, gastric emptying, and insulin regulation, they enable many patients to achieve meaningful fat loss—especially when combined with lifestyle changes.

However, these are not miracle drugs. They do not increase metabolism, do not work indefinitely without continued use, and are not effective without behavioral support. When used thoughtfully and under medical supervision, GLP-1 agonists offer a valuable option for individuals struggling with weight in the context of metabolic disease.

Patients considering these medications should consult a healthcare provider to weigh the benefits, risks, and long-term expectations. Like all chronic conditions, sustainable success with obesity treatment depends not just on the medication, but on the plan built around it.

Wilding JPH, Batterham RL, Calanna S, et al. (2021). Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine, 384(11), 989–1002. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

Wilding JPH, Batterham RL, Davies M, et al. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obesity & Metabolism, 24(8), 1553–1564. https://pubmed.ncbi.nlm.nih.gov/35441470/

Pi-Sunyer X, Astrup A, Fujioka K, et al. (2015). A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine, 373(1), 11–22. https://www.nejm.org/doi/full/10.1056/NEJMoa1411892

Marso SP, Daniels GH, Brown-Frandsen K, et al. (2016). Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 375(4), 311–322. https://www.nejm.org/doi/full/10.1056/NEJMoa1603827

Nauck MA, Meier JJ. (2018). Incretin hormones: Their role in health and disease. Diabetes, Obesity & Metabolism, 20(S1), 5–21. https://doi.org/10.1111/dom.13129

U.S. Food and Drug Administration. (2023). Wegovy (semaglutide) injection, for subcutaneous use – Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215256s007lbl.pdf

U.S. Food and Drug Administration. (2023). Saxenda (liraglutide) injection, for subcutaneous use – Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206321s016lbl.pdf