T3 or Semaglutide: What Is the Difference

Triiodothyronine (T3) in the «cutting» scene has for years been regarded as a means of revving up metabolism, while semaglutide in just a few years has become the most well-known drug for treating obesity. Both substances affect body weight, but from completely opposite sides of the energy balance. The editors explain how they differ and why official medicine treats them so differently.

What T3 Is and What Semaglutide Is

T3, or triiodothyronine, is the most active thyroid hormone. Most of the T3 in the body is formed not in the gland itself, but in tissues from thyroxine (T4) under the action of deiodinase enzymes. The medicinal form of T3 is called liothyronine; it is used in hypothyroidism in certain clinical situations, as well as in emergency conditions, for example in myxedema coma. The standard of treatment for hypothyroidism is levothyroxine (T4).

Semaglutide is a synthetic analog of the gut hormone glucagon-like peptide-1 (GLP-1) with a modified structure that provides a long duration of action. It is administered subcutaneously once a week (the drugs Ozempic for treating type 2 diabetes and Wegovy for treating obesity), and there is also a tablet form for treating diabetes.

The fundamental difference lies in the indications. Semaglutide is officially registered for the chronic management of body weight in people with obesity or overweight with comorbidities. T3 is not registered anywhere for the treatment of obesity, and the prescribing information for thyroid hormone drugs contains a direct warning against such use.

Both substances are prescription-only, but their roles in medicine are opposite: T3 is replacement therapy for a hormone deficiency, semaglutide is a modulator of appetite and glucose metabolism in excess body weight or diabetes.

Energy Expenditure vs. Energy Intake

T3 acts through nuclear thyroid hormone receptors, which are present in practically all cells. It regulates the expression of hundreds of genes, increases basal metabolism, enhances thermogenesis, heart rate and myocardial contractility, and accelerates the metabolism of proteins, fats and carbohydrates. The review by Mullur, Liu and Brent (2014) describes in detail how thyroid hormones control energy metabolism.

When T3 comes from outside in amounts exceeding the requirement, the body enters a state of drug-induced thyrotoxicosis. Energy expenditure increases, but along with fat mass, proteins, in particular muscle, are also broken down. In parallel, the pituitary gland reduces the production of thyroid-stimulating hormone (TSH), and one's own thyroid gland reduces its work.

Semaglutide affects the other side of the balance — energy intake. Activation of GLP-1 receptors in the brain enhances satiety and reduces hunger and cravings for food, and the slowing of gastric emptying prolongs the feeling of fullness. In addition, semaglutide glucose-dependently stimulates insulin secretion and suppresses glucagon (Drucker, 2018).

So T3 forces the body to expend more, «revving up» all systems, including the heart, whereas semaglutide helps a person eat less without a direct load on the cardiovascular system.

The Evidence Base Regarding Body Weight

For semaglutide the evidence base is the program of large randomized STEP studies. In the STEP 1 study (Wilding et al., 2021) almost 2,000 adults with obesity or overweight without diabetes received semaglutide 2.4 mg per week or placebo together with a lifestyle change program. Over 68 weeks the average reduction in body weight was about 15% in the semaglutide group versus approximately 2.4% in the placebo group.

In the SELECT study (Lincoff et al., 2023), which included more than 17,000 people with cardiovascular disease and overweight without diabetes, semaglutide reduced the risk of major cardiovascular events by about 20% compared with placebo. That is, the drug not only reduces weight but also has a proven benefit for the heart in this group of patients.

Regarding thyroid hormones, a systematic review by Kaptein, Beale and Chan (2009) analyzed studies of their use in obesity. The authors concluded that although in individual works body weight decreased more than without hormones, a significant proportion of the losses came from fat-free mass, and the risks did not justify such use.

Risks and Official Warnings

The prescribing information for thyroid hormone drugs, in particular for liothyronine, contains a boxed warning: thyroid hormones should not be used for the treatment of obesity or weight loss; in people with normal thyroid function ordinary doses are ineffective, and large ones can cause serious or even life-threatening toxicity, especially in combination with sympathomimetics.

An excess of T3 manifests as tachycardia, atrial fibrillation, tremor, sweating, insomnia, anxiety and loss of muscle mass. With prolonged exposure the risk of bone mass loss increases, and in people with heart disease — angina and heart failure.

The side effects of semaglutide are mostly gastrointestinal: nausea, vomiting, diarrhea, constipation. Among the more serious risks are pancreatitis, gallstone disease, and dehydration with impaired kidney function. The prescribing information contains a warning about C-cell tumors of the thyroid gland, detected in rodents, so the drug is contraindicated in a history of medullary thyroid cancer and MEN 2 syndrome.

• T3:a direct warning in the prescribing information against use for weight loss; risks for the heart, bones and muscles.
• Semaglutide:a registered indication for obesity; risks mostly digestive, controlled by a physician.

What Happens After Discontinuation

After stopping T3 in a person with normal thyroid function, the body must restore its own regulation. While the pituitary again ramps up TSH production, and the gland — hormones, a period of reduced function is possible, with fatigue, sensitivity to cold and weight gain.

For semaglutide there are data from the extended phase of the STEP 1 study (Wilding et al., 2022): a year after discontinuing the drug, participants regained approximately two-thirds of the lost weight, and improvements in cardiometabolic indicators largely disappeared. This confirms that obesity is a chronic condition, and pharmacotherapy is often needed long-term.

So neither agent «cures» excess weight forever. But whereas semaglutide, after discontinuation, simply stops acting, abuse of T3 can leave behind disturbances in the work of the thyroid gland and loss of muscle mass.

In any case a lasting result is possible only in combination with long-term changes in nutrition and physical activity.

Editorial Conclusions

T3 and semaglutide affect body weight from different sides: T3 increases energy expenditure at the cost of a load on the heart and loss of muscle, semaglutide reduces appetite and food intake.

Semaglutide has a large evidence base and a registered indication for the treatment of obesity, and for some patients — a proven cardiovascular benefit. T3 is not officially recommended for weight loss, and the prescribing information directly warns against such use.

If you are concerned about weight or you suspect thyroid problems, start with tests for TSH and free T4 and a consultation with an endocrinologist.

We also recommend reading our articles on thyroid hormone tests, on the side effects of semaglutide, and on how to preserve muscle during weight loss.

References

1. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002.
2. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221–2232.
3. 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.
4. Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab. 2009;94(10):3663–3675.
5. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355–382.
6. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–756.
7. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–1751.