Incretin receptor agonists.

Over the past decade, a family of molecules known as incretin receptor agonists has transformed research into metabolism, glycemic control, and body-weight regulation. What began as a drug class for type 2 diabetes ended up opening an entire field of study on how the body regulates hunger, satiety, and energy expenditure.

This article explains, clearly and based on published evidence, what incretins are, how these molecules work, and what clinical research has shown about the three generations of agonists: single-receptor (GLP-1), dual (GIP/GLP-1), and triple (GIP/GLP-1/glucagon).

Content for informational and scientific-education purposes only. It does not constitute medical advice or a product offer.

What are incretins?

Incretins are hormones the gut releases when we eat. Their role is to signal the pancreas that nutrients are on the way, so it can anticipate the insulin response. The two main ones are:

• GLP-1 (glucagon-like peptide-1)
• GIP (glucose-dependent insulinotropic polypeptide)

The phenomenon whereby an oral meal produces greater insulin secretion than the same amount of glucose given intravenously is called the "incretin effect." Molecules in this pharmacological class mimic or amplify that natural signal.

Mechanism of action of GLP-1

GLP-1 works through several pathways at once:

1. Glucose-dependent insulin secretion: it stimulates insulin release only when glucose is elevated, which lowers the risk of hypoglycemia relative to other mechanisms.
2. Glucagon suppression: it reduces the hormone that raises hepatic glucose output.
3. Slowed gastric emptying: food stays longer in the stomach, prolonging satiety.
4. Central appetite action: it acts on brain regions that regulate hunger and satiety, reducing intake.

This combination explains why GLP-1 agonists, first studied for diabetes, later showed marked effects on body weight.

The role of GIP

GIP is the other major incretin hormone. Its role in energy metabolism is more complex and still under active investigation: it participates in insulin signaling and lipid handling, and, according to studies, it potentiates GLP-1's effects when both receptors are activated together. This observation was the basis for developing dual GIP/GLP-1 agonists.

Glucagon receptor agonism and triple agonists

The third generation adds activation of the glucagon receptor. Although glucagon is usually associated with raising glucose, its controlled agonism is associated in research with increased energy expenditure and effects on hepatic metabolism, including reduced liver fat. A triple agonist (GIP + GLP-1 + glucagon) aims to combine appetite suppression with greater caloric expenditure. It is the current frontier of research in this field.

Research into multi-receptor agonists rests on a simple premise: coordinating activation across more relevant receptors may amplify the effect on weight regulation and metabolism.

Clinical evidence

The following summarizes body-weight reduction data reported in the highest-profile published clinical trials for each generation of agonists.

Semaglutide (GLP-1 class reference)

In the STEP 1 trial, subcutaneous semaglutide at 2.4 mg weekly produced a mean body-weight reduction of about 15 % at 68 weeks in adults with overweight or obesity without diabetes, versus roughly 2–3 % with placebo (Wilding et al., NEJM 2021). It is the benchmark against which newer molecules are compared.

Tirzepatide (dual GIP/GLP-1 agonist)

In the phase 3 SURMOUNT-1 trial, tirzepatide at 15 mg weekly produced a mean body-weight reduction of approximately 20.9 % at 72 weeks in adults with obesity without diabetes, versus about 3 % with placebo (Jastreboff et al., NEJM 2022). In type 2 diabetes, the SURPASS-2 trial compared it directly with semaglutide (Frías et al., NEJM 2021). Tirzepatide holds regulatory approval for human use in several countries (for example, the United States, the European Union, and Japan) under the brands Mounjaro (type 2 diabetes) and Zepbound (weight management).

Retatrutide (triple GIP/GLP-1/glucagon agonist)

In the phase 2 trial (Jastreboff et al., NEJM 2023), retatrutide was evaluated in 338 adults with obesity without diabetes, at doses of 1 to 12 mg weekly. In the 12 mg group, mean body-weight reduction was approximately 24.2 % at 48 weeks, with a reduction in liver fat of around 86 % in that subgroup. It is important to stress that retatrutide is an investigational compound (phase 3 ongoing) and, as of this article's date, has no approval for human use in any country. The cited data come exclusively from controlled clinical trials.

Safety profile, adverse effects, and contraindications

The most frequent adverse effects across this class are gastrointestinal: nausea, vomiting, diarrhea, and constipation, generally mild to moderate and most common during the dose-escalation phase in the trials.

Safety considerations reported in the literature and in the prescribing information of the approved products:

• Contraindicated in people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2), due to thyroid C-cell tumor findings in rodents.
• Caution with a history of pancreatitis.
• Monitoring for gallbladder disease, dehydration, and renal function in the setting of vomiting or diarrhea.
• Safety not established in pregnancy and lactation.
• Investigational compounds (such as retatrutide) have a long-term safety profile that is not yet fully characterized.

Regulatory status in Colombia

In Colombia, the commercialization and human use of any pharmaceutical preparation require INVIMA sanitary registration and a medical prescription. Regulatory classification depends on the actual intended use, not on the product label. To check the current registration status of a specific active ingredient, consult INVIMA's sanitary-registration lookup system directly. Retatrutide has no approval for human use in any jurisdiction.

Important note

References

1. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002.
2. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6):503-515.
3. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216.
4. Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234-1247.
5. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972.

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