GLP-1 Receptor Agonists

The incretins GLP-1 and GIP stimulate insulin secretion after an oral glucose load — the incretin effect — and both are inactivated by DPP-4. In type 2 diabetes this effect can become blunted or absent, but pharmacological levels of GLP-1 can restore insulin secretion. Native GLP-1(7-37) has a half-life of only 1.5 to 2 minutes because DPP-4 and neutral endopeptidases degrade it, so the drugs are analogs built to resist them.

The GLP-1 receptor on the β cell is coupled to adenylyl cyclase by the stimulatory G protein Gs. An agonist raises intracellular cAMP, which releases insulin in the presence of elevated glucose; the secretion subsides as glucose falls toward normal, and glucagon secretion is lowered in a glucose-dependent manner. The glucagon response to low glucose is not impaired, so the class causes little hypoglycemia unless it is combined with insulin or a sulfonylurea. Glucose also falls because gastric emptying is delayed, slowing the rate at which glucose from a meal reaches the circulation, and GLP-1 increases satiety through direct actions on the hypothalamus — the class produces an average weight loss of 2.9 kg compared with placebo.

Liraglutide (97% sequence homology to native GLP-1) carries a C-16 fatty acid (palmitic acid) on lysine 26. Self-association that delays absorption, plasma protein binding and stability against DPP-4 and neutral endopeptidases give it a half-life of 13 hours, suiting once-daily dosing. Semaglutide (94% homology) is modified at position 8 to resist DPP-4 and carries a C18 fatty diacid at lysine 26 that binds albumin, which lowers renal clearance and protects it from degradation: its half-life is about 1 week, and it stays in the circulation for about 5 weeks after the last dose. Dulaglutide is a fusion protein — a GLP-1 analog, 90% homologous to native GLP-1, linked to the Fc portion of a modified human IgG4 heavy chain — with a half-life of about 5 days.

The class is usually injected because of poor oral bioavailability. Semaglutide tablets are co-formulated with the absorption enhancer SNAC (salcaprozate sodium), and absorption occurs mainly in the stomach — yet bioavailability is only about 0.4% to 1% for RYBELSUS (1% to 2% for OZEMPIC tablets). Absorption is higher after a longer post-dose fast, so the tablet is taken on an empty stomach in the morning with no more than 4 ounces of water, swallowed whole, and followed by at least 30 minutes without food, other drinks or other oral medications.

Tirzepatide is built on the GIP sequence, with a C20 fatty diacid that binds albumin and prolongs its half-life to about 5 days. It selectively binds and activates both the GIP and GLP-1 receptors, the targets of the native hormones. It enhances first- and second-phase insulin secretion and lowers glucagon, both in a glucose-dependent manner; it also increases insulin sensitivity (shown in a hyperinsulinemic euglycemic clamp study), decreases food intake and reduces body weight.

It delays gastric emptying too — most after the first dose, an effect that diminishes over time. That delay can reduce the efficacy of oral hormonal contraceptives, so the label advises switching to a non-oral method or adding a barrier method for 4 weeks after starting and for 4 weeks after each dose escalation; hormonal contraceptives not taken by mouth should not be affected.

In rodents, each of these drugs causes dose- and treatment-duration-dependent thyroid C-cell tumors, and liraglutide stimulated calcitonin release in rodent models, with C-cell hyperplasia and tumors. Whether the drugs cause C-cell tumors, including medullary thyroid carcinoma (MTC), in humans is unknown: postmarketing MTC cases with liraglutide are insufficient to establish or exclude a causal relationship.

The contraindication covers the patients already at risk of MTC. The tumor arises from the thyroid’s parafollicular C cells, which originate from the neural crest and produce calcitonin. About 25% of cases are inherited, most commonly as MEN 2A, followed by MEN 2B, and all inherited forms carry germline mutations in the RET proto-oncogene. Every label contraindicates the drugs with a personal or family history of MTC or with MEN 2, and the box says to counsel patients on the symptoms of thyroid tumors — a neck mass, dysphagia, dyspnea, persistent hoarseness. Routine calcitonin or thyroid-ultrasound monitoring is of uncertain value: calcitonin has low specificity against a high background of thyroid disease, so screening may lead to unnecessary procedures, but an elevated calcitonin (patients with MTC usually have values above 50 ng/L) or a thyroid nodule is evaluated further.

The GI adverse reactions — nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation, abdominal pain — are the most common and can be severe, and the drugs are not recommended in severe gastroparesis. Because the class increases satiety, transient mild nausea may occur if a patient eats while full, and doses are increased slowly when nausea is present. With dulaglutide the gastric-emptying delay is dose-dependent but attenuated by dose escalation, and it is largest after the first dose and diminishes with later doses.

The downstream risks follow from the GI effects. Fluid lost to nausea, vomiting or diarrhea can cause acute kidney injury, in some cases requiring hemodialysis, so renal function is monitored in patients with these reactions, especially as doses are started and raised. The rare reports of pulmonary aspiration during general anesthesia or deep sedation involved residual gastric contents despite preoperative fasting, so patients tell their clinicians before any planned procedure. Slower emptying may also affect the absorption of oral drugs, and levels of oral medications with a narrow therapeutic index, such as warfarin, are monitored.

The other class warnings are acute pancreatitis, including fatal hemorrhagic or necrotizing cases (its mechanism remains largely unknown; the drug is stopped if pancreatitis is suspected); acute gallbladder disease such as cholelithiasis or cholecystitis; serious hypersensitivity (anaphylaxis, angioedema); and, with semaglutide, dulaglutide and tirzepatide, diabetic retinopathy complications — rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.