Liraglutide / Semaglutide

Mechanism

Pharmacological Class and Group

Agonists or analogues of the glucagon-like peptide 1 receptor (arGLP-1).

Mechanism of Action

Endogenous GLP-1 is a peptide secreted by the L cells of the ileum after food intake, which enhances glucose-dependent insulin secretion (incretin effect). However, it is degraded within minutes by the enzyme dipeptidyl peptidase-4 (DPP-4). Analogues are structurally modified to resist enzymatic cleavage:

• Liraglutide: 97% amino acid sequence homology to native GLP-1, with substitution of lysine 34 with arginine and the addition of a palmitic fatty acid side chain (C16) via a glutamic acid spacer, promoting albumin binding.
• Semaglutide: Substitution of alanine with alpha-aminoisobutyric acid in position 8 (resistance against DPP-4) and acylation of lysine in position 26 with a C18 fatty diacid that significantly prolongs the half-life.

Signaling and Physiological Effects

1. GLP-1 receptor binding (GLP-1R): Gs protein-coupled receptors in the beta cells of the pancreas. Agonist binding stimulates adenylate cyclase, increasing intracellular cyclic AMP (cAMP), which activates protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor 2 (Epac2).

2. Glucose-Dependent Insulin Secretion: The increase in PKA and Epac2 sensitizes the exocytic machinery to intracellular calcium. As a consequence, insulin is released from its reserve vesicles only in the presence of elevated plasma glucose concentrations, virtually eliminating the risk of hypoglycemia in monotherapy.

3. Glucagon Suppression: Inhibits glucagon secretion from pancreatic alpha cells indirectly by increasing somatostatin from delta cells and insulin from beta cells, decreasing hepatic gluconeogenic flux.

4. Delayed Gastric Emptying: Transiently reduces gastric motility by modulating efferent vagal tone, reducing the postprandial glycemic peak of complex carbohydrates.

5. Satiety at the Level of the Central Nervous System: It crosses brain barriers or acts via receptors in the area postrema and nucleus of the solitary tract (NTS), activating POMC/CART neurons and inhibiting NPY/AgRP neurons, inducing satiety and decreasing caloric palatability.

Pharmacokinetics

High Resolution Pharmacokinetics

Note on Semaglutide Oral: Requires co-formulation with sodium salcaprozate (SNAC). SNAC increases the local pH in the gastric mucosa, preventing acidic enzymatic degradation and promoting passive transcellular absorption of semaglutide.

Indicators and dose

Clinical Indications and Off-Label Uses

• Type 2 Diabetes Mellitus: To optimize glycemic control and reduce cardiovascular risk.
• Chronic weight control / Obesity: Indicated in patients with BMI 30 kg/m², or 27 kg/m² with associated comorbidities (hypertension, dyslipidemia).
• Secondary cardiovascular prevention: In adult patients with DM2 and established atherosclerotic cardiovascular disease.
• Non-alcoholic Steatohepatitis (MASH/NASH) (off-label): Reduction of liver fat content and fibrosis in initial stages.

Dosage and Clinical Adjustment

Subcutaneous Semaglutide (Ozempic) - Weekly:

• Initial Dose: 0.25 mg once a week for the first 4 weeks.
• Escalation: Increase to 0.5 mg weekly. If after a month greater glycemic control is required, escalate to 1 mg, and eventually to 2 mg once a week.

Oral Semaglutide (Rybelsus) - Daily:

• Initial Dose: 3 mg once a day for 30 days, taken at least 30 minutes before the first meal, drink or oral medication of the day, with a volume of plain water no greater than 120 mL.
• Maintenance: Escalate to 7 mg daily after one month; maximum dose of 14 mg once a day.

Subcutaneous Liraglutide (Saxenda - Obesity) - Daily:

• Weekly Escalation Scheme: Week 1: 0.6 mg/day Week 2: 1.2 mg/day Week 3: 1.8 mg/day Week 4: 2.4 mg/day Week 5 and maintenance: 3.0 mg/day SC.

Adjustment in Renal/Hepatic Insufficiency: No dose adjustment is required in patients with renal or hepatic insufficiency, regardless of the degree. Use with caution in patients with eGFR < 15 mL/min/1.73 m² due to lack of robust clinical experience.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Personal or family history of Medullary Thyroid Carcinoma (MTC).
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (induced risk of C cell hyperplasia due to stimulation of the GLP-1R receptor).
• Documented severe hypersensitivity.
• History of acute pancreatitis.

Relative Contraindications

• Chronic inflammatory bowel disease or severe diabetic gastroparesis (may markedly worsen stasis).
• Concomitant use with other GLP-1 agonists or DPP-4 inhibitors (no added efficacy).
• Pregnancy in progress or planned in the short term.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Transient dose-dependent gastrointestinal disorders: Nausea, vomiting, diarrhea or constipation. They tend to be self-limiting with a tiered dosing protocol.
• Common (1%-10%): Dyspepsia, gastroesophageal reflux, flatulence, belching, cholelithiasis and cholecystitis (due to drug-induced decrease in gallbladder contractility), generalized fatigue, dizziness.
• Uncommon (0.1%-1%): Increase in pancreatic lipase and amylase, alteration in resting heart rate (increase of 2-4 bpm due to stimulation of the SA node).
• Rare: Acute necrotizing pancreatitis, prerenal acute renal failure due to dehydration, transient worsening of pre-existing diabetic retinopathy (Semaglutide SC in initial studies due to ultra-rapid decrease in HbA1c).

Toxicity Alert: Risk of Thyroid C Cells and Pancreatitis

In rodents, prolonged activation of GLP-1 receptors in thyroid follicular C cells induces adenomas and medullary carcinomas in a dose-dependent manner. Although the density of these receptors in humans is significantly lower, GLP-1 agonists are formally contraindicated in patients with a history of CMT or MEN 2.

On the other hand, the patient should be warned about the detection of severe upper abdominal pain that radiates to the back, accompanied by persistent vomiting, suggestive of acute pancreatitis. In this situation, suspend the drug and do not resume it under any circumstances.

Drug Interactions of Clinical Relevance

• Drugs with a narrow therapeutic range with rapid oral absorption (Levothyroxine, Digoxin, Oral contraceptives, Single-dose antibiotics): The marked delay in gastric emptying can delay the maximum concentration of these compounds. It is recommended to separate the intake at least 1 hour after administering oral semaglutide.
• Insulins and insulin secretagogues: Hypoglycemic synergism that requires titrating the base doses downwards to mitigate the risks of severe neuroglycopenia.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Contraindicated. Animal studies have shown reproductive and skeletal toxicity related to fetal growth restriction due to reduced nutrient intake. It is recommended to discontinue semaglutide at least 2 months before conceiving a pregnancy due to its long systemic persistence.
• Breastfeeding: Not recommended. Preclinical studies indicate milk transfer of liraglutide and semaglutide in low amounts, but neonatal clinical safety is not guaranteed.