Usage
Semaglutide is prescribed for the treatment of type 2 diabetes mellitus in adults, as an adjunct to diet and exercise. It is also indicated for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, dyslipidemia), and to reduce the risk of major adverse cardiovascular events (MACE) such as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke in adults with type 2 diabetes mellitus and established cardiovascular disease.
Semaglutide belongs to the pharmacological class of glucagon-like peptide-1 (GLP-1) receptor agonists, also known as incretin mimetics.
It works by mimicking the effects of the naturally occurring GLP-1 hormone, which helps regulate blood glucose levels, reduces appetite, and promotes weight loss.
Alternate Names
Semaglutide is the generic name. Brand names include Ozempic, Rybelsus, and Wegovy. There are no widely recognized international or regional variations of the name.
How It Works
Pharmacodynamics: Semaglutide activates GLP-1 receptors, which are found in various tissues, including the pancreas, brain, and gastrointestinal tract. This leads to several effects:
- Increased insulin secretion: Glucose-dependent insulin secretion is stimulated, leading to lower blood glucose levels.
- Decreased glucagon secretion: Glucagon, a hormone that raises blood sugar, is suppressed, contributing to improved glycemic control.
- Delayed gastric emptying: This promotes satiety and contributes to weight loss.
- Reduced appetite: Effects on the central nervous system lead to decreased food intake.
- Cardioprotective effects: While the exact mechanisms are still being investigated, potential benefits include improved endothelial function and reduced inflammation.
Pharmacokinetics:
- Absorption: Subcutaneous semaglutide is absorbed slowly and reaches peak concentration in 1-3 days. Oral semaglutide has lower bioavailability.
- Metabolism: Semaglutide is metabolized by proteolytic cleavage, not through CYP450 enzymes.
- Elimination: Primarily eliminated through the kidneys. The half-life is approximately one week.
Mode of Action: Semaglutide binds to and activates GLP-1 receptors, a G protein-coupled receptor. This activation initiates intracellular signaling pathways, ultimately leading to the pharmacodynamic effects described above.
Receptor Binding: Semaglutide selectively binds to GLP-1 receptors.
Enzyme Inhibition/Neurotransmitter Modulation: Semaglutide’s primary mechanism is receptor activation, not enzyme inhibition or direct neurotransmitter modulation. However, its actions indirectly influence the release of other hormones and neurotransmitters involved in appetite regulation and glucose metabolism.
Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- Type 2 Diabetes (Ozempic): Initial dose is 0.25 mg subcutaneously once weekly for 4 weeks, then increased to 0.5 mg weekly. If further glycemic control is needed, the dose can be increased to 1 mg weekly after at least 4 weeks. The maximum dose is 2 mg weekly.
- Weight Management (Wegovy): Initial dose is 0.25 mg subcutaneously once weekly for 4 weeks, then titrated upwards every 4 weeks (0.5 mg, 1 mg, 1.7 mg, 2.4 mg) as tolerated, to a maximum of 2.4 mg weekly.
- Type 2 Diabetes (Rybelsus - Oral): Initial dose is 3 mg orally once daily for 30 days, then increased to 7 mg daily. If needed, the dose can be increased to 14 mg daily after at least 30 days on 7 mg.
Children:
Semaglutide (Wegovy injection) is approved for children 12 years and older for chronic weight management. The dosing follows the same titration schedule as adults, starting at 0.25 mg weekly and increasing as tolerated up to a maximum of 2.4 mg weekly. Pediatric use for type 2 diabetes is not approved for Ozempic and Rybelsus.
Special Cases:
- Elderly Patients: No dose adjustment is generally required based on age alone.
- Patients with Renal Impairment: No dose adjustment is recommended for mild to moderate renal impairment. Semaglutide is not recommended for patients with end-stage renal disease. Caution is advised in severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is recommended for mild to moderate hepatic impairment. Use with caution in severe hepatic impairment.
- Patients with Comorbid Conditions: Dose adjustments may be needed depending on specific comorbid conditions. Careful monitoring is recommended.
Clinical Use Cases
Semaglutide is not indicated for use in acute settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is for the chronic management of type 2 diabetes and weight management in adults.
Dosage Adjustments
Dose modifications are based primarily on tolerability and efficacy, with titration upwards as needed and tolerated. If gastrointestinal side effects occur during dose escalation, consider delaying the increase for 4 weeks.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness.
Rare but Serious Side Effects
Pancreatitis, gallbladder disease, acute kidney injury, hypoglycemia (especially with concomitant sulfonylurea or insulin), angioedema, retinal complications in patients with diabetic retinopathy.
Long-Term Effects
Potential long-term effects are still being studied. Some concerns include thyroid C-cell tumors (seen in rodent studies), pancreatic and gallbladder complications.
Adverse Drug Reactions (ADR)
Serious ADRs include pancreatitis, gallbladder disease, angioedema, and severe hypoglycemia.
Contraindications
- History of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
- Hypersensitivity to semaglutide or any of the components.
- Diabetic ketoacidosis.
- Severe gastrointestinal disease, including gastroparesis.
Drug Interactions
Semaglutide can delay gastric emptying, affecting the absorption of oral medications. Monitor for altered drug levels when co-administering with other oral drugs, especially those with narrow therapeutic indexes. No significant interactions are expected with drugs metabolized by CYP450 enzymes.
Pregnancy and Breastfeeding
- Pregnancy: Limited human data. Animal studies suggest potential adverse developmental effects. Semaglutide should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
- Breastfeeding: Not known if semaglutide is excreted in human milk. A decision should be made whether to discontinue breastfeeding or to discontinue semaglutide, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Drug Profile Summary
- Mechanism of Action: GLP-1 receptor agonist. Enhances glucose-dependent insulin secretion, suppresses glucagon secretion, delays gastric emptying, and reduces appetite.
- Side Effects: Nausea, vomiting, diarrhea, constipation, abdominal pain, headache, pancreatitis (rare), gallbladder disease (rare).
- Contraindications: MTC, MEN 2, hypersensitivity, diabetic ketoacidosis.
- Drug Interactions: Can delay gastric emptying, affecting absorption of oral medications.
- Pregnancy & Breastfeeding: Use with caution. Potential risks to fetus/infant.
- Dosage: See detailed dosage guidelines above.
- Monitoring Parameters: HbA1c, fasting blood glucose, body weight, blood pressure, renal function, liver function tests.
Popular Combinations
Semaglutide is often used in combination with metformin, sulfonylureas, SGLT2 inhibitors, and insulin, when these agents alone do not provide adequate glycemic control.
Precautions
- Assess renal and hepatic function before starting semaglutide.
- Monitor for gastrointestinal side effects, pancreatitis, and gallbladder disease.
- Patients with diabetes should be educated on hypoglycemia risk, particularly when used with insulin or sulfonylureas.
- Monitor thyroid function periodically in patients with a history of thyroid disease.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Semaglutide?
A: See detailed dosage guidelines above based on indication and formulation (Ozempic, Rybelsus, Wegovy), including adjustments for special populations.
Q2: What are the most common side effects of semaglutide?
A: Nausea, vomiting, diarrhea, and constipation are the most frequent side effects.
Q3: How does semaglutide work for weight loss?
A: Semaglutide acts on GLP-1 receptors in the brain, reducing appetite and promoting satiety, which leads to weight loss. It also delays gastric emptying.
Q4: Can semaglutide be used in patients with type 1 diabetes?
A: No, semaglutide is not indicated for type 1 diabetes.
Q5: Are there any serious side effects associated with semaglutide?
A: Yes, although rare, pancreatitis and gallbladder disease are potential serious side effects. Patients should be monitored for these conditions.
Q6: How should semaglutide be administered?
A: Ozempic and Wegovy are administered subcutaneously once weekly. Rybelsus is an oral tablet taken once daily.
Q7: Does semaglutide interact with other medications?
A: Semaglutide can delay gastric emptying, potentially affecting the absorption of oral medications. Monitor drug levels of concomitant oral medications.
Q8: Can semaglutide be used during pregnancy?
A: Use with caution during pregnancy. Limited human data are available. Animal studies suggest potential fetal risks. The potential benefit should outweigh the risk.
Q9: Is semaglutide safe for breastfeeding mothers?
A: It is unknown if semaglutide is excreted in human milk. Consider the benefits of breastfeeding for the child and the need for semaglutide therapy for the mother when making a decision.
