Semaglutide

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA biotechnology, with approximately 94% homology to human GLP-1. Structural modifications make it less susceptible to enzymatic degradation by DPP-4 and enable high-affinity binding to plasma albumin (>99%), giving it a half-life of approximately one week and supporting once-weekly subcutaneous dosing or once-daily oral administration.

Mechanism of Action

Semaglutide selectively binds to and activates the GLP-1 receptor on pancreatic islet cells and other tissues, increasing intracellular cAMP. This produces:

• Glucose-dependent insulin secretion from pancreatic beta cells.
• Suppression of glucagon secretion in a glucose-dependent manner (counter-regulatory glucagon response to hypoglycemia is preserved).
• Delayed gastric emptying, particularly in the early postprandial phase.
• Central appetite regulation: reduces hunger, food cravings, and caloric intake via action on hypothalamic centers.
• Cardiovascular and metabolic effects: reduction in systolic blood pressure, lower fasting triglycerides and VLDL cholesterol, reduced atherosclerotic progression and vascular inflammation.

Pharmacokinetics

• Bioavailability: ~89% after subcutaneous injection.
• Tmax: 1–3 days subcutaneous; steady state reached after 4–5 weeks.
• Volume of distribution: 8–9.4 L.
• Protein binding: >99% to albumin — the basis for its prolonged half-life.
• Metabolism: cleaved at the peptide backbone followed by β-oxidation of the fatty acid chain; metabolized by DPP-4 and neutral endopeptidase (neprilysin). Six metabolites identified in plasma; ~83% of an administered dose remains as unchanged drug.
• Half-life: ~168 hours (~7 days).
• Clearance: ~0.05 L/h.
• Excretion: 53% in urine, 18.6% in feces, ~3.2% exhaled.
• Hepatic impairment: does not significantly affect clearance; no dose adjustment needed for mild–moderate impairment.

In clinical trials in patients with type 2 diabetes mellitus, semaglutide demonstrated sustained, statistically superior reductions in HbA1c and body weight compared with placebo and active comparators (sitagliptin, insulin glargine, exenatide ER, dulaglutide). In patients with type 2 diabetes and high cardiovascular risk, semaglutide reduced the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke).

In clinical trials for chronic weight management, semaglutide produced average weight reductions of approximately 15% of initial body weight over 68 weeks, with substantial proportions of patients achieving ≥10% weight loss. Improvements were observed in waist circumference, blood pressure, lipid parameters, and glycemic measures.

Type 2 Diabetes Mellitus

In adult patients with type 2 diabetes mellitus, on a background of diet and exercise, to improve glycemic control as:

• Monotherapy when metformin is not tolerated or contraindicated.
• Combination therapy with other antidiabetic agents (metformin, sulfonylureas, thiazolidinediones, SGLT-2 inhibitors, insulin) in patients who have not achieved adequate glycemic control.

In patients with type 2 diabetes and established cardiovascular disease, semaglutide is indicated to reduce the risk of major cardiovascular events as an adjunct to standard cardiovascular therapy.

Chronic Weight Management

As an adjunct to a reduced-calorie diet and increased physical activity:

• Adults with obesity (BMI ≥30 kg/m²), or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, dyslipidemia).
• Pediatric patients ≥12 years old with an initial BMI at the 95th percentile or greater for age and sex.

Cardiovascular Risk Reduction (Wegovy)

To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight.

Chronic Kidney Disease in Type 2 Diabetes (Ozempic, Jan 2025)

To reduce the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes mellitus and chronic kidney disease.

Metabolic-Associated Steatohepatitis (Wegovy, Aug 2025)

Granted FDA Accelerated Approval for the treatment of metabolic-associated steatohepatitis (MASH) in adults with moderate-to-advanced liver fibrosis.

• Hypersensitivity to semaglutide or any of the excipients.
• Personal or family history of medullary thyroid carcinoma (MTC).
• Multiple endocrine neoplasia syndrome type 2 (MEN 2).
• Type 1 diabetes mellitus.
• Diabetic ketoacidosis.
• Pregnancy and breastfeeding.
• Severe hepatic impairment.
• End-stage renal failure (creatinine clearance < 15 mL/min).
• New York Heart Association functional class IV chronic heart failure.

• Renal impairment.
• History of pancreatitis.
• Diabetic retinopathy (especially with concomitant insulin therapy).
• Severe gastrointestinal disease.

Very Common (>10%): nausea, diarrhea, vomiting, abdominal pain, constipation.

Common (1–10%): decreased appetite, dyspepsia, gastritis, gastroesophageal reflux, eructation, flatulence, headache, dizziness, fatigue, injection site reactions, cholelithiasis, increased heart rate, hypoglycemia (when used with insulin or sulfonylureas), increased lipase and amylase activity.

Uncommon: dysgeusia, diabetic retinopathy complications.

Rare: anaphylactic reactions, acute pancreatitis, severe hypersensitivity reactions.

Most gastrointestinal effects are mild to moderate in intensity and tend to decrease over time with continued use and gradual dose escalation.

• Oral medications: delayed gastric emptying may affect absorption of co-administered oral drugs that require rapid gastrointestinal absorption.
• Insulin and insulin secretagogues: increased risk of hypoglycemia; consider dose reduction.
• Warfarin: monitor INR when initiating or discontinuing semaglutide.

Semaglutide should not be mixed with other medications, including infusion solutions.

Semaglutide is administered once weekly by subcutaneous injection (abdomen, thigh, or upper arm), at any time, regardless of meals. The injection site may be rotated without dose adjustment. Do not administer intravenously or intramuscularly.

The oral tablet formulation (Rybelsus) is taken once daily on an empty stomach, with no more than 4 ounces (120 mL) of plain water, at least 30 minutes before the first food, drink, or other oral medication of the day.

If a dose is missed and the next scheduled dose is more than 48 hours away, it should be administered as soon as possible (within 5 days of the scheduled dose). If more than 5 days have passed, skip the dose and resume the regular weekly schedule. The day of weekly administration may be changed provided there are at least 3 days (72 hours) between injections.

Type 2 Diabetes — Dose Escalation

1. Weeks 1–4: 0.25 mg once weekly (initiation dose, not therapeutic).
2. Week 5 onwards: 0.5 mg once weekly.
3. After at least 4 weeks at 0.5 mg, may increase to 1 mg once weekly for further glycemic control.
4. After at least 4 weeks at 1 mg, may increase to 2 mg once weekly if needed.

Chronic Weight Management — Dose Escalation

1. Weeks 1–4: 0.25 mg once weekly.
2. Weeks 5–8: 0.5 mg once weekly.
3. Weeks 9–12: 1 mg once weekly.
4. Weeks 13–16: 1.7 mg once weekly.
5. Week 17 onwards: 2.4 mg once weekly (maintenance dose).

If a dose is not tolerated during escalation, dose escalation may be delayed for 4 weeks. If the maintenance dose is not tolerated, dose may be reduced to the previous step.

Special Patient Populations

• Elderly (≥65 years): no dose adjustment based on age. Limited experience in patients ≥75 years.
• Hepatic impairment: no adjustment for mild/moderate impairment; contraindicated in severe impairment.
• Renal impairment: no adjustment required; contraindicated in end-stage renal failure.
• Pediatric: not recommended in patients under 18 years.

In clinical trials, single overdoses up to 4 mg and weekly overdoses up to 4 mg have been reported, with nausea as the most common adverse reaction; all patients recovered without complications. There is no specific antidote. Given the long elimination half-life (approximately one week), prolonged observation and symptomatic treatment may be required.

Pancreatitis Risk

Cases of acute pancreatitis have been observed with GLP-1 receptor agonist therapy. Patients should be informed about characteristic symptoms (severe persistent abdominal pain, pain radiating to the back, nausea, vomiting). Discontinue if pancreatitis is suspected.

Thyroid C-cell Tumors

In animal studies, GLP-1 receptor agonists have been associated with thyroid C-cell tumors. Patients should be counseled about symptoms of thyroid tumors (neck mass, dysphagia, dyspnea, persistent hoarseness). Use is contraindicated in patients with personal or family history of medullary thyroid carcinoma or MEN type 2.

Diabetic Retinopathy

Caution is warranted in patients with diabetic retinopathy receiving insulin therapy; rapid improvement of glucose control may be associated with temporary worsening of retinopathy.

Gallbladder Disease

Substantial weight loss may increase the risk of cholelithiasis. Patients should be informed about symptoms of gallstones.

Hypoglycemia

Semaglutide alone does not cause hypoglycemia, but the risk increases when used with insulin or insulin secretagogues. Dose adjustment of these concomitant medications may be required.

Compounded and Salt Forms — FDA Safety Warning

In May 2023, the FDA issued a warning regarding compounded semaglutide products following adverse event reports. The use of salt forms (semaglutide sodium and semaglutide acetate) has not been demonstrated to be safe or effective. Only FDA-approved finished products from authorized manufacturers should be used.

Effect on Ability to Drive

Semaglutide has minimal effect on the ability to drive or operate machinery. Patients on concomitant insulin or sulfonylureas should be aware of the risk of hypoglycemia.

Before first use: store at 2°C to 8°C in a refrigerator. Do not freeze. Protect from light. Keep in the original package.

After first use: depending on formulation, may be stored at room temperature (not exceeding 30°C) or refrigerated (2–8°C) for up to 4 to 6 weeks. Keep the cap on when not in use to protect from light.

Store out of reach of children. Dispose of used pens safely according to local regulations.

3 years when stored properly. Do not use after the expiry date indicated on the label and packaging.

Prescription required.