Semaglutide

Semaglutide is a long-acting GLP-1 receptor agonist given as a weekly subcutaneous injection, or as a daily oral tablet. It lowers HbA1c by about 1.5 to 1.8% and body weight by about 4 to 6 kg in diabetes doses, and about 15% at the 2.4 mg weekly weight-management dose. It reduces major cardiovascular events in type 2 diabetes and in people with obesity and established cardiovascular disease without diabetes, and it slows kidney disease progression in type 2 diabetes with chronic kidney disease. It carries a thyroid C-cell tumour warning.

Classification. GLP-1 receptor agonist, human GLP-1 analogue with a fatty diacid chain for albumin binding. Subcutaneous pens (0.25, 0.5, 1, 1.7, 2 and 2.4 mg weekly doses) and oral tablets (3, 7 and 14 mg; higher strengths exist for weight management in some markets).

Mechanism. Activates the GLP-1 receptor, increasing glucose-dependent insulin release, suppressing glucagon, slowing gastric emptying and reducing appetite through central appetite circuits.

Pharmacodynamics. Lowers fasting and post-meal glucose with low hypoglycaemia risk alone. Reduces energy intake, body weight, blood pressure and triglycerides, and raises resting heart rate by 2 to 4 beats a minute.

Pharmacokinetics. Subcutaneous bioavailability about 89%; peak 1 to 3 days; over 99% albumin bound. Degraded by proteases and beta-oxidation of the fatty chain, with no single organ of elimination; excreted in urine and faeces as metabolites. Half-life about 1 week; steady state after 4 to 5 weeks. Oral bioavailability is about 1% and needs the absorption enhancer in the tablet.

Type 2 diabetes, adults, subcutaneous.

• Start 0.25 mg subcutaneously once weekly for 4 weeks (a tolerability dose that does not lower glucose enough).
• Increase to 0.5 mg weekly; after at least 4 weeks increase to 1 mg weekly if needed, and after at least 4 more weeks to 2 mg weekly if needed.
• Maximum 2 mg weekly. No loading dose.

Type 2 diabetes, adults, oral.

• Start 3 mg orally once daily for 30 days, then 7 mg once daily; after at least 30 days increase to 14 mg once daily if needed. Maximum 14 mg daily.
• Take on an empty stomach with up to 120 mL of plain water, and wait at least 30 minutes before food, drink or other oral medicines. Swallow whole.

Weight management (2.4 mg weekly presentation).

• Adults with obesity, or overweight with weight-related disease: 0.25 mg weekly for 4 weeks, 0.5 mg weekly for 4 weeks, 1 mg weekly for 4 weeks, 1.7 mg weekly for 4 weeks, then 2.4 mg weekly as maintenance.
• Adolescents from 12 years with obesity: same schedule.
• If a step is not tolerated, wait 4 more weeks before trying again. Stop if there is no clinically useful weight loss after 6 months at the maintenance dose.

Cardiovascular and kidney risk reduction.

• Established cardiovascular disease with obesity, with or without diabetes: 2.4 mg weekly, reached by the 4-weekly steps used for weight management.
• Type 2 diabetes with chronic kidney disease: 1 mg weekly, started at 0.25 mg weekly and raised to 1 mg weekly on the diabetes schedule.

Combination use. Adds to metformin, sulphonylureas, SGLT2 inhibitors, pioglitazone and basal insulin. Reduce the sulphonylurea or insulin dose when adding semaglutide. Do not combine with a DPP-4 inhibitor or another GLP-1 receptor agonist.

Missed doses (weekly). Give within 5 days of the missed day; if more than 5 days have passed, skip it and give the next dose on the usual day. If two or more consecutive doses are missed, restart at a lower step as clinically judged.

Adjustments.

• Kidney: no change in mild, moderate or severe impairment; monitor fluid status with vomiting or diarrhoea.
• Liver: no change in mild to moderate impairment; limited data in severe impairment.
• Older adults: no change.
• Weight: no weight-based dosing in adults.
• Children: licensed from 12 years for obesity only.

Boxed-warning-level risk. Thyroid C-cell tumours occurred in rodents. Contraindicated with a personal or family history of medullary thyroid carcinoma and in multiple endocrine neoplasia type 2. Advise patients to report a neck mass, dysphagia, dyspnoea or persistent hoarseness.

Contraindications. Hypersensitivity; medullary thyroid carcinoma history; multiple endocrine neoplasia type 2; pregnancy (weight-management presentation).

Serious adverse effects.

• Acute pancreatitis: stop if suspected and do not restart if confirmed.
• Gallbladder disease: cholelithiasis and cholecystitis, more with rapid weight loss.
• Diabetic retinopathy complications with rapid HbA1c fall in patients with existing retinopathy; screen before starting.
• Non-arteritic anterior ischaemic optic neuropathy: very rare; stop and refer for sudden painless visual loss.
• Acute kidney injury from dehydration with vomiting and diarrhoea.
• Hypoglycaemia with sulphonylureas or insulin.
• Delayed gastric emptying: aspiration risk during sedation or anaesthesia.
• Mood changes and suicidal thoughts reported with the weight presentation.

Common adverse effects. Nausea, vomiting, diarrhoea, constipation, abdominal pain, reduced appetite, fatigue; mostly during dose escalation. Loss of lean mass accompanies weight loss.

Major interactions.

• Insulin and sulphonylureas: hypoglycaemia.
• Oral semaglutide raises levothyroxine exposure by about one third; check TSH after starting.
• Delayed gastric emptying may alter the absorption of other oral medicines; monitor INR with warfarin when starting.
• Oral contraceptive absorption is not clinically changed by semaglutide.

Special groups.

• Pregnancy: avoid; stop at least 2 months before a planned pregnancy because of the long half-life; use insulin for diabetes in pregnancy.
• Breastfeeding: avoid.
• Children: licensed from 12 years for obesity; not for type 2 diabetes.
• Older adults: dehydration and loss of lean mass in frail adults.
• Kidney and liver impairment: no change at any stage of kidney impairment; limited data in severe liver impairment.
• East Africa: unopened pens need a fridge (2 to 8 degrees Celsius) and must not freeze; in-use pens keep at room temperature up to 30 degrees Celsius for the period stated on the label, so power cuts and heat need planning. Cost and supply restrict use; prioritise those with established cardiovascular disease, chronic kidney disease or obesity with diabetes.

Administration (subcutaneous). Inject into the abdomen, thigh or upper arm once weekly on the same day, at any time, with or without food; rotate sites. Pen needles are single-use. The day can be changed if the previous dose was at least 3 days earlier.

Perioperative. Tell the anaesthetist; delayed gastric emptying can leave food in the stomach after fasting. Practice varies between withholding the weekly dose before the procedure and continuing with a 24 hour clear-fluid diet beforehand.

Baseline. HbA1c, eGFR, weight, history of pancreatitis, gallstones and thyroid disease, retinal screening result.

Monitoring.

• HbA1c at 3 and 6 months, then every 6 months.
• Weight and gastrointestinal symptoms at each visit.
• eGFR when vomiting or diarrhoea occur.
• Retinal screening before starting and within the usual interval; earlier if vision changes.
• Capillary glucose when on sulphonylurea or insulin.
• TSH after starting oral semaglutide in patients on levothyroxine.

Stopping thresholds. Stop with suspected pancreatitis, thyroid mass with suspicion of medullary carcinoma, sudden visual loss, severe hypersensitivity, pregnancy, or inadequate response (HbA1c reduction under 1% or weight loss under 5% at 6 months for diabetes use).

Referral and escalation. Admit severe abdominal pain with vomiting for pancreatitis assessment; assess biliary symptoms by ultrasound. Refer a neck mass for thyroid ultrasound and calcitonin, and sudden visual loss for urgent ophthalmology.