Semaglutide

Semaglutide belongs to the active substance group of GLP-1 receptor agonists. Semaglutide is used to treat both type 2 diabetes mellitus and obesity. The effect of semaglutide is based on its ability to activate the GLP-1 receptor, which helps to improve glycemic control and weight reduction.

Semaglutide is a GLP-1 receptor agonist (glucagon-like peptide-1 receptor agonist) that activates the GLP-1 receptors in the body. Semaglutide thereby promotes glucose-dependent insulin secretion from the beta cells of the pancreas and at the same time inhibits the release of glucagon, a hormone that increases blood sugar levels. This leads to an improvement in blood sugar control, especially in patients with type 2 diabetes. Semaglutide also slows down gastric emptying, which leads to a reduction in the postprandial rise in glucose. In addition to its blood sugar-lowering effect, semaglutide influences the central nervous system and reduces the feeling of hunger, which contributes to weight reduction. Due to its longer half-life, semaglutide can be administered subcutaneously once a week.

Psoriasis and semaglutide: Since psoriasis vulgaris is often associated with abdominal obesity and type 2 diabetes (T2D), it made sense to observe psoriasis during treatment with semaglutide (see psoriasis vulgaris below). PASI and DLQI decreased by 98.3% and 95%, respectively, during treatment, indicating a significant improvement in psoriatic skin lesions and a significant improvement in the patient's quality of life compared to baseline (Malavazos AE et al. 2023).

Extended half-life: Semaglutide has an extended half-life of approximately 1 week compared to native GLP-1, which allows once-weekly subcutaneous administration. This is achieved by albumin binding, which results in reduced renal clearance and protection from enzymatic degradation. Semaglutide is stable against degradation by the enzyme DPP-4.

Absorption: Maximum concentration in the blood is reached 1 to 3 days after injection. Steady-state is reached after 4-5 weeks of regular weekly administration. The bioavailability of subcutaneous semaglutide is about 89%.

Distribution: Semaglutide is distributed in a mean volume of approximately 12.5 liters and binds to plasma albumin to over 99%.

Biotransformation: Semaglutide is metabolized by proteolytic cleavage and beta-oxidation of the fatty acid side chain prior to excretion; the enzyme neutral endopeptidase (NEP) is involved in the metabolism.

Elimination: Excretion is via urine and feces (approximately 2/3 via urine and 1/3 via feces). About 3 % of the dose is excreted unchanged in the urine.

The half-life is about 1 week and the drug remains in the body for up to 5 weeks after the last dose.

Special populations

Elderly patients: Age does not affect pharmacokinetics.

Gender and ethnicity: No relevant differences in pharmacokinetics.

Body weight: Higher body weight reduces exposure, but the effect remains adequate over a wide weight range.

Impaired renal and hepatic function: No significant effects on pharmacokinetics, even with varying degrees of renal or hepatic insufficiency.

Note on special populations:

• Elderly patients: Age does not affect pharmacokinetics.
• Gender and ethnicity: No relevant differences in pharmacokinetics.
• Body weight: Higher body weight reduces exposure, but the effect remains adequate over a wide weight range.
• Impaired renal and hepatic function: No significant effects on pharmacokinetics, even with varying degrees of renal or hepatic insufficiency.

Semaglutide is an incretin mimetic and belongs to the glucagon-like peptide (GLP)-1 agonists. Its indications include the treatment of:

• Diabetes mellitus type 2: For the treatment of inadequately controlled diabetes mellitus type 2 as monotherapy when the use of metformin is unsuitable due to intolerance or contraindications or in addition to other antidiabetic agents.
• Obesity, overweight

Adults

Used as an adjunct to a calorie-restricted diet and increased physical activity for weight management, including weight loss and weight maintenance, in adult patients with a baseline BMI of:

• ≥ 30 kg/m2 (obesity)
• or
• ≥ 27 kg/m2 to < 30 kg/m2 (overweight) who have at least one weight-related concomitant disease, such as dysregulation of glycemic control (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease.

Adolescents (≥ 12 years)

As a supplement to a calorie-reduced diet and increased physical activity to regulate weight in:

• Obesity ( BMI percentiles ≥ 95) according to the gender and age-specific BMI growth charts and body weight over 60 kg. Treatment should be discontinued and reassessed if adolescent patients have not reduced their BMI by at least 5% after 12 weeks on 2.4 mg or the maximum tolerated dose.

Semaglutide must not be used during pregnancy, as animal studies have shown reproductive toxicity and only limited data are available on its use in pregnant women. If a patient is planning to become pregnant or if pregnancy occurs, semaglutide must be discontinued. Due to its long half-life, the drug should be discontinued at least two months before a planned pregnancy.

Lactation: Semaglutide must not be used during lactation, as it passes into the breast milk of nursing rats and a risk for the breastfed child cannot be excluded.

Diabetes mellitus type 2

Adults:

• Starting dose: 0.25 mg once a week for 4 weeks.
• Increase: After 4 weeks to 0.5 mg once a week.
• Further increase: After at least 4 weeks at 0.5 mg, the dose may be increased to 1 mg.
• Maximum increase: After at least 4 weeks with 1 mg, the dose may be increased to 2 mg.
• Maximum dose: 2 mg once a week (higher doses are not recommended).

Concomitant therapies:

• Metformin/thiazolidinedione/SGLT-2 inhibitor: The existing dosage may remain unchanged.
• Sulfonylurea/insulin: Dose reduction should be considered to avoid hypoglycemia.

Obesity, overweight

Adults:

• Starting dose: 0.25 mg weekly (week 1-4)
• Increase: 0.5 mg (week 5-8), 1 mg (week 9-12), 1.7 mg (week 13-16)
• Maintenance dose: 2.4 mg from week 17
• Note: If side effects occur, increase dose more slowly.

Adolescents (from 12 years):

• Same dose escalation as for adults. Maximum dose: 2.4 mg weekly.

Gastrointestinal side effects: nausea (17-19.9%), diarrhea (12.2-13.3%) and vomiting (6.4-8.4%). In some cases, these led to discontinuation of treatment (3.9-5%). There is a risk of fluid loss and subsequent possible renal dysfunction. Patients should be made aware of the dangers and advised to avoid dehydration.

Hypoglycemia: Severe hypoglycemia occurred mainly with concomitant use with sulfonylureas (1.2%) or insulin (1.5%).Acute pancreatitis: Rare, with an incidence of 0.3% in clinical trials.

Diabetic retinopathy: More common in patients at high cardiovascular risk in one study (3% semaglutide vs. 1.8% placebo).

Injection site reactions: Minor, in 0.5-0.6% of patients.

Increase in heart rate: Slightly increased, on average by 1-6 beats per minute.

Dehydration: Semaglutide may cause gastrointestinal side effects leading to fluid loss and, in rare cases, worsening of renal function. Patients should be advised of the risk of dehydration and encouraged to drink sufficient fluids.

Acute pancreatitis: Acute pancreatitis has been reported with GLP-1 receptor agonists. Patients should be aware of the symptoms of pancreatitis. If pancreatitis is suspected, semaglutide should be discontinued immediately and treatment should not be resumed if pancreatitis is confirmed. Particular caution should be exercised in patients with a history of pancreatitis.

Hypoglycemia: There is an increased risk of hypoglycemia when semaglutide is combined with sulfonylureas or insulin. Reducing the dose of sulphonylurea or insulin may reduce this risk.

Diabetic retinopathy: An increased risk of complications has been observed in patients with diabetic retinopathy using semaglutide and insulin. These patients should be closely monitored and treated according to clinical guidelines.

Unstudied populations: Semaglutide has not been studied in the following patient populations and is therefore not recommended in patients with type 1 diabetes, severe renal or hepatic impairment, NYHA stage IV heart failure or in patients undergoing bariatric surgery.

Cutaneous side effects:

• Cutaneous side effects are rather rare. However, serious cutaneous adverse reactions have been reported, including eosinophilic panniculitis, bullous pemphigoid, morbilliform drug rashes (Salazar CE et al. 2024) and leukocytoclastic vasculitis with both daily and weekly application (Pinheiro MM et al. 2024).

The following interactions should be considered when using semaglutide:

• Delayed gastric emptying: Semaglutide may delay gastric emptying and thus affect the rate of absorption of oral drugs taken at the same time. Caution should be exercised with drugs that require rapid absorption.
• Paracetamol: Semaglutide reduces the rate of absorption of paracetamol, but the overall effect remains unchanged. A dose adjustment of paracetamol is not necessary.
• Oral contraceptives: Semaglutide has no clinically relevant effect on the efficacy of oral contraceptives. The exposure of ethinylestradiol remains unchanged, while levonorgestrel is slightly increased. A dose adjustment is not necessary.
• Atorvastatin: Semaglutide decreases the Cmax of atorvastatin by 38%, which is not considered clinically relevant. A dose adjustment is not necessary.
• Digoxin: Semaglutide does not affect the overall exposure or Cmax of digoxin.
• Metformin: Semaglutide has no effect on the overall exposure or Cmax of metformin.
• Warfarin and other coumarin derivatives: Semaglutide does not alter the effect of warfarin to a clinically relevant extent, but cases of INR decreases have been reported with concomitant use of acenocoumarol. Close monitoring of INR is recommended at the start of semaglutide treatment.

Semaglutide has no or only a negligible effect on the ability to drive or operate machinery. However, if semaglutide is used in combination with a sulphonylurea or insulin, patients should be advised to take measures to avoid hypoglycaemia, especially when driving or operating machinery.

Depending on the indication for semaglutide, the following drug alternatives may be considered:

Type 2 diabetes

• GLP-1 agonists: liraglutide, dulaglutide, exenatide, lixisenatide, albiglutide
• DPP-4 inhibitors: sitagliptin, linagliptin, saxagliptin, vildagliptin
• SGLT-2 inhibitors: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
• Insulin preparations: long-acting and short-acting insulins
• Metformin, sulfonylureas

1. Aroda VR et al. (2017) Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomized, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol 5:355-366.
2. Chao AM et al. (2023) Semaglutide for the treatment of obesity. Trends Cardiovasc Med 33:159-166.
3. Koliaki C et al. (2011) Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus. Diabetes Ther 2:101-121.
4. Malavazos AE et al. (2023) Semaglutide therapy decreases epicardial fat inflammation and improves psoriasis severity in patients affected by abdominal obesity and type-2 diabetes. Endocrinol Diabetes Metab Case Rep 2023:23-0017.
5. Pinheiro MM et al. (2024) The first report of leukocytoclastic vasculitis induced by once-weekly subcutaneous semaglutide. Curr Med Res Opin 40:1525-1531.
6. Salazar CE et al. (2024) Rare cutaneous adverse reactions associated with GLP-1 agonists: a review of the published literature. Arch Dermatol Res 316:248.
7. Vilarrasa E et al. (2024) Glucagon-Like Peptide-1 Agonists for Treating Obesity in Patients With Immune-Mediated Skin Diseases. Actas Dermosifiliogr 115:56-65.