Semaglutide

Semaglutide is an Anti-diabetic Agent belonging to the pharmacological class of long-acting Glucagon-like peptide-1 receptor agonists (GLP-1 RA).

For individuals with type 2 diabetes mellitus, semaglutide is an approved drug to help regulate blood sugar levels. In individuals with type 2 diabetes and established cardiovascular disease (CVD), it also reduces the risk of significant cardiovascular events, including stroke, heart attack, or death.

Semaglutide is absorbed slowly from the injection site, reaching peak levels in about one week. It binds to albumin and undergoes proteolytic degradation. Metabolism primarily occurs via enzymatic degradation. The main elimination route is through the kidneys. The terminal half-life is approximately one week, allowing for once-weekly dosing.

Nausea, vomiting, diarrhoea, reduced appetite, exhaustion, and constipation are a few of the most common side effects of semaglutide. Hypoglycemia, or low blood sugar, might also result, primarily if patients already use medications to manage their diabetes, such as sulfonylureas or insulin. Semaglutide is available in the form of injection solutions and oral tablets.

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Semaglutide is an Anti-diabetic Agent belonging to the pharmacological class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RA).

Mechanism of glycemic control:

GLP-1 is a physiological hormone that supports glycemic control by inhibiting postprandial glucagon production, decreasing stomach emptying, and secreting insulin. The pancreatic beta cells, which release hormones, including insulin and amylin, are necessary for glucose homeostasis. Semaglutide and human GLP-1 are 94% identical. Semaglutide is an analogue of this hormone that increases pancreatic islet cell activity while decreasing glucagon release to enhance the manufacture of insulin. They selectively and directly bind to the GLP-1 receptor, leading to several advantageous downstream actions that lower blood sugar in a glucose-dependent manner.

Mechanism of Cardiovascular Advantage and Weight Loss

Semaglutide is thought to slow the development of atherosclerosis in hypercholesterolemia by lowering intestinal permeability and inflammation.7 Following the administration of semaglutide, it is thought there would be a decrease in appetite and food cravings, leading to weight loss.

The data duration of Semaglutide action is approximately seven days after a single subcutaneous dose.

The Data of Tmax of Semaglutide approximately 9-15 hours post-injection.

The Data of Cmax of Semaglutide is approximately 48.3 ng/mL after a single subcutaneous dose.

Semaglutide is available in the form of injectable solutions and oral tablets.

Injectable solutions: To be administered parenterally, as applicable.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

Semaglutide is mainly used to treat type 2 diabetes in adults. It helps control blood sugar levels by increasing insulin release, reducing the amount of glucose produced in the liver, and slowing down digestion. Additionally, it may aid in weight management by promoting a feeling of fullness.

In Treatment of Type 2 diabetes mellitus

Semaglutide helps lower the body's blood sugar levels, encourages weight reduction, and reduces the risk of cardiovascular events. With a once-weekly dosing regimen, it enhances convenience and adherence.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

• When type 2 diabetes mellitus is diagnosed in adults, Semaglutide is administered with diet and exercise to enhance glycemic control. Semaglutide is not an excellent first-line treatment option for diabetes that hasn't responded to diet and exercise, though. Additionally, pancreatitis patients have not been investigated with it. In individuals with type 1 diabetes or to treat diabetic ketoacidosis, Semaglutide is not recommended for treatment.
• Semaglutide is indicated for use as a combination with a diet that is low-calorie and increases physical activity in those individuals who are obese or overweight and have at least one weight-related ailment (such as type 2 diabetes mellitus, high blood pressure, or high cholesterol). In paediatric patients who are 12 years of age and older with an initial Body Mass Index at or above the 95th percentile for age and sex, Semaglutide is also recommended for managing chronic weight.

Limitations of Use:

• Patients who are insufficiently managed by diet and exercise are not advised to use this medication as their first line of treatment.
• Has not been investigated in people with a history of pancreatitis.
• Consider another antidiabetic therapy: Not recommended for treating diabetes mellitus type 1 or diabetic ketoacidosis.

Semaglutide is available as an injection solution and oral tablets that can be administered parenterally and orally.

• Parenterally: Semaglutide should be administered subcutaneously in the abdomen, thigh, or upper arm. They must help it once weekly, at any time of day, with or without meals. It is permissible to change the day of weekly administration, provided there is a gap of at least two days (over 48 hours) between doses. The person should also ensure the rotation of injection sites within the same body region. Before use, they should visually inspect the solution, which should appear clear and colourless. The medication should not be used if any particulate matter or discolouration is observed. If semaglutide is used with insulin, the person should administer them separately and avoid mixing. Injecting them in the same body region is acceptable, but they should not be issued adjacent.
• Orally: Take at least 30 minutes before your first meal or beverage. If you miss one dose and the next scheduled dose is more than two days (48 hours) away, take the missed dose as soon as possible. If the next scheduled dose is less than two days (48 hours) away, do not take the missed dose and resume dosing on your regular scheduled day. If you miss more than two consecutive doses, continue dosing as expected or, if necessary, reinitiate treatment and follow the dose escalation schedule to reduce the likelihood of gastrointestinal symptoms associated with restarting the treatment. Take with no more than 4 ounces of plain water only. Taking it with food, beverages (other than plain water), oral medications or waiting less than 30 minutes may decrease effectiveness by reducing semaglutide absorption. Waiting to take it after 30 minutes of eating may increase semaglutide absorption. Swallow the tablets whole; do not split, crush, or chew.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injection solutions prefilled (single dose pen):

• 2mg/1.5mL (1.34mg/mL); delivers doses of 0.25mg or 0.5mg per injection
• 4mg/3mL (1.34mg/mL); has 1mg per injection
• 8mg/3mL (2.68 mg/mL); has 2mg per injection
• 0.25mg/0.5mL
• 0.5mg/0.5mL
• 1mg/0.5mL
• 1.7mg/0.75mL
• 2.4mg/0.75mL

Oral Tablets:

• 3mg
• 7mg
• 14mg

Semaglutide is available in the form of injection solutions and oral tablets.

Dose Adjustment in Adult Patients:

Type 2 Diabetes Mellitus

SC

Initial dose of 0.25 mg SC week for four weeks; increase to 0.5 mg qWeek after that

If glycemic control is not established after at least four weeks on a dosage of 0.5 mg, it may be increased to 1 mg once a week.

If glycemic control is not established after at least four weeks on a 1-mg dose, the dosage may increase to 2 mg qWeek; nevertheless, the maximum amount is 2 mg.

Analysis: The initial 0.25-mg dosage is meant to start a course of action; it does not affect glycemic control.

Oral

Initial oral dosage: 3 mg PO qDay for 30 days; the 3-mg dose is only for initiating the medication and is ineffective for glycemic control.

3 mg/day for 30 days: Increase to 7 mg PO once daily

7 mg/day for 30 days: If more glycemic control is required, the dosage may be increased to 14 mg PO qDay.

Analysis: It is not advised to use two 7-mg pills to get a dosage of 14 mg.

Changing between SC and oral

14 mg/day PO: Change to 0.5 mg SC every week on the day after the previous PO dose

Changing from 0.5 mg/week SC to 7 mg or 14 mg PO beginning up to 7 days following the final SC injection

The 1-mg SC dosage has no comparable PO dose.

Semaglutide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Semaglutide, avoid large meals and maintain regular meals with balanced macronutrient content to help stabilize blood sugar levels.

Limit alcohol intake, as excessive alcohol can increase the risk of pancreatitis.

Minimize the intake of high-calorie, low-nutrient foods, such as sugary snacks and processed foods.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Semaglutide may be contraindicated in the following conditions:-

• Hypersensitivity reaction to Semaglutide or any of its excipients,

• Patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

• Medullary thyroid cancer (MTC) in the individual or the family.

• Even if the needle changes, prefilled Semaglutide pens should never be shared between patients. Sharing needles or syringes is not permitted for patients using Semaglutide vials. Transmitting blood-borne infections by sharing is unsafe.
• Semaglutide can cause thyroid C-cell tumours, including MTC, in people based on research in rats and mice; however, the human relevance of semaglutide-induced rodent thyroid C-cell tumours has not been established.
• Acute pancreatitis was observed in control trials (0.3 events subcutaneous and 0.1 events oral per 100 patient-years); following the start of treatment, check for signs and symptoms of pancreatitis (e.g., prolonged, severe pain in the abdomen that may radiate to the back and be accompanied by vomiting); if pancreatitis is suspected, stop taking semaglutide and do not resume if confirmed.
• Semaglutide patients had a higher incidence of diabetic retinopathy problems than placebo or comparators, and quick improvement in glucose management has been linked to a transitory worsening of diabetic retinopathy.
• Most reported events occurred in patients who had experienced nausea, vomiting, diarrhoea, or dehydration; monitor renal function when starting or increasing doses of semaglutide in patients reporting severe adverse GI reactions. Postmarketing reports showed acute kidney injury and worsening chronic renal failure, which may occasionally require hemodialysis in patients treated with GLP-1 receptor agonists.
• GLP-1 receptor agonists have been linked to severe hypersensitivity responses such as anaphylaxis and angioedema; if such reactions happen, stop taking the medication, treat them immediately, and closely monitor the patient until the symptoms disappear.
• GLP-1 receptor agonist trials and postmarketing monitoring have identified acute gallbladder disease events (such as cholelithiasis and cholecystitis); if suspected, gallbladder tests and adequate clinical follow-up are advised.

It is unsafe to consume Semaglutide with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Semaglutide in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.

Limit Alcohol, and avoid foods and drinks for at least 30 minutes before taking semaglutide.

The adverse reactions related to Semaglutide can be categorized as:

• Common Adverse Effects: Nausea, vomiting, diarrhoea, constipation, abdominal pain, and decreased appetite.
• Less Common Adverse Effects: Dizziness, hypoglycemia, headache, and fatigue.
• Rare Adverse Effects: Hypersensitivity, sometimes severe (e.g., severe urticaria, systemic rash, facial oedema, lip swelling), pancreatitis, kidney problems, or medullary thyroid carcinoma.

Reports on Postmarketing

Ileus, acute pancreatitis, and necrotizing pancreatitis, all of which can be fatal, are signs of gastrointestinal illnesses.

Hypersensitivity: angioedema, rash, urticaria, and anaphylaxis

Urinary and renal conditions: acute kidney damage

Hepatobiliary: Cholelithiasis and cholecystitis necessitating cholecystectomy.

The clinically relevant drug interactions of Semaglutide are briefly summarized here.

• Warfarin: Semaglutide might increase the International Normalized Ratio (INR) when used with warfarin, potentially impacting blood clotting.
• Insulin and Insulin-Secretagogues: Combining semaglutide with insulin or insulin-secretagogues (e.g., sulfonylureas) may increase the risk of hypoglycemia (low blood sugar). Dose adjustments may be needed.
• Oral Birth Control: Semaglutide may affect the absorption of oral contraceptives, potentially reducing their effectiveness. Additional contraceptive measures may be necessary.
• Oral Medications: Gastric emptying is delayed due to semaglutide, which may affect how well oral drugs taken concurrently are absorbed. Semaglutide had no clinically significant effects on oral drug absorption in clinical pharmacology studies. However, caution should be used when semaglutide is given along with other oral drugs.

The most common side effects of Semaglutide include:

• Vomiting
• Nausea
• Diarrhoea
• Pain in the stomach
• Constipation
• A decreased appetite

• Pregnancy

Pregnancy Category C; Use with caution if the benefits outweigh the risks.

Drug usage data during pregnancy is insufficient to assess the possibility of severe birth abnormalities, miscarriages, or other adverse maternal or foetal outcomes linked to the medication.

Semaglutide exposure during pregnancy has the potential to harm the foetus, according to research on animal reproduction; it should only be taken during pregnancy if the benefit outweighs the risk.

Due to the prolonged washout time for semaglutide, stop medication in women at least two months before a planned pregnancy.

Clinical Considerations

Pre-gestational diabetes patients experience hypoglycemia and hyperglycemia more frequently during pregnancy; poorly controlled diabetes increases the risk for diabetic ketoacidosis, preterm delivery, stillbirth, preeclampsia, spontaneous abortions, and postpartum complications in the mother.

A fetus's chance of severe birth abnormalities, stillbirth, and macrosomia-related morbidity is increased by poorly managed diabetes.

All pregnant patients, including those already overweight or obese, are advised to gain the appropriate weight depending on their pre-pregnancy weight due to the mandatory weight growth in maternal tissues throughout pregnancy.

Animal Data

Based on maternal clinical exposure measured by AUC, structural abnormalities, growth changes, and embryofetal death were seen in pregnant rats given semaglutide throughout organogenesis.

Early pregnancy losses or structural abnormalities were noted at clinical exposure in rabbits and cynomolgus monkeys given semaglutide during organogenesis and at 2-fold the MRHD in monkeys. These findings were corroborated by a significant decrease in mother body weight in both animal species.

• Nursing mothers

There is no information on semaglutide's presence in human milk, its effects on breastfed children, or its impact on milk production. Milk from nursing rats contained semaglutide at levels 3- 12-fold lower than those in maternal plasma.

• Pediatric Use

  In paediatric patients aged 12 years with an initial Body Mass Index (BMI) at or above the 95th percentile standardised for age and sex (obesity), semaglutide is recommended as an addition to a low-calorie diet and high physical activity for chronic weight control.

Dose Adjustment in Pediatric Patients:

Weight Management

Schedule for increasing the SC dosage once per week

During weeks 1 to 4, use 0.25 mg SC qWeek

Weeks 5 to 8: 0.5 mg SC

Weeks 9 to 12: 1 mg SC qWeek

Week 13 to 16: 1.7 mg SC qWeek

Maintenance dosage

Weeks 17 and later: 2.4 mg SC qWeek Unable to handle maintenance 2.4 mg administered once every week: may lower the maintenance dose to 1.7 mg SC qWeek If 1.7 mg dosage is intolerable, stop taking the medication.

•  Geriatric Use

In the general population of glycemic control studies, 1229 (30%) of the semaglutide-treated patients were 65 or older, and 199 (5%) were 75 or older. In the PIONEER 6 cardiovascular outcomes study, semaglutide was used to treat 891 (56%) patients 65 or older and 200 (13%) patients who were 75 or older.

For patients between 65 years of age and older and younger adult patients, no variations in semaglutide's general safety or efficacy have been found.

Dose Adjustment in Kidney Impairment Patients:

There are no specific dosage adjustments provided.

Dose Adjustment in Hepatic Impairment Patients:

There are no specific dosage adjustments provided.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Semaglutide.

Overconsumption of Semaglutide may include non-severe hypoglycemia and mild to moderate gastrointestinal events (e.g., nausea and vomiting).

Management

There is no specific antidote or treatment for excessive intake of Semaglutide. However, immediate medical attention is essential. Semaglutide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

If hypoglycemia (low blood sugar) occurs, appropriate measures should be taken to raise blood glucose levels, such as administering glucose or high-sugar foods and beverages.

Hospitalization and intravenous (IV) glucose administration may be required in severe cases.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

Semaglutide lowers body weight, systolic blood pressure, and HbA1c.6 By boosting insulin production and reducing glucagon release (often linked with rises in blood sugar) after 12 weeks of therapy, semaglutide lowered fasting and postprandial glucose. Additionally enhancing cardiovascular health, semaglutide decreases fasting triglycerides and VLDL cholesterol.

Rodent medullary thyroid cell cancer has been linked to the drug semaglutide. Although its therapeutic significance to humans is uncertain, the FDA warns against giving this medication to those with a personal or family history of medullary thyroid cancer. Pancreatitis and dehydration are some side effects of semaglutide. While taking semaglutide, patients must be adequately hydrated, and back-to-abdomen discomfort should be reported to a doctor immediately. Because this medication slows stomach emptying, one must maintain vigilant tabs on any potential adverse effects or ineffectiveness of other oral medications.

Pharmacokinetics:

Absorption

In a clinical experiment, semaglutide had a Cmax of 10.9 nmol/L, an AUC of 3123.4 nmol h/L, and a Tmax of 56 h, and was influential in 1-3 days. 89% of the bioavailable material is bioavailable.15. The oral pill takes 4-5 weeks to reach its steady-state concentration. The range of semaglutide's mean steady-state concentrations following a dose of 0.5- 1 mg is 16 nmol/L to 30 nmol/L.

Subcutaneously

Bioavailability: 89%

Peak plasma time: 1 to 3 days.

Plasma concentration, steady-state

65 ng/mL (0.5 mg/week) and 123 ng/mL (1 mg/week); related exposure is achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm

Orally

Absolute bioavailability: 0.4 to 1%

Peak plasma time: 1 hr

Plasma concentration, steady-state: 6.7 nmol/L (7 mg/day) and 14.6 nmol/L (14 mg/day)

Steady-state: 4 to 5 weeks

Distribution

The distribution volume of semaglutide ranges from 8L to 9.4L. Rats' placentas are affected by it. Semaglutide's strong affinity for plasma albumin supports high drug stability.2. It is 99% or more linked to albumin.

Vd: 12.5 L (SC); 8 L (PO)

Protein binding: >99% (bound to plasma albumin)

Metabolism

Semaglutide undergoes peptide backbone cleavage, and the fatty acid chain is oxidised. Dipeptidyl peptidase 4 (DPP4) and other enzymes, which are found in abundance throughout human tissues, efficiently metabolise naturally produced GLP-1. Semaglutide has changed chemical structures, making it less vulnerable to gastrointestinal DPP4 enzymes' enzymatic breakdown. It is widely and slowly metabolised, with 83% of the given dosage found in the plasma as an unmodified substance. Another enzyme that metabolises this medication is neutral endopeptidase (NEP). Semaglutide's N-terminal region is truncated by DPP-4, which also inactivates the drug, and NEP dissolves peptide linkages. The human plasma contains six distinct semaglutide metabolites. About 7.7% of the dosage consumed comprises the primary metabolite P3.

Excretion

The kidneys mainly eliminate the drug, which can be detected as an excretion product in urine and faeces. 53% of a radiolabeled dosage consumed is excreted in the urine, with 18.6% ending up in faeces, the primary elimination pathway. 3.2% was shown to be inhaled in a lesser amount. There is no evidence that hepatic impairment affects how well this medication is cleared. Thus, patients with impaired liver function do not need to change their dosage.

Half-life: ~1 week

Clearance: 0.05 L/hr (SC); 0.04 L/hr (PO)

• Garvey, W.T., Batterham, R.L., et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 28, 2083–2091 (2022). https://doi.org/10.1038/s41591-022-02026-4
• Ghusn, Wissam et al. “Weight Loss Outcomes Associated With Semaglutide Treatment for Patients With Overweight or Obesity.” JAMA Network Open vol. 5,9 e2231982. 1 Sep. 2022, doi:10.1001/jamanetworkopen.2022.31982
• Wilding, John P H et al. “Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.” Diabetes, obesity & metabolism vol. 24,8 (2022): 1553-1564. doi:10.1111/dom.14725
• Rubino D, Abrahamsson N, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Those Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414–1425. doi:10.1001/jama.2021.3224
• Sandhu, H., Xu, W., Olivieri, AV. et al. Once-weekly subcutaneous Semaglutide 2.4 mg Injection is Cost-Effective for Weight Management in the United Kingdom. Adv Ther 40, 1282–1291 (2023). https://doi.org/10.1007/s12325-022-02423-8

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