Semaglutide

Dosage for Semaglutide is highly individualized and typically follows a 'start low and go slow' titration (gradual increase) schedule to minimize gastrointestinal side effects.

• For Type 2 Diabetes (Injectable): The standard starting dose is 0.25 mg once weekly for 4 weeks. This is a sub-therapeutic dose intended for initiation only. After 4 weeks, the dose is typically increased to 0.5 mg once weekly. If additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, it may be increased to 1 mg, and eventually up to a maximum of 2 mg once weekly.
• For Chronic Weight Management (Injectable): The initiation dose is 0.25 mg once weekly for 4 weeks. The dose is then increased every 4 weeks (to 0.5 mg, 1 mg, 1.7 mg) until the maintenance dose of 2.4 mg once weekly is reached.
• For Type 2 Diabetes (Oral): Treatment begins with 3 mg once daily for 30 days. After 30 days, the dose is increased to 7 mg once daily. If further glycemic control is required, the dose can be increased to 14 mg once daily after at least 30 days on the 7 mg dose.

Semaglutide (as Wegovy) is FDA-approved for chronic weight management in pediatric patients aged 12 years and older. The dosing schedule mimics the adult titration: starting at 0.25 mg once weekly and increasing every 4 weeks to the target maintenance dose of 2.4 mg. If the 2.4 mg dose is not tolerated, the dose may be reduced to 1.7 mg. Semaglutide is not currently approved for use in children under the age of 12 or for the treatment of type 2 diabetes in pediatric patients.

Renal Impairment

No dosage adjustment is generally required for patients with mild, moderate, or severe renal impairment. However, because gastrointestinal adverse reactions can lead to dehydration, which may worsen renal function, healthcare providers should monitor kidney function (creatinine) closely in patients with pre-existing renal issues.

Hepatic Impairment

No dosage adjustment is recommended for patients with hepatic impairment. The pharmacokinetics of Semaglutide are not significantly altered by liver dysfunction.

Elderly Patients

No overall differences in safety or effectiveness have been observed between patients 65 years of age and older and younger patients, though some older individuals may be more sensitive to the medication's effects.

• Injectable Form: Administer once weekly, on the same day each week, at any time of day, with or without meals. Inject subcutaneously into the abdomen, thigh, or upper arm. Rotate injection sites with each dose to prevent skin issues. If you choose to change the day of the week, ensure at least 48 hours have passed since the last dose.
• Oral Form: Take at least 30 minutes before the first food, beverage, or other oral medications of the day. Take with no more than 4 ounces of plain water only. Waiting less than 30 minutes or taking it with food/other liquids will significantly reduce absorption and efficacy. Swallow the tablet whole; do not crush, chew, or split it.
• Storage: Store unused pens in the refrigerator (36°F to 46°F). After the first use, pens can typically be stored at room temperature or in the refrigerator for up to 56 days (check specific brand labeling). Do not freeze.

• Injectable: If you miss a dose, take it as soon as possible within 5 days of the missed dose. If more than 5 days have passed, skip the missed dose and take the next dose on your regularly scheduled day. Do not take two doses at once.
• Oral: If a dose is missed, skip the missed dose and take the next dose the following day. Do not double the dose.

Signs of Semaglutide overdose include severe nausea, severe vomiting, and severe hypoglycemia. If an overdose is suspected, contact a Poison Control Center or seek emergency medical attention immediately. Treatment is supportive, focusing on hydration and blood glucose monitoring.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop the medication without medical guidance, as this can lead to blood sugar spikes or weight regain.

The most frequently reported side effects of Semaglutide are gastrointestinal in nature, occurring most often during the dose-escalation phase. These include:

• Nausea: This is the most common side effect, affecting up to 40% of patients. It often feels like a persistent 'queasiness' and is usually most intense in the days following a dose increase.
• Vomiting: Often associated with eating too quickly or consuming high-fat meals while on the medication.
• Diarrhea: Loose or watery stools may occur as the body adjusts to the slowed gastric emptying.
• Abdominal Pain: General discomfort or cramping in the stomach area.
• Constipation: Due to the slowing of the digestive tract, some patients may experience difficulty with bowel movements.

Most of these symptoms are mild to moderate and tend to decrease over time as the body becomes accustomed to the medication.

• Dyspepsia (Indigestion): A feeling of burning or discomfort in the upper abdomen.
• Eructation (Burping): Some patients report 'sulfur-smelling' burps due to food sitting in the stomach longer.
• Flatulence: Increased gas production.
• Gastroesophageal Reflux Disease (GERD): Heartburn or acid reflux.
• Fatigue: A general feeling of tiredness or lack of energy.
• Dizziness: Often related to changes in blood pressure or blood sugar.

• Dysgeusia: A change in the sense of taste (e.g., a metallic taste in the mouth).
• Injection Site Reactions: Redness, itching, or slight swelling where the needle entered the skin.
• Delayed Gastric Emptying (Severe): In rare cases, the slowing of the stomach can be profound, leading to significant discomfort.

> Warning: Stop taking Semaglutide and call your doctor immediately if you experience any of these serious conditions:

1. 1Pancreatitis (Inflammation of the Pancreas): Characterized by severe, persistent abdominal pain that may radiate to the back, with or without vomiting. This is a medical emergency.
2. 2Gallbladder Problems: Symptoms include upper stomach pain, fever, yellowing of the skin or eyes (jaundice), and clay-colored stools. Semaglutide can cause gallstones or cholecystitis.
3. 3Kidney Injury: Dehydration from vomiting and diarrhea can lead to acute kidney failure. Signs include decreased urination or swelling in the legs and ankles.
4. 4Serious Allergic Reactions: Anaphylaxis, swelling of the face, lips, or throat, and difficulty breathing.
5. 5Hypoglycemia: While rare when used alone, the risk increases when combined with insulin or sulfonylureas. Symptoms include shakiness, sweating, confusion, and rapid heartbeat.
6. 6Diabetic Retinopathy Complications: Patients with a history of diabetic eye disease may experience a temporary worsening of vision.

Long-term use of Semaglutide has been associated with significant fat loss, which in some patients can lead to 'facial wasting' (often colloquially called 'Ozempic face'). There is also a theoretical risk of thyroid C-cell tumors based on animal studies, although this has not been definitively proven in humans. Long-term gastrointestinal changes may also persist in a small subset of users.

Semaglutide carries an FDA Black Box Warning regarding the risk of Thyroid C-Cell Tumors. In rodents, Semaglutide caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and carcinomas). It is unknown whether Semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. Semaglutide is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Patients should be informed of the potential risk and symptoms of thyroid tumors (e.g., a lump in the neck, difficulty swallowing, hoarseness).

Report any unusual symptoms to your healthcare provider. You may also report side effects to the FDA at 1-800-FDA-1088.

Semaglutide is a powerful metabolic modifier and must be used under strict medical supervision. It is not a substitute for insulin and should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Before starting treatment, ensure your healthcare provider has a full list of your medical history, particularly any history of digestive disorders, kidney disease, or pancreas problems.

RISK OF THYROID C-CELL TUMORS: Semaglutide causes thyroid C-cell tumors in rats and mice. It is unknown whether it causes these tumors in humans. This medication is strictly contraindicated in individuals with a personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). If you notice a lump or swelling in your neck, hoarseness, or trouble swallowing, contact your doctor immediately.

• Pancreatitis Risk: There have been post-marketing reports of acute pancreatitis in patients taking GLP-1 receptor agonists. If pancreatitis is suspected, Semaglutide should be discontinued immediately and not restarted unless an alternative etiology is found.
• Acute Kidney Injury: Patients may experience a worsening of renal function, sometimes requiring hemodialysis, often secondary to dehydration caused by gastrointestinal side effects. Monitoring of renal function is essential, especially when starting or escalating doses.
• Hypoglycemia with Concomitant Use: When used in combination with an insulin secretagogue (e.g., sulfonylureas) or insulin, the risk of hypoglycemia is significantly increased. A reduction in the dose of the concomitant medication may be necessary.
• Hypersensitivity: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported. If these occur, discontinue Semaglutide and seek immediate medical help.
• Suicidality: For patients taking Semaglutide for weight management (Wegovy), there is a requirement to monitor for depression or suicidal thoughts/behaviors. Discontinue the drug if these symptoms develop.

• HbA1c: Regularly monitored (usually every 3-6 months) to assess glycemic control.
• Renal Function: Blood urea nitrogen (BUN) and serum creatinine should be checked, especially in patients reporting severe GI distress.
• Vision Changes: Regular eye exams are recommended for patients with type 2 diabetes to monitor for the progression of diabetic retinopathy.
• Heart Rate: Periodic monitoring of resting heart rate is advised.

Semaglutide itself is unlikely to affect your ability to drive or use machines. However, if used in combination with other diabetes medications that cause hypoglycemia, dizziness or confusion could occur. Use caution until you know how the medication affects you.

Alcohol can affect blood sugar levels and may increase the risk of hypoglycemia. Additionally, heavy alcohol use is a known risk factor for pancreatitis. Patients should limit alcohol consumption while taking Semaglutide. Discuss your alcohol intake habits with your doctor.

There is no known 'withdrawal syndrome' associated with Semaglutide; however, stopping the medication will likely result in a rise in blood glucose levels (for diabetes patients) or weight regain (for weight management patients). Do not stop the medication abruptly without a transition plan from your healthcare provider.

> Important: Discuss all your medical conditions with your healthcare provider before starting Semaglutide, especially if you have a history of pancreatitis, gallstones, or kidney disease.

There are no absolute drug-drug contraindications listed in the FDA label that mandate total avoidance; however, Semaglutide should never be used in combination with other GLP-1 receptor agonists (e.g., Liraglutide, Dulaglutide, Exenatide) or DPP-4 inhibitors (e.g., Sitagliptin, Linagliptin). Combining these medications does not provide additional benefit and significantly increases the risk of severe gastrointestinal side effects and potential toxicity.

• Insulin and Sulfonylureas: Combining Semaglutide with insulin or insulin secretagogues (like Glipizide or Glyburide) significantly increases the risk of severe hypoglycemia. Healthcare providers often reduce the dose of insulin or sulfonylurea when initiating Semaglutide to mitigate this risk.
• Warfarin: Semaglutide may slightly alter the absorption of Warfarin due to delayed gastric emptying. Patients on Warfarin should have their International Normalized Ratio (INR) monitored more frequently when starting or changing the dose of Semaglutide.

• Oral Medications: Because Semaglutide delays gastric emptying, it has the potential to impact the absorption of any concomitantly administered oral medication. While clinical trials have not shown this to be a major issue for most drugs, medications with a narrow therapeutic index (where small changes in concentration lead to toxicity or failure) should be monitored closely.
• Levothyroxine: Some studies suggest that the absorption of thyroid hormones may be affected. Patients should have their TSH levels monitored if they notice symptoms of hypothyroidism or hyperthyroidism.

• Oral Semaglutide (Rybelsus): This is the most critical food interaction. Rybelsus must be taken on an empty stomach. If taken with food, the absorption is nearly zero, rendering the drug ineffective. You must wait at least 30 minutes after taking the tablet before consuming any food or beverage other than plain water.
• High-Fat Meals: Consuming very high-fat meals while on injectable Semaglutide can exacerbate nausea and vomiting due to the slowed digestion process.

• Fenugreek, Ginseng, and Alpha-lipoic Acid: These supplements may have glucose-lowering effects. Taking them with Semaglutide may increase the risk of hypoglycemia.
• St. John's Wort: While not directly interacting with Semaglutide's metabolic pathway, it can affect overall metabolic health and should be discussed with a provider.

Semaglutide is not known to interfere with common laboratory tests, although it will significantly change HbA1c and fasting glucose levels, which is the intended therapeutic effect. It may also slightly increase serum lipase or amylase levels; however, these increases do not necessarily indicate pancreatitis in the absence of clinical symptoms.

1. 1Mechanism: The primary interaction mechanism is the pharmacodynamic effect on blood sugar and the pharmacokinetic effect of delayed gastric emptying.
2. 2Consequence: The main risks are hypoglycemia or reduced efficacy of other oral medications.
3. 3Management: Space medications appropriately, monitor blood glucose frequently during titration, and perform regular lab work as ordered by your doctor.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers and vitamins.

Semaglutide must NEVER be used in the following circumstances:

1. 1Medullary Thyroid Carcinoma (MTC): Patients with a personal or family history of MTC are at risk because GLP-1 agonists have been shown to cause C-cell tumors in animal models. Activation of the GLP-1 receptor on thyroid C-cells could potentially stimulate tumor growth.
2. 2Multiple Endocrine Neoplasia Syndrome Type 2 (MEN 2): This is a genetic condition that predisposes individuals to thyroid and adrenal tumors. Due to the risk of MTC, these patients must avoid Semaglutide.
3. 3Known Hypersensitivity: Patients who have had a serious allergic reaction (anaphylaxis, angioedema) to Semaglutide or any of the excipients in the formulation (such as disodium phosphate dihydrate or propylene glycol) must not use the drug.

These conditions require a careful risk-benefit analysis by a healthcare professional:

• History of Pancreatitis: Because Semaglutide is associated with a risk of acute pancreatitis, patients with a prior history should use it with extreme caution, if at all.
• Severe Gastrointestinal Disease: Patients with gastroparesis (paralysis of the stomach) or inflammatory bowel disease (IBD) may find their symptoms significantly worsened by the slowed gastric emptying caused by Semaglutide.
• Diabetic Retinopathy: Rapid improvements in glucose control have been associated with a temporary worsening of diabetic retinopathy. Patients with unstable eye disease should be monitored closely.
• Pregnancy: Semaglutide is generally not recommended during pregnancy (see Special Populations) due to potential fetal harm observed in animal studies.

Patients who have had an allergic reaction to other GLP-1 receptor agonists (such as Liraglutide, Dulaglutide, or Tirzepatide) may be at an increased risk of a cross-allergic reaction to Semaglutide. If you have ever reacted poorly to a 'GLP-1' or 'incretin mimetic' injection, inform your doctor before starting Semaglutide.

> Important: Your healthcare provider will evaluate your complete medical history, including genetic predispositions, before prescribing Semaglutide to ensure it is safe for you.

Semaglutide is not recommended for use during pregnancy. Animal reproduction studies have shown that exposure to Semaglutide during organogenesis (when the fetus's organs are forming) resulted in structural abnormalities and embryofetal mortality at exposures below the maximum recommended human dose.

• Washout Period: Because Semaglutide has a very long half-life (staying in the body for weeks), the FDA recommends that women discontinue Semaglutide at least 2 months before a planned pregnancy to ensure the drug is completely cleared from the system. If you become pregnant while taking Semaglutide, stop the medication and contact your doctor immediately.

It is unknown whether Semaglutide is excreted in human milk. In animal studies (rats), Semaglutide was present in milk. Because of the potential for serious adverse reactions in a nursing infant, such as changes in growth or metabolism, the risk-benefit of breastfeeding while on Semaglutide must be carefully considered. Most providers recommend either discontinuing the drug or opting for formula feeding.

• Weight Management: Semaglutide (Wegovy) is approved for chronic weight management in pediatric patients aged 12 and older with an initial BMI at or above the 95th percentile for age and sex.
• Diabetes: Semaglutide is NOT currently FDA-approved for the treatment of type 2 diabetes in patients under 18 years of age.
• Safety: The safety profile in adolescents is generally similar to adults, though monitoring for bone growth and nutritional intake is important during significant weight loss phases.

In clinical trials, no overall differences in safety or efficacy were observed between patients over 65 and younger patients. However, elderly patients are more prone to dehydration and renal complications from gastrointestinal side effects. There is also a higher risk of 'silent' hypoglycemia in the elderly. Healthcare providers should use caution during dose titration and monitor kidney function closely.

No dosage adjustment is required for patients with renal impairment, including those with end-stage renal disease (ESRD). However, because Semaglutide can cause nausea and vomiting leading to volume depletion (dehydration), there is a risk of acute kidney injury. Patients with pre-existing kidney disease should have their renal function monitored more frequently during the initiation and titration of Semaglutide.

No dosage adjustment is required for patients with hepatic impairment (mild, moderate, or severe). The clearance of Semaglutide is not significantly affected by liver function, as it is primarily degraded by proteolysis rather than liver-specific enzymes.

> Important: Special populations require individualized medical assessment. Always disclose your pregnancy status or intentions to your healthcare provider.

Semaglutide is a potent agonist of the glucagon-like peptide-1 (GLP-1) receptor. It is produced by recombinant DNA technology using Saccharomyces cerevisiae (yeast). The molecular structure is modified from native human GLP-1 in three key ways:

1. 1Position 8: Alanine is replaced by alpha-aminoisobutyric acid, which protects the peptide from being broken down by the enzyme dipeptidyl peptidase-4 (DPP-4).
2. 2Position 26: Lysine is modified with a spacer and a C18 fatty diacid chain, which allows the molecule to bind to albumin. This binding prevents rapid renal clearance.
3. 3Position 34: Lysine is replaced by arginine to ensure the attachment of the fatty acid only occurs at the correct site.

By activating the GLP-1 receptor, it increases intracellular cyclic AMP (cAMP), leading to glucose-dependent insulin release and the suppression of inappropriate glucagon secretion.

Semaglutide lowers both fasting and postprandial (after-meal) blood glucose. The effect on insulin secretion is glucose-dependent; it does not stimulate insulin when glucose levels are low. It also reduces body weight primarily through a reduction in total caloric intake, driven by increased satiety and decreased hunger. Clinical studies show a significant reduction in HbA1c (often 1.5% to 2.0%) and substantial weight loss (up to 15% of body weight in some trials).

| Parameter | Value |

|---|---|

| Bioavailability | 89% (Subcutaneous); 0.4-1% (Oral) |

| Protein Binding | >99% (primarily to Albumin) |

| Half-life | ~1 week (165-184 hours) |

| Tmax | 1-3 days (Subcutaneous); 1 hour (Oral) |

| Metabolism | Proteolysis and Beta-oxidation |

| Excretion | Urine (3% as intact drug), Feces |

• Molecular Formula: C187H291N45O59
• Molecular Weight: 4113.58 Daltons
• Solubility: Soluble in water and physiological saline.
• Structure: A 31-amino acid peptide with a fatty acid side chain attached to the lysine at position 26.

Semaglutide is classified as a GLP-1 Receptor Agonist. It is part of the 'incretin mimetic' family. Related medications include Liraglutide (Victoza/Saxenda), Dulaglutide (Trulicity), and the dual agonist Tirzepatide (Mounjaro/Zepbound).