What are the indications, mechanism of action, uses, and side effects of Semaglutide (GLP-1 receptor agonist)?

Semaglutide: Indications, Mechanism of Action, Uses, and Side Effects

FDA-Approved Indications

Semaglutide is FDA-approved for two primary indications: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, and to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease. 1 Additionally, subcutaneous semaglutide 2.4 mg (Wegovy) is approved for chronic weight management in adults with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity such as hypertension, type 2 diabetes, or dyslipidemia. 2, 3

Key Limitations of Use

• Semaglutide has not been studied in patients with a history of pancreatitis, and another antidiabetic therapy should be considered in these patients. 1
• It is not indicated for use in type 1 diabetes mellitus or treatment of diabetic ketoacidosis. 1

Mechanism of Action

Semaglutide is a GLP-1 receptor agonist with 94% sequence homology to human GLP-1 that selectively binds to and activates GLP-1 receptors throughout multiple organ systems. 1

Glucose Regulation

• Semaglutide stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner, meaning when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. 1
• This glucose-dependent mechanism explains the low intrinsic risk of hypoglycemia with semaglutide monotherapy. 3
• Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes treated with semaglutide. 1

Appetite and Weight Loss Mechanisms

• Semaglutide acts on the hypothalamus to suppress appetite, increases satiety, and delays gastric emptying. 2, 3
• GLP-1 receptors are expressed in multiple organs including pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining the pleiotropic effects. 2, 3
• The medication causes a delay of early postprandial gastric emptying, reducing the rate at which glucose appears in the circulation. 1

Protraction and Pharmacokinetics

• The principal mechanism of protraction resulting in semaglutide's long half-life (approximately 1 week) is albumin binding, which decreases renal clearance and provides protection from metabolic degradation. 1
• Semaglutide is stabilized against degradation by the DPP-4 enzyme. 1
• Absolute bioavailability is 89%, with maximum concentration reached 1-3 days post-dose. 1

Clinical Uses and Efficacy

Weight Management

Semaglutide 2.4 mg weekly produces the most substantial weight loss of any FDA-approved obesity medication, achieving mean weight loss of 14.9-16.0% at 68 weeks compared to 2.4-5.7% with placebo. 2, 3

• In the STEP 1 trial, 64.9% of patients achieved ≥10% total body weight loss. 3
• Weight loss appears greater in non-diabetic individuals (6.1-17.4%) compared to those with type 2 diabetes (4-6.2%). 3
• After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term use. 2, 3

Glycemic Control

• Semaglutide reduces HbA1c by approximately 1.48% compared to placebo in patients with type 2 diabetes. 3
• Treatment resulted in reductions of 29 mg/dL (22%) for fasting glucose and 74 mg/dL (36%) for 2-hour postprandial glucose. 1

Cardiovascular Benefits

Semaglutide provides significant cardiovascular risk reduction, with a 26% reduction in the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR 0.74,95% CI 0.58-0.95) in the SUSTAIN-6 trial. 3

• In the SELECT trial, semaglutide 2.4 mg reduced cardiovascular events by 20% (HR 0.80) in patients with cardiovascular disease and BMI ≥27. 3
• Cardioprotective effects are mediated through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and improved lipid profiles. 3

Dosing and Administration

For Type 2 Diabetes (Ozempic)

• Semaglutide is administered as a once-weekly subcutaneous injection in the abdomen, thigh, or upper arm. 1
• Typical dosing for diabetes starts at 0.25 mg weekly, increasing to 0.5 mg weekly after 4 weeks, with potential escalation to 1.0 mg weekly if needed. 3

For Weight Management (Wegovy)

The recommended titration schedule for semaglutide 2.4 mg is: 0.25 mg weekly for 4 weeks, then 0.5 mg weekly for 4 weeks, then 1.0 mg weekly for 4 weeks, then 1.7 mg weekly for 4 weeks, and finally 2.4 mg weekly as the maintenance dose after 16 weeks. 3

• Slow titration is essential to minimize gastrointestinal side effects. 2, 3
• If 2 consecutive doses are missed and the patient previously tolerated the medication well, resume at the same dose. 3
• If 3 or more consecutive doses are missed, restart the titration schedule. 3

Side Effects and Safety Profile

Common Gastrointestinal Side Effects

Nausea, vomiting, diarrhea, constipation, and abdominal pain are the most frequently reported adverse effects, occurring in the majority of patients but typically being dose-dependent, mild-to-moderate, and transient. 2, 4

• Nausea occurs in 18-40% of patients taking semaglutide. 3
• Diarrhea occurs in approximately 12% of patients. 3
• Vomiting occurs in 8-16% of patients. 3
• These effects are most pronounced during initial treatment or dose escalation and typically improve with continued use. 4

Management of Gastrointestinal Side Effects

• Reduce meal size to help manage nausea and vomiting. 4
• Limit alcohol and carbonated drinks to reduce reflux symptoms. 4
• Avoid high-fat diets to help with constipation. 4
• Slow dose titration minimizes these side effects. 2, 3, 4

Serious Adverse Events

Clinical trials demonstrate a 38% higher risk of serious adverse events with semaglutide compared to placebo (95% CI, 1.10-1.73), including pancreatitis, cholelithiasis, cholecystitis, acute myocardial infarction, gastroenteritis, and suicidal ideation. 2, 4

Pancreatitis

• Acute pancreatitis has been reported in clinical trials, though causality has not been definitively established. 2, 3
• Current guidelines recommend using semaglutide with caution in patients with a history of pancreatitis. 3
• Monitor for persistent severe abdominal pain. 3

Gallbladder Disease

• Increased risk of cholelithiasis (gallstones) and cholecystitis requiring monitoring. 2, 3, 4
• Monitor for signs of gallbladder disease periodically. 4

Acute Kidney Injury

• Risk of acute kidney injury and worsening chronic renal failure, particularly from dehydration secondary to severe gastrointestinal effects. 4
• Monitor renal function closely when initiating or escalating doses, especially in patients with pre-existing kidney disease. 3, 4
• Ensure adequate fluid intake to prevent dehydration-related kidney injury. 4

Absolute Contraindications

Semaglutide is absolutely contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies showing thyroid C-cell tumors. 2, 3, 4

• Pregnancy or breastfeeding is an absolute contraindication. 4
• Discontinue semaglutide in women at least 2 months before a planned pregnancy due to the long washout period. 1

Relative Contraindications and Cautions

Gastroparesis

• Semaglutide is not recommended in patients with clinically meaningful gastroparesis, as it delays gastric emptying and may worsen symptoms. 4
• Patients with severe gastroparesis may experience worsened symptoms. 4

Diabetic Retinopathy

• Patients with a history of diabetic retinopathy should be monitored closely for progression. 4
• Increased risk of diabetic retinopathy complications has been reported. 4

Renal Impairment

• No dose adjustment is required for patients with renal impairment, including end-stage renal disease. 1
• However, careful monitoring is warranted due to increased risk of gastrointestinal side effects and potential dehydration. 4

Hypoglycemia Risk

• Minimal risk for hypoglycemia when used as monotherapy due to glucose-dependent mechanism. 3
• Increased risk when combined with insulin or insulin secretagogues (sulfonylureas, glinides), requiring dose reduction of these medications. 3, 4

Perioperative Considerations

Retained gastric contents are documented even after extended fasting periods in patients taking semaglutide, creating an aspiration risk during anesthesia. 3

• Cases reported in patients who stopped semaglutide 4-6 days before surgery. 3
• Increased residual gastric content found in 24.2% of semaglutide users versus 5.1% of controls undergoing endoscopy, despite 10-14 day discontinuation and 12-hour fasting. 3

Other Notable Side Effects

• Injection site reactions occur with subcutaneous administration. 4
• Elevated heart rate is a common side effect requiring monitoring. 4
• Suicidal ideation has been reported in clinical trials. 2, 4
• Insomnia has been reported. 4

Drug Interactions and Special Considerations

Medication Interactions

• Semaglutide should not be used with other GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors. 3
• Delayed gastric emptying may affect absorption of concomitantly administered oral medications, particularly those with narrow therapeutic indices like warfarin. 4
• For oral hormonal contraceptive users, switch to non-oral contraception or add barrier method for 4 weeks after initiation and each dose escalation. 3, 4

Monitoring Requirements

• Assess efficacy and safety at least monthly for the first 3 months, then at least quarterly thereafter. 4
• Monitor renal function, especially with severe gastrointestinal symptoms. 4
• Check for signs of gallbladder disease periodically. 4
• Monitor blood pressure as weight loss may necessitate antihypertensive medication adjustment. 3
• Evaluate treatment efficacy at 12-16 weeks on the maximum tolerated therapeutic dose. 3

Clinical Pearls and Common Pitfalls

Optimizing Treatment Success

• Semaglutide must be used in conjunction with lifestyle modifications including reduced-calorie diet and increased physical activity. 2, 3
• Early responders (≥5% weight loss after 3 months) should continue medication long-term unless clinical circumstances suggest otherwise. 3
• If a patient tolerates a submaximal dose well and achieves adequate response, continuing that dose long-term is acceptable rather than escalating. 4

Avoiding Common Errors

• Do not combine semaglutide with other GLP-1 receptor agonists due to overlapping mechanisms and potential harm. 3
• When initiating semaglutide in patients on insulin, reduce basal insulin by 20% to prevent hypoglycemia. 3
• Ensure patients understand that weight regain is expected after discontinuation, making lifelong treatment necessary for sustained benefits. 3
• Review all current medications to identify weight-promoting agents and consider alternatives. 3