How do I initiate semaglutide in an adult with type 2 diabetes, including the starting dose and titration schedule?

How to Start Semaglutide in Adults with Type 2 Diabetes

Starting Dose and Initial Titration

Begin semaglutide at 0.25 mg subcutaneously once weekly for the first 4 weeks, then increase to 0.5 mg once weekly. 1 This initial low dose is not therapeutic—it exists solely to minimize gastrointestinal side effects (nausea, vomiting, diarrhea) that occur in 44%, 25%, and 32% of patients respectively at higher doses. 2

• Administer the injection subcutaneously in the abdomen, thigh, or upper arm at any time of day, with or without meals. 1
• Rotate injection sites systematically within one anatomical region (e.g., stay in the abdomen for 4 weeks, then switch to thighs) rather than jumping between body regions each week, as this minimizes day-to-day variability in drug absorption. 3

Standard Titration Schedule for Type 2 Diabetes

After the initial 4-week period at 0.25 mg, follow this escalation protocol:

• Weeks 5–8: 0.5 mg once weekly (this is the standard maintenance dose for many patients). 3, 1
• If additional glycemic control is needed after at least 4 weeks at 0.5 mg: increase to 1.0 mg once weekly. 3, 1
• If further intensification is required after at least 4 weeks at 1.0 mg: increase to 2.0 mg once weekly (the maximum approved dose for type 2 diabetes). 3

The key principle is to wait at least 4 weeks at each dose level before escalating, allowing time for gastrointestinal adaptation and assessment of glycemic response. 4, 5

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Alternative: Slower, Flexible Titration (Reduces Adverse Events)

A 16-week flexible titration regimen starting at an even lower dose (0.0675 mg weekly, increased by 0.0675 mg increments each week) reduces treatment discontinuation due to gastrointestinal side effects from 19% to 2% compared with the standard 8-week label regimen, without compromising efficacy. 5 This approach is particularly valuable for patients with a history of gastrointestinal intolerance to other medications.

• With flexible titration, pause dose escalation if moderate-to-severe nausea or vomiting occurs, maintaining the current dose for an additional 1–2 weeks until symptoms resolve. 5
• Final HbA1c and BMI reductions are identical between standard and flexible titration, so slower escalation does not sacrifice effectiveness. 5

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Pre-Treatment Screening and Baseline Assessment

Before initiating semaglutide, complete the following:

• Screen for absolute contraindications:

  • Personal or family history of medullary thyroid carcinoma (MTC). 3
  • Multiple endocrine neoplasia syndrome type 2 (MEN 2). 3
  • Pregnancy or lactation. 3
  • History of severe hypersensitivity reaction to semaglutide. 3

• Obtain baseline HbA1c and fasting glucose to establish glycemic targets (generally <7% for most adults). 6

• Measure estimated glomerular filtration rate (eGFR): semaglutide requires no dose adjustment across all stages of chronic kidney disease, including eGFR <30 mL/min/1.73 m². 3, 7

• Document history of pancreatitis: semaglutide may be used with caution, as causality has not been definitively established, but patients should be monitored for persistent severe abdominal pain. 6, 3

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Concomitant Medication Adjustments

When starting semaglutide, reduce or discontinue medications that increase hypoglycemia risk:

• Reduce basal insulin by approximately 20% to prevent hypoglycemia, as semaglutide's glucose-dependent insulin secretion adds to exogenous insulin effects. 6, 3
• Discontinue sulfonylureas entirely or reduce the dose by 50% before initiating semaglutide, as the combination markedly increases hypoglycemia risk. 6, 3
• Stop all DPP-4 inhibitors (e.g., sitagliptin, linagliptin) before starting semaglutide, as concurrent use provides no additional glycemic benefit. 6, 3

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Monitoring During Titration

• Assess gastrointestinal tolerance at each dose escalation (weeks 4,8,12, and 16 if using standard titration). 2
• Monitor body weight every 4 weeks during titration to track early response. 2
• For patients on insulin or sulfonylureas, check fasting and pre-meal glucose more frequently during the first 4–8 weeks to detect hypoglycemia early. 2
• Re-measure HbA1c at 12–16 weeks after reaching the maintenance dose to assess glycemic response and decide whether further dose escalation is needed. 6, 2

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Missed Dose Management

• If a dose is missed and ≤5 days have passed since the scheduled injection, administer the dose as soon as possible, then resume the regular weekly schedule. 1
• If >5 days have passed since the missed dose, skip it and administer the next dose on the originally scheduled day. 1
• If 2 consecutive doses are missed, resume at the same dose if the patient previously tolerated it well; otherwise, consider lowering the next dose. 6
• If ≥3 consecutive doses are missed, restart the titration schedule from 0.25 mg weekly. 6

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Expected Efficacy and Cardiovascular Benefits

• Semaglutide reduces HbA1c by approximately 1.4–1.7% from baseline in patients with type 2 diabetes, with up to 81% of patients achieving an HbA1c <7%. 4
• In patients with type 2 diabetes and established cardiovascular disease, semaglutide reduces major adverse cardiovascular events (cardiovascular death, nonfatal MI, or nonfatal stroke) by 26% (HR 0.74,95% CI 0.58–0.95). 6, 3
• Semaglutide slows chronic kidney disease progression, reducing the risk of kidney failure, ≥50% eGFR decline, or kidney-related death by 24% (HR 0.76,95% CI 0.66–0.88). 7

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Common Pitfalls to Avoid

• Do not skip the initial 0.25 mg dose and start directly at 0.5 mg or higher, as this markedly increases gastrointestinal adverse events and treatment discontinuation. 4, 5
• Do not escalate doses faster than every 4 weeks, as this does not allow adequate time for gastrointestinal adaptation. 4, 5
• Do not forget to reduce or discontinue sulfonylureas, as the combination with semaglutide significantly raises hypoglycemia risk. 6, 3
• Do not combine semaglutide with other GLP-1 receptor agonists or DPP-4 inhibitors, as this provides no additional benefit and increases adverse effects. 6
• Do not assume renal dose adjustment is necessary—semaglutide dosing remains unchanged across all CKD stages, including dialysis. 3, 7

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When to Discontinue or Switch Therapy

• Stop semaglutide immediately if persistent severe abdominal pain develops, as this may indicate pancreatitis. 6, 3
• Discontinue if right-upper-quadrant pain with fever occurs, suggesting cholecystitis or gallbladder disease. 6
• Consider stopping therapy if weight loss is <5% after 3 months at the maximum tolerated dose (for patients using semaglutide primarily for weight management). 6

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Special Populations

• Chronic kidney disease (any stage, including eGFR <30 mL/min/1.73 m²): No dose adjustment required; semaglutide is a preferred GLP-1 receptor agonist for advanced CKD due to proven renal protection. 3, 7
• Established cardiovascular disease: Semaglutide is strongly recommended due to proven cardiovascular benefit (26% MACE reduction). 6, 3
• Elderly patients: No dose adjustment required, but monitor closely for dehydration from gastrointestinal side effects. 6