What is the recommended dosing and titration schedule for efsitora (once‑weekly basal insulin) in insulin‑naïve adults with type 2 diabetes, and how should it be adjusted for insulin‑experienced patients or those at risk of hypoglycemia?

Efsitora Dosing and Titration Guidelines

Initial Dosing for Insulin‑Naïve Adults with Type 2 Diabetes

For adults with type 2 diabetes who have never received insulin, start efsitora at a fixed dose of 100 units once weekly, administered subcutaneously on the same day each week. 1

Fixed‑Dose Titration Schedule

• Adjust the efsitora dose every 4 weeks (not weekly) based on fasting blood glucose levels, using the following fixed‑dose steps: 100 U → 150 U → 250 U → 400 U once weekly 1.
• Target fasting blood glucose of 80–130 mg/dL (4.4–7.2 mmol/L) 1.
• This fixed‑dose approach requires a median of only 2 dose adjustments over 52 weeks, compared with 8 adjustments for daily basal insulin 1.

Glycemic Efficacy and Outcomes

• Efsitora achieves comparable HbA1c reduction to once‑daily insulin degludec in both type 2 diabetes (mean difference 0.02%, P = 0.74) and type 1 diabetes (mean difference 0.11%, P = 0.08) 2.
• In insulin‑naïve adults with type 2 diabetes, once‑weekly efsitora reduced HbA1c by −1.19 percentage points from a baseline of 8.20%, achieving a mean HbA1c of 7.05% at 52 weeks 1.
• The mean total weekly insulin dose at 52 weeks was 289.1 units per week with efsitora versus 332.8 units per week with daily glargine, representing a 43.7 unit per week lower requirement 1.

Dosing for Insulin‑Experienced Patients

For adults with type 2 diabetes already on basal and prandial insulin, transition to efsitora using a treat‑to‑target approach with weekly dose adjustments based on fasting glucose patterns. 3

Conversion and Titration

• When converting from daily basal insulin, initiate efsitora at a dose that provides comparable weekly insulin exposure to the previous daily regimen 3.
• Titrate efsitora dose weekly or as needed to achieve fasting blood glucose of 80–130 mg/dL 3.
• Continue prandial insulin (e.g., insulin lispro) with meals, adjusting doses based on postprandial glucose readings 3.
• In the QWINT‑4 trial, efsitora reduced HbA1c by −1.01 percentage points from a baseline of 8.18%, achieving a mean HbA1c of 7.17% at 26 weeks 3.

Hypoglycemia Risk and Safety Profile

Reduced Hypoglycemia in Insulin‑Naïve Patients

• In insulin‑naïve adults with type 2 diabetes, efsitora demonstrated a 43% lower rate of combined clinically significant (glucose <54 mg/dL) or severe hypoglycemia compared with daily glargine (0.50 vs. 0.88 events per patient‑year; rate ratio 0.57,95% CI 0.39–0.84) 1.
• Nocturnal hypoglycemia risk was 15% lower with efsitora versus degludec in type 2 diabetes (risk ratio 0.85,95% CI 0.74–0.98; P = 0.03) 2.

Comparable Hypoglycemia in Insulin‑Experienced Patients

• In adults with type 2 diabetes on basal‑bolus therapy, rates of overall and nocturnal level 2 or level 3 hypoglycemia were similar between efsitora and glargine U100 (6.6 vs. 5.9 events per patient‑year; rate ratio 1.11,95% CI 0.85–1.44; P = 0.44) 3.

Type 1 Diabetes Considerations

• In adults with type 1 diabetes, efsitora showed higher rates of total adverse events, severe adverse events, and injection‑site reactions compared with daily degludec, though overall, severe, and nocturnal hypoglycemia rates were comparable 2.
• Efsitora is not currently recommended as first‑line therapy for type 1 diabetes due to the increased adverse event profile 2.

Monitoring and Adjustment Protocols

Glucose Monitoring Requirements

• Check fasting blood glucose at least once weekly during the titration phase to guide dose adjustments 1.
• For patients on basal‑bolus therapy, monitor pre‑meal and 2‑hour postprandial glucose to guide prandial insulin adjustments 3.
• Reassess HbA1c every 3 months during active titration 4.

Time in Range Outcomes

• Efsitora and daily degludec achieve comparable time in range, time above range, and time below range in both type 2 and type 1 diabetes 2.

Special Populations and Dose Modifications

Patients at Higher Risk of Hypoglycemia

• For older adults (>65 years), those with renal impairment, or patients with poor oral intake, start at the lower end of the dosing range (100 units once weekly for insulin‑naïve patients) and titrate more conservatively 5.
• If hypoglycemia occurs without a clear cause, reduce the efsitora dose by 10–20% immediately 5.

Renal Impairment

• In patients with CKD stage 5, reduce total daily insulin dose by 50% for type 2 diabetes and by 35–40% for type 1 diabetes when initiating or adjusting efsitora 5.

Critical Thresholds and Overbasalization

When to Add Prandial Insulin

• When basal insulin (including efsitora) approaches 0.5–1.0 units/kg/day without achieving glycemic targets, add prandial insulin rather than continuing to escalate basal insulin alone 5, 6.
• Clinical signals of overbasalization include: basal dose >0.5 units/kg/day, bedtime‑to‑morning glucose differential ≥50 mg/dL, hypoglycemia episodes, and high glucose variability 5.

Combination with GLP‑1 Receptor Agonists

• When basal insulin exceeds 0.5 units/kg/day, consider adding a GLP‑1 receptor agonist instead of further basal escalation to improve glycemic control while minimizing hypoglycemia and weight gain 5.

Practical Advantages of Once‑Weekly Dosing

Reduced Treatment Burden

• Once‑weekly efsitora requires significantly fewer dose adjustments (median 2 vs. 8 over 52 weeks) compared with daily basal insulin 1.
• The reduced injection frequency (52 injections per year vs. 365) may improve treatment adherence and persistence 7.
• Efsitora provides a flatter and more stable pharmacokinetic profile with less day‑to‑day variability compared with daily basal insulins 7.

Simplified Dosing Regimen

• The fixed‑dose titration schedule (100 → 150 → 250 → 400 units) eliminates the need for complex weekly dose calculations and reduces the cognitive burden on both patients and providers 1.

Common Pitfalls to Avoid

• Do not titrate efsitora more frequently than every 4 weeks in insulin‑naïve patients using the fixed‑dose regimen, as this can lead to dose stacking and hypoglycemia 1.
• Do not discontinue metformin when starting efsitora unless contraindicated, as metformin reduces total insulin requirements by 20–30% 5.
• Do not delay adding prandial insulin when fasting glucose is controlled but HbA1c remains above target after 3–6 months, or when basal insulin exceeds 0.5 units/kg/day 5.
• Do not use efsitora as monotherapy in type 1 diabetes without careful consideration of the increased adverse event profile 2.