Insulin Icodec Initiation Strategies and Day-4 Supplemental Dosing in Type 2 Diabetes

Background and rationale: Once-weekly insulin icodec has a half-life of approximately 196 hours, so its pharmacokinetic steady state is not reached until 3 to 4 weeks after initiation. This creates a mismatch with the clinical need to assess and achieve early fasting blood glucose (FBG) control within the first week. The glucose-lowering effect of icodec peaks on days 2 to 3 and remains near-maximal on day 4, offering an early time point to identify patients at risk of not reaching target. However, no prospective trial has compared icodec initiation strategies for early glycemic control or validated an early marker to guide supplemental dosing. This trial addresses that gap.

Design: This is a multicenter, randomized, open-label trial with a 3-by-2 factorial structure. Insulin-naive adults with type 2 diabetes who have not received insulin in the past 3 months are randomized 1:1:1 (stratified by center and baseline FBG) to one of three icodec initiation strategies: a fixed dose of 70 units per week; a dose based on fasting blood glucose (FBG in mmol/L multiplied by 7); or a dose based on body weight (body weight in kg multiplied by 0.15, then by 7). Within each initiation arm, participants are further randomized 1:1 to one of two day-4 management groups. In Group A, FBG is measured on day 4; if FBG is at or above 6.8 mmol/L, a one-time supplemental dose equal to 50% of the starting dose is given that day. In Group B, FBG is measured on day 4 but no supplemental dose is given. Because day-4 management is randomized independently of the day-4 FBG value, the comparison remains a valid randomized comparison.

Treatment and titration: Icodec is injected once weekly, on a fixed weekday, between 6:00 and 9:00 in the morning, in addition to the participant's existing non-insulin glucose-lowering therapy. The first injection defines study Day 1. From Day 15 (for participants who received a day-4 supplemental dose, whose Day 8 dose returns to the original starting dose) or from Day 8 (for those who did not), a standardized weekly titration algorithm adapted from the ONWARDS program is applied through Week 12. A blinded continuous glucose monitor is worn during the first 2 weeks and the last 2 weeks; it is not used for real-time titration decisions.

Primary endpoints: This trial has two independent co-primary endpoints, each tested at a two-sided alpha of 0.05 without alpha splitting across objectives. The first is the proportion of participants achieving target FBG (4.4 to 7.0 mmol/L) at the end of Week 1 (Day 8, before the second injection), compared across the three initiation strategies, with Bonferroni correction for the three pairwise comparisons. The second is the effectiveness of the day-4 threshold-based supplemental dosing rule, evaluated by comparing target attainment between the pooled Group A and Group B.

Follow-up: The randomized treatment period lasts 12 weeks, followed by a 5-week safety follow-up (Weeks 13 to 17) to capture delayed hypoglycemia after the last dose, given the prolonged action of icodec.

Inclusion criteria

• Age 18 years or older
• Diagnosis of type 2 diabetes mellitus for at least 180 days
• No insulin treatment of any kind within the past 3 months
• Currently treated with at least one non-insulin glucose-lowering agent (oral agent or GLP-1 receptor agonist) with inadequate glycemic control, and a clinical indication to start basal insulin
• HbA1c of 7.0% to 11.0% at screening
• Body mass index of 35.0 kg/m2 or lower
• Able and willing to wear a continuous glucose monitor per protocol, to undergo day-4 fasting blood glucose assessment, and to attend all scheduled visits
• Provides written informed consent

Exclusion criteria

• Type 1 diabetes, specific types of diabetes, or recent acute complications such as diabetic ketoacidosis or hyperosmolar hyperglycemic state
• Level 2 or level 3 hypoglycemia within the past 3 months, or hypoglycemia unawareness
• Current use, or use within the past 3 months, of systemic glucocorticoids (excluding inhaled or topical preparations) or other agents that markedly affect blood glucose
• Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2 by the CKD-EPI 2021 creatinine equation) or need for dialysis
• Active liver disease, abnormal liver function (ALT or AST above 3 times the upper limit of normal), or decompensated cirrhosis
• Marked edema, large-volume ascites, amputation, or other conditions that may impair accurate body weight measurement or distort weight-based dosing
• Known allergy to insulin icodec or its excipients
• Extensive skin lesions, allergy to continuous glucose monitor adhesive, or anticipated frequent magnetic resonance imaging that may interfere with monitor wear or interpretation
• Active malignancy
• Acute cardiovascular or cerebrovascular event (such as myocardial infarction, stroke, or unstable angina) within the past 6 months, or other major illness with short expected survival or poor compliance
• Pregnancy or lactation, or women of childbearing potential with pregnancy plans
• Participation in another drug or device clinical trial within the past 3 months
• Other conditions judged by the investigator to be unsuitable for enrollment or likely to affect participant safety or data reliability