A Randomized, Open-Label Comparison of Once-Weekly Insulin Icodec Titration Strategies Versus Once-Daily Insulin Glargine U100

Abstract

<b>OBJECTIVE</b> <p>Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated the efficacy and safety of icodec using different once-weekly titration algorithms.</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>This was a phase 2, randomized, open-label, 16-week, treat-to-target study. Insulin-naïve adults (<i>n</i> = 205) with type 2 diabetes and HbA1c 7–10% while treated with oral glucose-lowering medications initiated once-weekly icodec titrations A (pre-breakfast self-measured blood glucose target, 80–130 mg/dL; adjustment ±21U/week; <i>n</i> = 51), B (80–130 mg/dL; ±28U/week; <i>n</i> = 51), C (70–108 mg/dL; ±28U/week; <i>n</i> = 52), or once-daily insulin glargine U100 (IGlar U100; 80–130 mg/dL; ±4U/day; <i>n</i> = 51), <a>all </a><a>titrated weekly. </a>Percentage time in range (TIR; 70–180 mg/dL) during weeks 15&16 was measured using continuous glucose monitoring.</p> <p><b>RESULTS</b></p> <p>TIR improved from baseline (means: A, 57.0%; B, 55.2%; C, 51.0%; IGlar U100, 55.3%) to weeks 15&16 (estimated mean: A, 76.6%; B, 83.0%; C, 80.9%; IGlar U100, 75.9%). TIR was greater for titration B than for IGlar U100 (estimated treatment difference: 7.08%-points; 95% CI, 2.12%–12.04%; <i>P </i>= 0.005). No unexpected safety signals were observed. Level 2 hypoglycemia (<54 mg/dL) was low in all groups (0.05, 0.15, 0.38, 0.00 events per patient/year for icodec titrations A, B, C, IGlar U100, respectively), with no episodes of severe hypoglycemia.</p> <p><b>CONCLUSION</b></p> <p>Once-weekly icodec was efficacious and well tolerated across all three titration algorithms investigated. <a></a><a></a><a>Icodec titration A (80–130 mg/dL; ±21U/week) displayed the best balance between glycemic control and risk of hypoglycemia.</a> </p>

Rationale and design of the phase 3a development programme (ONWARDS 1–6 trials) investigating once‐weekly insulin icodec in diabetes

“…One unit of icodec has a comparable glucose‐lowering effect to one unit of comparator basal insulin; therefore, at randomization, the ‘once‐weekly’ dose of icodec corresponds to seven times the ‘once‐daily’ dose of comparator basal insulin (the once‐daily basal insulin dose is multiplied by seven) 9‐11 . A summary of comparator interventions is provided in Table 1.…”

“…Phase 2 trials conducted among insulin‐naive 9,10 and previously insulin‐treated 11 individuals with T2D have shown good tolerability and glucose‐lowering effects of once‐weekly icodec. Among insulin‐naive individuals, treatment with once‐weekly icodec, with or without background glucose‐lowering agents, was associated with a similar efficacy to once‐daily insulin glargine (glargine) U100, as shown by reductions from baseline in HbA1c.…”

“…Among insulin‐naive individuals, treatment with once‐weekly icodec, with or without background glucose‐lowering agents, was associated with a similar efficacy to once‐daily insulin glargine (glargine) U100, as shown by reductions from baseline in HbA1c. Furthermore, the rates of combined level 2 (<3.0 mmol/L) or level 3 (severe cognitive impairment requiring external assistance) hypoglycaemia were low in both the icodec and glargine U100 groups 9,10 . In previously insulin‐treated individuals, adding a one‐time additional dose of icodec to the first dose when switching to icodec resulted in effective glycaemic control without a transient elevation in fasting glucose levels during the switch and without an increased risk of clinically relevant hypoglycaemia when compared with once‐daily glargine U100 11 …”

Neue Entwicklungen in der Therapie des Diabetes mellitus Typ 2

“…Daher bedarf Insulin Icodec nur einer 1-mal wöchentlichen Gabe. Verglichen mit Insulin glargin U 100 zeigte Insulin Icodec ähnliche Glukose-senkende Effekte, ohne zu vermehrten Hypoglykämien zu führen, sodass auch das Sicherheitsprofil überzeugend wirkt 23 .…”

The ongoing evolution of basal insulin therapy over 100 years and its promise for the future

“…Indeed, in a double‐dummy placebo‐controlled trial in insulin‐naïve patients with T2DM, once‐weekly insulin icodec showed similar glucose‐lowering efficacy as daily glargine U‐100, with no increased incidence of clinically significant or severe hypoglycaemia 65 . Recently, trials evaluating a loading dose of icodec 66 and different titration algorithms 67 have supported the finding that weekly administration of this ultra‐long‐acting insulin formulation can provide comparable or even better glycaemic control than glargine U‐100, without increasing hypoglycaemic risk. A second ultra‐long‐acting formulation in development is basal insulin Fc, in which a novel single‐chain variant of insulin has been combined with a human IgG 2 Fc domain to yield a fusion protein that has a peak‐to‐trough ratio suggestive of a prolonged half‐life 63 .…”