LAUSR

Insulin was first isolated in 1921 and developed as a therapeutic agent in the 1920s. The initial crude preparations were injected multiple times daily because of their short duration of action. Consequently, there were many attempts to develop insulin preparations with prolonged biological availability in the hope that less frequent once-daily administration would be feasible (1). A host of such preparations were introduced, including protamine insulin, protamine zinc insulin, surfen insulin, globin insulin, iso-insulin, isophane insulin (NPH), and insulin zinc suspensions (lente insulins) (1) (Fig. 1). The goal was mainly to reduce the number of injections and thus the patient burden. Yet, with the development of a radioimmunoassay for insulin (2), it became apparent that physiologic insulin secretion involved two components: meal-related insulin secretion with postprandial spikes and basal insulin secretion that remains relatively constant with some minor pulsatility (3). Subsequently, as modern insulin therapy evolved, facilitated by patient self-monitoring of blood glucose (4,5), it became apparent that the inherent peaks in basal insulin preparations, such as with the nonsoluble NPH or lente insulins, created risk of hypoglycemia, especially if the insulin vials were not correctly rolled to create a proper suspension. Moreover, these insulins did not have sufficiently long duration of action to be used once daily. Consequently, in addition to making them soluble, two of the goals in development of basal insulin analogs, such as insulin glargine and insulin detemir, were to eliminate insulin peaks and to prolong the action to approach 24 h (6,7). Second-generation basal insulin analogs, such as insulin degludec and insulin glargine U300, came with further improvements by having flatter insulin profiles and sustained action beyond 24 h (8,9). Buoyed by the successful use of once-weekly glucagon-like peptide 1 receptor agonists (GLP-1 RA) for the treatment of type 2 diabetes, manufacturers have begun to develop once-weekly insulin preparations (10,11). A report on the initial clinical trial of one such preparation, insulin icodec, appeared last year (12). In that study of patients with type 2 diabetes naive to insulin therapy, insulin icodec once weekly was compared with insulin glargine once daily in a double-dummy placebo-controlled treat-to-target study. Despite the use of a rigorous titration algorithm (weekly dose increments of 28 units/week) and aggressive fasting glucose target of 70–108 mg/dL (3.9–6.0 mmol/L), the insulins did not differ in robust reduction of A1C or in frequency of significant or severe hypoglycemia (12). Two reports in this issue of Diabetes Care (13,14) further expand on the clinical potential of insulin icodec. In one, patients with type 2 diabetes inadequately controlled on basal insulin are switched to either insulin icodec or to insulin glargine (13). In this study, two approaches to initiation of insulin icodec were evaluated, one of which involved a loading dose in which double the initial dose was used, given the consideration that it would otherwise take longer to achieve steady-state insulin levels. It turned out that the primary outcome measure, time in range (TIR) of 70–180 mg/dL (3.9–10.0 mmol/ L) during weeks 15 and 16 as assessed by continuous glucose monitoring, was statistically significantly better with the loading dose versus insulin glargine and numerically better than when a loading dose was not used. Hypoglycemia rates were comparable versus the insulin glargine U100 and were not affected by the initial loading dose. In the second report, also involving insulin-naive patients with type 2 diabetes, three different titration strategies for insulin icodec were compared, along with an insulin glargine group (14). The insulin glargine group and two of the insulin icodec groups had a fasting glucose target of 80–130 mg/dL (4.4–7.2 mmol/L), one using weekly dose increments of 28 units/week (equivalent to the 4 units/day in the glargine group), while the other used a smaller dose increment of 21 units/week. The third insulin icodec group used both the aggressive fasting glucose target of 70–108 mg/dL (3.9–6.0 mmol/L) and the larger dose increment of 28 units/ week. Again, the primary outcome measure was TIR 70–180 mg/dL (3.9–10.0