Once-weekly insulins: a promising approach to reduce the treatment burden in people with diabetes

Abstract

Despite the availability of new classes of glucose-lowering drugs that improve glycaemic levels and minimise long-term complications, at least 20-25% of people with type 2 diabetes require insulin therapy. Moreover, a substantial proportion of these individuals do not achieve adequate metabolic control following insulin initiation. This is due to several factors: therapeutic inertia, fear of hypoglycaemia and/or weight gain, poor communication, complexity of insulin titration, and the number of injections needed, with the associated reduced adherence to insulin therapy. Once-weekly insulins provide a unique opportunity to simplify basal insulin therapy and to allow good glycaemic control with a low risk of hypoglycaemia. Several approaches to developing a stable and effective once-weekly insulin have been proposed, but, to date, insulin icodec and basal insulin Fc (insulin efsitora alfa) are the only two formulations for which clinical studies have been reported. The results of Phase I and II studies emphasise both efficacy (in term of glucose levels) and potential risks and adverse events. Phase III studies involving insulin icodec are reassuring regarding the risk of hypoglycaemia compared with daily basal insulin analogues. Despite some concerns raised in ongoing clinical trials, the available data suggest that weekly insulins may also be an option for individuals with type 1 diabetes, especially when adherence is suboptimal. For the first time there is an opportunity to make an important breakthrough in basal insulin therapy, particularly in people with type 2 diabetes, and to improve not only the quality of life of people with diabetes, but also the practice of diabetologists.

Keywords: Adherence; BIF; Icodec; Insulin; Review; Weekly.

Fig. 1

Molecular and pharmacokinetic features of icodec and BIF. The icodec molecule is characterised by three amino acid substitutions compared with human insulin (shown in red) and attachment to a C20 icosane fatty diacid, allowing strong, reversible binding to albumin and resulting in a half-life of 8.2 days. The BIF molecule consists of a homodimer of single-chain insulin molecules covalently fused with the Fc portion of human IgG2. This molecule has a half-life of 17 days. This figure is available as part of a downloadable slideset

Fig. 2

Proportion of TIR in Phase II clinical trials conducted with icodec (a–c) and BIF (d–f). (a) Insulin-naive participants with type 2 diabetes [23]; (b) insulin-treated participants with type 2 diabetes [25]; (c) insulin-naive participants with type 2 diabetes (titration study) [24]; (d) insulin-naive participants with type 2 diabetes [27]; (e) insulin-treated participants with type 2 diabetes [26]; (f) participants with type 1 diabetes [28]. TIR was defined as the proportion of time with glucose levels between 3.9 and 10 mmol/mol, except in the study by Rosenstock et al [23], in which a tighter range was chosen (3.9–7.8 mmol/l). LD, loading dose; NLD, no loading dose. This figure is available as part of a downloadable slideset

Fig. 3

Main results of the Phase III ONWARDS programme evaluating the safety and efficacy of once-weekly icodec compared with once-daily glargine, degludec or a basal analogue in individuals with type 1 and type 2 diabetes. The numbers at the top of the figure correspond to the different ONWARDS trials (1–6 [–34]). Features of the study populations included are shown in Table 2. ONWARDS 6 [34] included participants with type 1 diabetes. ^aStatistically significant for superiority. TAR, time above range; TBR, time below range. This figure is available as part of a downloadable slideset