Navigating the Efficacy-Safety Trade-off of Once-Weekly Insulin Icodec in Clinical Practice

Abstract

The recent FDA approval of insulin icodec (Awiqli) on 26 March 2026- the first once-weekly basal insulin for adults with type 2 diabetes(T2D), marks a significant advancement in insulin therapy[1]. Icodec has the potential to increase adherence and overcome therapeutic inertia, two enduring obstacles to the best possible glycemic control, by lowering basal insulin doses from 365 to 52 annually. However, the balance between this agent's greater glycemic effectiveness and the regularly noted rise in hypoglycemia should be carefully considered as clinicians get ready to use it. 

In the phase 3a ONWARDS study trial, Icodec showed better A1c reductions than daily basal insulins in insulin-naive individuals. Icodec significantly increased time in range (71.9% vs. 66.9%) and decreased A1c by 1.55 percentage points in ONWARDS 1 (n=984) compared to 1.35 with glargine U100 [2].A double-blind trial called ONWARDS 3 (n=588) verified a 0.2 percentage-point advantage over degludec[3]. A meta-analysis of seven RCTs encompassing 3,286 patients reported a pooled A1c advantage of 0.15 percentage points with improved time in range [4]. 

However, this efficacy benefit came with a warning that medical professionals shouldn't ignore. Combined clinically moderate or severe hypoglycemia happened at 0.30 versus 0.16 occurrences per person-year with glargine U100 in ONWARDS 1 [2]. At 26 weeks, this difference was statistically significant in ONWARDS 3 (0.35 vs. 0.12 occurrences per person-year; P=0.01) [3]. Level 1 hypoglycemia rates were continuously higher with icodec throughout the ONWARDS program, with rate ratios ranging from 1.25 to 1.88, and combined level 2/3 hypoglycemia was considerably raised by 71–89% in three out of six trials [5].

Crucially, despite icodec's extended half-life, absolute hypoglycemia rates in insulin-naive T2D populations remained below 1 incident per person-year, and the length of individual hypoglycemic episodes was not increased. Since ONWARDS 6 showed much greater hypoglycemia rates in type 1 diabetes, the approval was suitably limited to T2D. These findings suggest that the potential benefits and risks associated with the use of ICODEC would best support the treatment of newly diagnosed type 2 diabetes (T2D) patients who are naive to exogenous insulin. This is because their use of weekly dosing of ICODEC would likely provide both increased patient compliance as well as a lower risk of severe hypoglycemia compared to many other diabetes treatments. However, other types of diabetic patients such as those currently using multiple daily injections or continuous subcutaneous insulin infusion (basal-bolus therapy), older diabetic patients, diabetic patients with impaired kidney function and altered blood glucose awareness may require further evaluation prior to initiating ICODEC.