In T2DM uncontrolled with noninsulin glucose-lowering agents, weekly icodec reduced HbA1c vs. daily degludec at 26 wk
Weekly insulin icodec has shown potential benefit in recent trials, but data on its effects in patients with type 1 diabetes or renal or hepatic failure are still awaited, an ACP Journal Club commentary noted.
Two recent manufacturer trials tested once-weekly icodec against once-daily degludec and found that it offered noninferior glucose control. ONWARDS 3 randomized 588 patients in 11 countries, all with type 2 diabetes (T2DM) and an HbA1c level of 7% to 11%, to daily or weekly insulin, plus placebo, for 26 weeks. ONWARDS 1 included 984 similar patients, randomized to weekly insulin icodec or daily insulin glargine U100 for 52 weeks. Both trials were funded by Novo Nordisk.
The ONWARDS 3 study was published by JAMA on June 24, and ONWARDS 1 was published by the New England Journal of Medicine on July 27. The following commentary by Heiba Belal, MD, and Gunjan Y. Gandhi, MD, MSc, was published in the ACP Journal Club section of Annals of Internal Medicine on Oct. 3.
Medication adherence yields improved glycemic and clinical outcomes while enhancing cost-conscious health care utilization in diabetes management. Once-weekly agents have emerged as potent tools that enhance adherence and quality of life in patients with diabetes. On the horizon is a new weekly basal insulin, icodec, studied in 6 phase 3 randomized controlled trials (ONWARDS 1 to 6) to assess its efficacy and safety across various clinical scenarios.
The ONWARDS 3 blinded trial by Lingvay and colleagues showed superior glycemic control with weekly icodec insulin vs. daily degludec insulin in patients with insulin-naive T2DM at 26 weeks. In similar patients, the ONWARDS 1 open-label trial by Rosenstock and colleagues showed sustained superior glycemic control with once-weekly icodec insulin compared with once-daily insulin glargine U100 at 52 weeks. These results are promising enough to consider once-weekly icodec insulin on par with available once-daily basal insulins.
ONWARDS 3 and ONWARDS 1 showed slightly higher rates of level 2 (plasma glucose level <54 mg/dL [3 mmol/L]) and level 3 (hypoglycemia requiring assistance) hypoglycemia with icodec. In ONWARDS 3, more patients in the icodec group had preexisting diabetic nephropathy than in the degludec group. Because patients with an estimated glomerular filtration rate <30 mL/min/1.73 m2 were excluded from the trial, safe renal dosing remains to be established for icodec. The choice of degludec as a comparator in ONWARDS 3 is compelling given its lower rate of nocturnal hypoglycemia than glargine U100 in type 1 diabetes. Nonetheless, the trials showed that more patients receiving icodec achieved an HbA1c level <7% without clinically significant or severe hypoglycemia compared with glargine U100 or degludec.
A recent trial in patients with T2DM found that double or triple doses of once-weekly icodec led to risks for hypoglycemia similar to those with double or triple doses of once-daily glargine, and recovery from hypoglycemia by IV glucose was not delayed in the icodec insulin group. A post hoc analysis of 2 trials showed that hypoglycemic episode duration was similar for icodec and insulin glargine in insulin-naive and insulin-experienced patients with T2DM, regardless of titration algorithm or initial loading dose. Further studies are needed to investigate icodec-induced hypoglycemia incidence, pattern, and recovery.
ONWARDS 3 noted a higher occurrence of diabetic retinopathy with insulin icodec vs. degludec, although other icodec trials have not. The popular, once-weekly incretin mimetic semaglutide also showed higher rates of retinopathy in the SUSTAIN-6 trial. The possible association between icodec and diabetic retinopathy requires further investigation, especially considering that a fixed-dose combination of icodec–semaglutide is in development.
The emergence of weekly insulin icodec as a favorable option for possibly improving adherence, persistence, and clinical outcomes is encouraging. The results from the ONWARDS 5 real-world trial of icodec vs. degludec or glargine in T2DM have not yet been released. Moreover, the safety and benefit of icodec in patients with type 1 diabetes are currently being studied (ONWARDS 6). Finally, the efficacy and safety of icodec in patients who have diabetes plus renal failure, hepatic failure, and/or class 3 obesity have yet to be determined.