One hundred years after insulin became commercially available, new formulations are still being developed. A first once-weekly insulin has been introduced on various markets, and results of the registration studies of a second once-weekly insulin are becoming available. In this narrative review, we discuss the mechanisms of prolongation, early clinical research study results, and the registration studies of these insulins, with a critical appraisal.
Get full access to this article
View all access options for this article.
References
1.
HeinemannL. Insulin Pharmacology. Textbook of Diabetes. 2Blackwell Science: Oxford; 2003.
2.
WangXG, TangF, HuangC, et al.Pharmacokinetic and pharmacodynamic properties of a novel once-weekly insulin analogue GZR4 in people with type 2 diabetes. Diabetologia, 2024; 67(S1):A788.
3.
TrevisanR, ContiM, CiardulloS. Once-weekly insulins: A promising approach to reduce the treatment burden in people with diabetes. Diabetologia, 2024; 67(8):1480–1492.
4.
HubálekF, CramerCN, HellebergH, et al.Enhanced disulphide bond stability contributes to the once-weekly profile of insulin icodec. Nat Commun, 2024; 15(1):6124.
5.
RosenstockJ, JunejaR, BealsJM, et al.The basis for weekly insulin therapy: Evolving evidence with insulin icodec and insulin efsitora alfa. Endocr Rev, 2024; 45(3):379–413.
6.
NishimuraE, PridalL, GlendorfT, et al.Molecular and pharmacological characterization of insulin icodec: A new basal insulin analog designed for once-weekly dosing. BMJ Open Diabetes Res Care, 2021; 9(1).
7.
HaahrH, CieslarováB, HingstJR, et al.The effect of various degrees of renal or hepatic impairment on the pharmacokinetic properties of once-weekly insulin icodec. Clin Pharmacokinet, 2024; 63(6):819–830.
8.
PieberTR, AsongM, FluhrG, et al.Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 2 diabetes. Diabetes Obes Metab, 2023; 25(12):3716–3723.
9.
HövelmannU, EngbergS, HeiseT, et al.Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes. Diabetes Obes Metab, 2024; 26(5):1941–1949.
10.
HeiseT, ChienJ, BealsJM, et al.Pharmacokinetic and pharmacodynamic properties of the novel basal insulin Fc (insulin efsitora alfa), an insulin fusion protein in development for once-weekly dosing for the treatment of patients with diabetes. Diabetes Obes Metab, 2023; 25(4):1080–1090.
11.
BajajHS, BergenstalRM, ChristoffersenA, et al.switching to once-weekly insulin icodec versus once-daily insulin glargine u100 in type 2 diabetes inadequately controlled on daily basal insulin: A phase 2 randomized controlled trial. Diabetes Care, 2021; 44(7):1586–1594.
12.
Philis-TsimikasA, BajajHS, BegtrupK, et al.Rationale and design of the phase 3a development programme (ONWARDS 1-6 trials) investigating once-weekly insulin icodec in diabetes. Diabetes Obes Metab, 2023; 25(2):331–341.
13.
European Medicines Agency. Awiqli Summary of Product Characteristics, 2024.
14.
RosenstockJ, BainSC, GowdaA, et al.;ONWARDS 1 Trial Investigators. Weekly icodec versus daily glargine U100 in type 2 diabetes without previous insulin. N Engl J Med, 2023; 389(4):297–308.
15.
LingvayI, AsongM, DesouzaC, et al.Once-weekly insulin icodec vs once-daily insulin degludec in adults with insulin-naive type 2 diabetes: The ONWARDS 3 randomized clinical trial. JAMA, 2023; 330(3):228–237.
16.
BajajHS, AberleJ, DaviesM, et al.Once-weekly insulin icodec with dosing guide app versus once-daily basal insulin analogues in insulin-naive type 2 diabetes (ONWARDS 5): A randomized trial. Ann Intern Med, 2023; 176(11):1476–1485.
17.
Philis-TsimikasA, AsongM, FranekE, et al.Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): A phase 3a, randomised, open label, multicentre, treat-to-target trial. Lancet Diabetes Endocrinol, 2023; 11(6):414–425.
18.
MathieuC, ÁsbjörnsdóttirB, BajajHS, et al.Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): A phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. Lancet, 2023; 401(10392):1929–1940.
19.
Russell-JonesD, BabazonoT, CailleteauR, et al.Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): A phase 3a, randomised, open-label, treat-to-target trial. Lancet, 2023; 402(10413):1636–1647.
20.
In a first-of-its-kind fixed dose study, once weekly insulin efsitora alfa leads to A1C reduction similar to daily insulin. Eli Lilly press release. Sep 05, 2024.
21.
WyshamC, BajajHS, Del PratoS, et al;QWINT-2 Investigators. Insulin efsitora versus degludec in type 2 diabetes without previous insulin treatment. N Engl J Med, 2024; 391(23):2201–2211.
22.
With once-a-week Dosing, insulin efsitora alfa delivers A1C reductrion and safety profile consistent with daily insulin. Eli Lilly press release. 16 May 2024.
23.
BergenstalRM, WeinstockRS, MathieuC, et al.Once-weekly insulin efsitora alfa versus once-daily insulin degludec in adults with type 1 diabetes (QWINT-5): A phase 3 randomised non-inferiority trial. Lancet, 2024; 404(10458):1132–1142.
24.
BajajHS, ÁsbjörnsdóttirB, CarstensenL, et al.Continuous glucose monitoring-based metrics and hypoglycemia duration in insulin-experienced individuals with long-standing type 2 diabetes switched from a daily basal insulin to once-weekly insulin icodec: Post hoc Analysis of ONWARDS 2 and ONWARDS 4. Diabetes Care, 2024; 47(4):729–738.
25.
BajajHS, AsbjornsdottirB, BariTJ, et al.Once-weekly insulin icodec compared with daily basal insulin analogues in type 2 diabetes: Participant-level meta-analysis of the ONWARDS 1-5 trials. Diabetes Obes Metab, 2024; 26(9):3810–3820.
26.
European Medicines Agency. Assessment Report Awiqli, 2024.
HeiseT, AndersenG, PrattEJ, et al.Frequency and severity of hypoglycemia under conditions of increased hypoglycemic risk with insulin efsitora alfa versus insulin glargine treatment in participants with type 2 diabetes. Diabetes Ther, 2024; 15(8):1785–1797.
29.
PieberTR, ArfeltKN, CailleteauR, et al.Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: A randomised crossover trial. Diabetologia, 2023; 66(8):1413–1430.
30.
Philis-TsimikasA, BacheJK, BariTJ, et al.Once-weekly insulin icodec and hospitalisation: Insights from the ONWARDS 1-6 trials. Diabetologia, 2023; 66(S1):S401.
31.
RiddellMC, HellerS, AsongM, et al.No evidence of increased physical activity-related hypoglycaemia with once-weekly insulin icodec vs once-daily basal insulin in type 2 diabetes: ONWARDS 1-5. Diabetologia, 2024; 67(S1)A:787.
