11th June 2023, Dr Chee L Khoo
First, we have short acting GLP1-RA (exenatide) which requires twice a day injections. Then, we have once daily GLP1-RA injections (e.g. Exenatide ER, liraglutide, lixisenatide) which makes it more convenient for most patients. Of course, once daily injection is still too many. Once a week would be better, wouldn’t it? Of course, we now have weekly dulaglutide and semaglutide and patients love them. The same is happening to insulins. We started with short acting, then intermediate acting and then long-acting insulins (well, actually some are not really that long acting). We do have true long (>24 hours) acting insulins now (insulin glargine U300, insulin degludec). What about weekly insulins? Well, they are already here but does it work as well as the daily insulins?
Pharmacodynamic variability is particularly challenging for insulin, due to the large absorption variability associated with oral dosing in combination with a narrow therapeutic window with an overdose being associated with potentially life-threatening hypoglycaemia.
To overcome the potential variability of insulin absorption, ultra-long acting basal insulin analogues can overcome this limitation by addressing the critical issue of variability due to accumulation to steady state combined with a protracted action profile. Thus, an elimination half-life of >24 h combined with once daily dosing will lead to a steady-state exposure level accumulated from the dose of multiple consecutive days.
Insulin icodec (icodec) is a once-weekly basal insulin currently under development. Interestingly, icodec was discovered by systematic re-engineering of an ultra-long oral insulin, OI338 by reducing albumin binding and reducing the insulin receptor affinity thereby reducing insulin clearance and increasing half-life to 70 hours. In dog and rat studies, OI388 have shown to demonstrate safety and efficacy.
What about safety and efficacy in humans?
ONWARDS 2 aimed to assess the efficacy and safety of once-weekly icodec versus once-daily insulin degludec (degludec) in basal insulin-treated type 2 diabetes (2). It is a 26-week, randomised, open-label, active-controlled, multicentre, treat-to-target phase 3a trial was conducted in 71 sites in nine countries. Eligible patients with type 2 diabetes (T2D) inadequately controlled on once-daily or twice-daily basal insulin, with or without non-insulin glucose-lowering agents, were randomly assigned (1:1) to once-weekly icodec or once-daily degludec. The primary outcome was change from baseline to week 26 in HbA1c. Safety outcomes assessed include hypoglycaemic episodes and other adverse events.
526 were randomly assigned to icodec (n=263) or degludec (n=263). From a mean baseline of 8·17% for icodec and 8·10% for degludec, HbA1c was reduced to a greater extent with icodec than degludec (7·20% vs 7·42% respectively) at week 26. This translates to an estimated treatment difference (ETD) of −0·22 percentage points demonstrating non-inferiority (p<0·0001) and superiority (p=0·0028).
The estimated mean change from baseline to week 26 in bodyweight was +1·40 kg for icodec and −0·30 kg for degludec. Overall rates of combined level 2 or level 3 hypoglycaemia were less than one event per patient-year of exposure for both groups (0·73 [icodec] vs 0·27 [degludec]; estimated rate ratio 1·93 [95% CI 0·93 to 4·02]). Overall, 161 (61%) of 262 participants receiving icodec and 134 (51%) of 263 participants receiving degludec experienced an adverse event; 22 (8%) and 16 (6%), respectively, experienced a serious adverse event.
Thus, overall, among adults with basal insulin-treated type 2 diabetes, treatment with once-weekly icodec was at least as good as once-daily degludec (non-inferior) but actually statistically better in HbA1c reduction after 26 weeks albeit, associated with modest weight gain. Overall rates of hypoglycaemia were low, with numerically but not statistically significantly higher event rates of level 2 or level 3 hypoglycaemia with icodec versus degludec.
Note that ONWARDS-2 was a Phase 3A trial although it will probably be a while before icodec arrives in Australia. Not only will it improve HbA1c but also assist in patient adherence. I can see the care in my older patients who only see family members once a week will benefit.
References:
- Hubálek, F.; Refsgaard, H. H. F.; Gram-Nielsen, S.; Madsen, P.; Nishimura, E.; Münzel, M.; Brand, C. L.; Stidsen, C. E.; Claussen, C.; Wulf, E. M.; Pridal, L.; Ribel, U.; Kildegaard, J.; Porsgaard, T.; Johansson, E.; Steensgaard, D. B.; Hovgaard, L.; Glendorf, T.; Hansen, B. F.; Jensen, M. K.; Nielsen, P. K.; Ludvigsen, S.; Rugh, S.; Garibay, P. W.; Moore, M. C.; Cherrington, A. D.; Kjeldsen, T. Molecular engineering of safe and efficacious oral basal insulin. Nat. Commun. 2020, 11, 3746 DOI: 10.1038/s41467-020-17487-9
- Philis-Tsimikas A, Asong M, Franek E, Jia T, Rosenstock J, Stachlewska K, Watada H, Kellerer M. 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 Jun;11(6):414-425. doi: 10.1016/S2213-8587(23)00093-1.