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New faster acting insulin – how fast is faster?

6th June 2019, Dr Chee L Khoo

I thought short acting insulin was fast acting until fast acting insulin came along. Just when you think fast acting is truly fast acting, along came faster acting. So, what is this faster acting insulin aspart (fiasp)? Is it just another play with semantics? Or is it just another attempt in extending a patent? Does it make that much clinical difference anyway?

How is fiasp faster?

Rapid-acting insulin analogues have been developed to have faster absorption profiles and provide an earlier onset of action than regular human insulin (RHI). By changing one single amino acid in RHI,  Insulin aspart (IAsp), the injected insulin hexamers is rapid dissociated into dimers and monomers. This increases the speed of absorption into the circulation and insulin aspart reaches peak plasma concentrations more rapidly compared with RHI, to better mimic the normal mealtime insulin response.

Fiasp is a novel formulation of insulin aspart containing two excipients: niacinamide (Vitamin B3) and L-arginine. L-arginine stabilises the formulation.  Niacinamide belong to a group of compounds classified as hydrotropes which increase the solubility of poorly soluble substances in aqueous solution.. At high concentrations, niacinamide encourages insulin hexamers to become more dimers and monomers, making the readily absorbed monomer more abundant. It also acts as a vasodilator (1-3), and a possible increase in local blood flow at the injection site may also augment insulin absorption. All up, the insulin works earlier after injection.

In female pigs, niacinamide increased the relative monomer fraction of IAsp by ~35% and the apparent permeability of IAsp across an endothelial cell barrier by ~27%. Niacinamide also induced a concentration-dependent vasorelaxation of porcine arteries, and increased skin perfusion in pigs (4).

Does it actually make a difference in clinical practice?

Type 1 Diabetes – Onset 1 and Onset 8 trials

1143 patients with type 1 diabetes (T1DM) stabilised on Levemir were randomised to receive either fiasp or IAsp dosed 0-2 min after the start of a meal (mealtime dose) or fiasp dosed 20 mins after start of the meal (postmeal dose). At 26 weeks, mealtime fiasp improved HbA1c more than mealtime IAsp. Post meal fiasp was as good as (non-inferior) mealtime IAsp.

In other words, in T1DM, fiasp is better in reducing HbA1c than your usual insulin aspart if given at the beginning of the meal. It is as good as usual insulin aspart even if given after the meals. How good is that? Not unexpectedly, fiasp was better in reducing postprandial hyperglycaemia compared with IAsp. Obviously, by reducing post prandial hyperglycaemia, our HbA1c is better.

In the Onset 8 trial, the basal insulin used was degludec. Patients were randomised to either mealtime fiasp,  mealtime IAsp or postmeal fiasp . There was no significant difference in HbA1c between the groups but fiasp were better in reducing post prandial glucose. Perhaps, the better pharmacodynamics of degludec covers the mealtime hyperglycaemia better negating some of the advantage of fiasp.

Overall, there was no increase in the incidence of major hypoglycaemia in both Onset 1 or 8 trials although in a pooled post hoc analysis of both Onset 1 and 8, there was a suggestion of lower incidence of nocturnal hypoglycaemia in the fiasp group.

Type 2 Diabetes – Onset 2 and Onset 3 trials

In the Onset 2 trial, 689 patients with T2DM who were stabilised on basal insulin and oral anti-diabetic drugs were randomised to receive either fiasp or IAsp. At 26 weeks, obviously, both insulin asparts significantly reduced HbA1c but there were no difference between the two mealtime insulins. Fiasp was better in reducing the 1 hour postprandial glucose than IAsp but not after 2-4 hours. Overall there was no difference on hypoglycaemia episodes between the groups although the fiasp group had an increase in 0-2 hour post meal hypoglycaemia.

In the onset 3 trial, fiasp were added to basal insulin in a basal bolus regimen and was compared with basal insulin alone. Naturally, there was significant improvement in HbA1c and post prandial hyperglycaemia but with an increase in the frequency of hypoglycaemia and modest weight gain.

Other onset trials were also conducted: Onset 5 were used in insulin pumps in adults with T1DM.

In summary, fiasp indeed has faster onset of action. It appears to be more favourable in reducing post prandial hyperglycaemia especially in those that may forget to inject their mealtime insulin at the start of the meal as is frequently the case in our younger T1DM. It does not seem to matter in patients with T2DM perhaps because they are less likely to forget their mealtime dose or they may have residual beta cells to compensate for the delay in dosing.

Postprandial hyperglycaemic excursions also contribute to glycaemic variability, which may be related to tissue damage and diabetes complications independently of A1C levels (5,6). In addition, the risk for hypoglycaemia is directly related to increased glycaemic variability in type 1 and type 2 diabetes  (7). Any insulin that reduces postprandial hyperglycaemic fluctuations should be beneficial in reducing the variability.

References

  1. Geiger J, Zou AP, Campbell WB, Li PL. Inhibition of cADP-ribose formation produces vasodilation in bovine coronary arteries. Hypertension. 2000;35(1 Pt 2):397–402.
  2. Proctor AR, Ramirez GA, Han S, Liu Z, Bubel TM, Choe R. Validation of diffuse correlation spectroscopy sensitivity to nicotinamide-induced blood flow elevation in the murine hindlimb using the fluorescent microsphere technique. J Biomed Opt. 2018;23(3):1–9.
  3. Powell ME, Hill SA, Saunders MI, Hoskin PJ, Chaplin DJ.Human tumor blood flow is enhanced by nicotinamide and carbogen breathing. Cancer Res. 1997;57(23):5261–4.
  4. Jonas Kildegaard1 & Stephen T. Buckley1 & Rasmus H. Nielsen, et al. Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide. Pharm Res (2019) 36: 49 https://doi.org/10.1007/s11095-019-2578-7
  5. Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Glycaemic variability and complications in patients with diabetes mellitus: Evidence from a systematic review of the literature. Diabetes Obes Metab 2010;12:288-98.
  6. Hirsch IB. Glycemic variability and diabetes complications: Does it matter? Of course it does! Diabetes Care 2015;38:1610-4.
  7. Monnier L, Wojtusciszyn A, Colette C, Owens D. The contribution of glucose variability to asymptomatic hypoglycemia in persons with type 2 diabetes. Diabetes Technol Ther 2011;13:813-8.
  8. Peter Senior, Irene Hramiak. Fast-Acting Insulin Aspart and the Need for New Mealtime Insulin Analogues in Adults With Type 1 and Type 2 Diabetes: A Canadian Perspective. Can J Diabetes xxx (2019) 1-9
  9. Jonas Kildegaard, Stephen T. Buckley, Rasmus H. Nielsen, et al. Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide. Pharm Res (2019) 36: 49 https://doi.org/10.1007/s11095-019-2578-7

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