What is the value of faster acting prandial insulin? Focus on ultra rapid lispro

Abstract

Rapid‐acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra‐rapid–acting insulins, including ultra‐rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head‐to‐head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Accelerated absorption of regular insulin administered via a vascularizing permeable microchamber implanted subcutaneously in diabeticRattus norvegicus

“…One might argue that accelerating absorption via an IVM is an unnecessary redundancy now that ultra-rapid acting insulins are available. However, the very rapid peak plasma insulin concentrations achieved with regular insulin via IVM more closely mimic the normal human pancreas and are likely superior to even ultra-rapid acting insulins injected SC [16, 49, 50]. The insulin kinetic curves (Fig 2 B, D) are compatible with an “inject-eat continuum” strategy: this would, first, synchronize the insulin peak with the prandial requirement; and second, avoid the pitfalls of inopportune delays of a meal by simply postponing the injection.…”

“…Another argument sometimes made is that rapid uptake of insulin confers more risk than benefit, for example, by triggering hypoglycemic episodes. However, the clinical safety and efficacy, especially in post-prandial control, of ultra-rapid acting insulins is now supported by many studies [15, 16, 52, 53]. The factitious “too rapid” assertion also deflects the many advances in continuous glucose monitoring (CGM) devices, insulin dosage-predicting algorithms, precision-dosing insulin pumps, open and closed loop systems, and the “artificial pancreas” (AP) [6].…”

Therapie des Typ-2-Diabetes

“…Wegen des schnelleren Wirkungseintritts ist es noch besser steuerbar, insbesondere bei Menschen mit Typ-1-Diabetes und solchen mit einer Insulinpumpentherapie [294]. Die Insulinwirkung von ultraschnell wirkendem Insulin lispro (URLI = Ultra Rapid Lispro Insulin) führte zu einer deutlich besseren postprandialen Glukosekontrolle, ganz gleich ob dieses Insulin vor, während oder nach der Mahlzeit (-15 bis + 15 Minuten) s. c. gespritzt wurde [296]. Die postprandialen Glukose-Exkursionen über 5 Stunden wurden mit URLI um 29 % bis 105 % gesenkt.…”

Increased Time in Range with Ultra Rapid Lispro Treatment in Participants with Type 2 Diabetes: PRONTO-Time in Range

“…Ultra rapid lispro (URLi; Lyumjev ® ) is a formulation of insulin lispro with a faster onset and shorter duration of action compared to Lispro (Humalog ® ) and was developed to more closely match physiological insulin secretion and improve PPG control [ 12 ]. URLi has demonstrated non-inferiority to Lispro in HbA1c change from baseline after 26 weeks in people with type 1 diabetes (T1D) (PRONTO-T1D) and T2D (PRONTO-T2D) while providing superior PPG control when dosed at mealtime [ 13 , 14 ].…”

“…Studies have shown that introducing a rapid-acting prandial insulin as part of a basal-bolus multiple daily injection (MDI) regimen is more effective at managing PPG than a basal-only regimen [9][10][11]. Nevertheless, rapid-acting insulins still may not have fast enough onset to match carbohydrate absorption resulting in inadequate control of PPG [12].…”