Background Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog ® in patients with type 1 diabetes mellitus (T1DM). Methods This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Results Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39-41% lower, and exposure duration was reduced by 72-74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11-12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44-54% lower, and duration of action was reduced by 34-44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. Conclusion In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.

Aims To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D). Materials and Methods This was a randomized, double‐blind, four‐period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal. Results URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half‐maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post‐meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post‐meal with URLi were comparable to those in healthy subjects. Conclusions URLi demonstrated the fastest insulin absorption and the greatest numeric PPG‐lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.

Background and objective Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog ® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM). Methods This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Results Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated. Conclusions This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. ClinicalTrials.gov identifier: NCT03305822.

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This is the first lipokinetic model to describe the absorption of TGs from dietary fats into the blood stream and compares the dynamics of TGs in chylomicrons and large VLDL-V6 particles among lean, obese and very obese people. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.