Insulin Degludec / Insulin Aspart

Diabetes mellitus is a globally prevalent metabolic disorder with insulin therapy as its core intervention. Premixed insulins provide combined basal and prandial glucose control but lack systematic nonclinical validation of component interactions and species translation rules. This study evaluated the pharmacokinetic and pharmacodynamic profiles of insulin degludec (IDeg), insulin aspart (IAsp) and their 70/30 premixed formulation using a Beagle dog euglycemic clamp model. Twelve dogs received 0.75 IU/kg subcutaneous doses of each formulation in a randomized single-dose three-period crossover design with 7-day washouts. Blood glucose was clamped at 5.0 mmol/L for 24 hours while monitoring glucose infusion rate, plasma insulin and serum C-peptide. Drug concentrations were quantified by LC-MS/MS, and component interactions were assessed using Sigmoid-Emax and Loewe models. The clamp maintained stable blood glucose across all groups with no clinical hypoglycemia. Co-formulation induced modest shifts in time to maximum plasma concentration. Dose-normalized exposures were comparable between single and combined formulations with relative bioavailability below 110%. Elimination parameters remained unchanged supporting independent clearance pathways. IDeg exerted long-acting glucose-lowering effects while IAsp had rapid onset and short duration. IDegAsp integrated both dual characteristics. The C-peptide curve of IDeg closely resembled that of IDegAsp. Glucose infusion rate profiles of IAsp and IDegAsp were similar despite morphological differences. Both models confirmed additive rather than synergistic interactions. Marked interspecies differences necessitated component-specific bidirectional correction for clinical dose extrapolation. This study confirms IDegAsp achieves complementary glycemic control via independently acting components without significant interference, providing robust nonclinical support and a reference framework for premixed insulin development.

To systematically evaluate and compare the efficacy and safety of three fixed‐ratio combination products—insulin degludec/liraglutide (IDegLira), insulin glargine/lixisenatide (iGlarLixi), and insulin degludec/insulin aspart (IDegAsp)—in patients with type 2 diabetes.

We systematically searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP up to July 2025 for randomized controlled trials (RCTs) comparing the three combinations of primary interest (IDegLira, iGlarLixi, IDegAsp) and their individual components (insulin degludec, insulin glargine, liraglutide, and lixisenatide). Inclusion of the individual components enabled indirect comparisons. Data extraction, risk‐of‐bias assessment, and GRADE evaluation were performed. Network meta‐analysis was conducted using Stata 14.0, with treatments ranked by the surface under the cumulative ranking curve (SUCRA).

Twenty‐one RCTs involving 12,815 patients were included. Both IDegLira (OR = 1.69, 95% CI: 1.08–2.65) and iGlarLixi (OR = 1.67, 95% CI: 1.17–2.37) had a higher incidence of treatment‐emergent adverse events (TEAEs) than IDegAsp; no other significant pairwise differences were observed. Based on SUCRA values, which provide a probabilistic ranking (indicating the likelihood of being the best rather than direct statistical superiority), IDegLira had the highest probability of being optimal for reducing HbA1c (89.4%), fasting plasma glucose (81.8%), and incidence of hypoglycemic events (57.6%), while IDegAsp ranked highest regarding the incidence of TEAEs (97.9%). Inconsistency in the hypoglycemia network, likely due to varied definitions, warrants cautious interpretation.

Among the three fixed‐ratio combination products, IDegLira appears most effective for glycemic control (in terms of HbA1c and FPG reduction), whereas IDegAsp demonstrates the best safety profile regarding incidence of TEAEs.