Search

Background: We evaluated the effect of meloxicam on insulin lispro pharmacokinetics and glucose pharmacodynamics over 10 days of continuous subcutaneous insulin infusion (CSII) at one infusion site in people with type 1 diabetes (T1D)., Method: This phase 1, randomized, double-blind, single-center, two-way crossover study enrolled adults with T1D for ≥1 year on stable CSII for ≥3 months. Participants randomly received U100 insulin lispro and LY900027 (U100 insulin lispro + 0.25 mg/mL meloxicam). Primary end points were area under the insulin lispro curve from 0 to 5 hours (AUC Ins.0-5h ) after bolus administration prior to a mixed-meal tolerance test (MMTT) and maximum observed concentration of insulin lispro (C Ins.max ) on days 5, 7, and 10, versus day 3 (baseline)., Results: A total of 20 participants were randomized. Insulin absorption was accelerated for insulin lispro and LY900027 from days 1 to 7. The AUC Ins.0-5h was significantly lower on day 10 versus day 3 for LY900027 (-19%) and insulin lispro (-14%); the AUC Ins.0-5h did not differ significantly between treatments. The C Ins.max increased with LY900027 and insulin lispro (by ~14%-23% and ~16%-51%) on days 5, 7, and 10 versus day 3. The C Ins.max of LY900027 was ~14%-23% lower than insulin lispro C Ins.max on days 7 and 10 ( P ≤ .0805). Accelerated insulin absorption and a modest loss of total insulin exposure led to a loss of MMTT glycemic control at later time points., Conclusions: The pharmacokinetics of insulin changed over catheter wear time even when an anti-inflammatory agent was present. Postprandial glycemic control was adversely affected by the accelerated insulin absorption and decreased insulin exposure.

Introduction: Insulin efsitora alfa (efsitora) is a basal insulin with a flat pharmacokinetic profile and long half-life, enabling weekly dosing. These attributes may provide stable glucose levels. This exploratory phase 1 study aimed to assess the hypoglycemic risk during experimental conditions that mimic situations encountered in daily life. Methods: This was a single-site, open-label, two-period, fixed-sequence study in participants with type 2 diabetes (T2D) previously treated with basal insulin. The incidence, duration, and nadir glucose of hypoglycemia were assessed after treatment with efsitora versus insulin glargine (glargine) during three provocation conditions: 24-h prolonged fasting, prolonged fasting with exercise, and double dosing of study insulin. Results: The 54 enrolled adults (BMI 21.8–39.7 kg/m2, HbA1c 6.5–9.4%) achieved stable fasting glucose before undergoing provocation. Most hypoglycemic events were level 1 (≥ 54 to < 70 mg/dL) and resolved spontaneously or after oral glucose. The incidences of level 1 hypoglycemia for efsitora and glargine were not significantly different: for prolonged fasting, the incidences were 44.7 vs. 42.6% and the difference in proportion was 2.1% (95% CI: – 17.2, 21.4); for prolonged fasting with exercise, the corresponding values were 65.9 vs. 50.0% and 15.9% (– 3.0, 34.8); for double dosing, the corresponding values were 68.1 vs. 61.7% and 6.4% (– 12.8, 25.6). Level 2 hypoglycemia (< 54 mg/dL) was infrequent during both treatments and all provocations. No severe hypoglycemia was observed. Mean nadir glucose (range 62.8–66.3 mg/dL) and hypoglycemia duration (range 76.6–115.2 min) were also similar for the two treatments, depending on the provocation. Conclusion: Overall, weekly efsitora did not increase the incidence, duration, or severity of hypoglycemia compared to daily glargine during provocation periods in patients with T2D. Trial Registration: ClinicalTrials.gov identifier NCT04957914. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of basal insulin Fc (BIF; LY3209590), a fusion protein combining a novel single‐chain insulin variant together with human IgG2 Fc domain, following single and multiple once‐weekly BIF administration. Materials and Methods: The single ascending dose, 15‐day study assessed four BIF doses (5‐35 mg) in healthy participants and people with type 2 diabetes (T2D). In the 6‐week multiple ascending dose study, people with T2D, previously treated with basal insulin, received insulin glargine daily or a one‐time loading dose of BIF followed by 5 weeks of once‐weekly dosing (1‐10 mg). Safety, tolerability and PK and glucose PD were examined. Results: Mean ages of people with T2D (N = 57) and healthy participants (N = 16) in the single‐dose study were 58.4 and 35.8 years, respectively; mean body mass index values were 29.5 and 26.1 kg/m2. BIF had a PK half‐life of approximately 17 days, which led to a sustained, dose‐dependent decrease in fasting blood glucose for 5 days or longer. No severe hypoglycaemia was observed. The 6‐week ascending dose study included 33 people with T2D aged 40‐69 years. BIF showed a low peak‐to‐trough ratio of 1.14 after the last dose at week 6 (steady state). Over 6 weeks, BIF seven‐point glucose profiles remained constant and were similar to insulin glargine. Rates and duration of BIF hypoglycaemic events were similar to insulin glargine. Conclusions: BIF was well tolerated and the PK/PD profile enabled once‐weekly dosing with minimal variation in exposure in a treatment interval of 1 week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes. [ABSTRACT FROM AUTHOR]