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.

agonist designed to activate endothelial S1P 1 and provide endothelial-protective properties, while limiting S1P 1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P 1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flowmediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. Results: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] −0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. The authors confirm that the Principal Investigators for the clinical study were Grit Anderson and Leona Plum-Mörschel and that they had direct clinical responsibility for patients at the Neuss and Mainz sites, respectively. In addition, Grit Andersen was coordinating principal investigator.

URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion. This randomized, double-blind, 2 period, crossover, 10 h euglycemic clamp study assessed PK and glucodynamics after one 15U SC dose of URLi and lispro in 41 patients with T1D (mean ± SD age, 32.0 ± 6.8 y; duration of T1D, 17.7 ± 9.3 y; HbA1c, 7.2 ± 0.6%; BMI, 24.8 ± 2.4 kg/m2). After dosing URLi, onset of insulin lispro appearance in the serum was faster (1.3 vs. 6.8 min; p&lt;0.0001) and early insulin lispro exposure was greater (7.2 fold in the first 15 min and 2.7-fold in the first 30 min; both p&lt;0.0001) vs. lispro. The duration of exposure, when serum lispro levels fell below the limit of quantification, was 74 min shorter with URLi (p&lt;0.0001). Onset of insulin action was also faster (20 vs. 31 min; p=0.0007) and early action was increased 2.8 fold (p&lt;0.001) in the first 30 min for URLi vs. lispro. Late insulin action (glucose infused from 4 h to end of the clamp) was reduced by 54% (p&lt;0.0001) and duration of action was 43.6 min shorter with URLi (Figure). Total insulin lispro exposure and glucose infused during the clamp did not differ and tolerability was similar between URLi vs. lispro. In patients with T1D, URLi accelerated insulin absorption with a reduced late exposure and overall shorter duration vs. lispro, resulting in faster onset of insulin action and reduced late insulin action. Disclosure H. Linnebjerg: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. E.S. LaBell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company, Johnson & Johnson, Novartis AG. S. Reddy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D.E. Coutant: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. U. Hoevelmann: None. L. Plum-Moerschel: None. T. Herbrand: None. J. Leohr: Employee; Spouse/Partner; Accenture. Employee; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Accenture. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

BackgroundTranscatheter mitral valve repair (TMVR) has been shown to have acute effects on mitral valve geometry in patients with functional mitral regurgitation (FMR). This study investigates the impact of MitraClip® therapy-induced annular remodeling on clinical outcome and mitral regurgitation in heart failure patients.MethodsTMVR was performed successfully in 45 patients with FMR. In this study, mitral valve datasets were obtained before and directly after MitraClip® implantation using three-dimensional (3D) transesophageal echocardiography, and were analyzed offline retrospectively using dedicated 3D reconstruction software. Patients underwent clinical and echocardiographic evaluation at baseline and after 6 months. At follow-up, the patients were allocated into two groups according to their improvement in New York Heart Association (NYHA) functional class: a Low Responder group with ΔNYHA <1.5 (n = 25); and a High Responder group with ΔNYHA ≥1.5 (n = 20).ResultsAt 6-month follow-up, data analysis revealed that while mitral regurgitation was reduced significantly in both groups, only the High Responder group had experienced significant downsizing of the 3D circumference (137 ± 14 mm to 126 ± 13 mm; p < 0.01) and the anterior-to-posterior diameter (33 ± 5 mm to 29 ± 4 mm; p < 0.01) of the mitral annulus during the intervention. Furthermore, only the High Responder group with reverse annular remodeling as shown had substantial advances in quality of life (Minnesota living with heart failure questionnaire: 55 ± 10 to 34 ± 14 points; p < 0.01) and functional status (6-min walk distance: 290 ± 104 m to 462 ± 111 m; p = 0.07).ConclusionOur study demonstrates that instantaneous left ventricular annular remodeling during MitraClip® implantation is associated with improved clinical outcome of heart failure patients with functional mitral regurgitation. Trial registration The study was approved by the local ethics committee (Study Number 4497R, Registration ID: 2013121585). Trial registration: NCT02033811 Retrospectively registered January 9, 2014.