Search

OBJECTIVE To investigate the pharmacokinetic and pharmacodynamic properties and safety of a novel formulation of insulin aspart (AT247) versus two currently marketed insulin aspart formulations (NovoRapid [IAsp] and Fiasp [faster IAsp]). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 units/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 h. RESULTS Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 min [95% CI −14; −8], P = 0.0004) and faster IAsp (−2 min [−5; −2], P = 0.0003). Onset of action was accelerated compared with IAsp (−23 min [−37; −15], P = 0.0004) and faster IAsp (−9 min [−11; −3], P = 0.0006). Within the first 60 min, a higher exposure was observed for AT247 compared with IAsp by the area under the curve (AUC) glucose infusion rate (GIR) from 0 to 60 min (AUCAsp0–60min: treatment ratio vs. IAsp 2.3 [1.9; 2.9] vs. faster IAsp 1.5 [1.3; 1.8]), which was underpinned by a greater early glucose-lowering effect (AUCGIR,0–60min: treatment ratio vs. IAsp 2.8 [2.0; 5.5] vs. faster IAsp 1.7 [1.3; 2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 min [−58; −15], P = 0.0015) and faster IAsp (−27 min [−85; −15], P = 0.0017), while duration of the glucose-lowering effect, measured by time to late half-maximum effect, did not differ significantly. CONCLUSIONS AT247 exhibited an earlier insulin appearance, exposure, and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second-generation prandial insulin analogs to improve postprandial glycemic control.

BACKGROUND Lactulose is approved for the symptomatic treatment of constipation, a gastrointestinal (GI) complication common in individuals with diabetes. Lactulose products contain carbohydrate impurities (e.g., lactose, fructose, galactose), which occur during the lactulose manufacturing process. These impurities may affect the blood glucose levels of individuals with type 2 diabetes mellitus (T2DM) using lactulose for the treatment of mild constipation. A previous study in healthy subjects revealed no increase in blood glucose levels after oral lactulose intake. However, it is still unclear whether the intake of lactulose increases blood glucose levels in individuals with diabetes. AIM To evaluate the blood glucose profile after oral lactulose intake in mildly constipated, non-insulin-dependent subjects with T2DM in an outpatient setting. METHODS This prospective, double-blind, randomized, controlled, single-center trial was conducted at the Clinical Research Center at the Medical University of Graz, Austria, in 24 adult Caucasian mildly constipated, non-insulin-dependent subjects with T2DM. Eligible subjects were randomized and assigned to one of six treatment sequences, each consisting of four treatments stratified by sex using an incomplete block design. Subjects received a single dose of 20 g or 30 g lactulose (crystal and liquid formulation), water as negative control or 30 g glucose as positive control. Capillary blood glucose concentrations were measured over a period of 180 min post dose. The primary endpoint was the baseline-corrected area under the curve of blood glucose concentrations over the complete assessment period [AUCbaseline_c (0-180 min)]. Quantitative comparisons were performed for both lactulose doses and formulations vs water for the equal lactulose dose vs glucose, as well as for liquid lactulose vs crystal lactulose. Safety parameters included GI tolerability, which was assessed at 180 min and 24 h post dose, and adverse events occurring up to 24 h post dose. RESULTS In 24 randomized and analyzed subjects blood glucose concentration-time curves after intake of 20 g and 30 g lactulose were almost identical to those after water intake for both lactulose formulations despite the different amounts of carbohydrate impurities (≤ 3.0% for crystals and approx. 30% for liquid). The primary endpoint [AUCbaseline_c (0-180 min)] was not significantly different between lactulose and water regardless of lactulose dose and formulation. Also with regard to all secondary endpoints lactulose formulations showed comparable results to water with one exception concerning maximum glucose level. A minor increase in maximum blood glucose was observed after the 30 g dose, liquid lactulose, in comparison to water with a mean treatment difference of 0.63 mmol/L (95% confidence intervals: 0.19, 1.07). Intake of 30 g glucose significantly increased all blood glucose endpoints vs 30 g liquid and crystal lactulose, respectively (all P < 0.0001). No differences in blood glucose response were observed between the different lactulose formulations. As expected, lactulose increased the number of bowel movements and was generally well tolerated. Subjects experienced only mild to moderate GI symptoms due to the laxative action of lactulose. CONCLUSION Blood glucose AUCbaseline_c (0-180 min) levels in mildly constipated, non-insulin dependent subjects with T2DM are not affected by the carbohydrate impurities contained in 20 g and 30 g crystal or liquid lactulose formulations.

Objectives: To evaluate the effect of SGLT2i on the development of DKA during insulin depletion in T1DM. Methods: Sixteen male, C-peptide negative T1DM subjects were enrolled in this open, randomized, crossover, bicentric trial with two 7-day treatment periods (with/without SGLT2i). At the end of each treatment period, insulin was withdrawn for a maximum of 12h, followed by recovery phase (12h). Results: SGLT2i led to significantly lower plasma glucose (PG) values during insulin depletion (PGmax with/without SGLT2i: 174±40 (mean±SD) vs. 302±48 mg/dL; 95% CI for ratio: 0.51-0.60), but to higher beta-hydroxybutyrate (BHB) values (Figure) and a steeper BHB increase (delta BHB: 8.1±2.0 vs. 6.0±1.7 µmol/L/min; 95% CI for ratio: 1.22-1.49). pH, bicarbonate and base excess during insulin depletion were comparable. Baseline glucagon (7.8±2.5 vs. 5.0±1.6 pmol/L; 95% CI for ratio: 1.26-1.95) and FFA levels (0.65±0.27 vs. 0.43±0.31 mmol/L; 95% CI for ratio: 1.08-2.28) were higher with SGLT2i, but data indicate that after increase during insulin depletion comparable concentrations were reached for both. Conclusions: SGLT2i keeps PG in near normal ranges during DKA development and recovery, potentially impeding DKA diagnosis. While SGLT2i leads to higher ketone levels, increased baseline glucagon and FFA, an effect on pH and acidosis was not demonstrated. Disclosure I. Mursic: None. E. Svehlikova: None. W. Regittnig: None. T. Augustin: None. C. Magnes: None. A. Eberl: None. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. O. Klein: None. M. Wolf: None. M. Urschitz: None. M. Brunner: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K.