Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF.

BACKGROUND: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. METHODS: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable. RESULTS: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. CONCLUSION: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study.

OBJECTIVE: Inhibiting sodium-glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters. RESEARCH DESIGN AND METHODS: Using a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h. RESULTS: Changes from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed. CONCLUSIONS: Changes from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).

Ease of Use of the Insulin Glargine 300 U/mL Pen Injector in Insulin-Naïve People With Type 2 Diabetes.

BACKGROUND: Insulin glargine 300 U/mL (Gla-300) contains the same active ingredient as glargine 100 U/mL (Gla-100), and provides the same number of units in one-third of the volume. The SoloSTAR® injector pen has been modified to ensure accurate administration of this reduced volume and to improve user experience. METHODS: Insulin- and pen-naïve adults with type 2 diabetes (T2DM) inadequately controlled with oral antihyperglycemic drugs, who had glycated hemoglobin (HbA1c) levels of 7.0-11.0 % (53-97 mmol/mol) were studied. They received once-daily Gla-300 in this 4-week, multicenter, open-label, single-arm study (NCT02227212). Ease of use/ease of learning (the primary endpoint), glycemic control, safety, and reliability of the disposable (prefilled) Gla-300 injector pen (secondary endpoints) were evaluated. RESULTS: At week 4, 95.0% of 40 participating subjects assessed the pen as excellent/good and none as poor/very poor; 97.5% would recommend it to others. Total Diabetes Treatment Satisfaction Questionnaire scores were stable throughout the study. Mean (SD) fasting plasma glucose levels decreased from 166.1 (35.0) mg/dL at baseline to 124.2 (41.1) mg/dL at week 4. No product technical complaints (PTCs) or adverse events (AEs) related to PTCs were reported. The number of subjects experiencing hypoglycemic events of any kind and the incidence of AEs were low. No serious AEs were reported. CONCLUSIONS: The Gla-300 injector pen is easy to use and easy to learn to use, with demonstrable reliability and high degrees of acceptance and treatment satisfaction. Once-daily Gla-300 basal insulin treatment was well tolerated and effective in pen- and insulin-naïve adult T2DM subjects.

Improving Efficacy of Inhaled Technosphere Insulin (Afrezza) by Postmeal Dosing: In-silico Clinical Trial with the University of Virginia/Padova Type 1 Diabetes Simulator.

BACKGROUND: Technosphere(®) insulin (TI), an inhaled human insulin with a fast onset of action, provides a novel option for the control of prandial glucose. We used the University of Virginia (UVA)/Padova simulator to explore in-silico the potential benefit of different dosing regimens on postprandial glucose (PPG) control to support the design of further clinical trials. Tested dosing regimens included at-meal or postmeal dosing, or dosing before and after a meal (split dosing). METHODS: Various dosing regimens of TI were compared among one another and to insulin lispro in 100 virtual type-1 patients. Individual doses were identified for each regimen following different titration rules. The resulting postprandial glucose profiles were analyzed to quantify efficacy and the risk for hypoglycemic events. RESULTS: This approach allowed us to assess the benefit/risk for each TI dosing regimen and to compare results with simulations of insulin lispro. We identified a new titration rule for TI that could significantly improve the efficacy of treatment with TI. CONCLUSION: In-silico clinical trials comparing the treatment effect of different dosing regimens with TI and of insulin lispro suggest that postmeal dosing or split dosing of TI, in combination with an appropriate titration rule, can achieve a superior postprandial glucose control while providing a lower risk for hypoglycemic events than conventional treatment with subcutaneously administered rapid-acting insulin products.

New insulin glargine 300 Units · mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units · mL-1.

OBJECTIVE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units · mL(-1) (Gla-300), compared with insulin glargine 100 units · mL(-1) (Gla-100) at steady state in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind, crossover study (N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steady-state study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units · kg(-1) (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units · kg(-1) Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units · kg(-1) of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h. RESULTS: At steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼ 3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (≤ 105 mg · dL(-1)) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100. CONCLUSIONS: Gla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h.

Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes.

OBJECTIVE: In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units · kg(-1) glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng · mL(-1) (33 pmol · L(-1)) per analyte. RESULTS: Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC(0-30h)) was 1,261 (66), 2,867 (35), and 4,693 (22) pmol · h · L(-1) at doses of 0.3, 0.6, and 1.2 units · kg(-1), respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC(0-30h) of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points. CONCLUSIONS: After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine.