Blood pressure-lowering effect of the sodium glucose co-transporter-2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension.

This study compared the blood pressure-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic blood pressure (SBP; primary); daytime, night-time, seated predose SBP, 24-h, daytime, night-time, seated predose diastolic blood pressure, 24-h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.

Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes.

AIM: To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability. RESULTS: In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride). CONCLUSIONS: In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.

Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin.

AIM: To investigate the efficacy and safety of ertugliflozin, in a phase II dose-ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. METHODS: A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once-daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored. RESULTS: Ertugliflozin (1-25 mg/day) produced significant reductions in HbA1c concentration [placebo-corrected least-squares mean (LSM) -0.45% (1 mg) to -0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (-0.76%; p = 0.0001)], FPG (LSM -1.17 to -1.90 mmol/l; p < 0.0001) and body weight (-1.15 to -2.15%; p < 0.0001). The LSM SBP decreased by -3.4 to -4.0 mmHg from baseline with ertugliflozin 5-25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose-related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo. CONCLUSION: Ertugliflozin (1-25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated.

Characterization of gentamicin pharmacokinetics in patients hemodialyzed with high-flux polysulfone membranes.

To characterize the pharmacokinetics of gentamicin during and after hemodialysis (using polysulfone Fresenius F-80 membranes (Fresenius USA, Inc, Walnut Creek, CA), surface area 1.6 m(2)), eight patients with end-stage renal disease undergoing chronic hemodialysis receiving the drug for therapeutic indications were enrolled. Intradialytic gentamicin half-life, clearance, and amount of gentamicin recovered during a hemodialysis session were also determined. Serum gentamicin concentrations were analyzed using fluorescence polarization immunoassay. The amount of gentamicin recovered was 64.3 +/- 14.4 mg, whereas the intradialytic gentamicin half-life was 2.24 +/- 0.83 hours, with a clearance of 116 +/- 9 mL/min. Gentamicin concentrations rebounded by 27.86% +/- 16.4% at 1. 5 +/- 0.52 hours after the end of the hemodialysis session. The decrease in gentamicin concentrations comparing maximum rebound to prehemodialysis concentrations was 53.54% +/- 9.97%. A variable yet substantial amount of gentamicin is removed during hemodialysis using F-80 membranes; hence, supplemental doses are necessary to avoid potential treatment failures. The supplemental doses of gentamicin calculated based on gentamicin concentrations obtained immediately postdialysis could be overestimated if the postdialysis rebound concentrations are not considered. A dosing regimen is suggested using the pharmacokinetic parameters defined by the present study and population estimate of volume of distribution.

Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis.

BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.

Atrial fibrillation after bypass surgery: does the arrhythmia or the characteristics of the patients prolong hospital stay?

STUDY OBJECTIVES: The goal of this study was to determine whether prolonged hospital stay associated with atrial fibrillation or flutter (AF) after coronary artery bypass graft (CABG) surgery is attributable to the characteristics of patients who develop this arrhythmia or to the rhythm disturbance itself. DESIGN: An investigation was conducted through a prospective case series. SETTING: Patients were from a single urban teaching hospital. PARTICIPANTS: Consecutive patients undergoing isolated CABG surgery between December 1994 and May 1996 were included in the study. INTERVENTIONS: No interventions were involved. RESULTS: Of 436 patients undergoing isolated CABG surgery, 101 (23%) developed AF. AF patients were older and more likely to have obstructive lung disease than patients without AF, but both patients with and without AF had similar left ventricular function and extent of coronary disease. ICU and hospital stays were longer in patients with AF. Multivariate analysis, adjusted for age, gender, and race, demonstrated that postoperative hospital stay was 9.2+/-5.3 days in patients with AF and 6.4+/-5.3 days in patients without AF (p<0.001). CONCLUSIONS: Although AF is strongly associated with advanced age, most of the prolonged hospital stay appears to be attributable to the rhythm itself and not to patient characteristics.