Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study.

OBJECTIVE: Therapeutic options are limited for diabetes patients with renal disease. This report presents 52-week results from a study assessing the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus (T2DM) and renal impairment. DESIGN: Double-blind study in patients stratified by baseline renal impairment (moderate, severe or end-stage renal disease [ESRD] on haemodialysis) randomised to saxagliptin 2.5 mg once daily or placebo added to other antidiabetic drugs in use at baseline, including insulin. PATIENTS: A total of 170 adults with glycated haemoglobin (HbA(1c) ) 7-11% and creatinine clearance < 50 ml/min or ESRD were randomised and treated. MEASUREMENTS: Absolute changes in HbA(1c) and fasting plasma glucose (FPG) from baseline to week 52 were evaluated using analysis of covariance (ANCOVA) with last observation carried forward. Repeated-measures analyses were also performed. RESULTS: Adjusted mean decrease in HbA(1c) was greater with saxagliptin than placebo (difference, -0.73%, p < 0.001 [ANCOVA]). Reductions in adjusted mean HbA(1c) were numerically greater with saxagliptin than placebo in patients with renal impairment rated as moderate (-0.94% vs. 0.19% respectively) or severe (-0.81% vs. -0.49%), but similar to placebo for those with ESRD (-1.13% vs. -0.99%). Reductions in adjusted mean FPG were numerically greater with saxagliptin in patients with moderate or severe renal impairment. Saxagliptin was generally well tolerated; similar proportions of patients in the saxagliptin and placebo groups reported hypoglycaemic events (28% and 29% respectively). CONCLUSIONS: Saxagliptin 2.5 mg once daily offers sustained efficacy and good tolerability for patients with T2DM and renal impairment.

Cardiopulmonary dysfunction in a feline septic shock model: possible role of leukotrienes.

The aim of the present study was to explore the possible involvement of leukotrienes (LTs) in the development of cardiopulmonary dysfunction in experimental septic shock. Sepsis was induced in anesthetized cats by infusion of liver Escherichia coli bacteria. One series (N = 6) was pretreated with diethylcarbamazine (DEC), a 5-lipooxygenase inhibitor; another series (N = 7) was pretreated with FPL 55712, a LTC4-D4 antagonist; and a third series (N = 8) served as septic controls. After 2 hr of bacteremia, there were no differences in cardiac function in the three series. By subjecting the heart to volume load, two points on a Starling curve were obtained, indicating the limits of the functional cardiac reserve. This loading procedure disclosed a significantly better preserved left ventricular function in the DEC-pretreated group as compared with the other two groups. Pretreatment with DEC and FPL 55712 had no effects on early pulmonary vascular reactions. However, the tracheal pressure response was less pronounced after pretreatment compared with septic controls. Calculated airway resistance was less increased and pulmonary compliance less decreased in the two pretreated groups. Furthermore, arterial hypoxia was prevented by pretreatment. It is concluded that this study suggests that LTs are involved in the development of myocardial insufficiency in experimental bacteremic septic shock. Moreover, the results strongly indicate that LTs may be of importance in compromising pulmonary gas exchange, partly by effects on the smaller airways.

The role of prostanoids in the feline intestinal vascular and central haemodynamic responses to i.v. infusion of live E. coli.

Bacterial infusion in the cat, causing experimental septic shock, induces an early vascular response mainly characterized by pulmonary hypertension and intestinal vasoconstriction. Prostanoids are held to be important mediators of the pulmonary vascular reaction. This study was performed to explore the involvement of prostanoids in the central haemodynamics and the small intestinal vascular reactions in experimental septic shock. Aortic blood pressure was continuously monitored, as were aortic blood flow, the pressure in a. pulmonalis and the small intestinal venous outflow. All cats (n = 24) were given live E. coli (10(10) ml-1) as a continuous intravenous infusion. One series was pretreated with indomethacin, another with UK-38,485, a specific thromboxane A2 synthetase inhibitor, and a third series served as untreated control. The pulmonary hypertensive response was clearly attenuated in the two pretreated series, in fact abolished in the one given UK-38,485. The early intestinal vasoconstriction was eliminated in the two pretreated series. Later during bacteraemia, when untreated and indomethacin-pretreated cats showed intestinal vasoconstriction, UK-38-485-pretreated animals kept intestinal blood flow within the preseptic range. These data suggest that in the cat, thromboxane A2 is the prostanoid mediating the vascular reactions, not only in the lung but also in the small intestine.

Cardiopulmonary function as related to thromboxane A2 synthesis in experimental septic shock.

The aim of the present study was to explore the possible involvement of thromboxane A2(TxA2) in the development of cardiopulmonary dysfunction in experimental septic shock. Sepsis was induced in anesthetized cats by intravenous (i.v.) infusion of live Escherichia coli. One series (No. = 12) was pretreated with a specific TxA2 synthetase inhibitor, dazmegrel; another (No. = 8) served as a septic control series. In both series a systemic arterial hypotension developed after 2 hr; no differences in cardiac function were detected. After 2 hr bacteremia cardiac preload was increased by a rapid infusion of dextran. This showed that cardiac function was significantly more preserved in dazmegrel-pretreated cats compared with septic controls. Pretreatment with dazmegrel totally prevented the pulmonary vascular response to bacterial infusion. The pulmonary compliance decreased to 40% in controls but to only 75% in the dazmegrel series, and airway resistance increased to 300% and 140%, respectively. The ventilation-perfusion ratio was less impaired in the pretreated series. Pretreatment with dazmegrel abolished the increase in thromboxane B2 (TxB2), the stable metabolite of TxA2, seen in the untreated series. The rise in 6-keto-prostaglandin F1a (6-keto-PGF1a), the stable metabolite of prostaglandin I2PGI2, was evident in both series. We concluded that TxA2 is important for the impaired cardiac performance in septic shock. Furthermore, TxA2 is involved, but not as the only factor, in the development of pulmonary dysfunction.

Lung protein leakage in feline septic shock.

The aim of the present study was to explore lung microvascular leakage of protein and water in a feline model of septic shock, using a double isotope technique with external gamma camera detection and gravimetric lung water measurements. The experiments were performed on artificially ventilated cats. One group of cats (n = 8) was given an infusion of live Escherichia coli bacteria, and another group (n = 5) served as a control group receiving saline. Plasma transferrin was radiolabeled in vivo with indium-113m-chloride, and erythrocytes were labeled with technetium-99m. The distribution of these isotopes in the lungs was continuously measured with a gamma camera. A normalized slope index (NSI) was calculated, indicative of the transferrin accumulation corrected for changes in local blood volume that reflect protein leakage. In the septic group there was a protein leakage after bacterial infusion, with a NSI of 39 x 10(-4) +/- 5 x 10(-4) min-1 (mean +/- SEM), and the PaO2 diminished from 21 +/- 1 to 9.5 +/- 1 kPa. In control cats a slight protein leakage with a NSI of 9 +/- 10(-4) +/- 2 x 10(-4) min-1 was detected, probably caused by the operative procedure, but PaO2 did not change. Wet-to-dry-weight ratios of postmortem lungs were not significantly different between the groups. It was concluded that an intravenous infusion of live E. coli bacteria induces a lung capillary protein leakage without increased lung water and a concomitantly disturbed gas exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukotriene receptor antagonism prevents lung protein leakage and hypoxaemia in a septic cat model.

Products of the arachidonic acid cascade have been found to play an important role in the pathophysiology in experimental shock and in ARDS. The effect of cysteinyl-leukotriene (cLT) blockade on the development of respiratory failure during septic shock was examined. Ventilated cats received an infusion of Escherichia coli bacteria. Pretreatment was given with diethylcarbamazine (DEC), a leukotriene synthetase inhibitor, or a new potent cLT receptor antagonist, ICI 198,615. With a gamma camera, the distributions of plasmatransferrin radiolabelled with indium-113m chloride (113mIn) and erythrocytes radiolabelled with technetium-99m (99mTc) were measured over the lungs. A normalized slope index (NSI) reflecting protein leakage, based on the transferrin extravasation, was calculated. In the nonseptic control group (n = 7) NSI was 4.4 x 10(-4) +/- 0.7 x 10(-4).min-1 (mean +/- SEM). Unpretreated septic animals (n = 7) showed a protein leakage after bacterial infusion, with a NSI of 34 +/- 3.5 x 10(-4).min-1. Pretreatment with DEC (n = 6) significantly reduced NSI to 16 +/- 1.5 x 10(-4).min-1. In the group pretreated with ICI 198,615 (n = 8), NSI was 9 +/- 1.2 x 10(-4).min-1. Arterial oxygen tension (PaO2) remained at baseline level of 20 +/- 1.0 kPa during the experimental period in both the nonseptic control group and the ICI 198,615 pretreated group. In the unpretreated septic group, PaO2 fell progressively from a preseptic value of 21 +/- 0.9 to 12 +/- 1.5 kPa after 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)