Effect of canagliflozin on liver function tests in patients with type 2 diabetes.

AIMS: To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS: Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active-controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS: Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hy's law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS: Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin.

Effect of statin therapy on remnant lipoprotein cholesterol levels in patients with combined hyperlipidemia.

Clinical trials with statins have demonstrated significant reductions in cardiovascular events. Remnant lipoproteins are independent predictors of cardiovascular events. Because of the paucity of data on the effect of statins on remnant lipoproteins, we tested the effect of pravastatin, simvastatin, and atorvastatin on remnant lipoprotein cholesterol (RLP-C) levels in a randomized crossover study in patients with combined hyperlipidemia. After a 6-week diet phase, patients (n=22) were randomized to pravastatin (40 mg/d), simvastatin (20 mg/d), or atorvastatin (10 mg/d) for 6 weeks, with a 3-week washout between each drug. All 3 drugs significantly decreased total and low density lipoprotein (LDL) cholesterol (P<0.001). Mean reduction in LDL cholesterol with pravastatin, simvastatin, and atorvastatin was 21%, 29%, and 32%, respectively. None of the drugs affected high density lipoprotein cholesterol levels. Median levels of triglycerides were significantly reduced with simvastatin (26%, P=0.001) and atorvastatin (24%, P=0.0001) but not with pravastatin (9%, P=0.18). Non-high density lipoprotein cholesterol decreased significantly with all 3 statins (20%, 29%, and 32% with pravastatin, simvastatin, and atorvastatin, respectively; P<0.001). Median RLP-C levels were significantly reduced with simvastatin (6%, P<0.05) and atorvastatin (25.9%, P<0.001) but not with pravastatin (2.9%, P=0.58). Thus, atorvastatin and simvastatin, in addition to reducing LDL cholesterol and triglyceride levels, significantly reduced RLP-C levels. This could be another potential mechanism to explain their cardiovascular benefits.

Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels.

BACKGROUND: Prospective studies indicate that baseline levels of C-reactive protein (CRP), the prototypic marker of inflammation, are associated with an increased risk for cardiovascular events. Limited studies have examined therapies that influence high-sensitive CRP (hs-CRP) levels, especially in hyperlipidemic patients. Thus, we tested the effects of 3 hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), simvastatin (20 mg/d), pravastatin (40 mg/d), and atorvastatin (10 mg/d), on levels of hs-CRP in a randomized, double-blind, crossover trial of 22 patients with combined hyperlipidemia (LDL cholesterol >130 mg/dL and triglycerides of 200 to 600 mg/dL). METHODS AND RESULTS: After 6 weeks of an American Heart Association Step 1 diet, fasting blood samples were drawn at baseline and after 6 weeks of therapy with each drug. hs-CRP levels were significantly decreased after treatment with all 3 statins compared with baseline (median values: baseline, 2.6 mg/L; atorvastatin, 1.7 mg/L; simvastatin, 1.7 mg/L; and pravastatin, 1.9 mg/L; P<0.025). The reductions obtained with the 3 statins were similar. In addition, there was no significant effect on either plasma interleukin-6 or interleukin-6 soluble receptor levels. There was no relationship between reductions in hs-CRP and LDL cholesterol. CONCLUSIONS: Pravastatin, simvastatin, and atorvastatin significantly decreased levels of hs-CRP. These data support an anti-inflammatory effect of these drugs.

Comparison of models used for UV index calculations.

Eighteen radiative transfer models in use for calculation of UV index are compared with respect to their results for more that 100 cloud-free atmospheres, which describe present, possible future and extreme conditions. The comparison includes six multiple-scattering spectral models, eight fast spectral models and four empirical models. Averages of the results of the six participating multiple-scattering spectral models are taken as a basis for assessment. The agreement among the multiple-scattering models is within +/- 0.5 UV index values for more than 80% of chosen atmospheric parameters. The fast spectral models have very different agreement, between +/- 1 and up to 12 UV index values. The results of the empirical models agree reasonably well with the reference models but only for the atmospheres for which they have been developed. The data to describe the atmospheric conditions, which are used for the comparison, together with the individual results of all participating models and model descriptions are available on the Internet: http://www.meteo.physik.uni-muenchen.de/++ +strahlung/cost/.

Correcting global solar ultraviolet spectra recorded by a brewer spectroradiometer for its angular response error.

We present a methodology for correcting the global UV spectral measurements of a Brewer MKIII spectroradiometer for the error introduced by the deviation of the angular response of the instrument from the ideal response. This methodology is applicable also to other Brewer spectroradiometers that are currently in operation. The various stages of the methodology are described in detail, together with the uncertainties involved in each stage. Finally global spectral UV measurements with and without the application of the correction are compared with collocated measurements of another spectroradiometer and with model calculations, demonstrating the efficiency of the method. Depending on wavelength and on the aerosol loading, the cosine correction factors range from 2% to 7%. The uncertainties involved in the calculation of these correction factors were found to be relatively small, ranging from ~0.2% to ~2%.

Optical properties of tropospheric aerosols determined by lidar and spectrophotometric measurements (Photochemical Activity and Solar Ultraviolet Radiation campaign).

We present the results of the aerosol measurements carried out over the Aegean Sea during the Photochemical Activity and Solar Ultraviolet Radiation campaign held in Greece during June 1996. Simultaneous observations performed with a lidar and a double-monochromator spectrophotometer allowed us to retrieve the optical depth, the Angström coefficient, and the backscatter-to-extinction ratio. The Sun photometric data can be used to improve quantitative aerosol measurements by lidar in the Planetary Boundary Layer. Systematic errors could arise otherwise, because the value of the backscatter-to-extinction ratio has to be supplied. Instead this ratio can be retrieved experimentally by use of an iterative solution of the lidar equation.