The SGLT2 inhibitor empagliflozin for the treatment of type 2 diabetes mellitus: A bench to bedside review

INTRODUCTION: The treatment of type 2 diabetes mellitus (T2DM) continues to pose challenges for clinicians and patients. The dramatic rise in T2DM prevalence, which has paralleled the rise in obesity, has strained the healthcare system and prompted the search for therapies that not only effectively treat hyperglycemia, but are also weight neutral or promote weight loss. In most clinical situations after diagnosis, patients are advised to adopt lifestyle changes and metformin is initiated to help control blood glucose levels. However, metformin may not be tolerated, or may not be sufficient for those with higher glucose levels at diagnosis. Even among those who have initial success with metformin, the majority eventually require one or more additional agents to achieve their treatment goals. Because T2DM is a progressive disease, the requirement for combination treatment escalates over time, driving the need for therapies with complementary mechanisms of action. METHODS AND RESULTS: Online public resources were searched using “empagliflozin”, identifying 32 articles in PubMed, and 12 abstracts presented at the 2013 American Diabetes Association meeting. Peer-reviewed articles and abstracts describing preclinical studies and clinical trials were retrieved, and relevant publications included in this review. Trials registered on clinicaltrials.gov were searched for ongoing empagliflozin studies. CONCLUSION: The sodium–glucose co-transporter 2 (SGLT2) inhibitors are of great interest since they provide a novel, insulin-independent mechanism of action. The SGLT2 inhibitor empagliflozin has demonstrated promising pharmacodynamic and pharmacokinetic properties. In clinical trials, empagliflozin has demonstrated a good efficacy and safety profile in a broad range of patients with T2DM, and appears to be an attractive adjunct therapeutic option for the treatment of T2DM. Ongoing trials, including patients with T2DM and comorbidities such as hypertension, are expected to provide important additional data, which will further define the role of empagliflozin in a growing movement toward individualized approaches to diabetes care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13300-014-0063-1) contains supplementary material, which is available to authorized users

Carrier lifetimes in ion-damaged GaAs

Photoluminescence excitation correlation spectroscopy has been used to measure the dependence of carrier lifetime on the H+ ion implantation dose in GaAs. For doses greater than 1×10^12 cm^−2 the carrier lifetime is inversely proportional to the ion dose. The minimum lifetime measured was 0.6±0.2 ps for a dose of 1×10^14 cm^−2. Most important, there is no sign of saturation of carrier lifetime with ion dose down to this lifetime, thus still shorter lifetimes should be achievable with increased ion dose

Optimal use of β-blockers in high-risk hypertension: A guide to dosing equivalence

Hypertension is the number one diagnosis made by primary care physicians, placing them in a unique position to prescribe the antihypertensive agent best suited to the individual patient. In individuals with diabetes mellitus, blood pressure (BP) levels >130/80 mmHg confer an even higher risk for cardiovascular and renal disease, and these patients will benefit from aggressive antihypertensive treatment using a combination of agents. β-blockers are playing an increasingly important role in the management of hypertension in high-risk patients. β-blockers are a heterogeneous class of agents, and this review presents the differences between β-blockers and provides evidence-based protocols to assist in understanding dose equivalence in the selection of an optimal regimen in patients with complex needs. The clinical benefits provided by β-blockers are only effective if patients adhere to medication treatment long term. β-blockers with proven efficacy, once-daily dosing, and lower side effect profiles may become instrumental in the treatment of hypertensive diabetic and nondiabetic patients

Continuous monitoring of the lunar or Martian subsurface using on-board pattern recognition and neural processing of Rover geophysical data

The ultimate goal is to create an extraterrestrial unmanned system for subsurface mapping and exploration. Neural networks are to be used to recognize anomalies in the profiles that correspond to potentially exploitable subsurface features. The ground penetrating radar (GPR) techniques are likewise identical. Hence, the preliminary research focus on GPR systems will be directly applicable to seismic systems once such systems can be designed for continuous operation. The original GPR profile may be very complex due to electrical behavior of the background, targets, and antennas, much as the seismic record is made complex by multiple reflections, ghosting, and ringing. Because the format of the GPR data is similar to the format of seismic data, seismic processing software may be applied to GPR data to help enhance the data. A neural network may then be trained to more accurately identify anomalies from the processed record than from the original record

Highly electronegative metallic contacts to semiconductors using polymeric sulfur nitride

The Schottky barriers formed on n‐ZnS and n‐ZnSe by polymeric sulfur nitride have been compared to barriers formed by Au. Barrier energies as determined by photoresponse, current‐voltage, and capacitance‐voltage methods show that (SN)_x is approximately 1.0 eV higher than Au on n‐ZnS and 0.3–0.4 eV higher than Au on n‐ZnSe. We believe that this is the first report of any metallic contact more electronegative than Au

HgSe, a highly electronegative stable metallic contact for semiconductor devices

Schottky barriers formed by the highly electronegative substance HgSe on n-ZnS and on n-ZnSe have been characterized by capacitance-voltage and photoresponse measurements. The barriers are about 0.5 eV greater than Au barriers on these n-type substrates. HgSe contacts are stable under ambient conditions and are easily fabricated, making them attractive for device use

Electron tunneling time measured by photoluminescence excitation correlation spectroscopy

The tunneling time for electrons to escape from the lowest quasibound state in the quantum wells of GaAs/AlAs/GaAs/AlAs/GaAs double-barrier heterostructures with barriers between 16 and 62 Å has been measured at 80 K using photoluminescence excitation correlation spectroscopy. The decay time for samples with barrier thicknesses from 16 Å (≈12 ps) to 34 Å(≈800 ps) depends exponentially on barrier thickness, in good agreement with calculations of electron tunneling time derived from the energy width of the resonance. Electron and heavy hole carrier densities are observed to decay at the same rate, indicating a coupling between the two decay processes

Turnover of microbial biomass, plant residues and soil humic constituents under field conditions

Includes bibliographical references (pages 156-157).The effects of soil texture and climatic conditions on turnover rates of plant residues were measured under field conditions. Carbon-14- and 15N-labelled straw made it possible to follow degradation rates of the original substrate and of the soil organic constituents formed during the initial degradation process. Subsequent sampling measured the turnover of the active fraction. Carbon dating was used to measure the turnover rates of the more resistant fraction. Fractionation of the soil during the first two years showed greater accumulation of a condensed aromatic moiety (humic acid A) in the medium-textured Luvisolic soil and in the coarse-textured Dark Brown Chernozemic (Kastanozem). High clay grassland soils showed protection of aliphatic nitrogen from further humification. Much of the initial nitrogen and carbon mineralization of soil organic materials produced on decomposition of the straw came from the fulvic acids which contained a predominance of recently synthesized low molecular weight materials. Carbon and nitrogen incorporation into the > 0.2 μm fraction lagged behind incorporation into other fractions. Large quantities of immobilized carbon and nitrogen were contained in the > 0.2 μm fraction as well as in the 0.04 μm sedimentation fraction allowing these two fractions to act as sources of slowly released nitrogen. Residual humic acid carbon and nitrogen turnover was best estimated from carbon dating of the carbon after fractionation of the soil. The nitrogen turnover was calculated utilizing the C/N ratios of the fractions. Acid hydrolysis was found to be the simplest method of fractionation of large quantities of soil for carbon dating and for specific components. Na4P2O7 extraction followed by peptization and sediment analysis proved useful for measuring C and N transformations on a shorter term basis

Fractionation of soil and 15N nitrogen to separate the organic and clay interactions of immobilized N

Includes bibliographical references (pages 211-212).Labelled 15N was added to two soils in cylinders in the field, and allowed to equilibrate for two summers of crop growth. The labelled soils were fractionated to provide information on the effect of organic and inorganic colloids on the stabilization of immobilized, 15N. Organic materials removed by 0.5 N NaOH without pretreatment contained more 15N than those extracted by the same reagent following decalcification and removal of sesquioxides with dithionite and HCl. Both extracts had similar amino acid (contents) and similar degrees of hydrolability. A fractionation system using an initial 0.1 M NaOH–0.1 M Na4P2O7 extraction followed by sonication and peptization in H2O yielded a humic acid fraction and a sedimentation fraction (< 0.04 μm) which differed markedly in degree of hydrolyzability, 15N content and amino acid-N content. The N associated with inorganic colloids < 0.04 μm, and that remaining in solution after the removal of larger particles accounted for 50% of the amino acid-N in a clay soil, and 40% in a fine sandy loam soil. Removal of sesquioxides followed by a second 0.5 N NaOH extraction reduced the N content of the colloidal size fractions of both soils, indicating that amorphous iron and aluminum compounds on the surface of clays are probably the active agents in bonding organic N to inorganic colloids. It is suggested that the nonhydrolytic technique, based largely on dispersion of the inorganic–organic colloids and analyses of the sediment, could be used to interpret the fate of microbiologically immobilized N compounds in the soil. Materials removed by 0.1 M Na4P2O7 were associated with polyvalent cations in the soil. Materials such as cytoplasmic constituents, released from the biomass during ultrasonic vibration or as lytic products would be expected to be adsorbed to inorganic colloids. They should be concentrated in the < 0.04 μm-size fraction. Cell wall and other particulate debris with a faster setting velocity would be expected to appear in larger-sized sedimentation fractions