Aim
To assess the comparative efficacy and safety of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors in adults with type 2 diabetes.
Methods
We electronically searched randomized controlled trials ...(≥24 weeks) including canagliflozin, dapagliflozin or empagliflozin that were published up to 3 November 2015. Data were collected on cardiometabolic and safety outcomes and synthesized using network meta‐analyses.
Results
A total of 38 trials (23 997 participants) were included. Compared with placebo, all SGLT2 inhibitors reduced glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and blood pressure, and slightly increased HDL cholesterol. Canagliflozin 300 mg reduced HbA1c, FPG and systolic blood pressure and increased LDL cholesterol to a greater extent compared with other inhibitors at any dose. At their highest doses, canagliflozin 300 mg reduced: HbA1c by 0.2% 95% confidence interval (CI) 0.1–0.3 versus both dapagliflozin 10 mg and empagliflozin 25 mg; FPG by 0.6 mmol/l (95% CI 0.3–0.9) and 0.5 mmol/l (95% CI 0.1–0.8) versus dapagliflozin and empagliflozin, respectively; and systolic blood pressure by 2 mmHg (95% CI 1.0–3.0) versus dapagliflozin; and increased LDL cholesterol by 0.13 mmol/l (95% CI 0.03–0.23) and 0.15 mmol/l (95% CI 0.06–0.23) versus dapagliflozin and empagliflozin, respectively. The highest doses of inhibitors had similar effects on body weight reduction. Canagliflozin 300 and 100 mg increased the risk of hypoglycaemia versus placebo, dapagliflozin 10 mg and empagliflozin 10 mg odds ratios (ORs) 1.4–1.6. Dapagliflozin 10 mg increased the risk of urinary tract infection versus placebo and empagliflozin 25 mg (ORs 1.4). All inhibitors similarly increased the risk of genital infection (ORs 4–6 versus placebo).
Conclusions
Although they increase the risk of genital infection, SGLT2 inhibitors are effective in improving cardiometabolic markers in type 2 diabetes, with canagliflozin 300 mg performing better in this respect than other inhibitors. Further studies will clarify whether these differences are likely to translate into differing long‐term outcomes.
A number of inorganic (nitryl chloride, ClNO2; chlorine,
Cl2; and hypochlorous acid, HOCl) and chlorinated, oxygenated volatile
organic compounds (ClOVOCs) have been measured in Manchester, UK during
...October and November 2014 using time-of-flight chemical ionisation mass
spectrometry (ToF-CIMS) with the I− reagent ion. ClOVOCs appear to be
mostly photochemical in origin, although direct emission from vehicles is
also suggested. Peak concentrations of ClNO2, Cl2 and HOCl reach
506, 16 and 9 ppt respectively. The concentrations of ClNO2 are
comparable to measurements made in London, but measurements of ClOVOCs,
Cl2 and HOCl by this method are the first reported in the UK. Maximum
HOCl and Cl2 concentrations are found during the day and ClNO2
concentrations remain elevated into the afternoon if photolysis rates are
low. Cl2 exhibits a strong dependency on shortwave radiation, further
adding to the growing body of evidence that it is a product of secondary
chemistry. However, night-time emission is also observed. The contribution of
ClNO2, Cl2 and ClOVOCs to the chlorine radical budget suggests
that Cl2 can be a greater source of Cl than ClNO2, contributing
74 % of the Cl radicals produced on a high radiant-flux day. In contrast,
on a low radiant-flux day, this drops to 14 %, as both Cl2 production
and loss pathways are inhibited by reduced photolysis rates. This results in
ClNO2 making up the dominant fraction (83 %) on low radiant-flux
days, as its concentrations are still high. As most ClOVOCs appear to be formed
photochemically, they exhibit a similar dependence on photolysis,
contributing 3 % of the Cl radical budget observed here.
Manganese (Mn) oxides are among the strongest oxidants and sorbents in the environment, impacting the transport and speciation of metals, cycling of carbon, and flow of electrons within soils and ...sediments. The oxidation of Mn(II) to Mn(III/IV) oxides has been primarily attributed to biological processes, due in part to the faster rates of bacterial Mn(II) oxidation compared to observed mineral-induced and other abiotic rates. Here we explore the reactivity of biogenic Mn oxides formed by a common marine bacterium (
Roseobacter sp. AzwK-3b), which has been previously shown to oxidize Mn(II) via the production of extracellular superoxide. Oxidation of Mn(II) by superoxide results in the formation of highly reactive colloidal birnessite with hexagonal symmetry. The colloidal oxides induce the rapid oxidation of Mn(II), with dramatically accelerated rates in the presence of organics, presumably due to mineral surface-catalyzed organic radical generation. Mn(II) oxidation by the colloids is further accelerated in presence of both organics and light, implicating reactive oxygen species in aiding abiotic oxidation. Indeed, the enhancement of Mn(II) oxidation is negated when the colloids are reacted with Mn(II) in the presence of superoxide dismutase, an enzyme that scavenges the reactive oxygen species (ROS) superoxide. The reactivity of the colloidal phase is short-lived due to the rapid evolution of the birnessite from hexagonal to pseudo-orthogonal symmetry. The secondary particulate triclinic birnessite phase exhibits a distinct lack of Mn(II) oxidation and subsequent Mn oxide formation. Thus, the evolution of initial reactive hexagonal birnessite to non-reactive triclinic birnessite imposes the need for continuous production of new colloidal hexagonal particles for Mn(II) oxidation to be sustained, illustrating an intimate dependency of enzymatic and mineral-based reactions in Mn(II) oxidation. Further, the coupled enzymatic and mineral-induced pathways are linked such that enzymatic formation of Mn oxide is requisite for the mineral-induced pathway to occur. Here, we show that Mn(II) oxidation involves a complex network of abiotic and biotic processes, including enzymatically produced superoxide, mineral catalysis, organic reactions with mineral surfaces, and likely photo-production of ROS. The complexity of coupled reactions involved in Mn(II) oxidation here highlights the need for further investigations of microbially-mediated Mn oxide formation, including identifying the role of Mn oxide surfaces, organics, reactive oxygen species, and light in Mn(II) oxidation and Mn oxide phase evolution.
The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug ...targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13354/full. G protein‐coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.
The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug ...targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13348/full. G protein‐coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.
RATIONALE:Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the ...heritability of AAA.
OBJECTIVE:To identify additional AAA risk loci using data from all available genome-wide association studies.
METHODS AND RESULTS:Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9.
CONCLUSIONS:The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
Objectives
Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised ...controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio).
Design, Setting, Participants, and Intervention
Participants were Australians aged 60–84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation.
Results
The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was −0.001 (95% CI −0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration.
Conclusion
In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.
Diabet. Med. 27, 887–895 (2010)
Aims Risk assessment scores identify those at high risk of impaired glucose regulation and Type 2 diabetes mellitus. To date no risk assessment scores that can be ...completed by a lay person have been developed and validated specifically for multiethnic populations in the UK.
Methods We used data on 6186 subjects aged 40–75 years from a multiethnic UK screening study (73% white European, 22% South Asian). All participants were given a 75 g oral glucose tolerance test. We developed logistic regression models for predicting current impaired glucose regulation (impaired fasting glycaemia/impaired glucose tolerance) or Type 2 diabetes mellitus using data from anthropometric measurements and self‐reported questionnaires. Using the best‐fitting model, we developed the Leicester Risk Assessment score. We externally validated the score using data from 3171 subjects aged 40–75 years from a separate screening study.
Results The components of the final model are age, ethnicity white European vs. other (predominantly South Asian), sex, first degree family history of diabetes, antihypertensive therapy or history of hypertension, waist circumference and body mass index. The score ranges from 0 to 47. Validating this model using the data from the second screening study gave an area under the receiver operator characteristic curve of 72% (95% confidence interval, 69–74%). A cut point of 16 had a sensitivity of 81% and a specificity of 45%.
Conclusions The Leicester Risk Assessment score can be used to identify those at high risk of impaired glucose regulation and Type 2 diabetes mellitus in UK multiethnic populations. The score is simple (seven questions) and non‐invasive.
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