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There is a strong positive association between nutrition status and lung function in cystic fibrosis (CF). Improvements in clinical care have increased longevity for individuals with CF, and it is unknown how cystic fibrosis transmembrane regulator (CFTR) modulation therapy affects nutrition status over time. The objective of this systematic review of the literature was to examine anthropometric (height, weight, and body mass index [BMI; calculated as kg/m 2 ]) and body composition outcomes of CFTR modulation therapy. A literature search of Medline (Ovid), Embase, and CINAHL (EBSCO) databases was conducted for randomized controlled trials examining the effect of CFTR modulation therapy on anthropometric and body composition parameters, published in peer-reviewed journals from January 2002 until May 2018. Articles were screened, data were synthesized qualitatively, and evidence quality was graded by a team of content experts and systematic review methodologists. Significant weight gain with ivacaftor was noted in children and adults with at least 1 copy of G551D mutation. In adults with at least 1 copy of R117H the effect of ivacaftor on BMI was not significant. Effects on BMI were mixed in adults with class II mutations taking ivacaftor with lumacaftor. There was no significant change in BMI in children homozygous for F508del who took ivacaftor with tezacaftor. Elexacaftor-tezacaftor-ivacaftor increased BMI and body weight in individuals 12 years of age and older who were hetero- or homozygous for the F508del mutation. The effect of CFTR modulation therapy on anthropometric parameters depends on the genetic mutation and the type of modulation therapy used. More research is needed to understand the long-term clinical impact of these drugs on nutritional status, including body composition and the role of dietary intake., (Copyright © 2021 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Frequent and severe gastrointestinal disturbances have been reported with the use of diazoxide in adults and older children. However, no studies have investigated the incidence of necrotising enterocolitis (NEC) in diazoxide-exposed newborns., Objective: To evaluate a possible association between diazoxide treatment for neonatal hypoglycaemia and the occurrence of NEC., Design: Multicentre retrospective cohort study., Setting: Three tertiary neonatal intensive care units in Toronto, Canada., Patients: All patients treated with diazoxide for persistent hypoglycaemia between July 2012 and June 2017 were included. Overall incidence of NEC during those years on the participating units was obtained for comparison from the Canadian Neonatal Network database., Main Outcome: Incidence of NEC after diazoxide exposure., Results: Fifty-five neonates were exposed to diazoxide during the study period. Eighteen patients (33%) showed signs of feeding intolerance, and 7 developed NEC (13%). A diagnosis of NEC was more prevalent in the diazoxide-exposed, as compared with non-exposed infants of similar gestational age (OR 5.07, 95% CI 2.27 to 11.27; p<0.001), and greatest among infants born at 33-36 weeks' gestation (OR 13.76, 95% CI 3.77 to 50.23; p<0.001). All but one of the neonates diagnosed with NEC developed the disease within 7 days from initiation of diazoxide treatment., Conclusion: The present data suggest a possible association between diazoxide exposure and the development of NEC in neonates. Further evaluation of the diazoxide-associated risk of NEC in neonates treated for persistent hypoglycaemia is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Central nervous system (CNS) disorders like Alzheimer's disease (AD), Parkinson disease (PD), stroke, epilepsy, depression, and bipolar disorder have a high impact on both medical and social problems due to the surge in their prevalence. All of these neuronal disorders share some common etiologies including disruption of Ca 2+ homeostasis and accumulation of misfolded proteins. These misfolded proteins further disrupt the intracellular Ca 2+ homeostasis by disrupting the activity of several ion channels including transient receptor potential (TRP) channels. TRP channel families include non-selective Ca 2+ permeable channels, which act as cellular sensors activated by various physio-chemical stimuli, exogenous, and endogenous ligands responsible for maintaining the intracellular Ca 2+ homeostasis. TRP channels are abundantly expressed in the neuronal cells and disturbance in their activity leads to various neuronal diseases. Under the pathological conditions when the activity of TRP channels is perturbed, there is a disruption of the neuronal homeostasis through increased inflammatory response, generation of reactive oxygen species, and mitochondrial dysfunction. Therefore, there is a potential of pharmacological interventions targeting TRP channels in CNS disorders. This review focuses on the role of TRP channels in neurological diseases; also, we have highlighted the current insights into the pharmacological modulators targeting TRP channels., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: As their long-term prognosis improves, women with CF are increasingly choosing to have children, but the safety of CFTR modulators in pregnancy and breastfeeding is currently unknown., Methods: A survey was sent to lead clinicians of adult CF centres in Europe, the United Kingdom (UK), United States of America (USA), Australia and Israel requesting anonymised data on pregnancy outcomes in women using CFTR modulators before and during pregnancy and lactation., Results: We identified 64 pregnancies in 61 women taking IVA (n = 31), LUM/IVA (n = 26) or TEZ/IVA (n = 7), resulting in 60 live births. In 44 pregnancies, CFTR modulators were either continued throughout pregnancy or temporarily stopped and then restarted. Two maternal complications were deemed related to CFTR modulator therapy; cessation of modulator therapy resulted in clinical decline in 9 women prompting resumption of therapy during pregnancy. No modulator-related complications were reported in infants exposed in utero and/or during breastfeeding., Conclusions: CFTR modulators were reported to be generally well tolerated in pregnancy and breastfeeding, with only 2 maternal complications that were deemed related to CFTR modulator therapy. Women stopping CFTR modulators in pregnancy may experience a decline in clinical status and in the cases identified in this survey, restarting therapy led to a clinical improvement. Current experience remains limited and longer-term prospective follow-up is required to exclude delayed adverse effects., (Copyright © 2020. Published by Elsevier B.V.)

Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed., Competing Interests: Conflict of interest: M. Shteinberg reports grants, personal fees and nonfinancial support from GSK, grants and nonfinancial support from Novartis and Trudell, nonfinancial support from Actelion, and personal fees from Boehringer Ingelheim, AstraZeneca and Vertex, outside the submitted work. Conflict of interest: J. Taylor-Cousar reports grants and personal fees from Vertex, Proteostasis and Celtaxys, and personal fees from Gilead, Santhera and Protalix, outside the submitted work. She serves on the CF TDN Clinical Research Executive Committee and is Chair-Elect of the ATS Clinical Problems Assembly Programming Committee., (Copyright ©ERS 2020.)

Valbenazine and deutetrabenazine are FDA-approved as treatment for tardive dyskinesia (TD). Both medications are vesicular monoamine transporter type 2 (VMAT2) inhibitors, and both are effective for reducing TD symptoms. Clinicians need to be aware of the adverse effects of valbenazine and deutetrabenazine, as well as other key differences between the two, in order to individualize treatment. Using the Abnormal Involuntary Movement Scale assists clinicians in assessing progress for each patient. Treating TD effectively with these new medications will reduce the burden of the condition for patients., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Transient receptor potential (TRP) channels have been widely studied during the last decade. New studies uncover new features and potential applications for these channels. TRPA1 has a huge distribution all over the human body and has been reported to be involved in different physiological and pathological conditions including cold, pain, and damage sensation. Considering its role, many studies have been devoted to evaluating the role of this channel in the initiation and progression of different toxicities. Accordingly, we reviewed the most recent studies and divided the role of TRPA1 in toxicology into the following sections: neurotoxicity, cardiotoxicity, dermatotoxicity, and pulmonary toxicity. Acetaminophen, heavy metals, tear gases, various chemotherapeutic agents, acrolein, wood smoke particulate materials, particulate air pollution materials, diesel exhaust particles, cigarette smoke extracts, air born irritants, sulfur mustard, and plasticizers are selected compounds and materials with toxic effects that are, at least in part, mediated by TRPA1. Considering the high safety of TRPA1 antagonists and their efficacy to resolve selected toxic or adverse drug reactions, the future of these drugs looks promising.

Drug-induced long QT increases the risk of ventricular tachyarrhythmia known as torsades de pointes (TdP). Many biomarkers have been used to predict TdP. At present, however, there are few biomarkers for arrhythmias induced by QT-shortening drugs. The objective of the present study was to identify the best biomarkers for predicting arrhythmias caused by the 4 potassium channel openers ICA-105574, NS-1643, R-L3, and pinacidil. Our results showed that, at higher concentrations, all 4 potassium channel openers induced ventricular tachycardia (VT) and ventricular fibrillation (VF) in Langendorff-perfused guinea pig hearts, but not in rabbit hearts. The electrocardiography parameters were measured including QT/QTc, JT peak, Tp-e interval, JT area, short-term beat-to-beat QT interval variability (STV), and index of cardiac electrophysiological balance (iCEB). We found that the potassium channel openers at test concentrations shortened the QT/QTc and the JT peak interval and increased the JT area. Nevertheless, even at proarrhythmic concentrations, they did not always change STV, Tp-e, or iCEB. Receiver operating characteristic curve analysis showed that the JT peak interval representing the early repolarization phase and the JT area reflecting the dispersion of ventricular repolarization were the best predictors of VT/VF. Action potential recordings in guinea pig papillary muscle revealed that except for pinacidil, the potassium channel openers shortened APD 30 in a concentration-dependent manner. They also evoked early or delayed afterdepolarizations at fast pacing rates. Patch-clamp recordings in guinea pig ventricular cardiomyocytes showed that the potassium channel openers enhanced the total outward currents during the early phase of action potential repolarization, especially at proarrhythmic concentrations. We concluded that the JT peak interval and the JT area are surrogate biomarkers identifying the risk of proarrhythmia associated with the administration of QT-shortening agents. The acceleration of early-phase repolarization and the increased dispersion of ventricular repolarization may contribute to the occurrence of arrhythmias.

During recent years there has been a surge in developing and applying physiologically based pharmacokinetic (PBPK) models in pregnant women to better understand and predict changes in drug pharmacokinetics throughout pregnancy. As a consequence, the number of publications focusing on pregnancy PBPK models has increased substantially. However, to date these models, especially across various platforms, have not been systematically evaluated. Hence, this review aims to assess published PBPK models in pregnancy used for therapeutic purposes., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Drug transporter and cytochrome P450 expression is regulated by shared nuclear receptors and, hence, an inducer should induce both, although the magnitude may differ. The objective of this study was to establish relative induction relationships between CYP3A and drug transporters (P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP), and breast cancer resistance protein (BCRP)) or other P450s (CYP2C9 and CYP1A2) using ascending doses of the prototypical pregnane xenobiotic receptor (PXR) agonist, rifampin, to elicit weak, moderate, and strong PXR agonism. Healthy subjects received dabigatran etexilate, pravastatin, rosuvastatin, and a midazolam/tolbutamide/caffeine cocktail before and after rifampin 2, 10, 75, or 600 mg q.d. Unlike CYP3A, only moderate induction of P-gp, OATP, and CYP2C9 was observed and dose-dependent induction of P-gp, OATP, and CYP2C9 was always one drug-drug interaction category lower than observed for CYP3A, even when correcting for probe drug sensitivity. Data from this study establish proof-of-concept that P450 induction data can be leveraged to inform on the effect on transporters., (© 2018 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Rifampin demonstrated dose-dependent relative induction between cytochrome P (CYP)3A and P-glycoprotein (P-gp), organic anion transporting polypeptides (OATPs), or CYP2C9; P-gp, OATP, and CYP2C9 induction was one drug-drug interaction (DDI) category lower than that observed for CYP3A across a wide range of pregnane X receptor (PXR) agonism. The objective of this study was to determine if these relationships could be utilized to predict transporter induction by other CYP3A inducers (rifabutin and carbamazepine) and of another P-gp substrate, sofosbuvir. Healthy subjects received sofosbuvir and a six-probe drug cassette before and after 300 mg q.d. rifabutin or 300 mg b.i.d. carbamazepine. Induction of P-gp, CYP2C9, and decreased sofosbuvir exposure were successfully predicted by observed CYP3A induction. Carbamazepine induction of OATP was underpredicted, likely due to reported additional non-PXR agonism. The results demonstrate that the effect of a PXR agonist on CYP3A can be leveraged to inform on induction liability for other primarily PXR-regulated P450s/transporters, allowing for prioritization of targeted DDI assessments during new drug development., (© 2018 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use., Methods: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth., Results: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na + current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K + channel subspecies (for Class III), and novel molecular targets related to Ca 2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation., Conclusions: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.

The decrement in plasma glucose concentration with SGLT2 inhibitors (SGLT2i) is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. Subjects with type 2 diabetes ( n = 36) were randomized to 1 ) canagliflozin (CANA), 2 ) liraglutide (LIRA), or 3 ) CANA plus LIRA (CANA/LIRA). EGP was measured with [3- 3 H]glucose with or without drugs for 360 min. In the pretreatment studies, EGP was comparable and decreased (2.2 ± 0.1 to 1.7 ± 0.2 mg/kg ⋅ min) during a 300- to 360-min period ( P < 0.01). The decrement in EGP was attenuated with CANA (2.1 ± 0.1 to 1.9 ± 0.1 mg/kg ⋅ min) and CANA/LIRA (2.2 ± 0.1 to 2.0 ± 0.1 mg/kg ⋅ min), whereas with LIRA it was the same (2.4 ± 0.2 to 1.8 ± 0.2 mg/kg ⋅ min) (all P < 0.05 vs. baseline). After CANA, the fasting plasma insulin concentration decreased (18 ± 2 to 12 ± 2 μU/mL, P < 0.05), while it remained unchanged in LIRA (18 ± 2 vs. 16 ± 2 μU/mL) and CANA/LIRA (17 ± 1 vs. 15 ± 2 μU/mL). Mean plasma glucagon did not change during the pretreatment studies from 0 to 360 min, while it increased with CANA (69 ± 3 to 78 ± 2 pg/mL, P < 0.05), decreased with LIRA (93 ± 6 to 80 ± 6 pg/mL, P < 0.05), and did not change in CANA/LIRA. LIRA prevented the insulin decline and blocked the glucagon rise observed with CANA but did not inhibit the increase in EGP. Factors other than insulin and glucagon contribute to the stimulation of EGP after CANA-induced glucosuria., (© 2018 by the American Diabetes Association.)

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers ( e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended., Competing Interests: Conflict of interest: F. Bertozzi has patents IT 102017000028127 and IT 102017000028184 pending. T. Bandiera has patents IT 102017000028127 and IT 102017000028184 pending. L.J.V. Galietta has patents IT 102017000028127 and IT 102017000028184 pending., (Copyright ©ERS 2018.)

This study aimed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD). Thirty-two T2D patients with NAFLD diagnosed by computed tomography or abdominal sonography were recruited. Participants were randomly assigned to receive either luseogliflozin (2.5 mg, newly administered) or metformin (1500 mg, newly or additionally administrated). Data on the liver-to-spleen attenuation ratio (L/S), visceral fat area, body mass index, glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), fasting plasma glucose, C-peptide immunoreactivity (CPR), and CPR index were collected at baseline and after 6 months. The change in L/S was significantly greater in the luseogliflozin group than in the metformin group. Similarly, the changes in the visceral fat area, HbA1c, and body mass index were significantly greater in the luseogliflozin group than in the metformin group. The changes in ALT, fasting glucose, CPR, and CPR index were not significant in both groups. In conclusion, luseogliflozin significantly reduced liver fat deposition as compared to metformin, which may indicate clinical relevant benefits for NAFLD., (© 2017 John Wiley & Sons Ltd.)

Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP-4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed-dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between-group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (-0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To test the hypothesis that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, improves β-cell responses to incretin hormones (or β-cell incretin sensitivity) by alleviating glucose toxicity in people with type 2 diabetes mellitus (T2DM)., Methods: A total of 19 people with T2DM underwent a 3-hour hyperglycaemic clamp study with incretin infusion before and after 8-week treatment with dapagliflozin added to the background treatment. In addition, 10 people with normal glucose tolerance (NGT) underwent a single hyperglycaemic clamp study. The hyperglycaemic clamp was targeted at 15.5 mmol/L for 3 hours, with synthetic glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) infusion over a 60- to 180-minute and a 120- to 180-minute period, respectively., Results: Compared with baseline, the C-peptide response to GLP-1 (incremental area under the curve [iAUC] of C-peptide 60-120 minutes ) significantly increased (83.6 ± 42.1 to 106.6 ± 45.7 nmol/L × min; P = .011), and the C-peptide response to GIP/GLP-1 (iAUC of C-peptide 120-180 minutes ) tended to increase after dapagliflozin treatment (82.5 ± 58.4 to 101.9 ± 50.3 nmol/L × min; P = .087), whereas both the insulin responses to GLP-1 and GIP/GLP-1 increased significantly. First-phase C-peptide response, which reflects β-cell function, significantly increased after dapagliflozin treatment; however, all these improved values in the participants with T2DM were far lower than those in the participants with NGT. In addition, the improvement in insulin responses to hyperglycaemia was correlated with the improvement in insulin responses to incretin infusion., Conclusions: Dapagliflozin improved β-cell responses to incretin hormones as well as glucose during the hyperglycaemic clamp in patients with inadequately controlled T2DM., (© 2017 John Wiley & Sons Ltd.)

Aims: To compare the sodium-glucose-cotransporter-2 (SGLT-2) inhibitor dapagliflozin with dipeptidyl peptidase-4 (DPP-4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non-fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting., Methods: All patients with T2D prescribed glucose-lowering drugs (GLDs) during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors, matched 1:3 by propensity score, calculated by patient characteristics, comorbidities and drug treatment. Cox survival models were used to estimate hazard ratio (HR) per country separately, and a weighted average was calculated., Results: After matching, a total of 40 908 patients with T2D were identified as new users of dapagliflozin (n = 10 227) or a DPP-4 inhibitor (n = 30 681). The groups were well balanced at baseline; their mean age was 61 years and 23% had CV disease. The mean follow-up time was 0.95 years, with a total of 38 760 patient-years. Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95% confidence interval [CI] 0.67-0.94), 0.62 (95% CI 0.50-0.77), and 0.59 (95% CI 0.49-0.72), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [95% CI 0.72-1.16]), stroke (0.79 [95% CI 0.61-1.03]) and CV mortality (0.76 [95% CI 0.53-1.08]) Neutral associations with atrial fibrillation and severe hypoglycaemia were observed., Conclusions: Dapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are increasingly used for the treatment of type 2 diabetes (T2D) and can improve glucose control also in type 1 diabetes (T1D). In May 2015, regulatory agencies issued a warning that SGLT2is may cause diabetic ketoacidosis (DKA). We report details on 2 new cases of SGLT2i-associated DKA and review the literature for similar cases within randomized controlled trials (RCTs), cohort studies and single reports. We searched the medical literature for reports of SGLT2i-associated DKA cases. A quantitative analysis of frequency and clinical characteristics is reported. The 2 narrative cases illustrate that SGLT2i-associated DKA can occur in patients with T1D incorrectly diagnosed as T2D, perhaps without the presence of obvious DKA precipitating factors. The incidence of SGLT2i-associated DKA was less than 1/1000 in randomized controlled trials and 1.6/1000 person-years in cohort studies. We retrieved detailed data on 105 SGLT2i-associated DKA case reports, wherein 35% showed glucose levels of less than 200 mg/dL and 22% were not associated with typical triggers. In case reports and in pharmacovigilance databases, duration of SGLT2i treatment before DKA onset was extremely variable. Fatal SGLT2i-associated DKA episodes were found only in pharmacovigilance databases and represented 1.6% of all reported cases. DKA is a rare adverse event during SGLT2i therapy. Predisposing and precipitating factors are still incompletely understood, although a minority of cases lacked typical DKA triggers. More narrative case series and cohort studies are needed to better understand the true risk and the spectrum of this adverse event., (© 2017 John Wiley & Sons Ltd.)

Aims: To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM)., Materials and Methods: PubMed, Embase and ClinicalTrials.gov sites were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate outcomes., Results: In the analysis of 25 randomized trials, which involved 14 619 patients, SGLT-2is were associated with a significantly stronger reduction in haemoglobin A1c (HbA1c) (WMD 0.13%, 95% credible interval [CI], 0.04%-0.22%, P = .005) and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI, 0.58-1.01 mmol/L, P < .00001) than were DPP-4is. However, no significant difference between the 2 drug categories was found in the risk of hypoglycaemic events (RR, 0.99; 95% CI, 0.78-1.26, P = .92). SGLT-2is plus Met was associated with a more significant decrease in FPG (WMD 0.71 mmol/L, 95% CI, 0.43-1.00 mmol/L, P < .00001) than was DPP-4is plus Met. However, no differences were found in the reduction of HbA1c (WMD 0.11%, 95% CI, -0.03%-0.25%, P = .12) or the risk of hypoglycaemic events (RR, 1.02; 95% CI, 0.80-1.31, P = .86)., Conclusions: This review revealed that, compared to DPP-4is, SGLT-2is significantly reduced HbA1c, FPG and body weight without increasing the risk of hypoglycaemia in diabetes treatment., (© 2017 John Wiley & Sons Ltd.)

Aim: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy., Methods: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward)., Results: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug-related AEs were 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were -0.99% (95% confidence interval [CI] -1.12 to -0.85), -38.6 mg/dL (95% CI -43.4 to -33.9) and -3.92% (95% CI -4.53 to -3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52., Conclusions: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Stroke is a leading cause of long-term disability. All neuroprotectants targeting excitotoxicity have failed to become stroke medications. In order to explore and identify new therapeutic targets for stroke, we here reviewed present studies of ionic transporters and channels that are involved in ischemic brain damage., Method: We surveyed recent literature from animal experiments and clinical reports in the databases of PubMed and Elsevier ScienceDirect to analyze ionic mechanisms underlying ischemic cell damage and suggest promising ideas for stroke therapy., Results: Dysfunction of ionic transporters and disrupted ionic homeostasis are most early changes that underlie ischemic brain injury, thus receiving sustained attention in translational stroke research. The Na + /K + -ATPase, Na + /Ca 2+ Exchanger, ionotropic glutamate receptor, acid-sensing ion channels (ASICs), sulfonylurea receptor isoform 1 (SUR1)-regulated NC Ca-ATP channels, and transient receptor potential (TRP) channels are critically involved in ischemia-induced cellular degenerating processes such as cytotoxic edema, excitotoxicity, necrosis, apoptosis, and autophagic cell death. Some ionic transporters/channels also act as signalosomes to regulate cell death signaling. For acute stroke treatment, glutamate-mediated excitotoxicity must be interfered within 2 hours after stroke. The SUR1-regulated NC Ca-ATP channels, Na + /K + -ATPase, ASICs, and TRP channels have a much longer therapeutic window, providing new therapeutic targets for developing feasible pharmacological treatments toward acute ischemic stroke., Conclusion: The next generation of stroke therapy can apply a polypharmacology strategy for which drugs are designed to target multiple ion transporters/channels or their interaction with neurotoxic signaling pathways. But a successful translation of neuroprotectants relies on in-depth analyses of cell death mechanisms and suitable animal models resembling human stroke., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

To investigate whether sodium glucose co-transporter 2 inhibitors (SGLT2i), tofogliflozin or ipragliflozin, achieve optimal glycemic variability, when used together with insulin glargine 300 U/mL (Glargine 300). Thirty patients with type 2 diabetes were randomly allocated to 2 groups. For the first group: After admission, tofogliflozin 20 mg was administered; Fasting plasma glucose (FPG) levels were titrated using an algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using continuous glucose monitoring (CGM); Tofogliflozin was then washed out over 5 days; Subsequently, ipragliflozin 50 mg was administered; FPG levels were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using CGM. For the second group, ipragliflozin was administered prior to tofogliflozin, and the same regimen was maintained. Glargine 300 and SGLT2i were administered at 8:00 AM. Data collected on the second day of measurement (mean amplitude of glycemic excursion [MAGE], average daily risk range [ADRR]; on all days of measurement) were analyzed. Area over the glucose curve (<70 mg/dL; 0:00 to 6:00, 24-h), M value, standard deviation, MAGE, ADRR, and mean glucose levels (24-h, 8:00 to 24:00) were significantly lower in patients on tofogliflozin than in those on ipragliflozin. Tofogliflozin, which reduces glycemic variability by preventing nocturnal hypoglycemia and decreasing postprandial glucose levels, is an ideal SGLT2i when used together with Glargine 300 during basal insulin therapy.

Hyperuricemia has been linked to metabolic syndrome, cardiovascular disease, and chronic kidney disease. Hyperuricemia and type 2 diabetes mellitus were inter-related, type 2 diabetes mellitus was more at risk of having a higher serum uric acid level, and also individuals with higher serum uric acid had higher risk of developing type 2 diabetes in the future. Insulin resistance seems to play an important role in the causal relationship between metabolic syndrome, type 2 diabetes, and hyperuricemia. Oral diabetic drugs that would have additional beneficial effects on reducing serum uric acid levels are of importance. Selective SGLT2 inhibitors were extensively studied in type 2 diabetes mellitus and were found to have improvement of glycemic control, in addition to their proven metabolic effects on weight and blood pressure. Additional beneficial effect of SGLT2 inhibitors on serum uric acid level reduction is investigated. Recently, data have been accumulating showing that they have additional beneficial effects on serum uric acid reduction. As for the postulated mechanism, serum uric acid decreased in SGLT2 inhibitor users as a result of the increase in the urinary excretion rate of uric acid, due to the inhibition of uric acid reabsorption mediated by the effect of the drug on the GLUT9 isoform 2, located at the collecting duct of the renal tubule.

Aims: Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes., Materials and Methods: Obese adults without diabetes (N = 50; aged 18-70 years; body mass index, 30-45 kg/m 2 ) were initially randomized to double-blind oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or to placebo. They entered an open-label extension from 24 to 52 weeks during which all participants received active treatment., Results: Of the original 25 dapagliflozin + exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (-4.5 and -5.7 kg), total adipose tissue volume (-3.8 and -5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo → dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed., Conclusions: Dapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

In heart failure (HF), the heart cannot pump blood efficiently and is therefore unable to meet the body's demands of oxygen, and/or there is increased end-diastolic pressure. Current treatments for HF with reduced ejection fraction (HFrEF) include angiotensin-converting enzyme (ACE) inhibitors, angiotension receptor type 1 (AT 1 ) antagonists, β-adrenoceptor antagonists, aldosterone receptor antagonists, diuretics, digoxin and a combination drug with AT 1 receptor antagonist and neprilysin inhibitor. In HF, the risk of readmission for hospital and mortality is markedly higher with a heart rate (HR) above 70 bpm. Here, we review the evidence regarding the use of ivabradine for lowering HR in HF. Ivabradine is a blocker of an I funny current (I(f)) channel and causes rate-dependent inhibition of the pacemaker activity in the sinoatrial node. In clinical trials of HFrEF, treatment with ivabradine seems to improve clinical outcome, for example improved ejection fraction (EF) and less readmission for hospital, but the effect appears most pronounced in patients with HRs above 70 bpm, while the effect on cardiovascular death appears less consistent. The adverse effects of ivabradine include bradycardia, atrial fibrillation and visual disturbances, but ivabradine avoids the negative inotrope effects observed with β-adrenoceptor antagonists. In conclusion, in patients with stable HFrEF with EF<35% and HR above 70 bpm, ivabradine improves the outcome and might be a first choice of therapy, if beta-adrenoceptor antagonists are not tolerated. Further studies must show whether that can be extended to HF patients with preserved EF., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Aim: To compare the associations of individual sodium-glucose co-transporter-2 (SGLT2) inhibitors with adverse renal outcomes in patients with type 2 diabetes mellitus (T2DM)., Methods: PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were searched for studies published up to May 24, 2016, without language or date restrictions. Randomized trials that reported at least 1 renal-related adverse outcome in patients with T2DM treated with SGLT2 inhibitors were included. Pairwise and network meta-analyses were carried out to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and a cumulative meta-analysis was performed to assess the robustness of evidence., Results: In total, we extracted 1334 composite renal events among 39 741 patients from 58 trials, and 511 acute renal impairment/failure events among 36 716 patients from 53 trials. Dapagliflozin was significantly associated with a greater risk of composite renal events than placebo (OR 1.64, 95% CI 1.26-2.13). Empagliflozin seemed to confer a lower risk than placebo (OR 0.63, 95% CI 0.54-0.72), canagliflozin (OR 0.48, 95% CI 0.29-0.82) and dapagliflozin (OR 0.38, 95% CI 0.28-0.51). With regard to acute renal impairment/failure, only empagliflozin was significantly associated with a lower risk than placebo (OR 0.72, 95% CI 0.60-0.86). The cumulative meta-analysis indicated the robustness of our significant findings., Conclusions: The present meta-analysis indicated that dapagliflozin may increase the risk of adverse renal events, while empagliflozin may have a protective effect among patients with T2DM. Further data from large well-conducted randomized controlled trials and a real-world setting are warranted., (© 2017 John Wiley & Sons Ltd.)

In both phase III studies of LUM/IVA, as well as an extension study, worsening of mental health was not reported as a common side effect. Here we describe five cases in adolescent female patients that suggest a worsening of anxiety or depression associated with its use. In these five patients, two experienced suicidal ideation and three made suicide attempts that resulted in psychiatric hospitalizations., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Drug intensification is often required for patients with type 2 diabetes mellitus on stable metformin therapy. Among the potential candidates for a combination therapy, sodium-glucose transporter-2 (SGLT2) inhibitors have shown promising outcomes. This meta-analysis was performed to compare the efficacy and safety of SGLT2 inhibitors with non-SGLT2 combinations as add-on treatment to metformin., Methods: Literature search was carried out in multiple electronic databases for the acquisition of relevant randomized controlled trials (RCTs) by following a priori eligibility criteria. After the assessment of quality of the included RCTs, meta-analyses of mean differences or odds ratios (OR) were performed to achieve overall effect sizes of the changes from baseline in selected efficacy and safety endpoints reported in the individual studies. Between-studies heterogeneity was estimated with between-studies statistical heterogeneity (I) index., Results: Six RCTs fulfilled the eligibility criteria. SGLT2 inhibitors as add-on to metformin treatment reduced % HbA1c significantly more than non-SGLT2 combinations after 52 weeks (P = .002) as well as after 104 weeks (P < .00001). Among other endpoints, SGLT2 inhibitors also reduced fasting plasma glucose levels, body weight, systolic, and diastolic blood pressures after 52 weeks and 104 weeks significantly (P < .00001) more than non-SGLT2 combinations. Incidence of hypoglycemia was significantly lower (P = .02) but incidence of suspected or confirmed genital tract infections was significantly higher (P < .00001) in SGLT2 inhibitors treated in comparison with non-SGLT2 combinations., Conclusion: As add-on to metformin treatment, SGLT2 inhibitors are found significantly more efficacious than non-SGLT2 inhibitor combinations in the management of type 2 diabetes mellitus, although, SGLT2 inhibitor therapy is associated with significantly higher incidence of suspected or confirmed genital tract infections.

Aim: We investigated the efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF)., Methods: Data for patients randomized to dapagliflozin 10mg or placebo with a history of HF were pooled from five clinical trials. HbA 1c , weight and systolic blood pressure (SBP; two studies) were examined up to 52weeks using longitudinal repeated-measures models. Composite cardiovascular outcomes, hospitalizations for HF (HHF), and adverse events (AEs) were also assessed., Results: Patients (mean age 64years, T2DM duration ~14years, HbA 1c 8.2%, ~50% with New York Heart Association Class ≥II) received dapagliflozin (N=171) or placebo (N=149). Dapagliflozin produced clinically meaningful placebo-adjusted reductions in HbA 1c (-0.55%; 95% confidence interval [CI]: -0.80, -0.30), weight (-2.67kg; 95% CI: -3.88, -1.47), and SBP (-2.05mmHg; 95% CI: -5.68, 1.57) over 52weeks. HHF was rare, but numerically lower with dapagliflozin (n=1 [0.6%]) vs placebo (n=7 [4.7%]). Point estimates for hazard ratios of composite cardiovascular outcomes favored dapagliflozin vs placebo, although 95% CIs crossed unity., Conclusions: Dapagliflozin produced clinically meaningful reductions in HbA 1c , weight, and SBP in patients with T2DM and HF, and was well tolerated., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting., Methods: A multicentre observational study investigated adverse events, treatment discontinuation, FEV 1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV 1 below 40% predicted., Results: Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV 1 was +2.06% after one month of treatment (P=0.086) and +3.19% after 3 months (P=0.009). BMI was unchanged., Conclusions: Treatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory AEs. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Safety-data for lumacaftor/ivacaftor (LUM/IVA) combination therapy in patients with severe lung disease (percent predicted forced expiratory volume in 1s [ppFEV 1 ] <40) remain limited. We report immediate post-dose respiratory-related adverse events in 12 patients with severe cystic fibrosis (CF) lung disease (median [IQR] ppFEV 1 : 34 [31-36]) prescribed LUM/IVA. All patients experienced a decline in ppFEV 1 from baseline at 2-hours (median [IQR] relative change: -19 [-21 to -11]%, p<0.001) that persisted at 24-hours but recovered in most patients at 1-month. No pre- and post-differences in bronchodilator response were observed. Ten (83.3%) patients reported non-severe respiratory-related adverse events within 24-hours of LUM/IVA initiation. At 1-month, eight (67%) patients had persistent symptoms and six (50%) were treated for a pulmonary exacerbation. Our results highlight that LUM/IVA respiratory-related adverse events are common in patients with a ppFEV 1 <40. We recommend close assessment of adverse events. Further studies are required to evaluate the efficacy of LUM/IVA in patients with severe lung disease., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

This study investigated the safety and efficacy of the sodium-glucose co-transporter-2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate-adjusted meals for 14 days (days 1-14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8-14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5-8 and days 12-15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC-HGI group compared with the HC-HGI and HC-LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor-associated diabetic ketoacidosis., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes., Materials and Methods: This was a 52-week, double-blind, multicentre, randomized, parallel-group study with a 26-week, placebo-controlled treatment period (phase A), followed by a 26-week active-controlled treatment period (phase B) in 461 men and women, aged ≥18 years with inadequate glycaemic control (glycated haemoglobin [HbA1c] concentration 7.0% to 10.5% [53-91 mmol/mol], inclusive) despite diet and exercise. Results from phase A are reported in the present paper. The primary endpoint was the change in HbA1c from baseline to week 26., Results: At week 26, the placebo-adjusted least squares mean HbA1c changes from baseline were -0.99% and -1.16% for the ertugliflozin 5 and 15 mg doses, respectively ( P  < .001 for both doses). The odds of having HbA1c <7.0% (53 mmol/mol) were significantly greater in the ertugliflozin 5 and 15 mg groups compared with the placebo group. Both doses of ertugliflozin significantly lowered fasting plasma glucose and 2-hour postprandial glucose levels and body weight. The placebo-adjusted differences in changes from baseline in systolic blood pressure were not statistically significant. A higher incidence of genital mycotic infections occurred in men and women treated with ertugliflozin compared with placebo. There was no significant difference between treatments in the proportion of participants with symptomatic hypoglycaemia or adverse events associated with urinary tract infection or hypovolaemia., Conclusions: Ertugliflozin 5 and 15 mg treatment for 26 weeks provides effective glycaemic control, reduces body weight and is generally well tolerated, when used as monotherapy., (© 2017 John Wiley & Sons Ltd.)

Background: Previous studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors have different effects on the lipid profile in patients with type 2 diabetes. We investigated the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile in patients with type 2 diabetes., Methods: From January 2013 to December 2015, a total of 228 patients with type 2 diabetes who were receiving a DPP-4 inhibitor or SGLT2 inhibitor as add-on therapy to metformin and/or a sulfonylurea were consecutively enrolled. We compared the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile at baseline and after 24 weeks of treatment. To compare lipid parameters between the two groups, we used the analysis of covariance (ANCOVA)., Results: A total of 184 patients completed follow-up (mean age: 53.1 ± 6.9 years, mean duration of diabetes: 7.1 ± 5.7 years). From baseline to 24 weeks, HDL-cholesterol (HDL-C) levels were increased by 0.5 (95% CI, -0.9 to 2.0) mg/dl with a DPP-4 inhibitor and by 5.1 (95% CI, 3.0 to 7.1) mg/dl with an SGLT2 inhibitor (p = 0.001). LDL-cholesterol (LDL-C) levels were reduced by 8.4 (95% CI, -14.0 to -2.8) mg/dl with a DPP-4 inhibitor, but increased by 1.3 (95% CI, -5.1 to 7.6) mg/dl with an SGLT2 inhibitor (p = 0.046). There was no significant difference in the mean hemoglobin A1c (8.3 ± 1.1 vs. 8.0 ± 0.9%, p = 0.110) and in the change of total cholesterol (TC) (p = 0.836), triglyceride (TG) (p = 0.867), apolipoprotein A (p = 0.726), apolipoprotein B (p = 0.660), and lipoprotein (a) (p = 0.991) between the DPP-4 inhibitor and the SGLT2 inhibitor., Conclusions: The SGLT2 inhibitor was associated with a significant increase in HDL-C and LDL-C after 24 weeks of SGLT2 inhibitor treatment in patients with type 2 diabetes compared with those with DPP-4 inhibitor treatment in this study., Trial Registration: This study was conducted by retrospective medical record review.

The burden of type 2 diabetes (T2DM) in East Asia is alarming. Rapid modernization and urbanization have led to major lifestyle changes and a tremendous increase in the prevalence of obesity, metabolic syndrome, and diabetes mellitus. The development of T2DM at a younger age, with lower body mass index, higher visceral adiposity, and more significant pancreatic beta-cell dysfunction compared to Caucasians are factors responsible for the increased prevalence of T2DM in East Asians. Sodium-glucose Cotransporter-2 (SGLT2) inhibitors (canagliflozin, dapaglifozin, empagliflozin, etc.) reduce renal glucose reabsorption, leading to favorable effects on glycemic, blood pressure, and weight control. The insulin-independent mechanism enables their use as monotherapy or combination therapy with insulin and other oral antidiabetic agents. The role of SGLT2 inhibitors in the management of T2DM among East Asians is an interesting area of research, given that East Asians have been proven to be uniquely different from Caucasians. This review provides comprehensive coverage of the available literature not only on the efficacy and safety, but also on the recent cardiovascular and renal outcomes of SGLT2 inhibitors, focusing among East Asians., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [(2)H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating β-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The recently completed EMPA-REG study showed that empagliflozin significantly decreased the major adverse cardiac events (MACE) endpoint, which comprised cardiovascular death, non-fatal myocardial infarction (MI) and stroke, in patients with high-risk type 2 diabetes (T2DM), primarily through a reduction in cardiovascular death, without a significant decrease in either MI or stroke. In the PROactive study, pioglitazone decreased the MACE endpoint by a similar degree to that observed in the EMPA-REG study, through a marked reduction in both recurrent MI and stroke and a modest reduction in cardiovascular death. These observations suggest that pioglitazone might be an ideal agent to combine with empagliflozin to further reduce cardiovascular events in patients with high-risk diabetes as empagliflozin also promotes salt/water loss and would be expected to offset any fluid retention associated with pioglitazone therapy. In the present paper, we provide an overview of the potential benefits of combined pioglitazone/empagliflozin therapy to prevent cardiovascular events in patients with T2DM., (© 2016 John Wiley & Sons Ltd.)

Objective: The aim was to assess gabapentin enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS)., Methods: Data were pooled from three placebo-controlled, randomized, double-blind, 12-week trials for adults receiving GEn (600 mg or 1200 mg) or placebo once daily. QOL was assessed with the RLS QOL questionnaire in two studies. Mood was examined with the Profile of Mood States Brief Form (POMS-B), and as an exploratory analysis with International Restless Legs Scale (IRLS) item 9 (daily affairs) and item 10 (mood disturbance) across all three studies. Mood and QOL were secondary endpoints in the individual clinical trials. No adjustments for multiplicity were applied., Results: The QOL analysis modified intent-to-treat (MITT) population included 541 adults (placebo, n = 204; GEn 600 mg, n = 114; GEn 1200 mg, n = 223). Both GEn doses significantly improved QOL versus placebo (week 12; p < 0.01). The mood analysis MITT population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). GEn 600 mg significantly improved POMS vigor-activity versus placebo (week 12; p < 0.05); other POMS criteria were not significantly affected. GEn 1200 mg significantly improved POMS scores for total mood disturbance, depression-dejection, fatigue-inertia, vigor-activity, and confusion-bewilderment versus placebo at week 12 (p < 0.05); tension-anxiety and anger-hostility were not significantly affected. Both GEn doses significantly improved IRLS item 9 and item 10 versus placebo at week 12 (p < 0.05). The most frequent treatment-emergent adverse events with GEn were somnolence and dizziness., Conclusions: GEn (600 mg and 1200 mg) once daily significantly improved QOL in adults with moderate-to-severe primary RLS at all time points examined. While the only POMS item significantly improved by GEn 600 mg versus placebo at week 12 was vigor-activity, GEn 1200 mg significantly improved total mood disturbance and several other POMS items versus placebo at week 12. Both QOL and mood improvements were numerically greater with GEn 1200 mg versus 600 mg., Trial Registrations: Clinicaltrials.gov identifiers NCT00298623, NCT00365352, NCT01332305.

The constitutive anabolism of cancer cells not only supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death., (© 2016 Federation of European Biochemical Societies.)

The adverse outcome pathway (AOP) is a framework to mechanistically link molecular initiating events to adverse biological outcomes. From a regulatory perspective, it is of crucial importance to determine the confidence for the AOP in question as well as the quality of data available in supporting this evaluation. A weight of evidence approach has been proposed for this task, but many of the existing frameworks for weight of evidence evaluation are qualitative and there is not clear guidance regarding how weight of evidence should be calculated for an AOP. In this paper we advocate the use of a subject matter expertise driven approach for weight of evidence evaluation based on criteria and metrics related to data quality and the strength of causal linkages between key events. As a demonstration, we notionally determine weight of evidence scores for two AOPs: Non-competitive ionotropic GABA receptor antagonism leading to epileptic seizures, and Antagonist-binding and stabilization of a co-repressor to the peroxisome proliferator-activated receptor α (PPARα) signaling complex ultimately causing starvation-like weight loss., (Published by Elsevier Inc.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines., (© 2015 John Wiley & Sons Ltd.)

Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM., (Copyright © 2015 Elsevier Inc. All rights reserved.)