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Michael J Davies,1 Katherine W Merton,1 Ujjwala Vijapurkar,2 Dainius A Balis,2 Mehul Desai2 1Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 2Janssen Research & Development, LLC, Raritan, NJ, USA Objective: Metabolic syndrome refers to a collection of risk factors associated with the development of cardiovascular disease and type 2 diabetes mellitus (T2DM). Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves glycemic control and reduces body weight and blood pressure (BP) in a broad range of patients with T2DM. This post hoc analysis assessed the effects of canagliflozin on the components of metabolic syndrome in patients with T2DM and metabolic syndrome.Methods: This analysis was based on data from 2 head-to-head studies of canagliflozin in patients with T2DM on background metformin versus glimepiride (study 1) and background metformin plus sulfonylurea versus sitagliptin 100 mg (study 2). Changes from baseline in glycemic efficacy, anthropometric measures, BP, and lipids were evaluated with canagliflozin versus glimepiride and sitagliptin at week 52 in patients who met ≥2 of the criteria for metabolic syndrome (in addition to T2DM): triglycerides ≥1.7 mmol/L; high-density lipoprotein cholesterol (HDL-C) 90 cm (Asian men), or >80 cm (Asian women); diagnosis of hypertension or meeting BP-related criteria (systolic BP ≥130 mmHg or diastolic BP ≥85 mmHg). Safety was assessed based on adverse event reports.Results: In study 1, canagliflozin 100 and 300 mg provided similar and greater HbA1c reductions versus glimepiride, respectively. In study 2, canagliflozin 300 mg provided greater HbA1c lowering versus sitagliptin 100 mg. Canagliflozin also reduced fasting plasma glucose, body weight, body mass index, waist circumference, BP, and triglycerides, and increased HDL-C and low-density lipoprotein cholesterol versus glimepiride and sitagliptin. Canagliflozin was generally well tolerated in each study.Conclusion: Canagliflozin was associated with improvements in all components of metabolic syndrome in patients with T2DM and metabolic syndrome, whereas glimepiride and sitagliptin only improved glycemic components over 52 weeks. Keywords: canagliflozin, sodium glucose co-transporter 2, type 2 diabetes, metabolic syndrome

Hematopoietic defects in HOXA9(-/-) mice demonstrate a key role for this homeoprotein in blood cell development. Conversely, enforced HOXA9 expression is leukemogenic in mice, and HOXA9 is frequently activated in human acute myeloid leukemia (AML). Although HOXA9 is thought to function as a transcription factor, few downstream targets have been identified. We searched for early HOXA9 target genes by using a transient overexpression strategy in 3 hematopoietic cell lines (2 myeloid, 1 lymphoid). cDNA microarray analyses identified 220 genes whose expression was modulated at least 2-fold. Expression signatures in myeloid and lymphoid cells demonstrated that HOXA9 functions as both an activator and repressor of a variety of genes in cell-specific patterns suggesting that the transcriptional effects of HOXA9 are largely dependent on the cell context. Transient transcription assays and target gene expression patterns in HOXA9(-/-) marrow cells imply that we have identified direct physiologic targets. Many tar-get genes are expressed in CD34(+) stem cells or are members of gene families involved in proliferation or myeloid differentiation. Expression of 14 HOXA9 target genes correlated with high-level HOXA9 expression in primary AML. These data suggest that many genes identified in this survey may mediate the biologic effects of HOXA9 in normal and leukemic hematopoiesis. (C) 2004 by The American Society of Hematology.

Byline: Hans-Christoph Diener (1), P. Tfelt-Hansen (2), C. Dahlof (3), M. J. A. Lainez (4), G. Sandrini (5), Sh.-J. Wang (6), W. Neto (7), U. Vijapurkar (7), A. Doyle (7), D. Jacobs (7) Keywords: placebo--controlled; migraine; topiramate; prophylaxis; propranolol Abstract: Abstract. Topiramate (TPM) has shown efficacy in migraine prophylaxis in two large placebo--controlled, dose--ranging trials. We conducted a randomised, doubleblind, multicentre trial to evaluate the efficacy and safety of two doses of topiramate vs placebo for migraine prophylaxis, with propranolol (PROP) as an active control. Subjects with episodic migraine with and without aura were randomised to TPM 100 mg/d, TPM 200 mg/d, PROP 160 mg/d (active control), or placebo. The primary efficacy measure was the change in mean monthly migraine frequency from the baseline phase relative to the double--blind treatment phase. Five hundred and seventy--five subjects were enrolled from 61 centres in 13 countries. TPM 100 mg/d was superior to placebo as measured by reduction in monthly migraine frequency, overall 50% responder rate, reduction in monthly migraine days, and reduction in the rate of daily rescue medication use. The TPM 100 mg/d and PROP groups were similar with respect to reductions in migraine frequency, responder rate, migraine days, and daily rescue medication usage. TPM 100 mg/d was better tolerated than TPM 200 mg/d, and was generally comparable to PROP. No unusual or unexpected safety risks emerged. These findings demonstrate that TPM 100 mg/d is effective in migraine prophylaxis. TPM 100 mg/d and PROP 160 mg/d exhibited similar efficacy profiles. Author Affiliation: (1) Department of Neurology, University Essen, Hufelandstr 55, 45122, Essen, Germany (2) Department of Neurology, University of Copenhagen Glostrup Hospital, Glostrup, Denmark (3) Gothenburg Migraine Clinic, Gothenburg, Sweden (4) Department of Neurology, Hospital Clinico Universitario University of Valencia, Valencia, Spain (5) Headache Centre IRCC C. Mondino Foundation, University of Pavia, Pavia, Italy (6) Neurological Institute Taipei, Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan (7) Johnson &amp Johnson, Pharmaceutical Research and Development, LLC Raritan, NJ USA Article History: Registration Date: 01/01/2004 Received Date: 02/01/2004 Accepted Date: 08/03/2004

Background: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.Methods: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.Results: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).Conclusions: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.). [ABSTRACT FROM AUTHOR]

Cancer is associated with an increased risk of venous thromboembolism (VTE). In the CASSINI study, ambulatory cancer patients with a Khorana risk score ≥2 had a reduced risk of VTE while receiving rivaroxaban. This analysis used blood samples from CASSINI to compare biomarker levels between patients with and without VTE. VTE occurred in 62 patients during the 6 months of CASSINI (cases), and they were matched by age, sex, cancer type, tumor stage, and Khorana score to 62 controls. Baseline blood samples were analyzed for 280 biomarkers, and biomarker distribution was compared using the Wilcoxon rank-sum test between groups defined by VTE occurrence and vital status. Sparse Bayesian regression modeling was used to select a joint panel of potential VTE biomarkers. Biomarkers with the largest differences in baseline distribution among cancer patients with and without VTE included decreases in stromal cell-derived factor-1 (SDF-1), thyroid-stimulating hormone (TSH), and monocyte chemotactic protein 4 and increases in growth hormone (GH) and interleukin-1 receptor type 1 (IL-1R1). Between survivors and those who died, significantly different biomarkers included ST2, IL-8, and C-reactive protein. Regression analyses also identified decreases in SDF-1 and TSH. Pathway analysis indicated enrichment of cytokine and chemokine activity with IL-1R1, SDF-1, and GH, which are the strongest predictors of VTE or death. Our analyses highlight the interactions between hemostatic and inflammatory processes and identify candidate biomarkers of cancer-associated VTE. Prospective studies will determine clinical relevance of these biomarkers. This trial was registered at www.ClinicalTrials.gov as #NCT02555878., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Pancreatic cancer patients are at risk for venous thromboembolism (VTE); the value of thromboprophylaxis has not been definitively established., Methods: This trial randomized cancer patients initiating a new regimen and at high risk for VTE (Khorana score ≥2) to rivaroxaban 10 mg or placebo up to day 180. This analysis examined the subset of pancreatic cancer patients. The primary efficacy endpoint was the composite of symptomatic deep-vein thrombosis (DVT), asymptomatic proximal DVT, any pulmonary embolism, and VTE-related death. The primary safety endpoint was International Society on Thrombosis and Haemostasis-defined major bleeding., Results: In total, 49/1080 (4.5%) patients enrolled had baseline VTE on screening, with higher rates (24/362 [6.6%]) in pancreatic cancer and they were not randomized. Of 841 randomized patients, 273 (32.5%) had pancreatic cancer; 155/273 (57% in each arm) completed the double-blind period. The primary endpoint occurred in 13/135 (9.6%) patients in the rivaroxaban group and in 18/138 (13.0%) in the placebo group (hazard ratio [HR] = 0.70; 95% CI, 0.34-1.43; P = .328) in up-to-day-180 period and 5/135 (3.7%) patients receiving rivaroxaban and 14/138 (10.1%) receiving placebo in the intervention period (HR = 0.35; 95% CI, 0.13-0.97; P = .034). Major bleeding was similar (2 [1.5%] receiving rivaroxaban and 3 [2.3%] receiving placebo). Correlative biomarker studies demonstrated significant decline in D-dimer (weeks 8 and 16) in patients randomized to rivaroxaban compared to placebo (P < .01)., Conclusions: In ambulatory pancreatic cancer patients, rivaroxaban did not result in significantly lower incidence of VTE or VTE-related death in the 180-day period. During the intervention period, however, rivaroxaban substantially reduced VTE without increasing major bleeding, suggesting benefit of rivaroxaban prophylaxis in this setting., Trial Registration: ClinicalTrials.gov identifier, NCT02555878., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction  In the CASSINI study, rivaroxaban thromboprophylaxis significantly reduced primary venous thromboembolism (VTE) endpoints during the intervention period, but several thromboembolic events designated as secondary efficacy endpoints were not included in the primary analysis. This study was aimed to evaluate the full impact of rivaroxaban thromboprophylaxis on all prespecified thromboembolic endpoints occurring on study. Methods  CASSINI was a double-blind, randomized, placebo-controlled study in adult ambulatory patients with cancer at risk for VTE (Khorana score ≥2). Patients were screened at baseline for deep-vein thrombosis (DVT) and randomized if none was found. The primary efficacy endpoint was a composite of lower extremity proximal DVT, symptomatic upper extremity, or lower extremity distal DVT, any pulmonary embolism, and VTE-related death. This analysis evaluated all prespecified thromboembolic endpoints occurring on study to determine the full benefit of rivaroxaban prophylaxis. All endpoints were independently adjudicated. Results  Total thromboembolic events occurred in fewer patients randomized to rivaroxaban during the full study period (29/420 [6.9%] and 49/421 [11.6%] patients in rivaroxaban and placebo groups, respectively [hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.36-0.90; p  = 0.01]; number needed to treat [NNT] = 21). Similarly, fewer patients randomized to rivaroxaban experienced thromboembolism during the intervention period (13/420 [3.1%] patients) versus placebo (38/421 [9.0%] patients; HR = 0.33; 95% CI: 0.18-0.62; p < 0.001; NNT = 17). Conclusion  Our findings confirm the substantial benefit of rivaroxaban thromboprophylaxis when considering all prespecified thromboembolic events, even after excluding baseline screen-detected DVT. The low NNT, coupled with prior data demonstrating a high number needed to harm, should assist clinicians in determining the risk/benefit of thromboprophylaxis in high-risk patients with cancer., Competing Interests: Conflict of Interest A.A.K. received personal fees for serving as cochair of the steering committee for CASSINI and nonfinancial support for travel from Janssen during the conduct of the study; personal fees and nonfinancial support for travel from Bayer, Sanofi, Parexel, Janssen, Halozyme, Pfizer, AngioDynamics, Leo Pharma, Medscape/WebMD, and Seattle Genetics; personal fees from Pharmacyclics, Pharmacyte, and TriSalus; and grants to his institution from Merck, Array, Bristol-Myers Squibb, and Leap Pharma, outside the submitted work. He was the National Coordinator of the MARINER trial for Janssen. M.G.M. served as an advisory board member for Ipsen, Shire, Celgene, and Sirtex; received research support from NuCana BioMed Ltd. and Shire; received honoraria for participation in speakers' bureaus from Pfizer and Ipsen; and received travel expenses from Bayer. A.K.K. received personal fees from Janssen during the conduct of the study and from Bayer AG, Boehringer Ingelheim, Daiichi Sankyo Europe, Pfizer, Sanofi S.A., and Verseon outside the submitted work. His institution has received grant support from Bayer. M.B.S. received grant support and personal fees from Janssen for serving as the site PI for the CASSINI study and serving on an advisory board during the conduct of the study. Outside the submitted work, he received personal fees from Bayer for a CME lecture and for serving on an advisory board, from CSL Behring for serving on the outcome adjudication committee, and from Daiichi Sankyo and Pfizer for serving on an advisory board; grant support from Boehringer Ingelheim and Roche; and grant support and personal fees from Portola for a CME lecture and for serving on an advisory board. He served as an expert witness for various legal cases. H.R. received reimbursement for travel from Janssen Scientific Affairs during the conduct of the study and personal fees for serving on an advisory board from Janssen Scientific Affairs. Outside the submitted work, he received personal fees for lectures and serving on advisory boards for Bayer, Boehringer Ingelheim, and Daiichi Sankyo; for lectures for Bristol-Myers Squibb; for serving on an advisory board for Pfizer; and grant support from Charité IIT. U.V. is an employee of Janssen Pharmaceuticals, Inc. and owns stock in Johnson & Johnson. S.K. is an employee of Janssen Pharmaceuticals, Inc. and owns stock in Johnson & Johnson. She is also involved in the XARELTO development program at Janssen. P.W. is an employee of Janssen Scientific Affairs and owns stock in Johnson & Johnson. G.A.S. received personal fees from Janssen for participating in meetings for planning and discussion of results during the conduct of this and another study, and received grant support and personal fees from Janssen outside the submitted work.

Objective: Type 2 diabetes and obesity are pro-inflammatory states associated with increased risk of cardiovascular disease. Canagliflozin, an SGLT2 inhibitor, demonstrated superiority in lowering HbA1c versus glimepiride with less hypoglycemia and greater weight reduction via loss of fat mass in a 52-week trial of type 2 diabetes patients. This post hoc, exploratory analysis assessed the effects of canagliflozin versus glimepiride on select adipokines, inflammatory biomarkers, and chemokines., Methods: Changes from baseline to Week 52 in serum leptin, adiponectin, IL-6, TNFα, CRP, PAI-1, VCAM-1, and MCP-1 were measured in a randomly selected subset of type 2 diabetes patients on metformin receiving canagliflozin 300 mg (n = 100) or glimepiride (n = 100) in the overall study. Correlations between change in biomarkers and change in select metabolic and anthropometric variables were assessed., Results: At Week 52, canagliflozin decreased median serum leptin by 25% (95% CI: -34%, -15%) and increased median serum adiponectin by 17% (95% CI: 11%, 23%) compared with glimepiride. There was a 22% reduction in median serum IL-6 (95% CI: -34%, -10%) and a 7% increase in median serum TNFα (95% CI: 1%, 12%) with canagliflozin versus glimepiride. No between-group differences were observed with the other biomarkers. The decrease in serum leptin with canagliflozin was correlated with change in weight (r ≥ 0.3) only; the increase in adiponectin and decrease in IL-6 with canagliflozin occurred independently of changes in HbA1c, weight, or lipids., Conclusions: These results indicate that canagliflozin may improve adipose tissue function and induce changes in serum leptin, adiponectin, and IL-6 that favorably impact insulin sensitivity and cardiovascular disease risk., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In addition to achieving glycemic control, weight loss and blood pressure (BP) reduction are important components of type 2 diabetes mellitus (T2DM) management, as many patients with T2DM are overweight/obese and/or have hypertension. Canagliflozin, an SGLT2 inhibitor, has demonstrated improvements in HbA1c, body weight (BW), and systolic BP across a broad range of patients with T2DM. This analysis evaluated achievement of composite endpoints of HbA1c, BW, and systolic BP targets with canagliflozin versus placebo., Methods: This post hoc analysis evaluated the proportion of T2DM patients achieving the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4mmHg with canagliflozin 100 and 300mg compared with placebo using pooled data from four 26-week, phase 3 studies (N = 2313; NCT01081834, NCT01106677, NCT01106625, NCT01106690). The proportion of patients achieving the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg was also evaluated., Results: At week 26, greater proportions of patients met individual HbA1c, BW, and systolic BP targets with canagliflozin versus placebo. A greater proportion of patients treated with canagliflozin 100 or 300 mg versus placebo also achieved the composite endpoint of HbA1c reduction ≥0.5%, BW reduction ≥3%, and systolic BP reduction ≥4 mmHg at week 26 (21.1%, 25.3%, and 5.7%, respectively; odds ratios [95% CI] of 4.5 [3.1, 6.5] and 5.6 [3.8, 8.2]). A greater proportion of patients also achieved the composite endpoint of HbA1c <7.0%, BW reduction ≥3%, and BP <130/80 mmHg with canagliflozin 100 and 300 mg versus placebo (14.7%, 20.9%, and 3.3%, respectively; odds ratios [95% CI] of 5.2 [3.2, 8.4] and 8.4 [5.2, 13.5]). Canagliflozin was generally well tolerated, with a safety profile similar to that seen in other phase 3 studies., Conclusions: Patients with T2DM were more likely to achieve clinically important reductions in HbA1c, BW, and systolic BP with canagliflozin versus placebo.

Background: Sodium glucose co-transporter 2 inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM)., Objectives: The goal of this study was to examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM., Methods: In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, the study assessed the median percent change in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), soluble (s)ST2, and galectin-3 from baseline to 26, 52, and 104 weeks., Results: Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients, but they remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the difference in median percent change between pooled canagliflozin and placebo were -15.0%, -16.1%, and -26.8% for NT-proBNP, and -8.3%, -11.9%, and -10.0% for hsTnI at weeks 26, 52, and 104, respectively (all p < 0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks but not at 104 weeks. These results remained unchanged when only patients with complete samples were assessed., Conclusions: Compared with placebo, treatment with canagliflozin delayed the rise in serum NT-proBNP and hsTnI for over 2 years in older T2DM patients. These cardiac biomarker data provide support for the beneficial cardiovascular effect of sodium glucose co-transporter 2 inhibitors in T2DM. (A Safety and Efficacy Study of Canagliflozin in Older Patients [55 to 80 Years of Age] With Type 2 Diabetes Mellitus; NCT01106651)., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The objective of this study was to evaluate the effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on serum magnesium in hypomagnesemic patients with type 2 diabetes., Methods: This post hoc analysis was based on pooled data from four placebo-controlled studies of canagliflozin (N = 2313). The proportion of patients with baseline serum magnesium <0.74 mmol/L who achieved serum magnesium ≥0.74 mmol/L at week 26 was evaluated., Results: At week 26, canagliflozin 100 and 300 mg increased serum magnesium versus placebo in patients with baseline serum magnesium <0.74 mmol/L (17.0% and 19.0% vs 3.9%) and ≥0.74 mmol/L (4.9% and 7.0% vs -1.4%). More patients with baseline serum magnesium <0.74 mmol/L had serum magnesium ≥0.74 mmol/L at week 26 with canagliflozin 100 and 300 mg versus placebo (74.1% and 80.6% vs 28.8%)., Conclusions: Canagliflozin was associated with normalization of serum magnesium in hypomagnesemic patients with type 2 diabetes, potentially leading to improved cardiometabolic outcomes., Clinical Trial Registration: ClinicalTrials.gov Identifiers, NCT01081834, NCT01106677, NCT01106625, NCT01106690.

Background: Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors., Methods: Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports., Results: At week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (-0.95 and -1.07%) versus no history of CV disease (-0.71 and -0.90%), history of hypertension (-0.72 and -0.89%) versus no history of hypertension (-0.73 and -0.95%), baseline statin use (-0.77 and -0.99%) versus no statin use (-0.69 and -0.85%), and 0-1 CV risk factor (-0.72 and -0.87%) versus ≥2 CV risk factors (-0.74 and -1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups., Conclusions: The efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors. Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010.

Background: Physiologic determinants, such as pulse pressure [difference between systolic blood pressure (SBP) and diastolic BP (DBP)], mean arterial pressure (2/3 DBP + 1/3 SBP), and double product [beats per minute (bpm) × SBP], are linked to cardiovascular outcomes. The effects of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on pulse pressure, mean arterial pressure, and double product were assessed in patients with type 2 diabetes mellitus (T2DM)., Methods: This post hoc analysis was based on pooled data from four 26-week, randomized, double-blind, placebo-controlled studies evaluating canagliflozin in patients with T2DM (N = 2313) and a 6-week, randomized, double-blind, placebo-controlled, ambulatory BP monitoring (ABPM) study evaluating canagliflozin in patients with T2DM and hypertension (N = 169). Changes from baseline in SBP, DBP, pulse pressure, mean arterial pressure, and double product were assessed using seated BP measurements (pooled studies) or averaged 24-h BP assessments (ABPM study). Safety was assessed based on adverse event reports., Results: In the pooled studies, canagliflozin 100 and 300 mg reduced SBP (-4.3 and -5.0 vs -0.3 mmHg) and DBP (-2.5 and -2.4 vs -0.6 mmHg) versus placebo at week 26. Reductions in pulse pressure (-1.8 and -2.6 vs 0.2 mmHg), mean arterial pressure (-3.1 and -3.3 vs -0.5 mmHg), and double product (-381 and -416 vs -30 bpm × mmHg) were also seen with canagliflozin 100 and 300 mg versus placebo. In the ABPM study, canagliflozin 100 and 300 mg reduced mean 24-h SBP (-4.5 and -6.2 vs -1.2 mmHg) and DBP (-2.2 and -3.2 vs -0.3 mmHg) versus placebo at week 6. Canagliflozin 300 mg provided reductions in pulse pressure (-3.3 vs -0.8 mmHg) and mean arterial pressure (-4.2 vs -0.6 mmHg) compared with placebo, while canagliflozin 100 mg had more modest effects on these parameters. Canagliflozin was generally well tolerated in both study populations., Conclusions: Canagliflozin improved all three cardiovascular physiologic markers, consistent with the hypothesis that canagliflozin may have beneficial effects on some cardiovascular outcomes in patients with T2DM. Trial registration ClinicalTrials.gov Identifier: NCT01081834 (registered March 2010); NCT01106677 (registered April 2010); NCT01106625 (registered April 2010); NCT01106690 (registered April 2010); NCT01939496 (registered September 2013).

Objectives: To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions in both glycated hemoglobin (HbA1c) and body weight with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus sitagliptin over 52 weeks., Methods: Data were pooled from two, randomized, Phase 3 studies of canagliflozin 100 and 300 mg versus sitagliptin 100 mg as add-on to metformin, and canagliflozin 300 mg versus sitagliptin 100 mg as add-on to metformin plus sulfonylurea (N = 1856). The composite end points of change from baseline in both HbA1c <0% and body weight <0 kg, and attainment of HbA1c <7.0% and body weight reduction ≥5% at Week 52 were evaluated. Safety was assessed based on adverse event reports., Results: Canagliflozin provided reductions in HbA1c and body weight over 52 weeks versus sitagliptin. A greater proportion of patients had both HbA1c and body weight reductions with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (67.7%, 72.6%, and 44.1%, respectively). Among patients with HbA1c and body weight reductions, more patients achieved the composite end point of HbA1c <7.0% and body weight reduction ≥5% with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (18.9%, 18.3%, and 5.7%, respectively). Canagliflozin was generally well tolerated., Conclusions: A greater proportion of patients with T2DM achieved reductions in both HbA1c and body weight, and more patients with HbA1c and body weight reductions achieved HbA1c <7.0% and body weight reduction ≥5% with canagliflozin versus sitagliptin over 52 weeks., Clinical Trial Registration: www.ClinicalTrials.gov identifiers are NCT01106677; NCT01137812.

Background: The randomized, double-blind CANTATA-SU (CANagliflozin Treatment And Trial Analysis Sulfonyl Urea) clinical trial compared the use of canagliflozin (100 mg or 300 mg) and maximally tolerated glimepiride (6-8 mg) over 104 weeks as add-on therapy for patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Compared with glimepiride, canagliflozin use was associated with durable reductions in glycated hemoglobin (A1C), blood pressure (BP), and body weight. The aim of this post-hoc analysis of the CANTATA-SU trial was to assess the comparative efficacy of canagliflozin and glimepiride in the attainment of recently updated diabetes-related quality measures (QMs) for up to 104 weeks of treatment., Methods: This post-hoc analysis evaluated the proportions of patients achieving individual diabetes-related QMs using data from the randomized, double-blind, Phase 3 CANTATA-SU trial. Change in A1C from baseline, and proportions of the study population achieving QMs: A1C <7.0 %, <8.0 %, and >9.0 % were assessed. Secondary endpoints included change in BP from baseline, and the proportions of the study population achieving QMs related to BP and body weight., Results: The proportions of patients in the canagliflozin 100 mg, canagliflozin 300 mg, and glimepiride groups meeting criteria for all QMs were similar at baseline. At 52 and 104 weeks of treatment, canagliflozin 100 mg and canagliflozin 300 mg provided better or similar reductions in A1C from baseline and achievement of glycemic control QMs compared with glimepiride. At 52 and 104 weeks of treatment, the attainment of QMs related to reductions in body weight and BP all favored canagliflozin compared with glimepiride. Canagliflozin was associated with lower incidence of documented hypoglycemia and severe hypoglycemia compared with glimepiride., Conclusions: Using the recently adjusted and currently accepted diabetes-related QMs, this analysis observed superior glycemic control with canagliflozin compared with maximally tolerated glimepiride in patients with T2DM who were previously poorly controlled on metformin monotherapy. Compared with maximally tolerated glimepiride, canagliflozin resulted in better achievement of diabetes-related QMs related to weight loss and BP, and was associated with lower incidences of hypoglycemic events., Trial Registration: Clinical trial registry name: CANagliflozin Treatment And Trial Analysis-Sulfonylurea (CANTATA-SU) SGLT2 Add-on to Metformin Versus Glimepiride., Clinical Trial Registration Number: NCT00968812 , registered August 28, 2009.

The PI3K pathway is commonly activated in cancer. Only a few studies have attempted to explore the spectrum of phosphorylation signaling downstream of the PI3K cascade. Such insight, however, is imperative to understand the mechanisms responsible for oncogenic phenotypes. By applying MS-based phosphoproteomics, we mapped 2509 phosphorylation sites on 1096 proteins, and quantified their responses to activation or inhibition of PIK3CA using isogenic knock-in derivatives and a series of targeted inhibitors. We uncovered phosphorylation changes in a wide variety of proteins involved in cell growth and proliferation, many of which have not been previously associated with PI3K signaling. A significant update of the posttranslational modification database PHOSIDA (http://www.phosida.com) allows efficient use of the data. All MS data have been deposited in the ProteomeXchange with identifier PXD003899 (http://proteomecentral.proteomexchange.org/dataset/PXD003899)., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has demonstrated sustained improvements in glycemic control and body weight reductions with treatment for up to 104 weeks in a broad range of patients with type 2 diabetes mellitus (T2DM)., Methods: This was a post hoc analysis of individual patient data (N = 1450) from a randomized, double-blind, placebo-controlled, Phase 3 study comparing canagliflozin with glimepiride as add-on to metformin in patients with T2DM during a 52-week core period followed by a 52-week extension period. The number of patients who achieved a reduction from baseline in both HbA1c and body weight with canagliflozin 100 and 300 mg and glimepiride was assessed at Weeks 52 and 104. Safety was recorded as adverse events (AEs) during the study., Results: Canagliflozin 100 and 300 mg provided durable glycemic improvements and body weight reductions compared with glimepiride over 104 weeks. At Week 52, the proportion of patients who achieved reductions in both HbA1c and body weight was 72.4% with canagliflozin 100 mg, 78.5% with canagliflozin 300 mg, and 26.8% with glimepiride; similar results were observed at Week 104 (65.5%, 71.1%, and 26.8% with canagliflozin 100 and 300 mg and glimepiride, respectively). The AE profile of canagliflozin was comparable to that observed in previous studies, with increased incidence of AEs related to the mechanism of SGLT2 inhibition (e.g., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs) and a low risk of hypoglycemia., Conclusion: More patients treated with canagliflozin experienced reductions in both HbA1c and body weight compared with glimepiride for up to 104 weeks. Canagliflozin was generally well tolerated in patients with T2DM when used in combination with metformin., Clinical Trial Registration: ClinicalTrials.gov identifier, NCT00968812., Funding: Janssen Research & Development, LLC.

Objective: To assess the efficacy and safety of the sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin in patients of different ethnicities., Design Setting and Patients: Post hoc analysis of data pooled from four randomized, placebo-controlled, phase 3 studies of adults with inadequately controlled type 2 diabetes mellitus (T2DM)., Interventions: Once daily oral canagliflozin 100 mg or 300 mg, or placebo., Main Outcome Measures: Efficacy endpoints included change from baseline in HbA1c, body weight (BW), systolic blood pressure (SBP), and lipids at week 26; safety and tolerability were assessed by adverse event reports., Results: Of the 2,313 patients included in this pooled analysis, 609 self-identified as Hispanic/Latino. Hispanic/Latino patients had a mean age of 54 years, mean duration of T2DM of 7 years, mean HbA1c of 8.1%, mean body mass index of 31.2 kg/m(2), and mean SBP of 126.1 mm Hg. There were more women in the non-Hispanic/Latino cohort (63%) compared with the Hispanic/Latino cohort. Placebo-subtracted changes in HbA1c were -.82% with canagliflozin 100 mg and -.94% with canagliflozin 300 mg in the Hispanic/Latino cohort, which were similar to reductions observed in the non-Hispanic/Latino cohort. Significantly greater dose-related reductions in HbA1c, BW, and SBP were observed with both canagliflozin doses compared with placebo. Canagliflozin was generally well-tolerated. Genital mycotic infections were less frequent in Hispanic/Latino women than in non-Hispanic/Latino women., Conclusions: The SGLT2 inhibitor canagliflozin was generally well-tolerated and was associated with clinically meaningful reductions in HbA1c, BW, and SBP in both Hispanic/Latino and non-Hispanic/Latino patients with T2DM.

Objectives: To compare the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM), in individuals younger than 75 and those aged 75 and older., Design: Randomized Phase 3 studies., Setting: International study centers., Participants: Adults with T2DM., Measurements: Changes from baseline in glycosylated hemoglobin (HbA1c ), fasting plasma glucose (FPG), blood pressure (BP), and body weight were measured. Efficacy was evaluated using pooled data from six randomized, double-blind, placebo-controlled studies (N = 4,158; n = 3,975 aged <75, n = 183 aged ≥75). Safety was assessed based on adverse event (AE) reports from eight randomized, double-blind, placebo- and active-controlled studies (N = 9,439; n = 8,949 aged <75, n = 490 aged ≥75)., Results: Canagliflozin 100 and 300 mg were associated with placebo-subtracted mean reductions in HbA1c in participants younger than 75 (-0.69% and -0.85%, respectively) and aged 75 and older (-0.65% and -0.55%, respectively). Dose-related reductions in FPG, body weight, and BP were seen with canagliflozin 100 and 300 mg in participants in both age groups. Overall AE incidence was 67.1% with canagliflozin 100 mg, 68.6% with canagliflozin 300 mg, and 65.9% with non-canagliflozin (pooled group of comparators in all studies) in participants younger than 75, and 72.4%, 79.1%, and 72.3%, respectively, in those aged 75 and older, with a similar safety profile in both groups. The incidence of volume depletion-related AEs was 2.2%, 3.1%, and 1.4% in participants younger than 75 with canagliflozin 100 and 300 mg and non-canagliflozin, respectively, and 4.9%, 8.7%, and 2.6%, respectively, in those aged 75 and older., Conclusion: Canagliflozin improved glycemic control, body weight, and BP in participants aged 75 and older. The overall incidence of AEs was high across treatment groups in participants aged 75 and older and higher than in those younger than 75. The safety profile of canagliflozin was generally similar in both age groups, with a higher incidence of AEs related to volume depletion observed with canagliflozin in participants aged 75 and older than in those younger than 75. These findings support canagliflozin, starting with the 100-mg dose, as an effective therapeutic option for older adults with T2DM., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

This randomized, double-blind, placebo-controlled study evaluated the early effects of canagliflozin on blood pressure (BP) in patients with type 2 diabetes mellitus (T2DM) and hypertension. Patients were randomized to canagliflozin 300 mg, canagliflozin 100 mg, or placebo for 6 weeks and underwent 24-hour ambulatory BP monitoring before randomization, on day 1 of treatment, and after 6 weeks. The primary endpoint was change in mean 24-hour systolic BP (SBP) from baseline to week 6. Overall, 169 patients were included (mean age, 58.6 years; glycated hemoglobin, 8.1%; seated BP 138.5/82.7 mm Hg). At week 6, canagliflozin 300 mg provided greater reductions in mean 24-hour SBP than placebo (least squares mean -6.2 vs -1.2 mm Hg, respectively; P=.006). Numerical reductions in SBP were observed with canagliflozin 100 mg. Canagliflozin was generally well tolerated, with side effects similar to those reported in previous studies. These results suggest that canagliflozin rapidly reduces BP in patients with T2DM and hypertension., (© 2015 Wiley Periodicals, Inc.)

Background: Chronic kidney disease is commonly associated with type 2 diabetes mellitus (T2DM) and may impact the efficacy and safety of glucose-lowering therapies. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces blood glucose levels in patients with T2DM by lowering the renal threshold for glucose, thereby promoting urinary glucose excretion. This review describes the pharmacology, efficacy and safety of canagliflozin according to kidney function in participants with T2DM., Methods: Published articles that reported efficacy, safety and pharmacokinetics/pharmacodynamics data for canagliflozin in patients with T2DM and impaired renal function, and renal safety data with canagliflozin in various populations of patients with T2DM through May 2015 were included., Results: Early transient reductions in estimated glomerular filtration rate were observed with canagliflozin; these changes generally stabilized or attenuated over time and reversed after discontinuation, suggesting no renal (glomerular or tubular) damage with canagliflozin treatment. Urinary albumin-to-creatinine ratios were reduced with canagliflozin. Canagliflozin was generally well tolerated in patients with normal or mild to moderately impaired renal function, with a modestly higher incidence of renal-related adverse events and volume depletion-related adverse events in patients with moderate renal impairment. Adverse events related to potassium elevations were infrequent with canagliflozin 100 mg regardless of kidney function status; however, patients with moderately impaired kidney function experienced hyperkalemia more frequently with canagliflozin 300 mg compared with patients treated with either canagliflozin 100 mg or placebo. Canagliflozin was not associated with increased cardiovascular risk across studies; however, relatively few events among patients with impaired renal function meant that the analysis was not adequately powered to examine this outcome, and results from separate trials are awaited., Conclusions: Overall, canagliflozin is associated with small, transient changes in kidney function, and is well tolerated in patients with T2DM with varying kidney function status.

Objective: To evaluate attainment of diabetes-related treatment goals with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus placebo in patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: Data were pooled from four 26-week, placebo-controlled, Phase 3 studies of patients with T2DM (N = 2313). Goal attainment with canagliflozin 100 and 300 mg versus placebo was evaluated in the overall population, and in subgroups based on age and sex, at baseline and Week 26., Clinical Trial Registration: ClinicalTrials.gov NCT01081834, NCT01106677, NCT01106625, NCT01106690., Main Outcome Measures: Proportion of patients achieving hemoglobin A1C (A1C) < 7.0% and ≤ 6.5%, systolic blood pressure (SBP) < 140 and < 130 mmHg, diastolic blood pressure (DBP) < 90 and < 80 mmHg, low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL (2.6 mmol/L), high-density lipoprotein cholesterol (HDL-C) ≥ 40 mg/dL (1.0 mmol/L), and the composite endpoint of A1C < 7.0%, BP < 130/80 mmHg, and LDL-C <100 mg/dL (2.6 mmol/L) at baseline and Week 26, and proportion with body weight reduction ≥ 5% at Week 26., Results: At baseline, similar proportions of patients met diabetes-related treatment goals across groups. At Week 26, a greater proportion of patients achieved A1C, SBP, DBP, and HDL-C goals with canagliflozin 100 and 300 mg compared with placebo. More patients achieved body weight reduction of ≥ 5% with canagliflozin 100 and 300 mg versus placebo at Week 26. Fewer patients had LDL-C < 100 mg/dL (2.6 mmol/L) at Week 26 with canagliflozin 100 and 300 mg versus placebo. Canagliflozin 100 and 300 mg also provided better attainment of the composite endpoint of A1C <7.0%, BP < 130/80 mmHg, and LDL-C < 100 mg/dL (2.6 mmol/L) compared with placebo. Attainment of diabetes-related treatment goals was generally similar regardless of age and sex. Key limitations of this analysis include the selection of specific treatment targets that may not be reflective of all patient experiences, the non-prespecified, post hoc nature of the analysis, and the short duration of studies included in the pooled population., Conclusion: Canagliflozin was associated with better attainment of diabetes-related treatment goals compared with placebo, and was generally well tolerated at 26 weeks.

Purpose: This post hoc analysis evaluated attainment of diabetes-related composite quality measures (CQMs) with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus (T2DM). We used pooled data from two 52-week Phase III clinical trials evaluating the efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg., Methods: CQMs assessed included the combined attainment of glycosylated hemoglobin (HbA1c), blood pressure (BP), and LDL-C. To assess on-treatment differences at 52 weeks, odds ratios (ORs) and associated 95% CIs were calculated based on a logistic regression model. CQM attainment was assessed in the overall population and for patients with a body mass index ≥25 kg/m(2) at baseline., Findings: Overall, baseline demographic and disease characteristics were comparable across treatment groups. Proportions of patients with T2DM meeting the CQMs HbA1c <7.0%, BP <130/80 mm Hg, and LDL-C <100 mg/dL and HbA1c <8.0%, BP <140/90 mm Hg, and LDL-C <100 mg/dL were similar at baseline. After 52 weeks of treatment, the proportion of patients meeting both CQMs was similar for canagliflozin 100 mg and sitagliptin 100 mg, and favored canagliflozin 300 mg versus sitagliptin 100 mg. For canagliflozin 300 mg, the OR was 1.79 (95% CI, 1.25-2.58) for the CQM HbA1c <7.0%, BP <130/80 mm Hg, and LDL-C <100 mg/dL; the OR was 1.49 (95% CI, 1.15-1.92) for the CQM HbA1c <8.0%, BP <140/90 mm Hg, and LDL-C <100 mg/dL. CQM attainments for patients with a body mass index ≥25 kg/m(2) were similar to those for the overall population., Implications: At 52 weeks of treatment, this analysis observed comparable CQM attainment for canagliflozin 100 mg, and superior CQM attainment for canagliflozin 300 mg, compared with sitagliptin 100 mg. ClinicalTrials.gov identifiers are NCT01106677 and NCT01137812., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, enhances urinary glucose excretion through an insulin-independent mode of action, and improves glycemic control in patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of canagliflozin across racial groups., Methods: The efficacy of canagliflozin 100 mg and 300 mg was evaluated by racial group using data pooled from four placebo-controlled phase 3 studies and two placebo-controlled sub-studies of a population of patients with inadequately controlled T2DM (N = 4158). Least-squares mean changes from baseline were calculated for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), body weight (BW), cholesterol, and triglycerides. Safety/tolerability evaluation included reporting of general and prespecified adverse events (AEs)., Results: A total of 75% of patients were White, 13% were Asian, 4% were Black/African American, and 8% were 'Other' (American Indian, Alaskan Native, mixed race, Native Hawaiian or other Pacific Islander, not reported, and unknown). Baseline demographics were similar for these groups. Dose-related reductions in HbA1c, BW, and SBP were observed with both canagliflozin doses in all racial groups. Canagliflozin was generally safe and well tolerated. Treatment with canagliflozin was associated with an increased rate of genital mycotic infections (GMIs) and urinary tract infections (UTIs) in all racial groups. GMIs were observed more often in Black/African American males and males from the 'Other' racial group, whereas UTIs and osmotic diuresis-related AEs were less common in Asians. Key study limitations include the high proportion of White patients compared with other racial groups and the fact that included studies were not powered to evaluate racial differences., Conclusion: Canagliflozin was generally well tolerated and consistently associated with reductions in HbA1c, BW, and SBP in patients with T2DM independent of racial background. (ClinicalTrials.gov numbers: NCT01081834; NCT01106677; NCT01106625; NCT01106690; and NCT01032629.).

Objective: To evaluate attainment of diabetes-related quality measures with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus., Study Design: This post hoc analysis used pooled data from two 52-week, randomized, double-blind, phase 3 clinical trials that evaluated the comparative efficacy of canagliflozin and sitagliptin. One trial evaluated patients on metformin at baseline with add-on canagliflozin 100 mg, canagliflozin 300 mg, or sitagliptin 100 mg; the other trial evaluated patients on metformin and a sulfonylurea at baseline with add-on canagliflozin 300 mg or sitagliptin 100 mg., Methods: Individual diabetes-related quality measures, including glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), and change in body weight, were assessed., Results: At baseline, the proportions of patients meeting criteria for all quality measures were similar between groups. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 100 mg demonstrated either comparable or superior glycemic control. Additionally, canagliflozin 100 mg versus sitagliptin 100 mg demonstrated superior attainment of BP, BMI, and weight-related quality measures; no difference was seen with respect to LDL-C. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 300 mg demonstrated superior glycemic control at all thresholds of A1C, and superior BP, BMI, and weight-related quality measures; there was no difference in LDL-C quality measure attainment., Conclusion: We evaluated the comparative efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg on quality measure attainment after 52 weeks of treatment. Compared with sitagliptin 100 mg, canagliflozin 100 mg demonstrated comparable or superior attainment of diabetes-related quality measures. Compared with sitagliptin 100 mg, canagliflozin 300 mg demonstrated superior diabetes-related quality measure attainment, including glycemic, BP, and weight-related quality measures; there was no difference in LDL-C quality measure attainment between either dosage of canagliflozin and the 100-mg dosage of sitagliptin.

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis- and intravascular volume reduction-related adverse events (AEs) were evaluated using pooled data from four placebo-controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (-4.3 mm Hg [-5.0 to -3.5], -5.0 mm Hg [-5.8 to -4.2], and -0.3 mm Hg [-1.2 to 0.5], respectively) and in diastolic BP (DBP; -2.5 mm Hg [-2.9 to -2.0], -2.4 mm Hg [-2.9 to -1.9], and -0.6 mm Hg [-1.1 to -0.02], respectively). Placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -4.0 mm Hg (-5.1 to -2.8) and -4.7 mm Hg (-5.8 to -3.5) and reductions in DBP were -1.9 mm Hg (-2.6 to -1.2) and -1.9 mm Hg (-2.6 to -1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (≥140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (-12.8 mm Hg [-15.2 to -10.5], -14.2 mm Hg [-16.4 to -12.0], and -6.8 mm Hg [-9.1 to -4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP ≥90 mm Hg at baseline (-5.9 mm Hg [-8.2 to -3.6], -9.0 mm Hg [-11.1 to -6.9], and -7.4 mm Hg [-9.6 to -5.1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -6.0 mm Hg (-9.1 to -2.9) and -7.4 mm Hg (-10.4 to -4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg (-1.6 to 4.5) and -1.6 mm Hg (-4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis-related AEs (e.g., pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction., (Copyright © 2014 Wiley Periodicals, Inc.)