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Background: High-quality colonoscopic surveillance can lead to earlier and increased detection of colorectal neoplasia in patients with inflammatory bowel disease (IBD). In IBD clinical trials, endoscopy is used to assess mucosal disease activity before and after treatment but also provides an opportunity to surveil for colorectal neoplasia during follow-up., Summary: Best practices for colorectal cancer identification in IBD clinical trials require engagement and collaboration between the clinical trial sponsor, site endoscopist and/or principal investigator, and central read team. Each team member has unique responsibilities for maximizing dysplasia detection in IBD trials., Key Messages: Sponsors should work in accordance with scientific guidelines to standardize imaging procedures, design the protocol to ensure the trial population is safeguarded, and oversee trial conduct. The site endoscopist should remain updated on best practices to tailor sponsor protocol-required procedures to patient needs, examine the mucosa for disease activity and potential dysplasia during all procedures, and provide optimal procedure videos for central read analysis. Central readers may detect dysplasia or colorectal cancer and a framework to report these findings to trial sponsors is essential. Synergistic relationships between all team members in IBD clinical trials provide an important opportunity for extended endoscopic evaluation and colorectal neoplasia identification., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Artificial intelligence shows promise for clinical research in inflammatory bowel disease endoscopy. Accurate assessment of endoscopic activity is important in clinical practice and inflammatory bowel disease clinical trials. Emerging artificial intelligence technologies can increase efficiency and accuracy of assessing the baseline endoscopic appearance in patients with inflammatory bowel disease and the impact that therapeutic interventions may have on mucosal healing in both of these contexts. In this review, state-of-the-art endoscopic assessment of mucosal disease activity in inflammatory bowel disease clinical trials is described, covering the potential for artificial intelligence to transform the current paradigm, its limitations, and suggested next steps. Site-based artificial intelligence quality evaluation and inclusion of patients in clinical trials without the need for a central reader is proposed; for following patient progress, a second reading using AI alongside a central reader with expedited reading is proposed. Artificial intelligence will support precision endoscopy in inflammatory bowel disease and is on the threshold of advancing inflammatory bowel disease clinical trial recruitment., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Inflammatory bowel disease encompasses Crohn's disease and ulcerative colitis and is characterized by uncontrolled, relapsing, and remitting course of inflammation in the gastrointestinal tract. Artificial intelligence represents a new era within the field of gastroenterology, and the amount of research surrounding artificial intelligence in patients with inflammatory bowel disease is on the rise. As clinical trial outcomes and treatment targets evolve in inflammatory bowel disease, artificial intelligence may prove as a valuable tool for providing accurate, consistent, and reproducible evaluations of endoscopic appearance and histologic activity, thereby optimizing the diagnosis process and identifying disease severity. Furthermore, as the applications of artificial intelligence for inflammatory bowel disease continue to expand, they may present an ideal opportunity for improving disease management by predicting treatment response to biologic therapies and for refining the standard of care by setting the basis for future treatment personalization and cost reduction. The purpose of this review is to provide an overview of the unmet needs in the management of inflammatory bowel disease in clinical practice and how artificial intelligence tools can address these gaps to transform patient care.

Background: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease., Methods: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed., Results: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod., Conclusions: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.)., (Copyright © 2021 Massachusetts Medical Society.)

Background and Aims: This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE]., Methods: Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study., Results: Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15-18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up., Conclusions: There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126]., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Central reading, that is, independent, off-site, blinded review or reading of imaging endpoints, has been identified as a crucial component in the conduct and analysis of inflammatory bowel disease clinical trials. Central reading is the final step in a workflow that has many parts, all of which can be improved. Furthermore, the best reading algorithm and the most intensive central reader training cannot make up for deficiencies in the acquisition stage (clinical trial endoscopy) or improve on the limitations of the underlying score (outcome instrument). In this review, academic and industry experts review scoring systems, and propose a theoretical framework for central reading that predicts when improvements in statistical power, affecting trial size and chances of success, can be expected: Multireader models can be conceptualised as statistical or non-statistical (social). Important organisational and operational factors, such as training and retraining of readers, optimal bowel preparation for colonoscopy, video quality, optimal or at least acceptable read duration times and other quality control matters, are addressed as well. The theory and practice of central reading and the conduct of endoscopy in clinical trials are interdisciplinary topics that should be of interest to many, regulators, clinical trial experts, gastroenterology societies and those in the academic community who endeavour to develop new scoring systems using traditional and machine learning approaches., Competing Interests: Competing interests: Klaus Gottlieb is an employee and stockholder of Eli Lilly and Company. Marco Daperno reports personal fee from AbbVie, Chiesi, Ferring, Janssen, MD, Pfizer, and Quintiles, grants and personal fees from Takeda, and nonfinancial support from SOFAR and Mundifarma.Keith Usiskin is an employee of Celgene now Bristol Myers Squibb. Bruce Sands has received personal fees from AbbVie, Akros Pharma, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Forward Pharma, Bristol-Myers Squibb, Immune Pharmaceuticals, Shire, Synergy Pharmaceuticals, Theravance Biopharma R&D, TiGenix, TopiVert Pharma, Receptos, Allergan, EnGene, Target PharmaSolutions, Lycera, Lyndra, Ironwood Pharmaceuticals, Salix; grants, personal fees and non-financial support from Celgene, Takeda, Pfizer, Janssen, personal fees and non-financial support from Prometheus Laboratories, Hoffman-La Roche, MedImmune, Lilly, Vivelix Pharmaceuticals, UCB, Oppilan Pharmaceuticals, Gilead, Rheos Medicines, Seres Therapeutics, 4D Pharma, Capella Bioscience, Otsuka, Ferring, Protagonist Therapeutics, Palatin Technologies.Harris Ahmad is an employee of Bristol-Myers Squibb. Colin Howden reports being a consultant for Phathom Pharmaceuticals, Ironwood, RedHill Biopharma, Alfasigma, OtsukaStockholder in Antibe Therapeutics andCo-Editor of Alimentary Pharmacology & Therapeutics.William Karnes reports that he is CMO, cofounder, shareholder and paid contractor for Docbot.Young Oh is an employee of Genentech, a member of the Roche Group and a Roche stock holder. Irene Modesto is and employee and stockholders of Pfizer. Colleen Marano is an employee of Janssen. Ryan Stidham reports consultancy for Abbvie, Janssen, Merck, Takeda. Investigator initiated research support from Abbvie. University of Michigan has filed a provisional patent on behalf of RWS related to machine learning for endoscopic evaluation in IBD.Walter Reinisch has served as a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, as a consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC, as an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC, and has received research funding from Abbott Laboratories, Abbvie, Aesca, Centocor, Falk Pharma, Immundiagnsotik, MD., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy., Methods: We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1., Results: Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea., Conclusions: Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: The objective was to assess the efficacy and safety of GED-0301, an antisense oligodeoxynucleotide to Smad7, in active Crohn's disease (CD)., Methods: This phase 3, blinded study randomized patients (1:1:1:1) to placebo or 1 of 3 once-daily oral GED-0301 regimens: 160 mg for 12 weeks followed by 40 mg continuously or alternating placebo with 40 or 160 mg every 4 weeks through week 52., Results: In all, 701 patients were randomized and received study medication before premature study termination; 78.6% (551/701) completed week 12, and 5.8% (41/701) completed week 52. The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo. More placebo vs GED-0301 patients achieved endoscopic response (>50% decrease from baseline Simple Score for CD) at week 12 (18.1% vs 10.1%). Additional endoscopic endpoints were similar between groups at weeks 12 and 52. More placebo vs GED-0301 patients had clinical response (≥100-point decrease in the CD Activity Index score) at week 12 (44.4% vs 33.3%); at week 52, clinical response rates were similar. Adverse events were predominantly gastrointestinal and related to active CD, consistent with lack of clinical and endoscopic response to treatment. Two deaths occurred (GED-0301 total group) due to small intestinal obstruction and pneumonia; neither was suspected by the investigator to be treatment-related., Discussion: GED-0301 did not demonstrate efficacy vs placebo in active CD.

GED-0301 is an antisense oligodeoxynucleotide with a sequence complementary to the Smad7 mRNA transcript. Smad7 is a negative regulator of transforming growth factor-β, which is increased in the intestinal mucosa of patients with active Crohn's disease (CD). We randomly assigned 63 CD patients to 4-, 8-, or 12-week treatment groups receiving oral GED-0301 (160 mg/day). The primary objective was to determine GED-0301's effect on endoscopic CD measures; secondary objectives included effects on clinical activity. Endoscopic improvement was observed in 37% of participants with evaluable endoscopy results at week 12. At week 12, 32% (4 weeks), 35% (8 weeks), and 48% (12 weeks) of patients receiving GED-0301 were in remission (CD activity index score <150); corresponding reductions from baseline in mean CD activity index scores were -124, -112, and -133 points. No new safety signals were observed. These findings support a GED-0301 benefit in active CD. ClinicalTrials.gov no: NCT02367183., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn's disease (CD)., Aim: In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy., Methods: Patients with steroid-dependent/resistant, active CD were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn's Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction ≥100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/≥5 years, human serum C-reactive protein (hsCRP) <3/≥3 mg/L, and CDAI at baseline ≤260/>260. Additional patient baseline and disease characteristics were explored., Results: Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI ≤260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated., Conclusions: Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.)., (© 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Context: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM)., Objective: Our objective is to describe the effects of canagliflozin on bone mineral density (BMD) and bone biomarkers in patients with T2DM., Design: This was a randomized study, consisting of a 26-week, double-blind, placebo-controlled period and a 78-week, double-blind, placebo-controlled extension., Setting: This study was undertaken in 90 centers in 17 countries., Patients: Patients were aged 55-80 years (N = 716) and whose T2DM was inadequately controlled on a stable antihyperglycemic regimen., Interventions: Canagliflozin 100 or 300 mg or placebo were administered once daily., Outcome and Measures: BMD was assessed using dual-energy x-ray absorptiometry at weeks 26, 52, and 104. Bone strength was assessed using quantitative computed tomography and finite element analysis at week 52. Serum collagen type 1 β-carboxy-telopeptide, osteocalcin, and estradiol were assessed at weeks 26 and 52., Results: Canagliflozin doses of 100 and 300 mg were associated with a decrease in total hip BMD over 104 weeks, (placebo-subtracted changes: -0.9% and -1.2%, respectively), but not at other sites measured (femoral neck, lumbar spine, or distal forearm). No meaningful changes in bone strength were observed. At week 52, canagliflozin was associated with an increase in collagen type 1 β-carboxy-telopeptide that was significantly correlated with a reduction in body weight, an increase in osteocalcin, and, in women, a decrease in estradiol., Conclusions: In older patients with T2DM, canagliflozin showed small but significant reductions in total hip BMD and increases in bone formation and resorption biomarkers, due at least in part to weight loss.

Context: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM)., Objective: The purpose of this study was to describe the effects of canagliflozin on bone fracture risk., Design and Setting: This was a randomized phase 3 study in patients with T2DM., Patients and Interventions: Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867)., Outcome Measures: The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed., Results: The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population., Conclusions: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.

Aims/hypothesis: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces HbA1c, body weight and systolic BP (SBP) in patients with type 2 diabetes. As weight loss is known to reduce both HbA1c and SBP, these analyses were performed to evaluate the contribution of weight loss resulting from treatment with canagliflozin to HbA1c and SBP reductions in patients with type 2 diabetes., Methods: Pooled data from four placebo-controlled Phase 3 studies (N = 2,250) in patients with type 2 diabetes were used in the analyses. In each study, patients were treated with placebo, canagliflozin 100 mg or canagliflozin 300 mg, once daily for 26 weeks. Changes from baseline in body weight, HbA1c and SBP were measured at week 26, and the contribution of weight loss to the lowering of HbA1c and SBP was obtained using ANCOVA., Results: Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p < 0.001 for each), and more patients had body-weight reductions >0%, ≥5% and ≥10% with canagliflozin treatment than with placebo. Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss., Conclusions/interpretation: In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c and SBP.

Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase-1 studies in healthy participants. In these open-label, fixed sequence studies, participants received: Study 1-glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4-8), canagliflozin with glyburide (Day 9); Study 2-metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4-7), metformin with canagliflozin (Day 8); Study 3-simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2-6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co-administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUC]) of glyburide and its metabolites (4-trans-hydroxy-glyburide and 3-cis-hydroxy-glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug-drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well-tolerated in healthy participants., (© 2014, The American College of Clinical Pharmacology.)

Aims: The long-term efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated over 104 weeks in patients aged 55-80 years with type 2 diabetes mellitus (T2DM) inadequately controlled on a stable antihyperglycaemic agent regimen., Methods: In this randomized, double-blind, phase III study, patients received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period (N = 714) and a 78-week extension period (n = 624). Efficacy endpoints at week 104 included change from baseline in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and systolic blood pressure, and percent change from baseline in body weight and fasting plasma lipids. Safety was assessed by adverse event (AE) reports., Results: At week 104, canagliflozin 100 and 300 mg were associated with reductions in HbA1c versus placebo (-0.32 and -0.43% vs 0.17%, respectively; overall mean baseline, 7.7%) and more patients achieved HbA1c <7.0% with canagliflozin 100 and 300 mg than with placebo (35.8 and 41.9% vs 20.3%, respectively). Reductions in FPG, body weight and systolic blood pressure, and increases in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were seen with canagliflozin compared with placebo. The overall incidence rates of AEs over 104 weeks were 88.0, 89.8 and 86.1% with canagliflozin 100 and 300 mg and placebo, respectively; serious AE rates were low across treatment groups. The incidence rates of urinary tract infections, genital mycotic infections and osmotic diuresis- and volume depletion-related AEs were higher with canagliflozin than with placebo., Conclusion: Canagliflozin improved glycaemic control, reduced body weight and systolic blood pressure, and was generally well tolerated in patients aged 55-80 years with T2DM over 104 weeks., (© 2014 John Wiley & Sons Ltd.)

Aim: This study evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and within a subset of Stage 3 chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] ≥ 30 and <50 ml/min/1.73 m(2))., Methods: In this 52-week, randomized, double-blind, placebo-controlled study, patients (N = 269; mean eGFR, 39.4 ml/min/1.73 m(2)) received canagliflozin 100 or 300 mg and placebo once daily. Efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and systolic blood pressure (BP); adverse events (AEs) were also recorded., Results: At week 52, canagliflozin 100 and 300 mg reduced HbA1c compared with placebo (-0.19, -0.33 and 0.07%, respectively); placebo-subtracted differences (95% confidence interval) were -0.27% (-0.53, 0.001) and -0.41% (-0.68, -0.14). Canagliflozin also lowered FPG, body weight and BP versus placebo. Overall AE incidence was 85.6, 80.9, and 86.7% with canagliflozin 100 and 300 mg and placebo, respectively. Osmotic diuresis-related AEs were more common with both canagliflozin doses, and incidences of urinary tract infections and volume depletion-related AEs were higher with canagliflozin 300 mg versus placebo. Decreases in eGFR (-2.1, -4.0 and -1.6 ml/min/1.73 m(2)) were seen with canagliflozin 100 and 300 mg compared with placebo. Canagliflozin 100 and 300 mg provided median percent reductions in urine albumin to creatinine ratio versus placebo (-16.4, -28.0 and 19.7%)., Conclusions: Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks., (© 2014 John Wiley & Sons Ltd.)

Objective: Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on serum electrolytes were evaluated using pooled data from studies of patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: Analyses were performed using two datasets, each including four placebo-controlled studies: Population 1 (N = 2215), patients with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) (mean = 89.6 mL/min/1.73 m(2)) and Population 2 (N = 721), patients with baseline eGFR ≥45 and <60 mL/min/1.73 m(2) (mean = 53.3 mL/min/1.73 m(2))., Clinical Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651., Main Outcome Measures: Mean percent changes from baseline in serum electrolytes (potassium, sodium, magnesium, bicarbonate, phosphate, calcium) and outlier analyses were assessed in patients receiving canagliflozin 100 and 300 mg or placebo. Potassium changes were further evaluated based on baseline therapy with anti-hypertensive agents that interfere with potassium excretion (renin-angiotensin aldosterone system-acting agents and/or potassium-sparing diuretics)., Results: Mean percent changes from baseline in potassium with canagliflozin 100 and 300 mg and placebo were 0.6%, 1.0%, and 0.5%, respectively (Week 26; Population 1); and 1.7%, 2.8%, and 0.7%, respectively (Week 18/26; Population 2). The proportion of patients who had potassium elevations meeting pre-defined outlier criteria (>5.4 mmol/L [5.4 mEq/L] and >15% increase from baseline) with canagliflozin 100 and 300 mg and placebo was 4.5%, 6.8%, and 4.7% (Population 1); and 5.2%, 9.1%, and 5.5% (Population 2). In both populations, potassium elevations were usually <6.5 mmol/L for patients treated with canagliflozin or placebo; elevations ≥6.5 mmol/L were rare but more frequent in patients taking anti-hypertensive agents that affect potassium excretion in both the canagliflozin and placebo groups. Small mean percent changes in sodium, bicarbonate, and calcium were seen across groups in both populations; small mean percent increases in magnesium and phosphate were seen with canagliflozin vs placebo, but without an increase in patients meeting outlier criteria. Adverse events related to changes in electrolytes were low across groups., Conclusions: In patients with T2DM, canagliflozin was generally associated with small mean percent changes in serum electrolytes. Infrequent episodes of potassium elevation occurred with canagliflozin 300 mg, but occurred more often in patients with reduced eGFR.

Objective: To characterize genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) using pooled data from Phase 3 studies., Research Design and Methods: Genital mycotic infections with canagliflozin 100 and 300 mg were evaluated in Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8), including patients from four placebo-controlled studies, and Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4), including patients from eight placebo/active-controlled studies (including older patients and those with renal impairment or high cardiovascular disease risk)., Clinical Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651; NCT00968812., Main Outcome Measures: Adverse events suggestive of genital mycotic infections were recorded, with additional information collected using supplemental electronic case report forms., Results: In Population 1, genital mycotic infection incidence was higher with canagliflozin 100 and 300 mg than placebo (95% confidence intervals excluded zero) in females (10.4%, 11.4%, 3.2%) and males (4.2%, 3.7%, 0.6%). These were generally mild to moderate in intensity, none were serious, and few led to discontinuation. Most events with canagliflozin were treated with antifungal therapies, and median symptom duration following treatment initiation was similar across groups; few patients had >1 event (females, 2.3%; males, 0.9%). Findings with canagliflozin 100 and 300 mg versus control were similar in Population 2 (females: 14.7%, 13.9%, 3.1%; males: 7.3%, 9.3%, 1.6%); a low proportion of males underwent circumcision across groups. Most events with canagliflozin occurred within the first 4 months in females and first year in males; no consistent evidence of dose dependence was observed. Key limitations included lack of laboratory confirmation for most events and variable treatment methods., Conclusions: Genital mycotic infection incidences were higher with canagliflozin than control in patients with T2DM; events were generally mild to moderate in intensity and responded to standard treatments.

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM)., Methods: The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters., Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690., Results: The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis-related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful., Conclusions: Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.

Background: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age., Methods: Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids., Results: Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets., Conclusions: Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM., Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.

Background/aims: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m(2). The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m(2))., Methods: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. RESULTS are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m(2)) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m(2))., Results: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis., Conclusion: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA1c, body weight, and blood pressure, and was generally well tolerated., (© 2014 S. Karger AG, Basel.)

Background: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, lowers plasma glucose in individuals with hyperglycemia by inhibiting renal glucose reabsorption and increasing glucosuria. Urinary tract infections (UTIs) were characterized in patients with type 2 diabetes mellitus enrolled in Phase III studies of canagliflozin., Methods: Analyses were performed in 2 pooled datasets: Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8) including patients from 4 placebo-controlled studies; Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4) including patients from 8 placebo- and active-controlled studies (including patients with renal impairment or high risk of cardiovascular disease, and older patients). Individual studies in special patient populations and 2 active-controlled studies were analyzed separately. Patients with a prior history of UTIs were not excluded from these studies. Urinary tract infection frequency and characteristics were systematically collected, with additional information for each event collected using supplemental electronic case report forms., Results: In Populations 1 and 2, canagliflozin 100 and 300 mg were associated with small increases in the incidence of UTIs compared with control, with no dose-dependence. Urinary tract infections with canagliflozin were similar to those with control in severity, and upper UTIs were infrequent across groups. No increase in serious events or those leading to discontinuation were seen with canagliflozin versus control. Time to the first occurrence of symptomatic UTIs tended to be earlier with canagliflozin than placebo in Population 1, and similar with canagliflozin and control in Population 2; median duration of events was similar across groups in both populations. The proportion of patients with recurrent events was low across groups., Conclusion: Canagliflozin was associated with a small increase in incidence of UTIs in patients with type 2 diabetes mellitus, with no increase in serious or upper UTIs.

Aims: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM., Methods: Patients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52)., Results: HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo., Conclusions: Canagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks., (© 2013 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd.)

Aims: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m(2)]., Methods: In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated., Results: Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (-0.33, -0.44 and -0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin., Conclusion: Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD., (© 2013 Blackwell Publishing Ltd.)

Introduction: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). Our randomized, double-blind, placebo-controlled, phase 3 study (www.clinicaltrials.gov: NCT01106651) evaluated the efficacy and safety of canagliflozin therapy in older subjects (aged 55-80 years) with T2DM inadequately controlled on their current regimen of blood glucose-lowering agents (any approved oral or injectable treatment)., Methods: Subjects (N = 716) aged 55 to 80 years (mean, 63.6 years) with glycated hemoglobin (HbA1c) levels ≥ 7.0% to ≤ 10.0% were randomized. Seven hundred fourteen received canagliflozin 100 mg or 300 mg or placebo (1:1:1) daily. The prespecified primary endpoint was change from baseline in HbA1c level at week 26. Prespecified secondary endpoints included proportion of subjects achieving HbA1c levels < 7.0%, change from baseline in fasting plasma glucose (FPG) level and systolic blood pressure (BP), and percent change from baseline in body weight, triglyceride levels, and high-density lipoprotein cholesterol (HDL-C) level. Adverse events (AEs) were reported throughout the study., Results: At week 26, treatment with canagliflozin 100 mg and 300 mg significantly reduced HbA1c levels compared with placebo (-0.60%, -0.73%, -0.03%, respectively; P < 0.001); more subjects achieved HbA1c levels < 7.0% with both canagliflozin doses compared with placebo (P < 0.001). Both canagliflozin doses significantly reduced body weight, FPG level, and systolic BP, and increased HDL-C level compared with placebo (P < 0.001); low-density lipoprotein cholesterol level was increased with both canagliflozin doses compared with placebo. The overall AE incidence was slightly higher with canagliflozin 300 mg than with canagliflozin 100 mg or placebo (78.0%, 72.2%, 73.4%, respectively). Serious AE and AE-related discontinuation rates were low across groups. Both canagliflozin doses were associated with higher rates than placebo of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs (ie, pollakiuria, polyuria). Documented hypoglycemia rates were modestly higher with both canagliflozin doses compared with placebo., Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in older subjects with T2DM who were on background therapy with a variety of blood glucose-lowering agents.

Aims: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise., Methods: In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study., Results: At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (-0.77, -1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups., Conclusion: Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise., (© 2012 Blackwell Publishing Ltd.)

Background/objective: Women with type 2 diabetes mellitus (T2DM) are at increased risk for vaginal Candida colonization, perhaps because of glucosuria. Sodium glucose co-transporter 2 (SGLT2) inhibitors, in development for the treatment of T2DM, improve glycemic control by increasing urinary glucose excretion. Vaginal Candida colonization and symptomatic vulvovaginal adverse events (VVAE) were assessed in females with T2DM treated with canagliflozin, a SGLT2 inhibitor., Methods: In a double-blind study, subjects with T2DM and inadequate glycemic control on metformin were randomized to placebo; canagliflozin 50, 100, 200, 300 mg daily or 300 mg twice daily; or sitagliptin 100 mg daily for 12 weeks. Vaginal swabs for Candida culture were collected from 198 female subjects at baseline and week 12, and during the trial if symptoms consistent with vulvovaginal candidiasis occurred., Results: At baseline, 23/198 (12%) females had vaginal cultures positive for Candida (C. glabrata: 14; C. albicans: 5; other: 4), with age ≤55 years associated with increased risk (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.1-10.7). Of those with negative cultures at baseline, 31% of canagliflozin and 14% of placebo/sitagliptin subjects converted to positive at week 12 (OR, 2.8; 95% CI, 1.0-7.3 for canagliflozin vs. placebo/sitagliptin). Two placebo/sitagliptin (3%) and 16 canagliflozin subjects (10%) experienced VVAE. Positive vaginal culture for Candida species at baseline was a risk factor for VVAE (OR, 9.1; 95% CI, 2.4-34.0). All 9/9 subjects in the canagliflozin group with a vaginal culture taken at the time of the VVAE were positive for Candida species. Most VVAE were treated with antifungal therapy and resolved without study drug interruption; none led to discontinuation. Study limitations include small population, short duration, and not obtaining cultures in all women with VVAE., Conclusion: Canagliflozin treatment was associated with an increase in vaginal colonization with Candida species and in VVAE in women with T2DM.

Objective: To examine the effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor that lowers blood glucose by increasing urinary glucose excretion (UGE), on asymptomatic bacteriuria and urinary tract infections (UTIs)., Research Design and Methods: In a randomized, double-blind, placebo-controlled, multicenter, dose-ranging phase 2 study, subjects with type 2 diabetes with inadequate glycemic control while receiving metformin were enrolled and randomized to one of seven arms - placebo; canagliflozin doses 50 mg, 100 mg, 200 mg, 300 mg daily, or 300 mg twice daily; and sitagliptin 100 mg daily - for 12 weeks., Clinical Trial Registration: This study is registered under Clinicaltrials.gov identification number NCT00642278., Results: Canagliflozin increased renal glucose excretion by 35.4-61.6 mg/mg creatinine in the five dose groups. In the placebo group renal glucose excretion was increased by 1.9 mg/mg creatinine, and in the sitagliptin group it decreased by 1.9 mg/mg creatinine. Asymptomatic bacteriuria (ASB) were present in 6.4% of canagliflozin and 6.5% of placebo/sitagliptin (control) subjects at randomization and, at 12 weeks, in 7.7% and 6.3% of subjects, respectively (odds ratio [OR] 1.23; 95% confidence interval [CI], 0.45-3.89). For subjects with initially negative urine cultures at baseline, 3 out of 82 (3.7%) who received controls and 10 out of 207 (4.8%) who received canagliflozin developed bacteriuria (p = 0.76) at week 12. There were 21 adverse event (AE) reports of UTI; 16 (5.0%) in canagliflozin subjects and 5 (3.8%) in control subjects (OR 1.31; 95% CI, 0.45-4.68)., Conclusions: In this trial, when compared with control subjects, canagliflozin increased UGE but was not associated with increased bacteriuria or AE reports of UTI. However, further studies enrolling larger numbers of subjects with longer term exposure to canagliflozin will be necessary to more fully understand the impact of this agent on the risk of developing UTI.

Objective: To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy., Research Design and Methods: This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed., Results: Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low., Conclusions: Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.

Two distinct syndromes of osteoporosis have been postulated: type I, which is characterized by accelerated bone loss occurring in women during the early postmenopausal period; and type II, an age-related process of bone loss affecting both men and women in and after the seventh decade. Recently there has been indirect evidence linking local products of the immune system with bone remodeling. We therefore studied peripheral blood profiles of specific lymphocyte phenotypes in women with type I osteoporosis and in older women and men with type II osteoporosis. The ratio of CD4-bearing (T helper) cells to CD8-bearing (T cytotoxic-suppressor) cells (CD4/CD8 ratio) was elevated in women with symptomatic type I disease. In addition there was a significant negative correlation (r = -0.62, P less than 0.001) between the CD4/CD8 ratio and the spinal bone mineral density measured by dual-photon absorptiometry. In contrast, older men with a history of fracture (hip or spine) had CD4/CD8 ratios similar to control men. The number of T cells bearing IL-2R or VLA-1 was not different between osteoporotic subjects and controls in either men or women. This study supports the concept that local products of the immune system may be directly or indirectly involved in the pathogenesis of type I osteoporosis.