DOCSLIB.ORG

The Kidney As a Treatment Target for Type 2 Diabetes Betsy Dokken, NP, Phd, CDE

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Kidney As a Treatment Target for Type 2 Diabetes Betsy Dokken, NP, Phd, CDE Feature Article / Dokken The Kidney as a Treatment Target for Type 2 Diabetes Betsy Dokken, NP, PhD, CDE Abstract Type 2 diabetes is a complex and stages of clinical development for the progressive disease that affects 8.3% treatment of type 2 diabetes. Results of the U.S. population. Despite the from clinical trials show that these availability of numerous treatment compounds decrease plasma glucose options for type 2 diabetes, the and body weight in treatment-naive proportion of patients achieving patients and in patients receiving glycemic goals is unacceptably low; metformin or insulin and insulin therefore, new pharmacotherapies are sensitizers. Overall, SGLT2 inhibitors needed to promote glycemic control appear to be generally well tolerated, in these patients. but in some studies, signs, symptoms, The kidney normally reabsorbs and other reports of genital and 99% of filtered glucose and returns urinary tract infections have been it to the circulation. Glucose reab- more frequent in drug-treated groups sorption by the kidney is mediated than in placebo groups. by sodium-glucose co-transporters Additional clinical trials will (SGLTs), mainly SGLT2. SGLT2 determine whether this class of inhibition presents an additional compounds with a unique, insulin- option to promote glycemic control independent mechanism of action in patients with type 2 diabetes. becomes a treatment option for A number of SGLT2 inhibitors have reducing hyperglycemia in type 2 been synthesized and are in various diabetes. Worldwide, more than 220 million Randomized, controlled people have diabetes.1 In the United clinical trials from the 1990s, States, diabetes is present in 8.3% including the Diabetes Control and of the population.2 Type 2 diabetes Complications Trial (DCCT)9 and accounts for 90–95% of all diag- the U.K. Prospective Diabetes Study nosed cases of adult diabetes.2 The (UKPDS),10,11 found that intensive prevalence of type 2 diabetes is glycemic control (achieved A1C of projected to increase further, in ~ 7%) compared to conventional parallel with obesity,3 a major risk therapy (A1C of ~ 8–9%) can reduce factor for its development.4 the risk of microvascular complica- Hyperglycemia is the hallmark tions in patients with type 1 diabetes of diabetes and a key determinant and in patients with newly diag- of microvascular complications nosed type 2 diabetes. However, (e.g., retinopathy, neuropathy, and whether intensive glycemic control nephropathy).5 Type 2 diabetes is reduces cardiovascular events is less a major risk factor for the develop- certain.12 Long-term monitoring ment of cardiovascular disease6 and of patients from the DCCT13 and chronic kidney disease.7 It is also the UKPDS14 trials found significant Address correspondence to Betsy primary cause of end-stage renal dis- reductions in cardiovascular events Dokken, NP, PhD, CDE, University ease, requiring either chronic dialysis in patients originally randomized to of Arizona Department of Medicine, or renal transplantation,8 and new receive intensive therapy compared 1656 East Mabel St., Room 412, cases of blindness among U.S. adults to patients who received standard Tucson, AZ 85724-5218. aged 20–74 years.3 therapy. Diabetes Spectrum Volume 25, Number 1, 2012 29 Feature Article / Kidney and Type 2 Diabetes However, recent clinical tri- β-cell function can all contribute ~ 45% of ingested glucose is taken als such as the Action in Diabetes to failure in the achievement of up by the liver, and 30% is taken up and Vascular Disease: Preterax glycemic goals.26,27 Therefore, new by skeletal muscle and converted to and Diamicron Modified Release pharmacological therapies with novel glycogen.29 During an overnight fast, Controlled Evaluation (ADVANCE) mechanisms of action that are inde- glucose is released into the circula- trial, the Action to Control pendent of insulin secretion or action tion, the majority (80%) of which Cardiovascular Risk in Diabetes and have a low propensity to cause comes from the liver as the result of (ACCORD) trial, and the Veterans hypoglycemia may enhance patients’ glycogenolysis and gluconeogenesis. Affairs Diabetes Trial (VADT) ability to achieve glycemic control. The breakdown of muscle glycogen found no benefit,15–17 and possibly The deleterious effects of diabetes leads to the formation of lactate, a some harm, from intensive control.16 on the kidney are well established. gluconeogenic precursor.29 These trials were designed to test the Less appreciated is the role the However, it is now evident that effects of intensive glycemic control kidney plays in glucose homeostasis the kidney also contributes to the (achieved A1C of 6.4–6.9%) com- and the potential of the kidney as a maintenance of blood glucose levels pared to standard therapy (A1C of therapeutic target in type 2 diabetes. by taking up glucose for energy 7.3–8.4%) on cardiovascular events This article reviews the role of the needs, synthesizing glucose (through (death from cardiovascular causes, kidney in glucose regulation and the the process of gluconeogenesis), nonfatal myocardial infarction, and potential of inhibiting renal glucose and reabsorbing glucose from the nonfatal stroke) in relatively high- reabsorption as a new treatment glomerular filtrate and returning it risk patients with established type 2 option in type 2 diabetes. to the circulation. In humans, only diabetes. Recent treatment guidelines the liver and kidney possess the stress the importance of individual- Role of the Kidney in Glucose necessary gluconeogenic enzymes ized treatment goals in patients with Homeostasis to produce and release glucose.30 diabetes.4,18 For most people, the major source of Normally, the kidneys account for Lifestyle changes that include glucose is the diet. After a meal or ~ 40% of total gluconeogenesis and a healthy diet, weight loss, and glucose load, plasma glucose concen- ~ 20% of all glucose released into the increased physical activity have tration peaks at ~ 90 minutes and circulation in humans.31 The kidney many benefits in improving gly- thereafter declines over the course also takes up and metabolizes ~ 10% cemic control and cardiovascular of the ~ 4.5-hour postprandial of all glucose utilized by the body.28 28 risk factors in patients with type 2 period. During this time, ingested Because of the distribution of glucose 32,33 diabetes.19 However, weight loss and carbohydrate accounts for ~ 75% transporters and enzymes, the physical activity and their favorable of circulating glucose. After a meal, renal cortex is the primary site effects are difficult to maintain over the long term, and most patients will require pharmacotherapy to achieve and maintain their glycemic goals.20 Despite the availability of numer- ous treatment options for type 2 diabetes (e.g., insulin, sulfonyl- ureas, meglitinides, biguanides, α-glycosidase inhibitors, thiazoli- dinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, amylin analogs, a dopa- mine agonist, and a bile acid sequestrant)21–24 with a variety of mechanisms of action, the propor- tion of patients achieving glycemic goals is unacceptably low. A recent analysis of diabetic patients from the National Health and Nutrition Examination Survey from 1999 to 200625 found that only 57% of patients with diagnosed diabetes achieved an A1C of < 7%. Lack of treatment initiation and intensification, patient nonadher- Figure 1. Site of gluconeogenesis and glucose utilization in the kidney. The ence, the risk of hypoglycemia with kidney cortex is the primary site of renal gluconeogenesis, whereas the some commonly used antidiabetic medulla is the primary site for glucose utilization. Dashed line indicates the drugs, and progressive decline in boundary between the cortex and medulla. 30 Diabetes Spectrum Volume 25, Number 1, 2012 Feature Article / Dokken convoluted tubule and re-enter the circulation.43,48 Therefore, the kidney may contribute to hyperglycemia in type 2 diabetes by increasing gluconeogenesis30,44 and possibly by enhanced glucose reabsorption.45 Rationale for SGLT2 Inhibition In addition to controlling car- diovascular risk factors such as hypertension and hyperlipidemia, glycemic control is a primary goal of diabetes management.4 Because renal Figure 2. Glucose reabsorption by the proximal convoluted tubule. Gray glucose reabsorption contributes to arrows represent normal glucose transport. Red arrows represent the hyperglycemia, SGLT2 inhibition pharmacological effects of SGLT2 inhibition. Adapted with permission presents an additional option for gly- from Macmillan Publishers Ltd. From ref. 62. cemic control in patients with type 2 diabetes. Inhibition of reabsorp- of glucose synthesis and release, Once taken up into the proxi- tion would be predicted to enhance whereas the medulla is the primary mal convoluted tubule cell via glucose excretion and reduce site for glucose utilization in the SGLT2, glucose exits the basolat- hyperglycemia in type 2 diabetes 33 kidney (Figure 1). eral membrane into the interstitium independently of insulin secretion or by facilitative glucose transporters action. Glucose Transport in the Kidney (GLUTs), primarily GLUT2 and, to a Moreover, SGLT2 inhibition Glucose is freely filtered by the glom- lesser extent, GLUT136,41 (Figure 2). appears to be relatively benign in erulus. Under normal conditions, Glucose then re-enters the circulation humans. Evidence supporting the ~ 180 g of glucose are filtered by the via peritubular capillaries. In normal 34,35 safety of SGLT2 inhibition as
Load more

Recommended publications
  • Dapagliflozin – Structure, Synthesis, and New Indications
    Pharmacia 68(3): 591–596 DOI 10.3897/pharmacia.68.e70626 Review Article Dapagliflozin – structure, synthesis, and new indications Stefan Balkanski1 1 Bulgarian Pharmaceutical Union, Sofia, Bulgaria Corresponding author: Stefan Balkanski ([email protected]) Received 24 June 2021 ♦ Accepted 4 July 2021 ♦ Published 4 August 2021 Citation: Balkanski S (2021) Dapagliflozin – structure, synthesis, and new indications. Pharmacia 68(3): 591–596.https://doi. org/10.3897/pharmacia.68.e70626 Abstract Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitors used in the treatment of patients with type 2 diabetes. An aryl glycoside with significant effect as glucose-lowering agents, Dapagliflozin also has indication for patients with Heart Failure and Chronic Kidney Disease. This review examines the structure, synthesis, analysis, structure activity relationship and uses of the prod- uct. The studies behind this drug have opened the doors for the new line of treatment – a drug that reduces blood glucoses, decreases the rate of heart failures, and has a positive effect on patients with chronic kidney disease. Keywords Dapagliflozin, SGLT2-inhibitor, diabetes, heart failure Structure of dapagliflozin against diabetes (Lee et al. 2005; Lemaire 2012; Mironova et al. 2017). Embodiments of (SGLT-2) inhibitors include C-glycosides have a remarkable rank in medicinal chemis- dapagliflozin, canagliflozin, empagliflozin and ipragliflozin, try as they are considered as universal natural products shown in Figure 1. It has molecular formula of C24H35ClO9. (Qinpei and Simon 2004). Selective sodium-dependent IUPAC name (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4- glucose cotransporter 2 (SGLT-2) inhibitors are potent ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxa- medicinal candidates of aryl glycosides that are functional ne-3,4,5-triol;(2S)-propane-1,2-diol;hydrate.
    [Show full text]
  • Supplementary Material
    Supplementary material Table S1. Search strategy performed on the following databases: PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL). 1. Randomi*ed study OR random allocation OR Randomi*ed controlled trial OR Random* Control* trial OR RCT Epidemiological study 2. sodium glucose cotransporter 2 OR sodium glucose cotransporter 2 inhibitor* OR sglt2 inhibitor* OR empagliflozin OR dapagliflozin OR canagliflozin OR ipragliflozin OR tofogliflozin OR ertugliflozin OR sotagliflozin OR sergliflozin OR remogliflozin 3. 1 AND 2 1 Table S2. Safety outcomes of empagliflozin and linagliptin combination therapy compared with empagliflozin or linagliptin monotherapy in treatment naïve type 2 diabetes patients Safety outcome Comparator 1 Comparator 2 I2 RR [95% CI] Number of events Number of events / / total subjects total subjects i. Empagliflozin + linagliptin vs empagliflozin monotherapy Empagliflozin + Empagliflozin linagliptin monotherapy ≥ 1 AE(s) 202/272 203/270 77% 0.99 [0.81, 1.21] ≥ 1 drug-related 37/272 38/270 0% 0.97 [0.64, 1.47] AE(s) ≥ 1 serious AE(s) 13/272 19/270 0% 0.68 [0.34, 1.35] Hypoglycaemia* 0/272 5/270 0% 0.18 [0.02, 1.56] UTI 32/272 25/270 29% 1.28 [0.70, 2.35] Events suggestive 12/272 13/270 9% 0.92 [0.40, 2.09] of genital infection i. Empagliflozin + linagliptin vs linagliptin monotherapy Empagliflozin + Linagliptin linagliptin monotherapy ≥ 1 AE(s) 202/272 97/135 0% 1.03 [0.91, 1.17] ≥ 1 drug-related 37/272 17/135 0% 1.08 [0.63, 1.84] AE(s) ≥ 1 serious AE(s) 13/272 2/135 0% 3.22 [0.74, 14.07] Hypoglycaemia* 0/272 1/135 NA 0.17 [0.01, 4.07] UTI 32/272 12/135 0% 1.32 [0.70, 2.49] Events suggestive 12/272 4/135 0% 1.45 [0.47, 4.47] of genital infection RR, relative risk; AE, adverse event; UTI, urinary tract infection.
    [Show full text]
  • Role of Apple Phytochemicals, Phloretin and Phloridzin, in Modulating Processes Related to Intestinal Inflammation
    nutrients Article Role of Apple Phytochemicals, Phloretin and Phloridzin, in Modulating Processes Related to Intestinal Inflammation Danuta Zielinska 1, José Moisés Laparra-Llopis 2, Henryk Zielinski 3, Dorota Szawara-Nowak 3 and Juan Antonio Giménez-Bastida 3,4,* 1 Department of Chemistry, University of Warmia and Mazury, 10-727 Olsztyn, Poland; [email protected] 2 Group of Molecular Immunonutrition in Cancer, Madrid Institute for Advanced Studies in Food (IMDEA-Food), 28049 Madrid, Spain; [email protected] 3 Institute of Animal Reproduction and Food Research, Department of Chemistry and Biodynamics of Food, Polish Academy of Science, 10-748 Olsztyn, Poland; [email protected] (H.Z.); [email protected] (D.S.-N.) 4 Group on Quality, Safety and Bioactivity of Plant Foods, Centro de Edafología y Biología Aplicada del Segura (CSIC), 30100 Murcia, Spain * Correspondence: [email protected] Received: 25 April 2019; Accepted: 23 May 2019; Published: 25 May 2019 Abstract: Plant-derived food consumption has gained attention as potential intervention for the improvement of intestinal inflammatory diseases. Apple consumption has been shown to be effective at ameliorating intestinal inflammation symptoms. These beneficial effects have been related to (poly)phenols, including phloretin (Phlor) and its glycoside named phloridzin (Phldz). To deepen the modulatory effects of these molecules we studied: i) their influence on the synthesis of proinflammatory molecules (PGE2, IL-8, IL-6, MCP-1, and ICAM-1) in IL-1β-treated myofibroblasts of the colon CCD-18Co cell line, and ii) the inhibitory potential of the formation of advanced glycation end products (AGEs).
    [Show full text]
  • Natural Products As Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors
    Reviews Natural Products as Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors Author ABSTRACT Wolfgang Blaschek Glucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glu- Affiliation cose absorption, gluconeogenesis, biosynthesis and mobiliza- Formerly: Institute of Pharmacy, Department of Pharmaceu- tion of glycogen, glucose consumption in all tissues and glo- tical Biology, Christian-Albrechts-University of Kiel, Kiel, merular filtration, and reabsorption of glucose in the kidneys. Germany Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the Key words family of facilitative glucose transporters (GLUTs) or to the Malus domestica, Rosaceae, Phlorizin, flavonoids, family of sodium glucose cotransporters (SGLTs). The intesti- ‑ SGLT inhibitors, gliflozins, diabetes nal glucose absorption by endothelial cells is managed by SGLT1, the transfer from them to the blood by GLUT2. In the received February 9, 2017 kidney SGLT2 and SGLT1 are responsible for reabsorption of revised March 3, 2017 filtered glucose from the primary urine, and GLUT2 and accepted March 6, 2017 GLUT1 enable the transport of glucose from epithelial cells Bibliography back into the blood stream. DOI http://dx.doi.org/10.1055/s-0043-106050 The flavonoid phlorizin was isolated from the bark of apple Published online April 10, 2017 | Planta Med 2017; 83: 985– trees and shown to cause glucosuria. Phlorizin is an inhibitor 993 © Georg Thieme Verlag KG Stuttgart · New York | of SGLT1 and SGLT2. With phlorizin as lead compound, specif- ISSN 0032‑0943 ic inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of Correspondence type 2 diabetes.
    [Show full text]
  • The Na+/Glucose Co-Transporter Inhibitor Canagliflozin Activates AMP-Activated Protein Kinase by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels
    Page 1 of 37 Diabetes Hawley et al Canagliflozin activates AMPK 1 The Na+/glucose co-transporter inhibitor canagliflozin activates AMP-activated protein kinase by inhibiting mitochondrial function and increasing cellular AMP levels Simon A. Hawley1†, Rebecca J. Ford2†, Brennan K. Smith2, Graeme J. Gowans1, Sarah J. Mancini3, Ryan D. Pitt2, Emily A. Day2, Ian P. Salt3, Gregory R. Steinberg2†† and D. Grahame Hardie1†† 1Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK 2Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada 3Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, Scotland, UK Running title: Canagliflozin activates AMPK Corresponding authors: Dr. D. G. Hardie, Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK; Dr. G.R. Steinberg, Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada Tel: +44 (1382) 384253; FAX: +44 (1382) 385507; e-mail: [email protected] Tel: +1 (905) 525-9140 ext.21691; email: [email protected] Word count in main text: 3,996 Number of Figures: 7 †these authors made equal contributions to this study ††joint corresponding authors Diabetes Publish Ahead of Print, published online July 5, 2016 Diabetes Page 2 of 37 Hawley et al Canagliflozin activates AMPK 2 ABSTRACT Canagliflozin, dapagliflozin and empagliflozin, all recently approved for treatment of Type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose re- uptake by SGLT2 in the kidney, without affecting intestinal glucose uptake by SGLT1.
    [Show full text]
  • International Journal of Pharmacy & Life Sciences
    Research Article Nizami et al., 9(7): July, 2018:5860-5865] CODEN (USA): IJPLCP ISSN: 0976-7126 INTERNATIONAL JOURNAL OF PHARMACY & LIFE SCIENCES (Int. J. of Pharm. Life Sci.) Analytical method development and validation for simultaneous estimation of Ipragliflozin and Sitagliptin in tablet form by RP-HPLC method Tahir Nizami*, Birendra Shrivastava and Pankaj Sharma School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, (RJ) - India Abstract An economical RP-HPLC method using a PDA detector at 224 nm wavelength for simultaneous estimation of Ipragliflozin and Sitagliptin in pharmaceutical dosage forms has been developed. The method was validated as per ICH guidelines over a range of 50-150 µg/mL for Ipragliflozin and Sitagliptin respectively. Analytical column used was ACE Column C18, (150 mm x 4.6 mm i.d, 5μm) with flow rate of 1.0 mL / min at a temperature of 30°C ± 0.5°C. The separation was carried out using a mobile phase consisting of orthophosphoric acid buffer and methanol in the ratio of 60: 40%v/v. Retention times of 3.092 and 4.549 min were obtained for Ipragliflozin and Sitagliptin respectively. The percentage recoveries of Ipragliflozin and Sitagliptin are 100.12% and 99.42% respectively. The goodness of fit was close to 1 for all the three components. The relative standard deviations are always less than 2%. Keywords: Ipragliflozin and Sitagliptin, RP -HPLC, Simultaneous analysis, Tablets Introduction Ipragliflozin (IPRA) a novel SGLT2 selective The empirical formulaC16H15F6N5O and the inhibitor was investigated. In vitro, the potency of molecular mass 523.32. Sitagliptin is an orally-active Ipragliflozin to inhibit SGLT2 and SGLT1 and inhibitor of the dipeptidyl peptidase-4 (DPP-4) stability were assessed.
    [Show full text]
  • Comparison of Tofogliflozin 20 Mg and Ipragliflozin 50 Mg Used Together
    2017, 64 (10), 995-1005 Original Comparison of tofogliflozin 20 mg and ipragliflozin 50 mg used together with insulin glargine 300 U/mL using continuous glucose monitoring (CGM): A randomized crossover study Soichi Takeishi, Hiroki Tsuboi and Shodo Takekoshi Department of Diabetes, General Inuyama Chuo Hospital, Inuyama 484-8511, Japan Abstract. To investigate whether sodium glucose co-transporter 2 inhibitors (SGLT2i), tofogliflozin or ipragliflozin, achieve optimal glycemic variability, when used together with insulin glargine 300 U/mL (Glargine 300). Thirty patients with type 2 diabetes were randomly allocated to 2 groups. For the first group: After admission, tofogliflozin 20 mg was administered; Fasting plasma glucose (FPG) levels were titrated using an algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using continuous glucose monitoring (CGM); Tofogliflozin was then washed out over 5 days; Subsequently, ipragliflozin 50 mg was administered; FPG levels were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using CGM. For the second group, ipragliflozin was administered prior to tofogliflozin, and the same regimen was maintained. Glargine 300 and SGLT2i were administered at 8:00 AM. Data collected on the second day of measurement (mean amplitude of glycemic excursion [MAGE], average daily risk range [ADRR]; on all days of measurement) were analyzed. Area over the glucose curve (<70 mg/dL; 0:00 to 6:00, 24-h), M value, standard deviation, MAGE, ADRR, and mean glucose levels (24-h, 8:00 to 24:00) were significantly lower in patients on tofogliflozin than in those on ipragliflozin.
    [Show full text]
  • 202293Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202293Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology Office of Medication Error Prevention and Risk Management Final Risk Evaluation and Mitigation Strategy (REMS) Review Date: December 20, 2013 Reviewer(s): Amarilys Vega, M.D., M.P.H, Medical Officer Division of Risk Management (DRISK) Team Leader: Cynthia LaCivita, Pharm.D., Team Leader DRISK Drug Name(s): Dapagliflozin Therapeutic Class: Antihyperglycemic, SGLT2 Inhibitor Dosage and Route: 5 mg or 10 mg, oral tablet Application Type/Number: NDA 202293 Submission Number: Original, July 11, 2013; Sequence Number 0095 Applicant/sponsor: Bristol-Myers Squibb and AstraZeneca OSE RCM #: 2013-1639 and 2013-1637 *** This document contains proprietary and confidential information that should not be released to the public. *** Reference ID: 3426343 1 INTRODUCTION This review documents DRISK’s evaluation of the need for a risk evaluation and mitigation strategy (REMS) for dapagliflozin (NDA 202293). The proposed proprietary name is Forxiga. Bristol-Myers Squibb and AstraZeneca (BMS/AZ) are seeking approval for dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Bristol-Myers Squibb and AstraZeneca did not submit a REMS or risk management plan (RMP) with this application. At the time this review was completed, FDA’s review of this application was still ongoing. 1.1 BACKGROUND Dapagliflozin. Dapagliflozin is a potent, selective, and reversible inhibitor of the human renal sodium glucose cotransporter 2 (SGLT2), the major transporter responsible for renal glucose reabsorption.
    [Show full text]
  • Open-Label Study to Assess the Efficacy of Ipragliflozin for Reducing
    Clinical Drug Investigation (2019) 39:1213–1221 https://doi.org/10.1007/s40261-019-00851-z ORIGINAL RESEARCH ARTICLE Open‑Label Study to Assess the Efcacy of Ipraglifozin for Reducing Insulin Dose in Patients with Type 2 Diabetes Mellitus Receiving Insulin Therapy Hisamitsu Ishihara1 · Susumu Yamaguchi2 · Toshifumi Sugitani2 · Yoshinori Kosakai2 Published online: 24 September 2019 © The Author(s) 2019 Abstract Background and Objective To avoid insulin-induced hypoglycemia and weight gain, the minimum dose of insulin should be used. In this study, therefore, we examined insulin dose reduction by ipraglifozin add-on therapy in Japanese patients with type 2 diabetes mellitus treated with long-acting basal insulin. Methods In this multicenter, open-label study, patients received one ipraglifozin 50-mg tablet once daily in combination with basal insulin for 24 weeks. The primary efcacy endpoint was the change and percent change in insulin dose from base- line to Week 24. Secondary efcacy endpoints included changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), glycoalbumin, cholesterol, leptin, adiponectin, C-peptide, glucagon, body weight, and blood pressure, and number of patients achieving withdrawal of insulin at the end of treatment (EOT). Treatment-emergent adverse events (TEAEs) were evaluated for safety. Results In total, 114 patients were screened, 103 were registered, and 97 completed the study. The mean age was 59 years and 72.8% of patients were male. The mean change in insulin dose from baseline at Week 24 was − 6.6 ± 4.4 units/day (p < 0.001); the mean percent change was − 29.87%. HbA1c, FPG, glycoalbumin, glucagon levels, body weight, and blood pressure signifcantly decreased from baseline to EOT (p < 0.05).
    [Show full text]
  • Objectives Anti-Hyperglycemic Therapeutics
    9/22/2015 Some Newer Non-Insulin Therapies for Type 2 Diabetes:Present and future Faculty/presenter disclosure Speaker’s name: Dr. Robert G. Josse SGLT2 Inhibitors Grants/research support: Astra Zeneca, BMS, Boehringer Dopamine D2 Receptor Agonist Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Roche, Bile acid sequestrant sanofi, Consulting Fees: Astra Zeneca, BMS, Eli Lilly, Janssen, Merck, Dr Robert G Josse Division of Endocrinology & Metabolism Speakers bureau: Janssen, Astra Zeneca, BMS, Merck, St. Michael’s Hospital Professor of Medicine Stocks and Shares:None University of Toronto 100-year History of Objectives Anti-hyperglycemic Therapeutics 14 Discuss the mechanism of action of SGLT2 inhibitors, SGLT-2 inhibitor 12 Bromocriptine-QR dopamine D2 receptor agonists and bile acid sequestrants Bile acid sequestrant in the management of type 2 diabetes Number of 10 DPP-4 inhibitor classes of GLP-1 receptor agonist Amylinomimetic anti- 8 Glinide Basal insulin analogue Identify the benefits and risks of the newer non-insulin hyperglycemic Thiazolidinedione agents 6 Alpha-glucosidase inhibitor treatment options Phenformin Human Rapid-acting insulin analogue 4 Sulphonylurea insulin Metformin Intermediate-acting insulin Phenformin Describe the potential uses of these therapies in the 2 withdrawn Soluble insulin treatment of type 2 diabetes 0 1920 1940 1960 1980 2000 2020 Year UGDP, DCCT and UKPDS studies. Buse, JB © 1 9/22/2015 Renal handling of glucose Collecting (180 L/day) Glomerulus duct (1000 mg/L) Proximal =180 g/day Distal tubule S1 tubule Glucose ~90% filtration SGLT2 Inhibitors ~10% S3 Glucose reabsorption Loop No/minimal of Henle glucose excretion S1 segment of proximal tubule S3 segment of proximal tubule - ~90% glucose reabsorbed - ~10% glucose reabsorbed - Facilitated by SGLT2 - Facilitated by SGLT1 SGLT = Sodium-dependent glucose transporter Adapted from: 1.
    [Show full text]
  • Identification of SGLT2 Inhibitor Ertugliflozin As a Treatment
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.18.448921; this version posted June 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Identification of SGLT2 inhibitor Ertugliflozin as a treatment for COVID-19 using computational and experimental paradigm Shalini SaxenaA, Kranti MeherC, Madhuri RotellaC, Subhramanyam VangalaC, Satish ChandranC, Nikhil MalhotraB, Ratnakar Palakodeti B, Sreedhara R Voleti A*, and Uday SaxenaC* A In Silico Discovery Research Academic Services (INDRAS) Pvt. Ltd. 44-347/6, Tirumalanagar, Moula Ali, Hyderabad – 500040, TS, India B Tech Mahindra Gateway Building, Apollo Bunder, Mumbai-400001, Maharashtra, India C Reagene Innovation Pvt. Ltd. 18B, ASPIRE-BioNEST, 3rd Floor, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad – 500046, TS, India *Corresponding Authors email address: [email protected] [email protected] Abstract Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The RBD domain of SARS-CoV-2 Spike protein is a promising drug target due to its pivotal role in viral-host attachment. These specific structural domains can be targeted with small molecules or drug to disrupt the viral attachment to the host proteins. In this study, FDA approved Drugbank database were screened using a virtual screening approach and computational chemistry methods. Five drugs were short listed for further profiling based on docking score and binding energies. Further these selected drugs were tested for their in vitro biological activity.
    [Show full text]
  • Glucose Transporters As a Target for Anticancer Therapy
    cancers Review Glucose Transporters as a Target for Anticancer Therapy Monika Pliszka and Leszek Szablewski * Chair and Department of General Biology and Parasitology, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-22-621-26-07 Simple Summary: For mammalian cells, glucose is a major source of energy. In the presence of oxygen, a complete breakdown of glucose generates 36 molecules of ATP from one molecule of glucose. Hypoxia is a hallmark of cancer; therefore, cancer cells prefer the process of glycolysis, which generates only two molecules of ATP from one molecule of glucose, and cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by cancer cells is due to increased expression of glucose transporters. However, overexpression of glucose transporters, promoting the process of carcinogenesis, and increasing aggressiveness and invasiveness of tumors, may have also a beneficial effect. For example, upregulation of glucose transporters is used in diagnostic techniques such as FDG-PET. Therapeutic inhibition of glucose transporters may be a method of treatment of cancer patients. On the other hand, upregulation of glucose transporters, which are used in radioiodine therapy, can help patients with cancers. Abstract: Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP.
    [Show full text]