DOCSLIB.ORG

FDA Introductory Remarks January 17, 2019 Endocrinologic and Metabolic Drugs Advisory Committee Meeting

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
FDA Introductory Remarks January 17, 2019 Endocrinologic and Metabolic Drugs Advisory Committee Meeting FDA Introductory Remarks January 17, 2019 Endocrinologic and Metabolic Drugs Advisory Committee Meeting Lisa Yanoff, MD, Acting Director Division of Metabolism and Endocrinology Products Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration Introduction • Diabetes mellitus affects over 30 million people in the United States – Approximately 5-10% are type 1 diabetes • Increases risk of micro- and macro-vascular complications • Improving glycemic control has been main goal of treatment – Reduce risk for microvascular complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy 2 Establishing Benefit of a Drug for Diabetes • HbA1c (hemoglobin A1c / glycated hemoglobin) – Irreversible attachment of glucose to hemoglobin – Directly proportional to the ambient glucose concentration – Correlates with average blood glucose over the preceding 2 or 3 months. – Standardized assay • HbA1c reduction is surrogate for benefit on microvascular disease – Clinical trials have established that glycemic lowering results in a reduction in the onset and progression of microvascular complications (DCCT, UKPDS) DCCT: Diabetes Control and Complications Trial; UKPDS: United Kingdom Prospective Diabetes Study 3 Available Therapies for Diabetes Mellitus Drug Class Drug Products Insulin and insulin analogs Multiple products including basal, prandial, and mixed insulin Biguanides Metformin Sulfonylureas Chlorpropamide, Glimepiride, Glipizide, Glyburide Thiazolidinediones Rosiglitazone, Pioglitazone Meglitinides Repaglinide, Nateglinide Alpha glucosidase inhibitors Acarbose, Miglitol Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin, Saxagliptin, Alogliptin, Linagliptin Glucagon-like peptide-1 (GLP-1) receptor agonists Exenatide (as a twice daily and as a once weekly), Liraglutide, Albiglutide, Dulaglutide, Lixisenatide, Semaglutide Sodium glucose cotransporter-2 (SGLT2) inhibitors Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin Amylin analogs Pramlintide Bile acid sequestrants Colesevelam Dopamine agonists Bromocriptine Drugs in bold and red font are indicated for type 1 diabetes 4 SGLT2 Inhibitors • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus – Canagliflozin (2013) – Dapagliflozin (2014) – Empagliflozin (2014) – Ertugliflozin (2017) • Cardiovascular indications in adult patients with type 2 diabetes mellitus and established cardiovascular disease – Empagliflozin (2016) – Canagliflozin (2018) There are no SGLT inhibitors approved as adjunct to insulin treatment of T1DM 5 Sotagliflozin • SGLT2: acts systemically at renal proximal tubule to inhibit reabsorption of filtered glucose – Increased urinary glucose excretion – Lower plasma glucose levels • SGLT1: present in the small intestine – Clinical impact unclear • Adjunct to insulin in adults with type 1 diabetes mellitus • Proposed doses are 200 mg daily and 400 mg daily SGLT2i: sodium glucose co-transporter 2 inhibitor 6 Meeting Agenda • Presentations from Applicant • Presentations from FDA • Open Public Hearing • Questions to the Panel 7 Question 1 (Discussion) Discuss the benefits claimed by the applicant, e.g. glycemic control, effects on body weight and risk for hypoglycemia, for patients with type 1 diabetes. Comment on the strength of the statistical evidence and clinical meaningfulness of each of these claimed benefits. 8 Question 2 (Discussion) Discuss your level of concern about the observed risk of diabetic ketoacidosis (DKA) in adult patients in the sotagliflozin clinical studies and DKA risk associated with sotagliflozin use in a real-world setting. 9 Question 3 (Discussion) Comment on any relevant differences in efficacy and/or safety observed between the two proposed doses of sotagliflozin (200 mg and 400 mg). In your discussion please consider the clinical pharmacology data as well as clinical trial data, i.e. improvement in glycemic control and risk for DKA. 10 Question 4 (Discussion) Discuss the overall benefit risk profile of sotagliflozin for patients with type 1 diabetes. What specific benefits and risks did you consider; what was your approach and rationale for how they were weighed against each other? Specifically comment on the composite endpoint used by the applicant (HbA1c<7% with no episodes of severe hypoglycemia or diabetic ketoacidosis) to represent net benefit. If you would recommend an alternative strategy, please explain your rationale. 11 Question 5 (Vote) Do the available data suggest that the benefits outweigh the risks and support approval of sotagliflozin, administered orally once daily, as an adjunct to insulin to improve glycemic control in adults with type 1 diabetes mellitus? a. If yes, comment on whether you recommend any labeling restrictions, whether any additional studies should be required after approval, and comment on whether your vote indicates support for both proposed doses of sotagliflozin (200 mg and 400 mg). b. If no, please describe your rationale and what further studies you believe the applicant should conduct to establish a favorable benefit risk profile to support approval. 12 Overview of the Clinical Pharmacology and Development Program for Sotagliflozin January 17, 2019 Endocrinologic and Metabolic Drugs Advisory Committee Meeting Mitra Rauschecker, MD Division of Metabolism and Endocrinology Products Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration 1 Outline of FDA Presentations • Clinical Pharmacology • Sotagliflozin development program • Efficacy findings • Diabetic Ketoacidosis (DKA) in the Sotagliflozin Clinical Development Program • Presentation of DKA cases from the FDA Adverse Event Reporting System (FAERS) • Sentinel Analysis of DKA cases 2 Clinical Pharmacology of Sotagliflozin Clinical Pharmacology Agenda • Pharmacokinetics of Sotagliflozin • Pharmacodynamics of sotagliflozin: SGLT-1 and SGLT-2 – Mechanistic study in healthy subjects – Dose-ranging study in Type 1 Diabetes (T1DM) • Correlation of relevant clinical observations to sotagliflozin systemic exposure – Insulin dose – Glucose (urinary glucose excretion) – HbA1c SGLT: sodium glucose co-transporter 4 Sotagliflozin Clinical Pharmacokinetics Representative Pharmacokinetic Profile of Single 400 mg Dose in Healthy Subjects (n=8) • Once-daily dosing supported with >20 hour t1/2 • Exposure affected by: . body weight . renal impairment (>1.5-fold in eGFR < 45) . hepatic impairment (>3-fold in moderate and severe) • Not proposed for eGFR<45 and moderate and severe hepatic impairment eGFR=estimated glomerular filtration rate 5 Sotagliflozin Effect on Urinary Glucose Excretion (UGE) in T1DM • Study 206 - Randomized, double-blind, parallel design dose ranging study in T1DM • Placebo, 75, 200, and 400 mg once daily dosing over 12 weeks • This dose ranging study was conducted in parallel with the phase 3 studies • Sotagliflozin increases UGE in a dose dependent manner 6 Sotagliflozin Effect on Glucose Absorption Absorption rate of Glucose • Study 111- Randomized, single dose, crossover study in healthy subjects (n=24) Placebo • Isotope tracer glucose drink within 15 minutes after 400 mg sotagliflozin or placebo Sotagliflozin • Sotagliflozin delays glucose absorption without change in the total amount of glucose absorbed 7 Sotagliflozin Effect on Self-Monitored Blood Glucose (SMBG) SMBG Data from Phase 3 Trial 309 8 Insulin Dose Change with Sotagliflozin Treatment Insulin Data from Phase 3 Trial 309 Transient bolus insulin dose reductions may affect post-prandial glucose excursions 9 Distribution of Average Plasma Concentrations 10 Flat Exposure-Response Relationship for HbA1c Pooled Data from Phase 3 Trial 309 and 310 11 Sotagliflozin Exposure - UGE and Insulin Dose Relationship Trend in UGE had a mirror image pattern with insulin dose reduction 12 Clinical Development Program for Sotagliflozin Study 309/310- Trial Design Insulin Screening Core Treatment Period Extension Follow-up Optimization/Single- Period 24 weeks Period Period Blind Run-In Period Inclusion criteria: Sotagliflozin 200 mg adults 18 yrs or older with T1DM Randomization Sotagliflozin 400 mg HbA1c 7.0-11.0% BMI≥18.5 kg/m2 Placebo eGFR ≥45 ml/min/m2 Week -8 Week -6 Week -2 Day 1-Baseline Week 24 Week 52 14 Study 312- Trial Design Double-blind Screening Single-Blind Placebo Follow-up Treatment Period Period Run-In Period Period 24 weeks Inclusion criteria: Sotagliflozin 400 mg adults 18 yrs or older with T1DM HbA1c 7.0-11.0% Randomization BMI≥18.5 kg/m2 eGFR ≥45 ml/min/m2 Placebo Week -4 Week -2 Day 1 Week 24 Baseline 15 Study Outcomes • Efficacy Outcomes – HbA1c – Fasting Plasma Glucose – Body Weight – Insulin Dose – CGM time-in-range in small subset • Safety Outcomes – Adverse Events – Deaths – Adverse Events of Special Interest (AESI) • DKA • Hypoglycemia CGM=continuous glucose monitoring 16 Results of Phase 3 Studies Study Disposition Study 309/310 Study 312 200 mg 400 mg Placebo 400 mg Placebo Randomized patients/ 524 525 1049 700 705 mITT population Discontinued before 24 weeks 45 (8.6) 49 (9.3) 55 (10.5) 95 (13.6) 81 (11.5) n (%) Completed 24 weeks n (%) 479 (91.4) 476 (90.7) 471 (89.5) 605 (86.4) 624 (88.5) 18 Demographic Characteristics Study 309 Study 310 Study 312 200 mg 400 mg Placebo 200 mg 400 mg Placebo 400 mg Placebo Randomized patients 263 262 268 261 263 258 699 703 Duration of T1DM (yrs) 25.0 24.0 24.2 18.2 18.9 18.1 20.5 19.6 Age in years (mean) 46.6 46.4 45.2 42.3 41.7 39.7 43.3 42.4 HbA1c (%) 7.6 7.6 7.5 7.7 7.7 7.8 8.3 8.2
Load more

Recommended publications
  • 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]
  • Annexes to the Annual Report of the European Medicines Agency 2014
    Annexes to the annual report of the European Medicines Agency 2014 Table of contents Annex 1 – Members of the Management Board ............................................................................. 2 Annex 2 – Members of the Committee for Medicinal Products for Human Use ................................... 4 Annex 3 – Members of the Pharmacovigilance Risk Assessment Committee ...................................... 6 Annex 4 – Members of the Committee for Medicinal Products for Veterinary Use ............................... 8 Annex 5 – Members of the Committee on Orphan Medicinal Products ............................................ 10 Annex 6 – Members of the Committee on Herbal Medicinal Products .............................................. 12 Annex 07 – Committee for Advanced Therapies .......................................................................... 14 Annex 8 – Members of the Paediatric Committee ........................................................................ 16 Annex 9 – Working parties and working groups .......................................................................... 18 Annex 10 – CHMP opinions in 2014 on medicinal products for human use ...................................... 22 Annex 11 – CVMP opinions in 2014 on medicinal products for veterinary use .................................. 36 Annex 12 – COMP opinions in 2014 on designation of orphan medicinal products ............................ 41 Annex 13 – HMPC European Union herbal monographs in 2014....................................................
    [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]
  • Dapagliflozin As an Adjunct Therapy to Insulin in Patients with Type 1 Diabetes Mellitus: Efficacy and Safety of This Combination
    Review Diabetes Dapagliflozin as an Adjunct Therapy to Insulin in Patients with Type 1 Diabetes Mellitus: Efficacy and Safety of this Combination Johan H Jendle,1 Francisco J Ampudia-Blasco,2 Martin Füchtenbusch3 and Paolo Pozzilli4 1. Institution of Medical Sciences, Örebro University, Örebro, Sweden; 2. Endocrinology and Nutrition Department, Clinic University Hospital Valencia, INCLIVA Biomedical Research Institute, Valencia, Spain; 3. Diabetes Centre at Marienplatz, Munich, Germany, Diabetes Research Study Group e.V. at Helmholt Zentrum Munich, Germany; 4. University Campus Bio-Medico, Rome, Italy he prevalence of type 1 diabetes (T1D) is increasing worldwide. T1D reduces life expectancy due to complications including cardiovascular disease. Sodium–glucose co-transporter (SGLT) inhibitors are a new class of drugs developed to treat type 2 diabetes T(T2D), and now they can be used as an adjunct to insulin in T1D. In clinical trials, they have been shown to improve glycaemic control and decrease body weight without the risk of increased hypoglycaemia and with a reduction in insulin dose. Four SGLT2 inhibitors have been approved in Europe for the treatment of T2D, while only dapagliflozin and sotagliflozin, a dual SGLT1 and SGLT2 inhibitor approved in 2019, have been approved for the treatment of T1D. Both can be used as an adjunct therapy in combination with insulin in adults with a body mass index (BMI) of ≥27 kg/m2, inadequately controlled with insulin. In Europe, dapagliflozin is the only currently available SGLT2 inhibitor indcated as adjunct therapy for patients with T1D. The subgroup of patients with a BMI of ≥27 kg/m2 from the DEPICT-1 and -2 trials (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 diabetes) showed similar reduction in hyperglycaemia and body weight but no significant increased risk of diabetic ketoacidosis (DKA) than the overall trial population.
    [Show full text]
  • Sotagliflozin As an Adjunct to Insulin for Type 1 Diabetes
    CO-1 Sotagliflozin as an Adjunct to Insulin for Type 1 Diabetes January 17, 2019 Sanofi / Lexicon Pharmaceuticals Endocrinologic and Metabolic Drugs Advisory Committee CO-2 Introduction Rene Belder, MD Vice President Diabetes and Cardiovascular Clinical Development Sanofi CO-3 Insulin: Life-Saving But Difficult to Dose Correctly Underdosing Overdosing Imprecision Hyperglycemia Hypoglycemia Glucose Variability Diabetic Weight gain ketoacidosis Distress (DKA) CO-4 Sotagliflozin: Dual Inhibitor of SGLT1 and SGLT2 Lumen of Intestinal Small intestine Kidneys proximal lumen tubule glucose SGLT1 SGLT2 ◼ SGLT1 inhibition blunts and delays ◼ SGLT2 inhibition reduces glucose absorption and reduces glucose reabsorption, lowering postprandial glucose (PPG) excursions1 blood glucose2 1. Dobbins RL et al. 2015; 2. Rieg T et al. 2014 CO-5 Sotagliflozin Proposed Indication and Dosing ◼ Sotagliflozin, an inhibitor of the sodium-dependent glucose co-transporters (SGLT) 1 and SGLT2, is indicated as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes mellitus who have failed to achieve desired glycemic control despite optimal insulin therapy. ◼ Recommended dose ▪ 200 mg orally, once daily before first meal ▪ Dose may be increased to 400 mg in patients who tolerate 200 mg and need additional glycemic control CO-6 Sotagliflozin Clinical Development Program Largest to Date in Adults with T1D ◼ 30 clinical studies including 4,010 adults Phase 3 Study Total Duration N 309 52 weeks 793 (North America) 310 52 weeks 782
    [Show full text]
  • Growing Our Future in Diabetes Care: Where Are We Now and Where Are We Going?
    GROWING OUR FUTURE IN DIABETES CARE: WHERE ARE WE NOW AND WHERE ARE WE GOING? Ashley Firm, Pharm.D. Lindsey Meston, Pharm.D. Disclosure Neither Dr. Firm nor Dr. Meston have anything to disclosure concerning possible financial or personal relationships with commercial entities (or their competitors) mentioned in this presentation. Objectives ■ Summarize key differences and updates to guidelines related to the care of diabetic patients, especially updates in the 2018 American Diabetes Association Standard of Medical Care in Diabetes ■ Select most appropriate treatment regimens for sample patients based on diabetic presentation and co-morbid conditions ■ Evaluate new products to the market for the treatment of diabetes, including place in therapy, pros and cons of use, major adverse effects, and other pertinent pharmacokinetic and pharmacodynamic properties. SOC-36238233 Socrative Join Code Which of the following correctly pairs a basal insulin and GLP1-RA coformulation? A. Insulin glargine- semaglutide B. Insulin determir- dulaglutide C. Insulin degludec- liraglutide Which new agent was accepted by the FDA for regulatory filing as a dual inhibitor of SGLT-2 in the treatment of type 1 diabetes? A. Sotagliflozin B. Empagliflozin C. Dapagliflozin D. Canagliflozin Under the ADA Standards of Care 2018, a patient with a history of a myocardial infarction would be recommended for which class of medication in addition to metformin? A. Thiazolidinediones B. Sulfonylureas C. Sodium Glucose Co-Transporter 2 Inhibitor D. Alpha Glucosidase Inhibitor Under the updated guidelines of the American Association of Clinical Endocrinologists, a patient failing to achieve A1C goal with metformin would be most appropriately treated with a medication from which class? A.
    [Show full text]
  • Standards of Medical Care in Diabetes—2019
    S90 Diabetes Care Volume 42, Supplement 1, January 2019 9. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment: Standards of Medical Care in Diabetesd2019 Diabetes Care 2019;42(Suppl. 1):S90–S102 | https://doi.org/10.2337/dc19-S009 The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES Recommendations 9.1 Most people with type 1 diabetes should be treated with multiple daily 9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT injections of prandial and basal insulin, or continuous subcutaneous insulin infusion. A 9.2 Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A 9.3 Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E 9.4 Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age.
    [Show full text]
  • Clinical Trials Appendices R&D Pipeline – New Molecular Entities(*)
    Clinical Trials Appendices R&D Pipeline – New Molecular Entities(*) Phase 1 Phase 2 Phase 3 Registration (Total:16) (Total:13) (Total:8) (Total:3) SAR439794 SAR228810 SAR440340(**) ST400(8) isatuximab cemiplimab(**) TLR4 agonist Anti-protofibrillar AB mAb Anti-IL33 mAb ZFN Gene Editing Technology Anti-CD38 mAb PD-1 inhibitor mAb Peanut Allergy Alzheimer’s Disease Asthma Beta thalassemia 3L Relapsing Refractory MM (ICARIA) Advanced CSCC (U.S./EU) SAR408701 SAR442168(4) SAR156597 SAR422459 avalglucosidase alfa ZynquistaTM(**) n Maytansin-loaded anti-CEACAM5 mAb BTK inhibitor IL4/IL13 bi-specific mAb ABCA4 gene therapy Neo GAA Oral SGLT-1&2 inhibitor Solid Tumors Multiple Sclerosis Systemic Scleroderma Stargardt Disease Pompe Disease Type 1 Diabetes (U.S./EU) TM SAR439459 UshStat® GZ389988 SAR425899 venglustat Cablivi anti-TGFb mAb Myosin 7A gene therapy TRKA antagonist GLP-1/GCG dual agonist Oral GCS inhibitor Bivalent anti-vWF Nanobody Advanced Solid Tumors Usher Syndrome 1B Osteoarthritis Obesity/Overweight in T2D ADPKD(10) acquired Thrombotic Thrombocytopenic Purpura (EU) O REGN3767(1) SAR438335 Combination SAR407899 fitusiran Anti LAG-3 mAb GLP-1/GIP dual agonist ferroquine / OZ439(**) rho kinase siRNA targeting anti-thrombin Advanced Cancers Type 2 Diabetes Antimalarial Microvascular Angina Hemophilia A and B O (1) (5)(**) (11) REGN4659 SAR440181 ALX0171 HIV sutimlimab Anti-CTLA-4 mAb Myosin activation Anti RSV Nanobody Anti Complement C1s mAb Viral vector prime & rgp120 boost vaccine Cancer Dilated Cardiomyopathy Respiratory Syncitial
    [Show full text]
  • Appraisal of Sotagliflozin As Adjunctive Therapy for Type 1 Diabetes
    https://www.jresearchvalley.com/ Journal of Clinical Endocrinology and Diabetes Research Mini Review Open Access Appraisal of Sotagliflozin as Adjunctive Therapy for Type 1 Diabetes Nasser Mikhail* Professor of Medicine, David-Geffen School of Medicine, Olive View-UCLA Medical Center, USA Abstract Background: Sotagliflozin is a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2) approved in Europe as adjunctive treatment to insulin in patients with type 1 diabetes. Objective: To review the efficacy and safety of sotagliflozin in type 1 diabetes. Methods: Literature search (English, Spanish, French) of clinical trials, meta-analysis and expert opinions until March 2, 2020. Search terms included sotagliflozin, SGLT1 and SGLT2 inhibitors, glycated hemoglobin (HbA1c), efficacy, safety, diabetic ketoacidosis (DKA), hypoglycemia. Results: When added to insulin, sotagliflozin is associated with modest reduction in mean levels by 0.34% compared with placebo. Incidence of overall hypoglycemia and severe hypoglycemia are significantly decreased by 22-31% with sotagliflozin versus placebo. Patients randomized to sotagliflozin had significant decrease in mean total daily insulin doses by approximately 9%, weight by 3.5%, systolic blood pressure (SBP) by 3.8 mmHg, and diastolic blood pressure (DBP) by 1.4 mmHg compared with placebo. Diabetic ketoacidosis was the most frequent and serious adverse effect of sotagliflozin, and the commonest cause of drug discontinuation. Following DKA, other adverse effects of sotagliflozin were genital mycotic infections, diarrhea, and volume depletion. Conclusions: Sotagliflozin may be a useful addition to insulin in a limited number of patients with type 1 diabetes with body mass index ≥ 27 kg/m2, and those who are at high risk for severe hypoglycemia.
    [Show full text]
  • SGLT2 Inhibitors: the Star in the Treatment of Type 2 Diabetes?
    diseases Review SGLT2 Inhibitors: The Star in the Treatment of Type 2 Diabetes? Yoshifumi Saisho Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan; [email protected]; Tel.: +81-3-3353-1211 Received: 21 April 2020; Accepted: 8 May 2020; Published: 11 May 2020 Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents which increase urinary glucose excretion by suppressing glucose reabsorption at the proximal tubule in the kidney. SGLT2 inhibitors lower glycated hemoglobin (HbA1c) by 0.6–0.8% (6–8 mmol/mol) without increasing the risk of hypoglycemia and induce weight loss and improve various metabolic parameters including blood pressure, lipid profile and hyperuricemia. Recent cardiovascular (CV) outcome trials have shown the improvement of CV and renal outcomes by treatment with the SGLT2 inhibitors, empagliflozin, canagliflozin, and dapagliflozin. The mechanisms by which SGLT2 inhibitors improve CV outcome appear not to be glucose-lowering or anti-atherosclerotic effects, but rather hemodynamic effects through osmotic diuresis and natriuresis. Generally, SGLT2 inhibitors are well-tolerated, but their adverse effects include genitourinary tract infection and dehydration. Euglycemic diabetic ketoacidosis is a rare but severe adverse event for which patients under SGLT2 inhibitor treatment should be carefully monitored. The possibility of an increase in risk of lower-extremity amputation and bone fracture has also been reported with canagliflozin. Clinical trials and real-world data have suggested that SGLT2 inhibitors improve CV and renal outcomes and mortality in patients with type 2 diabetes (T2DM), especially in those with prior CV events, heart failure, or chronic kidney disease.
    [Show full text]
  • The Effects of SGLT2 Inhibitors on Lipid Metabolism
    H OH metabolites OH Review The Effects of SGLT2 Inhibitors on Lipid Metabolism Zsolt Szekeres 1, Kalman Toth 2 and Eszter Szabados 1,* 1 1st Department of Medicine, Division of Preventive Cardiology and Rehabilitation, University of Pecs, Medical School, H-7624 Pecs, Hungary; [email protected] 2 1st Department of Medicine, Division of Cardiology, University of Pecs, Medical School, H-7624 Pecs, Hungary; [email protected] * Correspondence: [email protected]; Tel.: +36-72-533-133; Fax: +36-72-536-146 Abstract: Sodium glucose co-transporter 2 (SGLT2) inhibitors are effective antihyperglycemic agents by inhibiting glucose reabsorption in the proximal tubule of the kidney. Besides improving glycemic control in patients with type 2 diabetes, they also have additional favorable effects, such as lower- ing body weight and body fat. Several clinical studies have demonstrated their positive effect in reducing cardiovascular morbidity and mortality. Furthermore, the use of SGLT2 inhibitors were associated with fewer adverse renal outcomes comparing to other diabetic agents, substantiating their renoprotective effect in diabetic patients. SGLT2 inhibitors have also remarkable effect on lipid metabolism acting at different cellular levels. By decreasing the lipid accumulation, visceral and subcutaneous fat, they do not only decrease the body weight but also change body composition. They also regulate key molecules in lipid synthesis and transportation, and they affect the oxidation of fatty acids. Notably, they shift substrate utilization from carbohydrates to lipids and ketone bodies. In this review we intended to summarize the role of SGLT2 inhibitors in lipid metabolism especially on lipoprotein levels, lipid regulation, fat storage and substrate utilization.
    [Show full text]
  • New Medications on the Horizon Diana Isaacs Andrew Bzowyckyj
    7/31/2019 New Medications on the Horizon Diana Isaacs PharmD, BCPS, BC-ADM, CDE Clinical Pharmacy Specialist Cleveland Clinic Diabetes Center Cleveland, OH Andrew Bzowyckyj PharmD, BCPS, CDE Associate Professor Pacific University Oregon School of Pharmacy Hillsboro, OR 1 7/31/2019 Disclosure to Participants • Notice of Requirements For Successful Completion – Please refer to learning goals and objectives – Learners must attend the full activity and complete the evaluation in order to claim continuing education credit/hours • Conflict of Interest (COI) and Financial Relationship Disclosures: – Presenter: Diana Isaacs, PharmD, BCPS, BC-ADM, CDE – Advisory Board: Sanofi; Becton, Dickinson & Co. – Presenter: Andrew Bzowyckyj, PharmD, BCPS, CDE – No COI/Financial Relationship to disclose • Non-Endorsement of Products: – Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity • Off-Label Use: – Participants will be notified by speakers to any product used for a purpose other than for which it was approved by the Food and Drug Administration. Session Objectives • Describe new agents approved and in the pipeline for type 1 and type 2 diabetes. • Compare and contrast new diabetes medications and formulations to what was previously available. • Discuss factors to consider when adding these new medications for specific patient populations. Drug Selection Factors Mechanism of Risk of Cost Action Hypoglycemia Impact on Route of Adverse Effects Glucose
    [Show full text]