DOCSLIB.ORG

SEMPA 2019 Dangerous Acidosis All of These Patients Are Acidotic … Corey M

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SEMPA 2019 Dangerous Acidosis All of These Patients Are Acidotic … Corey M 4/16/2019 SEMPA 2019 Dangerous Acidosis All of these patients are acidotic … Corey M. Slovis, M.D. Vanderbilt University Medical Center What is the diagnosis? Metro Nashville Fire Department Nashville International Airport Nashville, TN Name That Acidosis Name That Acidosis • Blindness • Hypoxia • Urine Findings • Hypocalcemia • Papilledema • Abdominal Pain • “In a snow storm” • Funny Breath • pH < 6.8 • Hypoglycemia • IV lorazepam • Carbon monoxide • Status Seizures Name That Acidosis Metabolic Acidosis Acidotic Diabetic “not in HCO3 pH DKA” with relatively WNL Blood Glucose 1 4/16/2019 Respiratory Alkalosis pCO2 Experts in Acid-base can tell if there is Compensation vs. a Second Primary Process pH Compensation is Respiratory Compensation in Metabolic Acidosis Always the Opposite HCO pH 3 pCO2 Acidosis Alkalosis Metabolic Respiratory pH Anion Gap Anion Gap • The gap is the Positives minus the Negatives • An elevated gap = MUDPILES + - - • The gap is Na -[Cl + HCO3 ] • WNL Gap but HCO3 = HARDUP • The gap should be about 8-12 (± 2) • The gap should always be less than 15 2 4/16/2019 Elevated Anion Gap Normal Gap Acidosis + - - (Na -[Cl + HCO3 ] 15) (Low Bicarb but A.G. is NOT Elevated) M Methanol H Hyperventilation (compensation) U Uremia A Acids, Addison’s, Carbonic Anhydrase DK DKA, AKA, Starvation Ketoacidosis Inhibitors P Phenformin/Metaformin, Paracetamol, Propylene Glycol RRTA I INH and Iron D Diarrhea L Lactic Acidosis U Ureteral Diversion, Ureterosigmoidostomy E Ethylene Glycol P Pancreatic Fistula, Pancreatic Drainage S Salicylates, Solvents Elevated Anion Gaps •Never secondary Always check the Anion Gap •Never benign Even if the BMP looks normal!! •Never chronic •Always potentially lethal •Can never be ignored Beware Acidotic Diabetes How Sick in DKA? • Are they compensated or is PCO2 telling • Mental Status you there is a Respiratory Acidosis or Primary Respiration Alkalosis • BP/Pulse • Is it “Euglycemic” DKA • Respiratory Rate • Finger Stick Glucose • Is it a big lactic acidosis due to … •Serum pH 3 4/16/2019 Venous pH Can an adult patient have VpH = 0.01 – 0.03 of Art pH “euglycemic DKA”? SGLT2 Inhibitors Sodium Glucose Cotransporter 2 Inhibitors J Clin Endocrinol Metab 2015;100:2849-52 • The Good Case Rep Crit Care 2016:ID 1656182 J Diab and Comp 2017;31:611-14 - Inhibits proximal tubular reabsorption of glucose • SGLT-2 may cause Euglycemic DKA - May decrease the rate of diabetic kidney disease • Glucose values 200-300 • The Bad • Yet severe acidosis - Increases reabsorption of ketones - Increases glucagon levels • May take longer to clear keto acids - Thus promoting hepatic ketogenesis • Be wary, use PE, VS & pH, not just glucose SGLT2 Inhibitors Big Time Lactic Acidosis in DKA • Invokana • Canagliflozin •Sepsis • Farxiga • Dapagliflozin • Dead gut • Jardiance • Empagliflozin • Glyxambi • Empagliflozin/linagliptin OR • Synjardy • Empagliflozin/metformin • Metformin induced lactic acidosis • Xigdou XR • Dapagliflozin/metformin 4 4/16/2019 JAMA IntMed;2018;178:903-10 An alcoholic comes in with altered • Rare but serious mental status and very ill appearing. • Seen in ODs Someone says he was drinking • Also: acute decline in renal function* “windex for car windshields”. • Lots of Bicarb acutely Is this methanol? • Dialysis with bicarbonate dialysate *beware GRF < 30 Toxic Alcohols • Ethanol Acetaldehyde The most common errors in alcoholics are made by doctors • Isopropyl Acetone and nurses who assume • Methanol Formic Acid "He's just drunk." • Ethylene Glycol Oxalic Acid Ten Commandments of Emergency Medicine Ann Emerg Med 1991;20:1146-1147 • Assume the Worst • Always err in a way the patient will suffer the least Ann Emerg Med 1991;20:1146-1147 5 4/16/2019 Methanol •CH3-OH; MW 32; 3.2 mg% of methanol = 1 mosm • Formic acid and formaldehyde once metabolized • Methanol is non-toxic; breakdown products are not • Diagnosis: Profound acidosis, blindness, retinal edema, pancreatitis Ethylene Glycol HO-CH2-CH2-OH MW 62 each 6.2 mg% = 1 mosm • Becomes oxalic acid once metabolized • An antifreeze agent • A sweetener for wine • 40 - 60 deaths a year in USA • Has no odor • Profound acidosis from oxalic acid • Renal failure from oxalate crystals in kidney Isopropyl Alcohol CH3-CHOH-CH3 MW 60 each 6.0 mg = 1 mosm • Becomes acetone once metabolized • Usually benign • Twice as drunk, twice as sick, twice as long • Ketosis without acidosis • No anion gap • Hemorrhagic gastritis, hypotension 6 4/16/2019 To check for Methanol Treatment of Methanol and and Ethylene Glycol: Ethylene Glycol 1) Get levels if available • Reverse Acidosis – 1 amp of bicarbonate for each 0.1 pH unit below 7.35 2) Check osmolar gap – 1 meq/kg over 5-10 min will raise pH by 0.1-0.15 – Get pH to 7.35-7.40 3) Treat based on history and/or physical and/or lab NOT just levels and/or gap • Block Metabolism – Block Alcohol Dehydrogenas If they have already metabolized the toxin, – Begin Fomepizole (4-MP) they can be acidotic with low or no detectable • 15 mg/kg IV then 10 mg/kg IV Q 12 H serum levels or osmolar gap! – Block Creation of Formic or Oxalic Acid Bicarbonate: Yes and No Is Bicarbonate Indicated Yes: in bicarbonate consuming overdoses like ASA, Methanol, Ethylene Glycol in Wide Gap Metabolic Replenish the consumed bicarbonate Acidosis? No: for diseases that cause acidosis like DKA, Sepsis and Lactic Acidosis Correct the underlying disease Using Bicarbonate Each amp raises pH by 0.1 if given in under 3-5 minutes Should you use bicarbonate in DKA? 1 meq/kg raises pH by 0.1 – 0.15 7 4/16/2019 Bicarbonate Use Recommendations on Potential Benefits Potential Risks Bicarbonate Reverses Acidosis Intracellular Acidosis It is generally agreed that: Improves Cardiac Output Increased Ca, H+, K fluxes • pH above 6.9 requires NO bicarbonate Increases Fibrillatory Threshold Hypokalemia, Tissue Hypoxia Improves Insulin Sensitivity Hyperosmolarity, • pH below 6.9 probably requires Hypernatremia bicarbonate Decreased Work of Breathing Increased CO2 Generation, Respiratory Acidosis • Be “forced” into using bicarbonate Decreased Length of Coma Paradoxical CSF Acidosis NEJM 2001;344:264-269 The only therapeutic variable associated with Rapid IV administration of cerebral edema in children with DKA was bicarbonate in DKA can cause a the administration of Bicarbonate respiratory acidosis in the brain • Low pH, low pCO2 levels and amount of dehydration also important determinants Rule 1: CO freely Crosses BBB 2 Rule 2: HCO3 does not cross BBB CO2 HCO3 CO2 CO2 CO2 8 4/16/2019 Bicarbonate is in equilibrium with C02 Rule 3: Hyperventilation is based on venous pH not HCO3 H2CO3 CO2 + H2O CSF pH BBB “Rules” Giving HCO3 raises CO2 •pCO2 crosses freely HCO3 H2CO3 CO2 •HCO3 doesn’t cross • Ventilation rate (pCO2) determined by venous pH If you give HCO3 rapidly IV: Bicarbonate is in equilibrium with C02 •Serum HCO3 will rise • Thus serum pH will rise HCO3 H2CO3 CO2 + H2O • If pH rises, less hyperventilation •Serum pCO2 will rise on venous side • Causing pCO2 to rise on CSF side too 9 4/16/2019 Push Bicarb in DKA ONLY For Giving IV Bicarbonate • Hyperkalemic emergency can cause CNS Hypercarbia • Impending cardiopulmonary arrest A 23 yo man presents with altered mental status. He is agitated, febrile and hyperventilating. Children are at Real Risk 140 100 BUN = 20 pH = 7.32 3.8 for Cerebral Edema. 10 GLU = 70 pCO2 = 20 pO2 = 80 Be Careful! . What is the differential of AMS? . Immediate Rule Out? (V pH 7.30) Status Seizures AMS Whenever you have a WGMA and a 1o Respiratory Alkalosis always • Vital Signs • Vital Signs immediately consider and rule out: • Toxic–Metabolic • Toxic–Metabolic • Structural • Structural ASPIRIN • Infectious • Infectious SEPSIS • Epilepsy • Psychiatric 10 4/16/2019 X 100,100 pH = 7.30 pH = 7.30 140 100 140 100 pCO2 = 30 pCO2 = 30 4.0 15 4.0 15 pO2 = 98 pO2 = 98 O2 sat = 100% O2 sat = 100% PE Decorticate, Papilledema . A 19 yo Jeet Kun Do Sensei is found ECG Diffuse ST and T waves changes down in his dojo. Any new Rule of 5 to use here? pH = 7.30 pCO2 = 30 pO2 = 98 O2 Sat = 100% Trust No One Believe Nothing 11 4/16/2019 Co-Oximetry • Measures true saturation's • Measures at 4 wavelengths • Specifically evaluates –Saturated Hgb (O2) –Desaturated Hgb (CO2) –Carbon Monoxide (CO) –Methemoglobin (Me) J Respir Dis 2001;22:289-29667 68 AMS of Unknown Cause 5 ABG Values •pO2 •pCO2 •pH • Measured O2 Sat •CO Level J Respir69 Dis 2008;29:74-82 Name That Acidosis • Blindness • Methanol • Urine Findings • Ethylene Glycol, DKA, RF Summary • Abdominal Pain • Methanol, Iron, DKA, Sepsis, ASA Test • Funny Breath • Uremia, DKA, Aspirin (Methyl Salycilate) • Hypoglycemia • ASA, Sepsis, Methanol, E.G. • Status Seizures • INH, Lactic Acidosis 12 4/16/2019 Name That Acidosis Name That Acidosis • Hypoxia • Lactic Acidosis • Hypocalcemia • Ethylene Glycol • Papilledema • Methanol Acidotic Diabetics “not in DKA” with relatively WNL • “In a snow storm” • Methanol Blood Glucose • pH < 6.8 • INH, ME, EG • IV lorazepam • Propylene glycol SGLT2 Inhibitors • Carbon monoxide • Lactic acidosis • AMS, toxic delirium • Febrile and thrashing Status Seizures • Seizing refractory to anti-seizure medications • DIC/MOSF INH • Hypoglycemic, Hypokalemic Aspirin Papilledema vs Renal Failure Severe acidosis that disappears with D NSS vs Ketotic but not acidotic 5 AKA Methanol vs EG vs Isopropyl 13 4/16/2019 Gold or silver faces and a WGMA Anxious, healthy and WNL gap acidosis Solvents Hyperventilation Elevated Anion Gap + - - (Na -[Cl + HCO3 ] 15) M Methanol U Uremia DK DKA, AKA, Starvation Ketoacidosis SUMMARY P Phenformin/Metaformin, Paracetamol, Propylene Glycol I INH and Iron L Lactic Acidosis E Ethylene Glycol S Salicylates, Solvents Big Time Lactic Acidosis in DKA Whenever you have a WGMA and a •Sepsis 1o Respiratory Alkalosis always immediately consider and rule out: • Dead gut ASPIRIN OR SEPSIS • Metformin induced lactic acidosis 14 4/16/2019 Using Bicarbonate Each amp raises pH by 0.1 if given in under 3-5 minutes Always check the Anion Gap Even if the BMP looks normal!! 1 meq/kg raises pH by 0.1 – 0.15 15.
Load more

Recommended publications
  • Use of Metformin in the Setting of Mild-To-Moderate Renal Insufficiency
    Reviews/Commentaries/ADA Statements REVIEW Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency 1 KASIA J. LIPSKA, MD hepatic gluconeogenesis without raising 2 CLIFFORD J. BAILEY, PHD, FRCP fi 3 insulin levels, it rarely leads to signi cant SILVIO E. INZUCCHI, MD hypoglycemia when used as a monother- apy (8,11). As a result, metformin is widely considered an ideal first-line agent for the treatment of type 2 diabetes, as common clinical conundrum faces despite multiple trials of intensive glu- recommended by several clinical guide- all U.S. practitioners treating pa- cose control using a variety of glucose- lines (12–14). A fi tients with type 2 diabetes. Today’s lowering strategies, there is a paucity of In addition to such bene ts, metfor- U.S. Food and Drug Administration pre- data to support specificadvantageswith min reduces the risk of developing di- scribing guidelines for metformin contra- other agents on cardiovascular outcomes abetes in individuals at high risk for the indicate its use in men and women with (5–7). disease (15) and has been considered as a serum creatinine concentrations $1.5 In the original UK Prospective Di- reasonable “off-label” approach in se- and $1.4 mg/dL ($132 and $123 abetes Study (UKPDS), 342 overweight lected individuals for diabetes prevention mmol/L), respectively. In a patient toler- patients with newly diagnosed diabetes (16). ating and controlled with this medication, were randomly assigned to metformin should it automatically be discontinued therapy (8). After a median period of 10 — as the creatinine rises beyond these cut years, this subgroup experienced a 39% HISTORICAL PERSPECTIVE De- fi points over time? Stopping metformin of- (P = 0.010) risk reduction for myocardial spite these proven bene ts, metformin ten results in poorly controlled glycemia infarction and a 36% reduction for total remains contraindicated in a large seg- and/or the need for other agents with their mortality (P = 0.011) compared with con- ment of the type 2 diabetic population, own adverse-effect profiles.
    [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]
  • Valsartan in Combination with Metformin and Gliclazide in Diabetic
    Patra et al. Future Journal of Pharmaceutical Sciences (2021) 7:157 Future Journal of https://doi.org/10.1186/s43094-021-00307-2 Pharmaceutical Sciences RESEARCH Open Access Valsartan in combination with metformin and gliclazide in diabetic rat model using developed RP-HPLC method Rasmita Patra, Yedukondalu Kollati, Sampath Kumar NS and Vijaya R. Dirisala* Abstract Background: Oral administration of biguanides (metformin) and sulfonylureas (gliclazide) are the most common approach of management of type 2 diabetes in humans. Among these diabetic patients, approximately 40–60% suffers from hypertension. Hence, the need of the day is application of polytherapy. A major challenge in polytherapy is the drug-drug interactions that may arise. Hence, this study is focused to develop a reverse phase high-performance liquid chromatography (RP-HPLC) method for concurrent estimation of diabetic drug metformin and hypertension drug valsartan using C18 column and find any possible pharmacokinetic interactions between the two drug combinations strategies, i.e., metformin-valsartan and gliclazide-valsartan in streptozotocin-induced diabetic rats. Result: The bioanalysis of drug-drug interaction pharmacokinetic result showed no significant difference in the tmax of single treatment of gliclazide and single treatment of metformin or upon co-administration with valsartan. Conclusion: Our study has shown that polytherapy of valsartan, a drug administered for hypertension along with hypoglycemic drugs metformin and gliclazide, can be advantageous and safe in patients suffering from both diabetes and hypertension. Keywords: RP-HPLC, Metformin, Valsartan, Gliclazide, Hypertension, Diabetes mellitus Background disease if left undetected or untreated. Such patients re- Diabetes has become a growing epidemic, and the per- quire polytherapy wherein drug-drug interactions may centage of patient population is increasing in leaps and lead to adverse side effects [5, 6].
    [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]
  • Assessing the Value of Treatment For
    Tim Wilsdon ASSESSING THE VALUE OF Lilian Li TREATMENT FOR DIABETES TO PATIENTS, THE HEALTHCARE SYSTEM, AND WIDER SOCIETY – A CASE STUDY ON CHINA TABLE OF CONTENTS EXECUTIVE SUMMARY .................................................................................................................................... 4 1. INTRODUCTION ................................................................................................................................... 11 1.1. Background ............................................................................................................................12 1.2. Our approach .........................................................................................................................13 1.3. The structure of the report .....................................................................................................13 2. DIABETES ............................................................................................................................................. 14 2.1. Access to medicines for diabetes..........................................................................................20 2.2. The value of treatment for diabetes .......................................................................................25 2.3. The value of medicines for diabetes in HICs and MICs .........................................................31 3. POLICY IMPLICATIONS .....................................................................................................................
    [Show full text]
  • Phenformin Hydrochloride
    456 Antidiabetics 4. Levien TL, et al. Nateglinide therapy for type 2 diabetes melli- 2. Wolffenbuttel BHR, Huijberts MSP. Aminoguanidine, a poten- ing then treatment with pioglitazone should be stopped; treat- tus. Ann Pharmacother 2001; 35: 1426–34. tial drug for the treatment of diabetic complications. Neth J Med ment should also be stopped if jaundice develops. 1993; 42: 205–8. 5. Fonseca V. et al. Addition of nateglinide to rosiglitazone mono- 1. Maeda K. Hepatocellular injury in a patient receiving pioglita- therapy suppresses mealtime hyperglycemia and improves over- 3. Abdel-Rahman E, Bolton WK. Pimagedine: a novel therapy for zone. Ann Intern Med 2001; 135: 306. all glycemic control. Diabetes Care 2003; 26: 1685–90. diabetic nephropathy. Expert Opin Invest Drugs 2002; 11: 2. May LD, et al. Mixed hepatocellular-cholestatic liver injury af- 6. Campbell IW. Nateglinide—current and future role in the treat- 565–74. ter pioglitazone therapy. Ann Intern Med 2002; 136: 449–52. ment of patients with type 2 diabetes mellitus. Int J Clin Pract 4. Thornalley PJ. Use of aminoguanidine (pimagedine) to prevent 3. Pinto AG, et al. Severe but reversible cholestatic liver injury af- 2005; 59: 1218–28. the formation of advanced glycation endproducts. Arch Biochem ter pioglitazone therapy. Ann Intern Med 2002; 137: 857. Biophys 2003; 419: 31–40. 4. Chase MP, Yarze JC. Pioglitazone-associated fulminant hepatic Preparations failure. Am J Gastroenterol 2002; 97: 502–3. Proprietary Preparations (details are given in Part 3) 5. Farley-Hills E, et al. Fatal liver failure associated with pioglita- Arg.: Nateglin; Starlix; Braz.: Starlix; Canad.: Starlix; Chile: Gluconol; Star- zone.
    [Show full text]
  • Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings
    . REPORTS. Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings Francis M. Collins, MD Abstract ly 30%. The implications of these findings Diabetes mellitus affects approximately 17 mil- are profound in terms of long-term com- lion adults in the United States and has profound plications and their associated costs. Most implications in terms of long-term microvascular primary care providers and endocrinolo- and macrovascular complications and their associ- gists acknowledge that good glycemic con- ated costs. In type 2 diabetes, insulin resistance trol can prevent or at least delay many of and a relative β-cell defect are the underlying pathologic problems leading to hyperglycemia. the complications of diabetes. However, Notably, insulin resistance is also associated with prior to the Diabetes Control and 2 obesity, dyslipidemia, and hypertension. Diabetes Complications Trial (DCCT) and the can be defined as a disease of accelerated cardio- United Kingdom Prospective Diabetes vascular deterioration associated with elevated Study (UKPDS),3 limited evidence was blood glucose levels. Glycemic control has been available to support this belief. Earlier shown to reduce the long-term complications studies failed to show a significant preven- associated with diabetes. Although medical nutri- tive benefit, for the most part because the tion therapy and appropriately prescribed definitions of good glycemic control used increased physical activity are important compo- in the studies were set too high. Even for nents of a diabetes management plan, most those who believed that tight glycemic patients need medication to lower glucose to near- normal levels. Therapeutic options for treating control was beneficial, therapeutic choic- hyperglycemia include sulfonylureas and other es for monitoring and treating hyper- insulin secretagogues, biguanides, α-glucosidase glycemia were limited.
    [Show full text]
  • The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates
    2784 Diabetes Volume 65, September 2016 Simon A. Hawley,1 Rebecca J. Ford,2 Brennan K. Smith,2 Graeme J. Gowans,1 Sarah J. Mancini,3 Ryan D. Pitt,2 Emily A. Day,2 Ian P. Salt,3 Gregory R. Steinberg,2 and D. Grahame Hardie1 The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels Diabetes 2016;65:2784–2794 | DOI: 10.2337/db16-0058 Canagliflozin, dapagliflozin, and empagliflozin, all recently transporters that carry glucose across apical membranes approved for treatment of type 2 diabetes, were derived of polarized epithelial cells against concentration gradi- from the natural product phlorizin. They reduce hypergly- ents, driven by Na+ gradients. SGLT1 is expressed in the cemia by inhibiting glucose reuptake by sodium/glucose small intestine and responsible for most glucose uptake cotransporter (SGLT) 2 in the kidney, without affecting across the brush border membrane of enterocytes, whereas intestinal glucose uptake by SGLT1. We now report that SGLT2 is expressed in the kidney and responsible for most fl canagli ozin also activates AMPK, an effect also seen glucose readsorption in the convoluted proximal tubules. with phloretin (the aglycone breakdown product of The first identified SGLT inhibitor was a natural product, fi phlorizin), but not to any signi cant extent with dapagli- phlorizin, which is broken down in the small intestine to flozin, empagliflozin, or phlorizin. AMPK activation oc- phloretin, the aglycone form (Fig. 1). Although phlorizin curred at canagliflozin concentrations measured in had beneficial effects in hyperglycemic animals (2), it in- human plasma in clinical trials and was caused by hibits SGLT1 and SGLT2, causing adverse gastrointestinal inhibition of Complex I of the respiratory chain, leading effects (3).
    [Show full text]
  • What Managed Care Needs to Know About Novel Therapies in The
    3/29/2017 What Managed Care Needs to Know About Novel Therapies in the Evolving Management of Type 2 Diabetes For Audio Please call 866‐206‐0240, Participant Code 64953949# If you are having difficulties logging in or calling in, please contact Jeremy at [email protected]. To Receive your certificate, please be sure to complete the online evaluation survey. Please email Katie at [email protected] for the survey link. Faculty Disclosure: Dr. Reid serves as a consultant and on an advisory board for Boehringer Ingelheim, Janssen, Lilly USA, Novo Nordisk and Sanofi. His presentation has been peer reviewed. Planning Committee Disclosure: Bill Williams, MD has no real or perceived financial relationships to disclose. Jacquelyn Smith, RN, BSN, MA, CMCN has no real or perceived financial relationships to disclose. Katie Eads has no real or perceived financial relationships to disclose. Will Williams has no real or perceived financial relationships to disclose. Accreditation: The National Association of Managed Care Physicians (NAMCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NAMCP designates this enduring material for a maximum of 1 AMA PRA Category I creditsTM. Each physician should claim credit commensurate with the extent of their participation in the activity. The American Association of Managed Care Nurses is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. Nurses who complete this activity and complete an evaluation form will receive 1 hour in continuing nursing credit. This activity has been approved by the American Board of Managed Care Nursing for 1.0 contact hour toward CMCN recertification requirements.
    [Show full text]
  • Canagliflozin, Dapagliflozin and Empagliflozin Monotherapy for Treating Type 2 Diabetes: Systematic Review and Economic Evaluation
    HEALTH TECHNOLOGY ASSESSMENT VOLUME 21 ISSUE 2 JANUARY 2017 ISSN 1366-5278 Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation Rhona Johnston, Olalekan Uthman, Ewen Cummins, Christine Clar, Pamela Royle, Jill Colquitt, Bee Kang Tan, Andrew Clegg, Saran Shantikumar, Rachel Court, J Paul O’Hare, David McGrane, Tim Holt and Norman Waugh DOI 10.3310/hta21020 Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation Rhona Johnston,1 Olalekan Uthman,2 Ewen Cummins,1 Christine Clar,3 Pamela Royle,2 Jill Colquitt,4 Bee Kang Tan,2 Andrew Clegg,5 Saran Shantikumar,2 Rachel Court,2 J Paul O’Hare,2 David McGrane,6 Tim Holt7 and Norman Waugh2* 1McMDC, Harrogate, UK 2Warwick Evidence, Division of Health Sciences, University of Warwick, Coventry, UK 3Berlin, Germany 4Effective Evidence, Waterlooville, UK 5University of Central Lancashire, Preston, UK 6Queen Elizabeth University Hospital, Glasgow, UK 7University of Oxford, Oxford, UK *Corresponding author Declared competing interests of authors: David McGrane has spoken at educational meetings sponsored by AstraZeneca, Eli Lilly, Sanofi, MSD, Takeda Pharmaceutical Company, Novo Nordisk, Janssen, and has served on Advisory Boards for Eli Lilly, Sanofi, Novo Nordisk. J Paul O’Hare has received lecture fees, advisory board meeting fees, and grants for research from Novo Nordisk and Sanofi. All fees are paid through University of Warwick to fund access to insulin projects in sub-Saharan Africa. Published January 2017 DOI: 10.3310/hta21020 This report should be referenced as follows: Johnston R, Uthman O, Cummins E, Clar C, Royle P, Colquitt J, et al.
    [Show full text]
  • Tight Control in Type 2 Diabetes: More Harm Than Good?
    Tight Control in Type 2 Diabetes: More Harm than Good? www.doh.dc.gov Collaborators www.doh.dc.gov More resources available at the DC Center for Rational Prescribing doh.dc.gov/dcrx www.doh.dc.gov Course Faculty • Adriane Fugh-Berman, MD • Tom Finucane, MD • Stephen Lippman, MD, PhD • Kofi Onumah, PharmD, RPh • Leonard Pogach, MD, MBA • Caroline Trapp, DNP, APN-BC, CDE, FAANP • Susan Wood, PhD www.doh.dc.gov Conflicts of Interest Disclosure • Adriane Fugh-Berman, MD is a paid expert witness at the request of plaintiffs in litigation regarding pharmaceutical marketing practices. • Tom Finucane, MD is a member of the Pharmacy and Therapeutics Committee for Anthem Inc. • Stephen Lippman, MD, PhD has been a paid expert witness at the request of plaintiffs in litigation regarding pharmaceutical marketing practices. • Kofi Onumah, PharmD, RPh has no conflicts of interest. • Leonard Pogach, MD, MBA has no conflicts of interest. • Caroline Trapp, DNP, APN-BC, FAANP has no conflicts of interest. • Susan Wood, PhD has no conflicts of interest. www.doh.dc.gov Important Information The video will progress at its own pace. Do not attempt to speed up the video. The post-test will only unlock after viewing the entire video. The video can be paused and resumed later. www.doh.dc.gov Course Objectives After completing this module, participants should be able to… 1. Discuss the risks 2. Describe the 3. Implement new and benefits of limitations of clinical strategies for metformin, insulin, evidence regarding counseling patients and other treatments tight control in about making for type 2 diabetes.
    [Show full text]
  • Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of Mtor Sonia R
    Published OnlineFirst April 24, 2018; DOI: 10.1158/1078-0432.CCR-18-0177 Cancer Therapy: Preclinical Clinical Cancer Research Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR Sonia R. Veiga1, Xuemei Ge1, Carol A. Mercer2, María I. Hernandez- Alvarez 3, Hala Elnakat Thomas2, Javier Hernandez-Losa4, Santiago Ramon y Cajal4, Antonio Zorzano3,5,6, George Thomas1,2,7, and Sara C. Kozma1,2 Abstract Purpose: Hepatocellular carcinoma (HCC) ranks second in Results: We found phenformin caused mitochondrial dys- cancer mortality and has limited therapeutic options. We recently function and fragmentation, inducing a compensatory shift to described the synergistic effect of allosteric and ATP-site compet- glycolysis. In contrast, dual inhibition of mTOR impaired cell itive inhibitors against the mTOR for the treatment of HCC. growth and glycolysis, while increasing mitochondrial fusion However, such inhibitors induce hyperglycemia and increase and efficiency. In a mouse model of human HCC, dual inhi- mitochondrial efficiency. Here we determined whether the mito- bition of mTOR, together with phenformin, was highly effica- chondrial complex I inhibitor phenformin could reverse both side cious in controlling tumor burden. However, more strikingly, effects, impose an energetic stress on cancer cells, and suppress the pretreatment with phenformin sensitized tumors to dual inhi- growth of HCC. bition of mTOR, leading to a dramatic improvement in Experimental Design: Human HCC cell lines were used in vitro survival. to access the signaling and energetic impact of mTOR inhibitors Conclusions: Treatment of HCC cells in vitro with the bigua- and phenformin, either alone or in combination. Next, the nide phenformin causes a metabolic shift to glycolysis, mitochon- therapeutic utility of these drugs alone or in combination was drial dysfunction and fragmentation, and dramatically sensitizes investigated preclinically in human orthotopic tumors implanted orthotopic liver tumors to dual inhibition of mTOR.
    [Show full text]