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4.
Ann Intern Med ; 171(6): 421-426, 2019 09 17.
Article in English | MEDLINE | ID: mdl-31525753

ABSTRACT

On 15 May 2015, the U.S. Food and Drug Administration (FDA) warned that administration of sodium-glucose cotransporter-2 (SGLT2) inhibitors could lead to ketoacidosis in patients with diabetes mellitus. This announcement came more than 2 years after the FDA's first approval of an SGLT2 inhibitor, although the phenomenon had been known for more than 125 years. Luminaries of diabetes research (including Josef von Mering, Frederick Allen, I. Arthur Mirsky, and George Cahill) had described ketosis and ketoacidosis induced by administration of the phytochemical phlorizin, the prototypical SGLT inhibitor, as well as in patients with familial renal glucosuria, a condition that is considered a natural model of SGLT2 inhibition. Neither government regulators nor manufacturers of SGLT2 inhibitors evinced an awareness of this extensive historical record. The absence of historical inquiry delayed notice of ketoacidosis as an adverse reaction, which could have reduced the burden of illness from these drugs.


Subject(s)
Drug Approval , Ketosis/history , Sodium-Glucose Transporter 2 Inhibitors/history , United States Food and Drug Administration/standards , Delayed Diagnosis , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/history , Glycosuria, Renal/complications , Glycosuria, Renal/history , History, 19th Century , History, 20th Century , History, 21st Century , Humans , Ketosis/chemically induced , Phlorhizin/adverse effects , Phlorhizin/history , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , United States
5.
Diabetes ; 68(6): 1109-1120, 2019 06.
Article in English | MEDLINE | ID: mdl-31109940

ABSTRACT

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the most recently approved class of diabetes drugs. Unlike other agents, SGLT2 inhibitors act on the kidney to promote urinary glucose excretion. SGLT2 inhibitors provide multiple benefits, including decreased HbA1c, body weight, and blood pressure. These drugs have received special attention because they decrease the risk of major adverse cardiovascular events and slow progression of diabetic kidney disease (1-3). Balanced against these impressive benefits, the U.S. Food and Drug Administration-approved prescribing information describes a long list of side effects: genitourinary infections, ketoacidosis, bone fractures, amputations, acute kidney injury, perineal necrotizing fasciitis, and hyperkalemia. This review provides a physiological perspective to understanding the multiple actions of these drugs complemented by a clinical perspective toward balancing benefits and risks.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Acute Kidney Injury/chemically induced , Blood Pressure , Body Weight , Diabetes Mellitus, Type 2/metabolism , Fasciitis, Necrotizing/chemically induced , Fractures, Bone/chemically induced , Glycated Hemoglobin/metabolism , Humans , Hyperkalemia/chemically induced , Ketosis/chemically induced , Reproductive Tract Infections/etiology , Sodium-Glucose Transporter 2/metabolism , Translational Research, Biomedical , Urinary Tract Infections/etiology , Weight Loss
6.
J Am Heart Assoc ; 7(4)2018 02 10.
Article in English | MEDLINE | ID: mdl-29440005

ABSTRACT

BACKGROUND: Dapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. METHODS AND RESULTS: Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d-1 of Na+ were randomized to bumetanide (1 mg·d-1), dapagliflozin (10 mg·d-1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d-1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74±7 mmol·d-1; P<0.005), which was not significantly different from both diuretics together (80±5 mmol·d-1; P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64±6 mmol·d-1), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101±8 mmol·d-1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05). CONCLUSIONS: First-dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide-induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865.


Subject(s)
Benzhydryl Compounds/administration & dosage , Bumetanide/administration & dosage , Glucosides/administration & dosage , Sodium Potassium Chloride Symporter Inhibitors/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Adolescent , Adult , Benzhydryl Compounds/adverse effects , Benzhydryl Compounds/pharmacokinetics , Bumetanide/adverse effects , Bumetanide/pharmacokinetics , Drug Interactions , Female , Glucosides/adverse effects , Glucosides/pharmacokinetics , Healthy Volunteers , Humans , Hyperuricemia/blood , Hyperuricemia/chemically induced , Hyperuricemia/prevention & control , Male , Middle Aged , Natriuresis/drug effects , Renal Elimination/drug effects , Risk Assessment , Sodium Potassium Chloride Symporter Inhibitors/adverse effects , Sodium Potassium Chloride Symporter Inhibitors/pharmacokinetics , Sodium, Dietary/urine , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics , Uric Acid/blood , Young Adult
8.
Diabetes Care ; 36(10): 3169-76, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23735727

ABSTRACT

OBJECTIVE: To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS: Subjects with type 2 diabetes (n=12) and matched healthy subjects (n=12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS: At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS: The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Glucosides/therapeutic use , Hypoglycemic Agents/therapeutic use , Kidney/metabolism , Adult , Benzhydryl Compounds , Female , Humans , Male , Middle Aged , Sodium-Glucose Transport Proteins/antagonists & inhibitors
10.
Am J Med Sci ; 330(6): 264-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16355009

ABSTRACT

The metabolic syndrome is an aggregation of biochemical and physical conditions that presage the development of atherosclerotic cardiovascular disease. The history of the metabolic syndrome is rooted in the recognition of adipose tissue as a heterogeneous, biologically active organ, as well as in the concepts of insulin resistance and its consequences. Establishment of the metabolic syndrome as a disease entity has been hindered by non-uniform criteria for its diagnosis.


Subject(s)
Adipose Tissue/metabolism , Adiposity , Body Fat Distribution , Metabolic Diseases/metabolism , History, 19th Century , History, 20th Century , Humans , Metabolic Diseases/history , Syndrome
11.
J La State Med Soc ; 156(3): 159-62, 2004.
Article in English | MEDLINE | ID: mdl-15233390

ABSTRACT

In the presence of atrial fibrillation, impulses of supraventricular origin that are transmitted through the ventricles during periods of relative refractoriness to impulse conduction exhibit anomalous configurations. These "aberrant beats" can be difficult to distinguish from ventricular ectopic beats, and groups of aberrant beats may be mistaken for ventricular tachycardia. Richard Ashman, PhD, a physiologist at Louisiana State University School of Medicine in New Orleans, noted that ventricular refractoriness varied with the lengths of cardiac cycles; that aberrant beats typically ended short cycles following long cycles; and that aberrant beats often have a right bundle branch block configuration. This observation, known as the "Ashman phenomenon," has become a principle of cardiology. Its recognition may allow clinicians to distinguish aberrant beats from ventricular ectopy. Ashman made a variety of other fundamental contributions to electrocardiography and was also an accomplished poet.


Subject(s)
Electrocardiography/history , Cardiology/history , History, 20th Century , Humans , Louisiana , Physiology/history
12.
J La State Med Soc ; 154(3): 144-8, 2002.
Article in English | MEDLINE | ID: mdl-12139360

ABSTRACT

The famous nineteenth century American physician and medical educator, Austin Flint, Sr., was a professor at the New Orleans School of Medicine and a visiting physician at Charity Hospital in New Orleans from 1858 to 1861. Best remembered for the heart murmur that bears his name, Flint was also responsible for advances in the diagnosis and treatment of infectious diseases in the era that preceded the germ theory and the discovery of antibiotics. His experiences at Charity Hospital and his exposure to the French style of medicine as practiced by the Creole physicians of New Orleans encouraged him to advocate conservative treatment for pneumonia, in contrast to the bloodletting and other heroic measures that were popular at the time. His recommendations, based on statistical analysis of his clinical data from Charity Hospital, were one of the earliest examples of evidence-based medicine in America.


Subject(s)
Evidence-Based Medicine/history , Education, Medical/history , History, 19th Century , Humans , Louisiana , Schools, Medical/history
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