title: Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function.
abstract: OBJECTIVE
  Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood.
  
  
  METHODS
  This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m2, eGFR≥60 to <90 ml/min per 1.73 m2, and eGFR≥90 ml/min per 1.73 m2).
  
  
  RESULTS
  Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (Pvalue interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (Pvalue interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients.
  
  
  CONCLUSIONS
  The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediatedvianonglucosuric-dependent mechanisms.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Sergei
authors.initials: S
authors.lastname: Petrykiv
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: C David
authors.initials: CD
authors.lastname: Sjöström
authors.affiliation: AstraZeneca Gothenburg, Mölndal, Sweden.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Greasley
authors.affiliation: AstraZeneca, Gaithersburg, Maryland; and.
authors.forename: John
authors.initials: J
authors.lastname: Xu
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Persson
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hiddo J L
authors.initials: HJL
authors.lastname: Heerspink
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control*; D017326:Clinical Trials, Phase III as Topic; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065840:Protective Factors; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
chemical_list: D001559:Benzhydryl Compounds; D015415:Biomarkers; D001786:Blood Glucose; D003404:Creatinine; D005960:Glucosides; D006442:Glycated Hemoglobin; D006454:Hemoglobins; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C089180:SLC5A2 protein, human; C517652:hemoglobin A1c protein, human; C529054:dapagliflozin
keywords: Benzhydryl Compounds; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucosides; Hematocrit; Humans; Hypoglycemic Agents; Natriuresis; albuminuria; blood pressure; cardiovascular; diabetic nephropathy; glomerular filtration rate; risk factors