title: Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial.
abstract: BACKGROUND
  Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance.
  
  
  OBJECTIVE
  The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled study.
  
  
  METHODS
  This trial was conducted at Vanderbilt Clinical Research Center.
  
  
  METHODS
  Participants included overweight individuals with prediabetes.
  
  
  METHODS
  Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment.
  
  
  METHODS
  The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion.
  
  
  RESULTS
  Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per μU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per μU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 μg/mg Cr. This effect persisted 3 months after sildenafil discontinuation.
  
  
  CONCLUSIONS
  Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Ramirez
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Hui
authors.initials: H
authors.lastname: Nian
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gamboa
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: James M
authors.initials: JM
authors.lastname: Luther
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
authors.affiliation: Departments of Medicine (C.E.R., J.L.G., J.M.L., N.J.B., C.A.S.) and Biostatistics (H.N., C.Y.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Cyndya A
authors.initials: CA
authors.lastname: Shibao
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000517:prevention & control; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000150:complications; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011236:Prediabetic State / Q000188:drug therapy* / Q000503:physiopathology; D000068677:Sildenafil Citrate / Q000627:therapeutic use*
chemical_list: D007328:Insulin; D058986:Phosphodiesterase 5 Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D000068677:Sildenafil Citrate; D005947:Glucose