title: No effects of atorvastatin (10 mg/d or 80 mg/d) on nitric oxide, prostacyclin, thromboxane and oxidative stress in type 2 diabetes mellitus patients of the DALI study.
abstract: The present study describes the effects of atorvastatin on whole body synthesis of nitric oxide (NO), prostacyclin (PGI2), and thromboxane A2 (TxA2), on oxidative stress and nitrite/nitrate-related renal carbonic anhydrase (CA) activity in patients with type 2 diabetes mellitus (T2DM). A double-blind, randomized, placebo-controlled parallel-group trial (the DALI study group) on 217 patients with T2DM and dyslipidemia was performed. Urinary samples were collected before and after administration of a standard dose (10 mg/d, n=73), a maximal dose atorvastatin (80 mg/d, n=72) or placebo (n=72) for 30 weeks. Urinary nitrite and nitrate were measured to assess whole body NO synthesis. The urinary molar ratio of nitrate to nitrite (UNOxR) served as a measure of renal CA activity. Free radical- and cyclooxygenase (COX)-catalyzed lipid peroxidation was estimated by measuring urinary 8-iso-prostaglandin F2α (8-iso-PGF2α). In subgroups, systemic PGI2 and TxA2 synthesis was assessed by measuring their major urinary metabolites 2,3-dinor-6-keto-prostaglandin F1α and 2,3-dinor-thromboxane B2, respectively. All biochemical parameters were measured by GC-MS and GC-MS/MS methods. T2DM patients had elevated levels of nitrate, nitrite, UNOxR, and 8-iso-PGF2α compared to healthy non-diabetic and normolipidemic subjects. Thirty-week treatment with atorvastatin (10 or 80 mg/d) did not significantly alter NO, PGI2, TxA2 and 8-iso-PGF2α synthesis and did not improve the renal reabsorption of nitrite which is considered an important reservoir of NO. Our study suggests that atorvastatin (10 or 80 mg/d) does not provide cardiovascular benefit beyond its cholesterol lowering effect in patients with T2DM.
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany. Electronic address: Tsikas.Dimitros@mh-hannover.de.
authors: Dimitrios
authors: D
authors: Tsikas
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: Vu Vi
authors: VV
authors: Pham
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: Maria-Theresia
authors: MT
authors: Suchy
authors: Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors: Marcel A
authors: MA
authors: van de Ree
authors: Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors: Menno V
authors: MV
authors: Huisman
authors: Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany.
authors: Jürgen C
authors: JC
authors: Frölich
authors: TNO Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors: Hans M G
authors: HM
authors: Princen
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000368:Aged; D000069059:Atorvastatin / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects*; D044062:Prostaglandins I / Q000096:biosynthesis*; D013931:Thromboxanes / Q000096:biosynthesis*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D044062:Prostaglandins I; D013931:Thromboxanes; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D000069059:Atorvastatin; D003404:Creatinine; D015237:Dinoprost
keywords: 8-iso-Prostaglandin F(2α); Carbonic anhydrase; Cardiovascular disease; Diabetes mellitus type 2; Nitric oxide; Oxidative stress; Prostacyclin; Statins; Thromboxane