A Randomized Controlled Trial Comparing the Effects of Sitagliptin and Glimepiride on Endothelial Function and Metabolic Parameters: Sapporo Athero-Incretin Study 1 (SAIS1)

Objectives The DPP-4 inhibitors are incretin-related drugs that improve hyperglycemia in a glucose-dependent manner and have been reported to exert favorable effects on atherosclerosis. However, it has not been fully elucidated whether DPP-4 inhibitors are able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of sitagliptin, a DPP-4 inhibitor, on endothelial function and glycemic metabolism compared with that of the sulfonylurea glimepiride. Materials and Methods In this multicenter, prospective, randomized parallel-group comparison study, 103 outpatients with type 2 diabetes (aged 59.9 ± 9.9 years with HbA1c levels of 7.5 ± 0.4%) with dietary cure only and/or current metformin treatment were enrolled and randomly assigned to receive sitagliptin or glimepiride therapy once daily for 26 weeks. Flow-mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force® Monitor), and serum metabolic markers were assessed before and after the treatment. Results During the study period, no statistically significant change in %FMD was seen in both groups (sitagliptin, 5.6 to 5.6%; glimepiride, 5.6 to 6.0%). Secretory units of islets in transplantation, TNF-α, adiponectin and biological antioxidant potential significantly improved in the sitagliptin group, and superoxide dismutase also tended to improve in the sitagliptin group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Conclusions Regardless of glycemic improvement, early sitagliptin therapy did not affect endothelial function but may provide favorable effects on beta-cell function and on inflammatory and oxidative stress in patients with type 2 diabetes without advanced atherosclerosis. Trial Registration UMIN Clinical Trials Registry System UMIN 000004955

[1]  I. Shimomura,et al.  Sitagliptin Attenuates the Progression of Carotid Intima-Media Thickening in Insulin-Treated Patients With Type 2 Diabetes: The Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE) , 2016, Diabetes Care.

[2]  Y. Kurihara,et al.  A Comparison of the Effects of the GLP-1 Analogue Liraglutide and Insulin Glargine on Endothelial Function and Metabolic Parameters: A Randomized, Controlled Trial Sapporo Athero-Incretin Study 2 (SAIS2) , 2015, PloS one.

[3]  M. Pencina,et al.  Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. , 2015, The New England journal of medicine.

[4]  Deepak L. Bhatt,et al.  Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Moderate or Severe Renal Impairment: Observations From the SAVOR-TIMI 53 Trial , 2014, Diabetes Care.

[5]  S. Rani,et al.  Apoptosis of beta cells in diabetes mellitus. , 2014, DNA and cell biology.

[6]  Yining Yang,et al.  Adiponectin Abates Atherosclerosis by Reducing Oxidative Stress , 2014, Medical science monitor : international medical journal of experimental and clinical research.

[7]  T. Funahashi,et al.  A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus- a randomized controlled trial START-J study , 2014, Cardiovascular Diabetology.

[8]  Yan Wu,et al.  Angiotensin II Receptor Blockers Improve Peripheral Endothelial Function: A Meta-Analysis of Randomized Controlled Trials , 2014, PloS one.

[9]  L. Bardram,et al.  GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. , 2014, Endocrinology.

[10]  T. Okamoto,et al.  Acute effect of brisk walking with graduated compression stockings on vascular endothelial function and oxidative stress , 2013, Clinical physiology and functional imaging.

[11]  F. Pattou,et al.  The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization. , 2013, The Journal of clinical endocrinology and metabolism.

[12]  Harumi Uto-Kondo,et al.  Dipeptidyl Peptidase‐4 Inhibitors Attenuate Endothelial Function as Evaluated by Flow‐Mediated Vasodilatation in Type 2 Diabetic Patients , 2013, Journal of the American Heart Association.

[13]  S. Hahn,et al.  Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis , 2013, Diabetologia.

[14]  Ryuzo Kawamori,et al.  Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. , 2013, Endocrinology.

[15]  K. Mizuno,et al.  The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes , 2012, Journal of Korean medical science.

[16]  H. Takagi,et al.  Low-density lipoprotein-independent improvement of flow-mediated dilatation with atorvastatin: a meta-analysis and meta-regression of randomized controlled trials. , 2012, International journal of cardiology.

[17]  S. Yamagishi,et al.  Sitagliptin Augments Protective Effects of GLP-1 against Advanced Glycation End Product Receptor Axis in Endothelial Cells , 2011, Hormone and Metabolic Research.

[18]  M. Netea,et al.  Vildagliptin Improves Endothelium-Dependent Vasodilatation in Type 2 Diabetes , 2011, Diabetes Care.

[19]  A. Dear,et al.  A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model , 2011, Diabetes & vascular disease research.

[20]  A. Dear,et al.  Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen [corrected] activator inhibitor-1 expression. , 2010, The Journal of endocrinology.

[21]  R. D. de Boer,et al.  Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species–Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[22]  The Emerging Risk Factors Collaboration.  Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies , 2010, The Lancet.

[23]  R. Kawamori,et al.  Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4 , 2010, Diabetes.

[24]  S. Hollenberg,et al.  Bench-to-bedside review: Nitric oxide in critical illness – update 2008 , 2009, Critical care.

[25]  K. Naka,et al.  Pioglitazone vs glimepiride: Differential effects on vascular endothelial function in patients with type 2 diabetes. , 2009, Atherosclerosis.

[26]  D. Doudet,et al.  Inhibition of Dipeptidyl Peptidase IV With Sitagliptin (MK0431) Prolongs Islet Graft Survival in Streptozotocin-Induced Diabetic Mice , 2008, Diabetes.

[27]  T. Rabelink,et al.  Endothelial function and dysfunction: testing and clinical relevance. , 2007, Circulation.

[28]  Yue Feng,et al.  Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic β-Cell Mass and Function in a Rodent Model of Type 2 Diabetes , 2006, Diabetes.

[29]  T. Wascher,et al.  Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance , 2005, European journal of clinical investigation.

[30]  S. Kazui,et al.  Mortality and Cause of Death after Hospital Discharge in 10,981 Patients with Ischemic Stroke and Transient Ischemic Attack , 2005, Cerebrovascular Diseases.

[31]  J. Holst,et al.  Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. , 2004, American journal of physiology. Endocrinology and metabolism.

[32]  L. Bouter,et al.  Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not; The Hoorn Study. , 2004, Atherosclerosis.

[33]  B. Sobel,et al.  Maladaptive arterial remodeling with systemic hypertension associated with increased concentrations in blood of plasminogen activator inhibitor type-1 (PAI-1). , 2004, The American journal of cardiology.

[34]  B. Lewis,et al.  Brachial artery endothelial function in residents and fellows working night shifts. , 2004, The American journal of cardiology.

[35]  E. Benjamin,et al.  Clinical Correlates and Heritability of Flow-Mediated Dilation in the Community: The Framingham Heart Study , 2004, Circulation.

[36]  F. Ruschitzka,et al.  Mental Stress Induces Prolonged Endothelial Dysfunction via Endothelin-A Receptors , 2002, Circulation.

[37]  Peter Libby,et al.  Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. , 2002, JAMA.

[38]  E. Benjamin,et al.  Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. , 2002, Journal of the American College of Cardiology.

[39]  J. Callés-Escandon,et al.  Diabetes and endothelial dysfunction: a clinical perspective. , 2001, Endocrine reviews.

[40]  A. Zeiher,et al.  Insulin-mediated stimulation of protein kinase Akt: A potent survival signaling cascade for endothelial cells. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[41]  A. Nicolaides,et al.  A simple test to monitor oxidative stress. , 1999, International angiology : a journal of the International Union of Angiology.

[42]  A. Henderson.  Endothelial dysfunction: a reversible clinical measure of atherogenic susceptibility and cardiovascular inefficiency. , 1997, International journal of cardiology.

[43]  P. Vallance,et al.  Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. , 1997, Circulation.

[44]  J. Polak,et al.  Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group. , 1993, Circulation.

[45]  S. Marklund,et al.  CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. , 1981, The Biochemical journal.

[46]  T. Sawada,et al.  Comparison of effects of α-Glucosidase inhibitors and glinide drugs on endothelial dysfunction in diabetic patients with coronary artery disease. , 2014, Circulation journal : official journal of the Japanese Circulation Society.

[47]  K. Kario,et al.  A multicenter study design to assess the clinical usefulness of semi-automatic measurement of flow-mediated vasodilatation of the brachial artery. , 2012, International heart journal.

[48]  H. Kumagai,et al.  Seasonal variation of endothelium-dependent flow-mediated vasodilation measured in the same subjects. , 2012, American journal of cardiovascular disease.

[49]  M. Hollenberg,et al.  Review Bench-to-bedside review: Nitric oxide in critical illness - update , 2009 .

[50]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .