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Current Vascular Pharmacology


ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

Switching Dipeptidyl Peptidase-4 Inhibitors to Tofogliflozin, a Selective Inhibitor of Sodium-Glucose Cotransporter 2 Improve Arterial Stiffness Evaluated by Cardio-Ankle Vascular Index in Patients with Type 2 Diabetes: A Pilot Study

Author(s): Munehisa Bekki, Nobuhiro Tahara*, Atsuko Tahara, Sachiyo Igata, Akihiro Honda, Yoichi Sugiyama, Tomohisa Nakamura, Jiahui Sun, Yuki Kumashiro, Takanori Matsui, Yoshihiro Fukumoto and Sho-ichi Yamagishi*

Volume 17, Issue 4, 2019

Page: [411 - 420] Pages: 10

DOI: 10.2174/1570161116666180515154555

Price: $65


Background: We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in Type 2 Diabetes Mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of Sodium-Glucose Cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients.

Methods: Nineteen T2DM patients who had received DPP-4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin.

Results: At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), γ-glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (ΔCAVI), baseline serum levels of AGEs were significantly higher in the low ΔCAVI group (high responder) than in the high one (low responder). ΔAST and ΔGTP were positively correlated with ΔCAVI.

Conclusion: The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin.

Keywords: Advanced glycation end products, arterial stiffness, cardio-ankle vascular index, SGLT2 inhibitor, diabetes mellitus, tofogliflozin.

Graphical Abstract
Yamagishi S, Matsui T. Protective role of sodium-glucose co-transporter 2 inhibition against vascular complications in diabetes. Rejuvenation Res 2016; 19: 107-14.
Lee YJ, Lee YJ, Han HJ. Regulatory mechanism of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl 2007; 72: 27-35.
Santer R, Calado J. Familial renal glucosuria and SGLT2: From a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 2010; 5: 133-41.
Novikov A, Vallon V. Sodium glucose cotransporter 2 inhibition in the diabetic kidney: An update. Curr Opin Nephrol Hypertens 2016; 25: 50-8.
Wang XX, Levi J, Luo Y, et al. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J Biol Chem 2017; 292: 5335-48.
Nakamura N, Matsui T, Ishibashi Y, Yamagishi S. Insulin stimulates SGLT2-mediated tubular glucose absorption via oxidative stress generation. Diabetol Metab Syndr 2015; 7: 48.
Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005; 54: 3427-34.
Norton L, Shannon CE, Fourcaudot M, et al. Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects. Diabetes Obes Metab 2017; 19: 1322-6.
Mikhail N. Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes. World J Diabetes 2014; 5: 854-9.
Maliha G, Townsend RR. SGLT2 inhibitors: Their potential reduction in blood pressure. J Am Soc Hypertens 2015; 9: 48-53.
Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: Sodium glucose co-transport (SGLT) inhibitors: Systematic review and meta-analysis of randomized trials. Ann Med 2012; 44: 375-93.
Guthrie RM. Sodium-glucose co-transporter 2 inhibitors and the potential for cardiovascular risk reduction in patients with type 2 diabetes mellitus. Postgrad Med 2013; 125: 21-32.
Katsiki N, Mikhailidis DP, Theodorakis MJ. Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management. Curr Pharm Des 2017; 23: 1522-32.
Katsiki N, Athyros VG, Mikhailidis DP. Cardiovascular effects of sodium-glucose cotransporter 2 inhibitors: Multiple actions. Curr Med Res Opin 2016; 32: 1513-4.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-57.
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-34.
Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 2008; 60: 470-512.
Yamagishi S, Matsui T. Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes. Curr Pharm Des 2011; 17: 4379-85.
Yamagishi S, Fukami K, Matsui T. Crosstalk between advanced glycation end products (AGEs)-receptor RAGE axis and dipeptidyl peptidase-4-incretin system in diabetic vascular complications. Cardiovasc Diabetol 2015; 14: 2.
Tran S, Retnakaran R, Zinman B, Kramer CK. Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: A meta-analysis of randomized clinical trials. Diabetes Obes Metab 2018; 20(Suppl. 1): 68-76.
Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-26.
White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-35.
Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373: 232-42.
Tahara N, Yamagishi SI, Bekki M, et al. Anagliptin, A dipeptidyl peptidase-4 inhibitor ameliorates arterial stiffness in association with reduction of remnant-like particle cholesterol and alanine transaminase levels in type 2 diabetic patients. Curr Vasc Pharmacol 2016; 14: 552-62.
Duvnjak L, Blaslov K. Dipeptidyl peptidase-4 inhibitors improve arterial stiffness, blood pressure, lipid profile and inflammation parameters in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 2016; 8: 26.
Ishibashi Y, Matsui T, Maeda S, Higashimoto Y, Yamagishi S. Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovasc Diabetol 2013; 12: 125.
Matsui T, Nishino Y, Takeuchi M, Yamagishi S. Vildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressing advanced glycation end product-receptor axis. Pharmacol Res 2011; 63: 383-8.
Sakata K, Hayakawa M, Yano Y, et al. Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE) - receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes. Diabetes Metab Res Rev 2013; 29: 624-30.
Yamagishi S. Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. Exp Gerontol 2011; 46: 217-24.
Yamagishi S. Potential clinical utility of advanced glycation end product cross-link breakers in age- and diabetes-associated disorders. Rejuvenation Res 2012; 15: 564-72.
Kajikawa M, Nakashima A, Fujimura N, et al. Ratio of serum levels of ages to soluble form of rage is a predictor of endothelial function. Diabetes Care 2015; 38: 119-25.
Yamagishi S, Fukami K, Matsui T. Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: A novel marker of vascular complications in high-risk patients for cardiovascular disease. Int J Cardiol 2015; 185: 263-8.
Tahara N, Yamagishi S, Kodama N, et al. Clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues by FDG-PET/CT. J Clin Endocrinol Metab 2015; 100: 739-47.
Matsui T, Joo HD, Lee JM, et al. Development of a monoclonal antibody-based ELISA system for glyceraldehyde-derived advanced glycation end products. Immunol Lett 2015; 167: 141-6.
Sun CK. Cardio-ankle vascular index (CAVI) as an indicator of arterial stiffness. Integr Blood Press Control 2013; 6: 27-38.
Satoh-Asahara N, Kotani K, Yamakage H, et al. Cardio-ankle vascular index predicts for the incidence of cardiovascular events in obese patients: A multicenter prospective cohort study (Japan Obesity and Metabolic Syndrome Study: JOMS). Atherosclerosis 2015; 242: 461-8.
Mizuguchi Y, Oishi Y, Tanaka H, et al. Arterial stiffness is associated with left ventricular diastolic function in patients with cardiovascular risk factors: Early detection with the use of cardio-ankle vascular index and ultrasonic strain imaging. J Card Fail 2007; 13: 744-51.
Otsuka K, Fukuda S, Shimada K, et al. Serial assessment of arterial stiffness by cardio-ankle vascular index for prediction of future cardiovascular events in patients with coronary artery disease. Hypertens Res 2014; 37: 1014-20.
Saiki A, Sato Y, Watanabe R, et al. The role of a novel arterial stiffness parameter, cardio-ankle vascular index (CAVI), as a surrogate marker for cardiovascular diseases. J Atheroscler Thromb 2016; 23: 155-68.
Tahara N, Yamagishi S, Takeuchi M, et al. Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [(18)F]fluorodeoxyglucose positron emission tomography. Diabetes Care 2012; 35: 2618-25.
Shimomura M, Oyama J, Takeuchi M, et al. Acute effects of statin on reduction of angiopoietin-like 2 and glyceraldehyde-derived advanced glycation end-products levels in patients with acute myocardial infarction: A message from SAMIT (statin for acute myocardial infarction trial). Heart Vessels 2016; 31: 1583-9.
Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014; 13: 28.
Solini A, Giannini L, Seghieri M, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: A pilot study. Cardiovasc Diabetol 2017; 16: 138.
Chung GE, Choi SY, Kim D, et al. Nonalcoholic fatty liver disease as a risk factor of arterial stiffness measured by the cardioankle vascular index. Medicine 2015; 94: 654.
Luo ZX, Zeng Q, Luo R, Wang Y, Ge Q. Relative contributions of ectopic liver and abdominal fat accumulation to arterial stiffness. Endocr Pract 2015; 21: 574-80.
Hyogo H, Chayama K, Yamagishi S. Nonalcoholic fatty liver disease and cardiovascular disease. Curr Pharm Des 2014; 20: 2403-11.
Athyros VG, Tziomalos K, Katsiki N, Doumas M, Karagiannis A, Mikhailidis DP. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update. World J Gastroenterol 2015; 21: 6820-34.
Athyros VG, Alexandrides TK, Bilianou H, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement. Metabolism 2017; 71: 17-32.
Fracanzani AL, Tiraboschi S, Pisano G, et al. Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up. Atherosclerosis 2016; 246: 208-13.
Lee YJ, Lee JW, Kim JK, et al. Elevated white blood cell count is associated with arterial stiffness. Nutr Metab Cardiovasc Dis 2009; 19: 3-7.
Nagayama D, Yamaguchi T, Saiki A, et al. High serum uric acid is associated with increased cardio-ankle vascular index (CAVI) in healthy Japanese subjects: A cross-sectional study. Atherosclerosis 2015; 239: 163-8.
Yildiz BO, Haznedaroglu IC. Rethinking leptin and insulin action: Therapeutic opportunities for diabetes. Int J Biochem Cell Biol 2006; 38: 820-30.

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