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Horm Metab Res 2021; 53(07): 470-477
DOI: 10.1055/a-1517-6643
Endocrine Care

Effect of Lisinopril and Verapamil on Angiopoietin 2 and Endostatin in Hypertensive Diabetic Patients with Nephropathy: A Randomized Trial

Mohamed Salem
1   Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
,
Al-Aliaa M. Sallam‡
2   Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
3   Biochemistry Department, Badr University in Cairo (BUC), Badr City, Cairo, Egypt
,
Eman Abdel-Aleem
1   Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt
,
Hala O. El-Mesallamy 
2   Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
4   Biochemistry Department, Faculty of Pharmacy, Sinai University, Kantara Branch, Cairo, Egypt
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Abstract

Angiogenesis is a multistep process implicated in the pathophysiology and progression of diabetic nephropathy (DN). Angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) have an important role in DN. We performed a randomized-controlled trial of lisinopril alone (an ACEI) or in combination with verapamil (a CCB) as a therapy for DN in type 2 diabetes mellitus (T2DM) patients with hypertension (HTN) and urinary albumin creatinine ratio (UACR) (30–300 mg/g) also to evaluate their effect on UACR, the angiogenic proteins: Angiopoietin 2 (Ang-2) and Endostatin (EST). Forty T2DM patients with microalbuminuria, aged 45–65 years were included. Patients were randomly assigned into group 1 receiving oral lisinopril and group 2 receiving oral lisinopril and verapamil once daily. After 3 months follow-up fasting blood glucose (FPG), HbA1c, lipid profile, UACR, serum urea and creatinine levels were assessed. EST and Ang-2 were measured using ELISA technique. Baseline Ang-2 and EST levels were elevated in both groups compared with controls (p<0.001). After follow-up, group 2 had significantly decreased FPG, HbA1c, UACR, EST and Ang-2 compared with their baseline levels (p<0.001 for all comparisons) and with group 1 (p<0.001). No adverse reactions were reported. Baseline EST and Ang-2 were positively correlated to UACR (r=0.753, p<0.001) (r=0.685, p<0.001). Lisinopril/verapamil combination enhanced glycemic control and kidney function via diminishing EST and Ang-2. This combination can be considered as a safe and effective approach for early stage nephropathy therapy in T2DM.

Key words

diabetic nephropathy - lisinopril - verapamil - angiopoietin - endostatin


Publication History

Received: 02 January 2021

Accepted: 14 May 2021

Article published online:
19 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Carranza K, Veron D, Cercado A. et al. Cellular and molecular aspects of diabetic nephropathy; The role of VEGF-A. Nefrol [English Ed.] Socied Españ Nefrol 2015; 35: 131-138
    PubMedGoogle Scholar
  • 2 Dronavalli S, Duka I, Bakris GL. The pathogenesis of diabetic nephropathy. Nat Rev 2008; 4: 444-452
    PubMedGoogle Scholar
  • 3 Zheng Y, Ley S, Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrin 2018; 14: 88-98
    CrossrefPubMedGoogle Scholar
  • 4 Matsushita K, van der Velde M, Astor BC. et al. Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet 2010; 375: 2073-2081
    CrossrefPubMedGoogle Scholar
  • 5 El-Shazly AAA, Sallam AM, El-Hefnawy MH. et al. Epidermal growth factor receptor and podocin predict nephropathy progression in type 2 diabetic patients through interaction with the autophagy influencer ULK-1. J Diabetes Complications 2019; 33: 128-133
    CrossrefPubMedGoogle Scholar
  • 6 El-Dawla NMQ, Sallam AM, El-Hefnawy MH. et al. E-cadherin and periostin in early detection and progression of diabetic nephropathy: Epithelial-to-mesenchymal transition. Clin Exp Nephrol 2019; 23: 1050-1057
    CrossrefPubMedGoogle Scholar
  • 7 Nazir N, Siddiqui K, Al-qasim S. et al. Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways. BMC Med Genet 2014; 15: 103
    CrossrefPubMedGoogle Scholar
  • 8 Natale G, Bocci G, Lenzi P. Looking for the Word ‘Angiogenesis’ in the History of Health Sciences : From Ancient Times to the First Decades of the Twentieth Century. World J Surg 2017; 41: 1625-1634
    CrossrefPubMedGoogle Scholar
  • 9 Zent R, Pozzi A. Angiogenesis in Diabetic Nephropathy. Semin Nephrol 2007; 27: 161-171
    CrossrefPubMedGoogle Scholar
  • 10 Gnudi L, Benedetti S, Woolf AS. et al. Vascular growth factors play critical roles in kidney glomeruli. Clin Sci 2015; 1225-1236
    CrossrefPubMedGoogle Scholar
  • 11 Li L, Zheng-qing Y, Juan-yu H. et al. Association between interleukin-19 and angiopoietin-2 with vascular complications in type 2 diabetes. Nat Pub Group 2016; 7: 895-900
    PubMedGoogle Scholar
  • 12 Tsai Y, Lee C, Hsu Y. et al. Angiopoietin-2, Renal deterioration, major adverse cardiovascular events and all- cause mortality in patients with diabetic nephropathy. Kidney Blood Press Res 2018; 807: 545-554
    CrossrefPubMedGoogle Scholar
  • 13 Carlsson AC, Ruge T, Sundström J. et al. Association Between Circulating Endostatin, Hypertension Duration, and Hypertensive Target-Organ Damage. Hypertension 2013; 1146-1151
    CrossrefPubMedGoogle Scholar
  • 14 Carlsson AC, Östgren CJ, Länne T. et al. The association between endostatin and kidney disease and mortality in patients with type 2 diabetes. Diabetes Metab 2016; 351-357
    CrossrefPubMedGoogle Scholar
  • 15 Sabuncu T, Korkmaz H, Hakim C. The effects of calcium channel blockers on nephropathy and pigment epithelium-derived factor in the treatment of hypertensive patients with type 2 diabetes mellitus. Clin Exp Hypertens 2015; 37: 177-183
    CrossrefPubMedGoogle Scholar
  • 16 Roscioni S, Heerspink H, De Zeeuw D. The effect of RAAS blockade on the progression of diabetic nephropathy. Nat Rev Nephro 2014; 10: 77
    CrossrefPubMedGoogle Scholar
  • 17 Fried L, Emanuele N, Zhang J. et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Eng J Med 2013; 369: 1892-1903
    CrossrefPubMedGoogle Scholar
  • 18 Usuelli V, La Rocca E. Novel therapeutic approaches for diabetic nephropathy and retinopathy. Pharmacol Res. 2015: 39-44
    PubMedGoogle Scholar
  • 19 Keri KC, Samji NS, Blumenthal S. Diabetic nephropathy: Newer therapeutic perspectives. J Community Hosp Intern Med Perspect 2018; 8: 200-207
    CrossrefPubMedGoogle Scholar
  • 20 Srivastava SP, Goodwin JE, Kanasaki K. et al. Metabolic reprogramming by N-acetyl-seryl-aspartyl-lysyl-proline protects against diabetic kidney disease. Br J Pharmacol 2020; 177: 3691-3711
    CrossrefPubMedGoogle Scholar
  • 21 American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care 2015; 38: S50-S93
    PubMedGoogle Scholar
  • 22 Donaghue KC, Marcovecchio ML, Wadwa RP. et al. ISPAD clinical practice consensus guidelines 2018: Microvascular and macrovascular complications in children and adolescents. Pediatr Diabetes 2018; 19 (Suppl. 27) 262-274
    CrossrefPubMedGoogle Scholar
  • 23 Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol 1969; 22: 158-161
    CrossrefPubMedGoogle Scholar
  • 24 Degenhardt TP, Alderson NL, Arrington DD. et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int 2002; 61: 939-950
    CrossrefPubMedGoogle Scholar
  • 25 Kinaan M, Yau H, Martinez S. et al. Concepts in Diabetic Nephropathy : From Pathophysiology to Treatment. J Renal Hepat Disord 2017; 1: 10-24
    CrossrefPubMedGoogle Scholar
  • 26 Lozano-Maneiro L, Puente-García A. Renin-angiotensin-aldosterone system blockade in diabetic nephropathy. Present evidences J Clin Med 2015; 4: 1908-1937
    CrossrefPubMedGoogle Scholar
  • 27 Biaoxue R, Shuanying Y, Wei L. et al. Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer. World J Surg Oncol 2012; 10: 170
    CrossrefPubMedGoogle Scholar
  • 28 Rubio-guerra AF, Castro-serna D. Current concepts in combination therapy for the treatment of hypertension: Combined calcium channel blockers and RAAS inhibitors. Integr Blood Press Control 2009; 55-62
    CrossrefPubMedGoogle Scholar
  • 29 Xu G, Chen J, Jing G. et al. Preventing b -Cell Loss and Diabetes With Calcium Channel Blockers. Diabetes 2012; 61: 848-856
    CrossrefPubMedGoogle Scholar
  • 30 Yin T, Kuo S, Chang Y. et al. Verapamil use is associated with reduction of newly diagnosed diabetes mellitus. J Clin Endocr Metab 2017; 102: 2604-2610
    CrossrefPubMedGoogle Scholar
  • 31 Khodneva Y, Shalev A, Frank S. et al. Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study. Diabet Res Clini Pract 2016; 115: 115-121
    CrossrefPubMedGoogle Scholar
  • 32 Rubio-Guerra AF, Vargas-Robles H, Vargas-Ayala G. et al. The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. Clin Exp Hypertens 2008; 30: 682-688
    PubMedGoogle Scholar
  • 33 KDIGO Kidney Int. 2012 76. 1-2
    PubMedGoogle Scholar
  • 34 Watanabe Y, Kikuchi T, Mitsuhashi T. et al. Administration of Angiotensin Receptor II Blockade Improves Vascular Function, Urinary Albumin Excretion, and Left Ventricular Hypertrophy in Low-Risk Essential Hypertensive Patients Receiving Antihypertensive Treatment with Calcium Channel Blockers. Clin Exp Hypertens 2013; 35: 87-94
    CrossrefPubMedGoogle Scholar
  • 35 Chi C, Tai C, Bai B. et al. Angiotensin System Blockade Combined With Calcium Channel Blockers Is Superior to Other Combinations in Cardiovascular Protection With Similar Blood Pressure Reduction: A Meta-Analysis in 20, 451 Hypertensive Patients. J Clin Hypertens 2016; 18: 801-808
    CrossrefPubMedGoogle Scholar
  • 36 Siddiqui K, Joy SS, Nawaz SS. Serum Angiopoietin-2 levels as a marker in type 2 diabetes mellitus complications. Int J Diabetes Dev Ctries 2019; 387-393
    CrossrefPubMedGoogle Scholar
  • 37 Invest J, Yamamoto Y, Kato I. et al. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Investigat 2001; 108: 261-268
    CrossrefPubMedGoogle Scholar
  • 38 Rosenthal K. T-Type Ca Channel Blockade as a Determinant of Kidney Protection. Keio J Med 2010; 84-95
    PubMedGoogle Scholar
  • 39 Tabur S, Oğuz E, Sabuncu T. et al. The effects of calcium channel blockers on nephropathy and pigment epithelium-derived factor in the treatment of hypertensive patients with type 2 diabetes mellitus. Clin Exp Hypertens 2015; 37: 177-183
    CrossrefPubMedGoogle Scholar