EFFICACY OF COMBINED ANTIHYPERTENSIVE THERAPY IN ACHIEVEMENT OF TARGET BLOOD PRESSURE IN DIABETIC PATIENTS

Aim. To evaluate the efficacy of long-term combined antihypertensive therapy (AHT) based on renin-angiotensin-aldosterone system (RAAS) blockers, indapamide and calcium channel blocker (CCB) in hypertensive patients with diabetes mellitus (DM) in accordance with target blood pressure (BP) <130/80 mm Hg achievement rate, dynamics of 24-hour BP profile, metabolic indices, and local stiffness of the main arteries. Besides, to study the effects of the CCB addition to dual therapy on these parameters. Material and methods. Patients (16 men, 31 women, 57.2±6.6 years old) with arterial hypertension degrees 1–3 and mild to moderate DM type 2 were included into the study. The patients were treated with perindopril (5–10 mg/day) or valsartan (80–160 mg/day) in combination with indapamide SR (1.5 mg/day) and amlodipine (5–10 mg/day). Examination included office BP measurement and ambulatory BP monitoring (ABPM), common carotid arteries sonarography , evaluation of serum levels of potassium, creatinine, uric acid, glucose metabolism and lipid profile parameters, calculation of insulin resistance index (HOMA) at baseline and after 30–32 weeks of treatment. Results. Target BP was achieved in 86.7% of patients. Evenly reduction of day and night BP without reflex tachycardia and hypotension episodes was observed. Office BP decreased from 149.5±12.0/90.0±8.3 to 125.0±7.6/76.8±4.9 mm Hg (p<0.05) and average daily BP (ABPM) decreased to 120.1±10.0/71.7±6.9 mmHg. Three drugs were needed to achieve target BP in baseline systolic BP >150 mm Hg (office) or >134 mmHg (ABPM). Marked beneficial effect on the morphological and functional characteristics of the vascular wall and its elastic properties, improvement of glycemic control, tissue insulin sensitivity and lipids profile were found. These effects were associated mainly with amlodipine inclusion into the therapy. Conclusion. The combined AHT based on RAAS blockers, indapamide SR and CCB provides achievement of target BP in the most of hypertensive patients with DM and accompanied by positive changes in vascular remodeling and metabolism.

1. American Heart Association. Heart Disease and Stroke Statistics — 2005 Update. Dallas, TX: American Heart Association; 2005.

2. National guidelines for the diagnosis and treatment of hypertension (fourth revision). Sistemnye Gipertenzii 2010; (3): 5–26. Russian (Национальные рекомендации по диагностике и лечению артериальной гипертонии (четвертый пересмотр). Системные гипертензии 2010; (3): 5–26).

3. The Task Force for the management of arterial hypertension of the European Society of Hypertension and of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension. J Hypertens 2007; 25: 1105–1187.

4. Tatti P., Paahron M., Byington R.P., et al. Outcome results of fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21: 597–603.

5. Jamerson K.A., Bakris G.L., Wun C.C., et al. Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens 2004;17(9):793–801.

6. Dahlöf B., Severs P.S., Poulter N.R., et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet 2010; 366: 895–906.

7. Ruschitzka F.T., Noll G., Luscher T.F. Combination of ACE inhibitors and calcium antagonists: a logical approach. J Cardiovasc Pharmacol 1998; 31: S5–16.

8. Izzo J.L., Zion A.S. Combined aliskiren-amlodipine treatment for hypertension in African Americans: clinical science and management issues. Ther Adv Cardiovasc Dis 2011;5(3):169–78.

9. Fernandez S.F., Huang M.H., Davidson B.A., et al. Modulation of angiotensin II responses in sympathetic neurons by cytosolic calcium. Hypertension 2003; 41: 56–63.

10. Fernandez S.F., Huang M.H., Davidson B.A. et al. Mechanisms of angiotensin II-mediated decreases in intraneuronal Ca2+ in calcium-loaded stellate ganglion neurons. Hypertension 2005; 45: 276–282.

11. Siragy H.M., Xue Ch., Webb R.L. Beneficial effects of combined benazepril-amlodipine on cardiac nitric oxide, cGMP, and TNF-α production after cardiac ischemia. J Cardiovasc Pharmacol 2006; 47: 636–642.

12. Standards of medical care in Diabetes – 2010. American Diabetes Association. Diabetes Care 2010; 33(Suppl 1): S11–61.

13. Touboul P.J., Hennerici M.G., Meairs S., et al. Mannheim Carotid Intima-Media Thickness Consensus (2004–2006) An Update on Behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007; 23: 75–80.

14. Hayashi K., Handa H., Nagasaka S., et al. Stiffness and elastic behavior of human intracranial and ex-tracranial arteries. J Biomech 1980; 13: 175–184.

15. Levy J.C., Mattheus D.R., Hermans M.P. Correct homeostasis model assessment (HOMA) evaluation uses the computer program (Letter). Diabetes Care 1998; 21: 2191–2192.

16. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362(17): 1575–1585.

17. The ONTARGET investigators. Telmisartan, ramipril or both in patientsat high risk for vascular events. N Engl J Med 2008; 358: 1547–1559.

18. Severe Hypoglycemia and Risks of Vascular Events and Death. Sophia Zoungas, Anushka Patel, John Chalmers, and ADVANCE Collaborative Group. N Engl J Med 2010; 363: 1410–1418.

19. Pepine C.J., Handberg-Thurmond E., Marks P. et al. Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an internet – based randomized trial in coronary artery disease patients with hypertension. JACC 1998; 32: 1228–1237.

20. Wald D.S., Law M., Morris J.K., et al. Combination therapy versus monotherapy in reduction blood pressure: meta-analysis on 11000 participants from 42 trials. Am J Med 2009; 122: 290–300.

21. Terpstra W.F., May J.F., Smit A.J., et al. Long-term effects of amlodipine and lisinopril on left ventricular mass and diastolic function in elderly, previously untreated hypertensive patients: the ELVERA trial. Hypertens 2001; 19: 303–309.

22. Farsang C. Advantages of lisinopril amlodipin fix combination therapy in hypertension. A comparative study of the efficacy and tolerability of amlodipin 5 mg and lisinopril 10 mg administrated separately and in combination in hypertension (HAMLET). Hypertonia es nephrologia 2004; 8(2): 72–78.

23. PROGRESS Collaborative Study Group. Randomised trial of perindopril based blood pressure-lowering regimen among 6108 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–1041.

24. Chazova I.E., Karpov Yu.A., Vikdorchik A.V. on behalf of the research team. The efficacy and safety of the combination of amlodipine and valsartan in the treatment of hypertension in clinical practice: first results of Russia's observational EKSTRA study. Sistemnye Gipertenzii 2010; (2): 18–26. Russian (Чазова И.Е., Карпов Ю.А., Викдорчик А.В. от лица исследовательской группы. Эффективность и безопасность комбинации амлодипина и валсартана в лечении артериальной гипертонии в условиях реальной клинической практики: первые результаты российского наблюдательного исследования ЭКСТРА. Системные Гипертензии 2010; (2): 18–26).

25. Elliot W.J., Meyer P.M. Incident diabetes in clinical trials of antihypertensive drugs: a new work meta-analysis. Lancet 2007; 369: 201–207.

26. Iimura O., Shimamoto K., Masuda A., et al. Effect of calcium channel blocker, manidipine, on insulin sensitivity in essential hypertensives. J Diabetes Complications 1995; 9(4): 215–219.

27. Rubio A.F., Arceo A., Vargas O. et al. The effect of trandolapril and its fixed-dose combination with verapamil on proteinuria in normotensive adults with type 2 diabetes. Diabetes Care 2004; 27: 1688– 1691.

28. Kannel W.B., McGee D.L. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979; 241: 2035–2038.

29. Howard G., O'Leary D.H., Zaccaro D. et al. Insulin sensitivity and atherosclerosis. Circulation 1996; 93: 1809–1817.

30. Emoto M., Nishizawa Y., Kawagishi T. et al. Stiffnes indexes beta of the common carotid and femoral arteries are associated with insulin resistance in NIDDM. Diabetes Care 1998; 21: 1178–1182.

31. Folkow B. Structure und function of the arteries in hypertension. Am Heart J 1987; 114: 938–948.

32. Franklin S.S., Khan S.A., Wong N.D. et al. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham heart study. Circulation 1999; 100: 354–360.

33. Booth R.F.G., Martin J.F., Honey A.C. et al. Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular amnipulation. Atherosclerosis 1989; 76: 257–268.

34. Pitt В. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). Circulation 2000; 102: 1503–1510.

35. Zanchetti A., Bond G., Hennig M., et al. Calcium antagonist lacidipine slows down progression asymptomatic carotid atherosclerosis. Principal results of the European lacidipine study on atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002; 106: 2422–2427.

36. The CAFE Investigators, for the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Investigators. Differential Impact of Blood Pressure-Lowering Drugs on Central Aortic Pressure and Clinical Outcomes Principal Results of the Conduit Artery Function Evaluation (CAFE) Study. Circulation 2006; 113: 466–471.

37. Winer N., Folker A., Murphy J.A. et al. Effect of fixed-dose ACE-inhibitor/calciim channel combination therapy vs. ACE-inhibitor monotherapy on arterial compliance in hypertensive patients with type 2 diabetes. Prev Cardiol 2005; 8: 87–92.

38. Rajala U., Päivänsalo M., Laakso M., et al. Associations of blood pressure with carotid intima-media thickness in elderly Finns with diabetes mellitus or impaired glucose tolerance. Journal of Human Hypertension 2003; 17: 705–711.

39. Messerli F.H. Vasodilatory edema: a common side effect of antihypertensive therapy. Curr Cardiol Rep 2002; 4 (6): 479–82.

40. Schrader J., Salvetti A., Calvo C., et al. The combination of amlodipine-valsartan 5/160 mg produces less peripheral oedema than amlodipine 10 mg in hypertensive patients not adequately controlled with amlodipine 5 mg. Int J Clin Pract 2009; 63 (2): 217–225.

41. Fogari R., Zoppi A., Derosa G., et al. Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens 2007; 21(3); 220–224.

42. Messerli F.H., Weir M.R., Neutel J.M. Combination therapy of amlodipine/benazepril versus monotherapy of amlodipine in a practice-based setting. Am J Hypertens 2002; 15(6): 550–556.