Clinical Drug Investigation

, Volume 31, Issue 6, pp 427–434

Manidipine for Hypertension not Controlled by Dual Therapy in Patients with Diabetes Mellitus

A Non-Comparative, Open-Label Study
Original Research Article

Abstract

Background and Objective: Little is known about the effects of the calcium channel antagonist manidipine when it is added as a third drug in non-controlled hypertensive patients with diabetes mellitus receiving dual anti-hypertensive therapy. The aim of this study was to evaluate the response in terms of blood pressure (BP) and microalbuminuria when manidipine is administered to patients with type 2 diabetes and uncontrolled hypertension who are already being treated with a combination of a low-dose diuretic plus an ACE inhibitor or an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]). We also evaluated the effects of addition of manidipine on plasma fasting glucose, glycosylated haemoglobin (HbA1c), serum uric acid, the lipid profile, serum creatinine and creatinine clearance.

Methods: This was a non-comparative, open-label study of hypertensive diabetic patients with systolic/diastolic BP >130/80 mmHg. All patients had been receiving treatment for ≥3 months with stable doses of a diuretic plus an ACE inhibitor or ARB. Manidipine 10 mg/day was added, increasing to 20 mg/day if the target BP was not reached after 3 months’ treatment. The follow-up period was 6 months. Patient compliance was verified by tablet count. The doses of statins being taken by patients prior to commencement of the trial were not modified during the study. All patients were treated with oral antihyperglycaemic agents only; patients receiving insulin were excluded from the study.

Results: 136 patients were enrolled in the trial and completed the study; 41.9% of the patients were males, the mean ± SD age of the study population was 64.4 ± 12.3 years, and the mean ± SD body mass index was 30.2 ± 4.9 kg/m2. The mean ± SD BP at baseline was 158.6 ± 15.6/86.7 ± 11.2 mmHg compared with 136.8 ± 12.0/78.0 ± 11.2 (−21.8/−8.7, respectively) mmHg at the end of the study period (p < 0.001). A total of 63.6% of the patients attained a BP of <140/90 mmHg and 20.9% attained a BP of <130/80 mmHg. The mean ± SD heart rate decreased from 75.1 ± 11.2 at baseline to 72.8 ± 11.2 beats/min at the end of the study (p = 0.06; not significant). Fifty percent (95% CI 41.6, 58.4) of the patients had microalbuminuria at baseline compared with 31.3% (95% CI 23.0, 39.6) at study end (p = 0.006). Reductions in mean ± SD fasting glucose levels (−10.2 ± 50.3 mg/dL; p < 0.05), HbA1c (−0.19 ± 0.97%; p = 0.05), total cholesterol (−11.9 ± 35.2 mg/dL; 95% CI −18.1, −5.8; p < 0.005), triglycerides (−10.8 ± 51.1 mg/dL; 95% CI −19.7, −1.8; p = 0.018) and low-density lipoprotein-cholesterol (−8.1 ± 27.7 mg/dL; 95% CI −13.2, −2.9; p = 0.002) were observed. No patients dropped out of the study because of adverse effects. The most frequent adverse effect encountered was malleolar oedema (9%).

Conclusion: Manidipine added as the third drug to a renin-angiotensin system inhibitor plus a low dose of diuretic significantly reduces BP, improves renal function, has favourable effects on the lipid and glucose profiles, and reduces microalbuminuria in uncontrolled hypertensive patients with type 2 diabetes. Long-term trials are necessary to evaluate time-related effects.

References

  1. 1.
    Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994 Apr; 50(2): 272–98PubMedGoogle Scholar
  2. 2.
    UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macro vascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13CrossRefGoogle Scholar
  3. 3.
    Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–87PubMedCrossRefGoogle Scholar
  4. 4.
    Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004; 363: 2049–51PubMedCrossRefGoogle Scholar
  5. 5.
    Williams B. Recent hypertension trials: implications and controversies. J Am Coll Cardiol 2005; 45: 813–27PubMedCrossRefGoogle Scholar
  6. 6.
    Zanchetti A, Omboni S, La Commare P,et al. Efficacy and tolerability and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential hypertension. J Cardiovasc Pharmacol 2001; 38: 642–50PubMedCrossRefGoogle Scholar
  7. 7.
    McKeage K, Scott LJ. Manidipine: a review of its use in the management of hypertension. Drugs 2004; 64: 1923–40PubMedCrossRefGoogle Scholar
  8. 8.
    Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27: 2121–58PubMedCrossRefGoogle Scholar
  9. 9.
    Fogari R, Corradi L, Zoppi A, et al. Addition of manidipine improves the antiproteinuric effect of candesartan in hypertensive patients with type II diabetes and microalbuminuria. Am J Hypertens 2007; 20: 1092–6PubMedCrossRefGoogle Scholar
  10. 10.
    Hayashi K, Ozawa Y, Fujiwara K, et al. Role of actions of calcium antagonists on efferente arterioles-with special references to glomerular hypertension. Am J Nephrol 2003; 23: 229–44PubMedCrossRefGoogle Scholar
  11. 11.
    Hayashi K, Wakino S, Sugano N, et al. Ca2+ channel subtypes and pharmacology in the kidney. Circ Res 2007; 100: 342–53PubMedCrossRefGoogle Scholar
  12. 12.
    The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575–85CrossRefGoogle Scholar
  13. 13.
    Futukawa T, Nukada T, Miura R. Differential blocking action of dihydropyridine Ca2+ antagonists on a T-type Ca2+ channel (alpha1G) expressed in Xenopus oocytes. J Cardiovasc Pharmacol 2005; 45: 241–6CrossRefGoogle Scholar
  14. 14.
    Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007; 50: 823–30PubMedCrossRefGoogle Scholar
  15. 15.
    Cook S, Togni M, Schaub MC, et al. High heart rate: a cardiovascular risk factor? Eur Heart J 2006; 27: 2387–93PubMedCrossRefGoogle Scholar
  16. 16.
    Fogari R, Zoppi A, Corradi L, et al. Effects of different dihydropyridine calcium antagonists on plasma norepinephrine in essential hypertension. J Hypertens 2000; 18: 1871–5PubMedCrossRefGoogle Scholar
  17. 17.
    Torlone E, Britta M, Rambotti AM, et al. Improved insulin action and glycemic control alter long-term angiotensin-converting enzyme inhibitor in subjects with arterial hypertension and type II diabetes. Diabetes Care 1993; 16: 1347–55PubMedCrossRefGoogle Scholar
  18. 18.
    Lind L, Berne C, Pollare T, et al. Metabolic effects of antihypertensive treatment with nifedipine or furosemide: a double-blind cross-over study. J Hum Hypertens 1995; 9: 137–41PubMedGoogle Scholar
  19. 19.
    Charles S, Ketelsleger JM, Buysshaert M, et al. Hyperglycemic effects of nifedipine. Br Med J 1981; 283: 19–20CrossRefGoogle Scholar
  20. 20.
    Vessby B, Abelin J, Finnson M. Effects of nifedipine treatment on carbohydrate and lipoprotein metabolism. Curr Ther Res 1983; 33: 1075–81Google Scholar
  21. 21.
    Beer NA, Jakawobicz DJ, Beer RM, et al. Effects of nitrendipine on glucose tolerance and serum insulin and dehydroepiandosterone sulfate levels in insulin-resistant obese and hypertensive men. J Clin Endocrinol Metab 1993; 76: 178–83PubMedCrossRefGoogle Scholar
  22. 22.
    Martínez Martín FJ. Manidipine in hypertensive patients with metabolic syndrome: the MARIMBA study. Expert Rev Cardiovasc Ther 2009; 7: 863–9PubMedCrossRefGoogle Scholar
  23. 23.
    Luque Otero M, Martell Claros N. Manidipine versus enalapril monotherapy in patients with hypertension type 2 diabetes mellitus: a multicenter randomized, double-blind, 24-week study. Clin Ther 2005; 27: 166–73CrossRefGoogle Scholar
  24. 24.
    Martínez-Martín FJ, Sáiz-Satjes M. Manidipine reduces insulin requirements in hypertensive type 2 diabetic patients [abstract]. J Hypertens 2009; 27(Suppl. 4): S132Google Scholar
  25. 25.
    Fogari R, Derosa G, Mugellini A, et al. Effect of manidipine-rosuvastatin combination on fibrinolysis, inflammation markers and insulin sensitivity in hypertensive hypercho-lesterolemic patients. ASH 2008; P-253Google Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Hypertension UnitHospital Clínico San Carlos, MadridMadridSpain
  2. 2.Department of Preventive Medicine and Public HealthUniversidad Autónoma de MadridMadridSpain

Personalised recommendations