Spironolactone Impairs Endothelial Function and Heart Rate Variability in Patients with Type 2 Diabetes

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2004 Sep 15

PMID 15365622

Citations 33

Authors

J I Davies

M Band

A Morris

A D Struthers

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Aldosterone blockade has followed in the footsteps of ACE inhibition in reducing mortality in patients with heart failure. This is associated with its beneficial effects on endothelial function and heart rate variability. Diabetes is another area, where angiotensin II withdrawal has proven to be of particular value. We postulated that aldosterone blockade with spironolactone might also have beneficial effects on the prognostic markers of endothelial function and heart rate variability in diabetic patients.

Methods: We assessed endothelial function by forearm venous occlusion plethysmography in 42 patients with type 2 diabetes mellitus after 1 month of treatment with spironolactone or placebo allocated in a randomised double-blind trial. Of the 42 patients, 20 were on ACE inhibitor therapy. We also assessed heart rate variability, HbA1c and plasma angiotensin II levels at the end of each treatment period.

Results: Compared to placebo, spironolactone decreased forearm blood flow response to acetylcholine by 44.56+/-14.56% (p=0.003) in the group as a whole and by 57.61+/-15.56% (p<0.001) in the 20 patients on ACE inhibition. Spironolactone also worsened heart rate variability parameters, with root mean squared standard deviation decreased by 1.99+/-0.93 ms (p=0.03), low-frequency normalised power increased by 2.00+/-0.91 normalised units (nu) (p=0.03), high-frequency normalised power decreased by 1.98+/-0.94 nu (p=0.04) and the low frequency : high frequency ratio increased by 0.40+/-0.19 (p=0.04). HbA1c and angiotensin II increased during treatment with spironolactone by 0.26+/-0.07% (p=0.001) and 8.12+/-1.94 pg/ml (p=0.001) respectively.

Conclusions/interpretation: Spironolactone worsened endothelial function and heart rate variability in patients with type 2 diabetes. These findings are possibly due to the worsening of glycaemic control and increase in plasma angiotensin II that were seen with spironolactone treatment. Thus the prescription of spironolactone to diabetic patients without heart failure does not seem to be justified.

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References

. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000; 355(9200):253-9. View

Modena M, Bonetti L, Coppi F, Bursi F, Rossi R . Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002; 40(3):505-10. DOI: 10.1016/s0735-1097(02)01976-9. View

ODriscoll G, Green D, Maiorana A, Stanton K, Colreavy F, Taylor R . Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1999; 33(6):1506-11. DOI: 10.1016/s0735-1097(99)00065-0. View

Lindholm L, Ibsen H, Dahlof B, Devereux R, Beevers G, de Faire U . Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359(9311):1004-10. DOI: 10.1016/S0140-6736(02)08090-X. View

Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T . Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001; 104(22):2673-8. DOI: 10.1161/hc4601.099485. View

Suwaidi J, Hamasaki S, Higano S, Nishimura R, Holmes Jr D, Lerman A . Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000; 101(9):948-54. DOI: 10.1161/01.cir.101.9.948. View

Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D . Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension. 1995; 25(5):918-23. DOI: 10.1161/01.hyp.25.5.918. View

Kontopoulos A, Athyros V, Didangelos T, Papageorgiou A, Avramidis M, Mayroudi M . Effect of chronic quinapril administration on heart rate variability in patients with diabetic autonomic neuropathy. Diabetes Care. 1997; 20(3):355-61. DOI: 10.2337/diacare.20.3.355. View

Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B . Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348(14):1309-21. DOI: 10.1056/NEJMoa030207. View

10.

Tsuji H, Larson M, Venditti Jr F, Manders E, Evans J, Feldman C . Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation. 1996; 94(11):2850-5. DOI: 10.1161/01.cir.94.11.2850. View

11.

. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352(9131):837-53. View

12.

Gokce N, Keaney Jr J, Hunter L, Watkins M, Menzoian J, Vita J . Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002; 105(13):1567-72. DOI: 10.1161/01.cir.0000012543.55874.47. View

13.

Mather K, Verma S, Anderson T . Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001; 37(5):1344-50. DOI: 10.1016/s0735-1097(01)01129-9. View

14.

Spieker L, Corti R, Binggeli C, Luscher T, Noll G . Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans. J Am Coll Cardiol. 2000; 36(1):213-8. DOI: 10.1016/s0735-1097(00)00674-4. View

15.

MacFadyen R, Barr C, Struthers A . Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res. 1997; 35(1):30-4. DOI: 10.1016/s0008-6363(97)00091-6. View

16.

Walker H, Jackson G, Ritter J, Chowienczyk P . Assessment of forearm vasodilator responses to acetylcholine and albuterol by strain gauge plethysmography: reproducibility and influence of strain gauge placement. Br J Clin Pharmacol. 2001; 51(3):225-9. PMC: 2015033. DOI: 10.1046/j.1365-2125.2001.00330.x. View

17.

ODriscoll G, Green D, Rankin J, Stanton K, Taylor R . Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest. 1997; 100(3):678-84. PMC: 508237. DOI: 10.1172/JCI119580. View

18.

Morton J, Webb D . Measurement of plasma angiotensin II. Clin Sci (Lond). 1985; 68(4):483-4. DOI: 10.1042/cs0680483. View

19.

Schachinger V, Britten M, Zeiher A . Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000; 101(16):1899-906. DOI: 10.1161/01.cir.101.16.1899. View

20.

Husain S, Andrews N, Mulcahy D, Panza J, Quyyumi A . Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998; 97(8):716-20. DOI: 10.1161/01.cir.97.8.716. View