Different Effects of Aliskiren and Losartan on Fibrinolysis and Insulin Sensitivity in Hypertensive Patients with Metabolic Syndrome

Abstract

The aim of this study was to compare the effect of aliskiren and losartan on fibrinolysis and insulin sensitivity (IS) in hypertensive patients with metabolic syndrome. After 2-week placebo period, 76 outpatients with mild to moderate hypertension and metabolic syndrome were randomized to aliskiren 300 mg od or losartan 100 mg od for 12 weeks. Clinic blood pressure (BP), plasma PAI-1 antigen, and tPA activity were evaluated after 2, 4, 8, and 12 weeks of treatment. At the end of each treatment period patients performed an euglycemic hyperinsulinemic clamp and IS was assessed by glucose infusion rate (GIR). Both aliskiren and losartan induced a significant and similar SBP/DBP reduction (−15.6/10.7 mmHg and –15.5/10.5 mmHg, p<0.001 vs. baseline, respectively). Both drugs decreased PAI-1 antigen and activity after 2 weeks of treatment; subsequently, only the decreasing effect of aliskiren was sustained throughout the 12 weeks [−7.5 ng/ml (−31%) p<0.05 vs. baseline], while with losartan PAI-1 increased at week 12 [+3.6 ng/ml (+15%), p<0.05 vs. baseline and p<0.01 vs. aliskiren)]. The tPA activity showed no significant change with aliskiren and a decrease with losartan [−0.04 IU/ml (−8%), p<0.05 vs. baseline and p<0.01 vs. aliskiren]. Aliskiren significantly increased GIR [+1.4 mg/min/kg (+28%), p<0.01 vs. baseline] while losartan did not change it [+0.2 mg/min/kg (+4%), NS vs. baseline, p<0.05 vs. aliskiren)]. These results indicated that in this type of patients, despite similar BP reduction, aliskiren improved the fibrinolytic balance as well as IS, while losartan worsened the fibrinolytic balance and did not affect IS. The clinical relevance of these different effects remains to be clarified.

PAI-1 antigen - tPA activity - AT1R blockers - renin inhibition

References

• 1 Juan Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events.  Thromb Haemost. 1997;  78 656-660
• 2 Poli KA, Tofler GH, Larson MG, Evans JC, Sutherland PA, Lipinska I, Mittleman MA, Muller JE, D’Agostino RB, Wilson PW, Levy D. Association of BP with fibrinolytic potential in the Framingham Offspring Population.  Circulation. 2000;  101 264-269
• 3 Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  Circulation. 1996;  94 2057-2063
• 4 Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (tPA) levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor.  Circulation. 1998;  98 2241-2247
• 5 Juan Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels: a possible link between insulin resistance and atherothrombosis.  Diabetologia. 1991;  34 457-462
• 6 Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1.  Hypertension. 1998;  32 965-971
• 7 Vaughan DE. Angiotensin, fibrinolysis and vascular homeostasis.  Am J Cardiol. 2001;  87 ((Suppl.)) 18C-24C
• 8 Wright RA, Flapan AD, Alberti KG, Ludlam CA, Fox KA. Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction.  J Am Coll Cardiol. 1994;  24 67-73
• 9 Sayer JW, Gutteridge C, Syndercombe-Court D, Wilkinson P, Timmis AD. Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin converting enzyme inhibitors.  J Am Coll Cardiol. 1998;  32 1962-1968
• 10 Sakata K, Shirotani M, Yoshida H, Urano T, Takada Y, Takada A. Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension.  Am Heart J. 1999;  137 1094-1099
• 11 Fogari R, Zoppi A, Preti P, Fogari E, Malamani G, Mugellini A. Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive post-menopausal women.  Am J Hypertens. 2001;  14 921-926
• 12 Fogari R, Mugellini A, Zoppi A, Corradi L, Preti P, Lazzari P, Derosa G. Losartan and perindopril effects on plasma fibrinogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetics.  Am J Hypertens. 2002;  15 316-320
• 13 Fogari R, Preti P, Lazzari P, Corradi L, Zoppi A, Fogari E, Mugellini A. Effect of benazepril amlodipine combination on fibrinolysis in hypertensive diabetic patients.  Eur J Clin Pharmacol. 2003;  59 271-275
• 14 Paterna S, Di Garbo V, Avellone G, Di Pasquale P, Cacia A, Tuttolomondo A, Follone G, Cardinale A, Maniscalchi T, Licata G. Effects of losartan and delapril on the fibrinolytic system in patients with mild to moderate hypertension.  Clin Drug Invest. 2003;  23 717-724
• 15 Blood Pressure Lowering Treatment Trialist's Collaboration. . Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.  J Hypertens. 2007;  25 951-958
• 16 Lottermoser K, Hertfelder HH, Vetter H, Dusing R. Fibrinolytic function in diuretic induced volume depletion.  Am J Hypertens. 2000;  13 359-363
• 17 Erdem Y, Usalan C, Haznedaroglu IC, Altun B, Arici M, Yasavul U, Turgan C, Ca+lar S. Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in system hypertension.  Am J Hypertens. 1999;  11 1071-1076
• 18 Matsumoto T, Minai K, Horie H, Ohira N, Takashima H, Tarutani Y, Yasuda Y, Ozawa T, Matsuo S, Kinoshita M, Horie M. Angiotensin converting enzyme inhibition but not angiotensin II type 1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients.  J Am Coll Cardiol. 2003;  41 1373-1379
• 19 Skurk T, Lee YM, Nicuta-Rolfs TO, Haastert B, Wirth A, Hauner H. Effect of the angiotensin II receptor blocker candesartan on fibrinolysis in patients with mild hypertension.  Diabetes Obes Metab. 2004;  6 56-62
• 20 Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV.  J Clin Invest. 1995;  96 2515-2520
• 21 Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release in human vasculature.  Hypertension. 1999;  33 1431-1435
• 22 Frampton JE, Curran MP. Aliskiren. A review of its use in the management of hypertension.  Drugs. 2007;  67 1767-1792
• 23 Gradman AH, Pinto R, Kad R. Current concepts: renin inhibition in the treatment of hypertension.  Curr Opin Pharmacol. 2008;  8 120-126
• 24 Rashid H. Direct renin inhibition: an evaluation of the safety and tolerability of aliskiren.  Curr Med Res Opin. 2008;  24 2627-2637
• 25 De Fronzo RA, Tobin JA, Andres B. Glucose clamp technique, a method for quantifying insulin secretion and resistance.  Am J Physiol. 1979;  237 214-223
• 26 Grundy SM, Cleeman JI, Daniels SR, Donato DJ, Krauss RM, Savage PJ, Smith Jr SC, Spertus JA, Costa F. American Heart Association; National Heart, Lung, and Blood Institute . Diagnosis and management of the metabolic syndrome An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.  Circulation. 2005;  112 2735-2752
• 27 Verheijen JH, Chang GTC, Kluff C. Evidence for the occurrence of a fast acting inhibitor of tissue-type plasminogen activator in plasma.  Thromb Haemost. 1984;  51 392-395
• 28 Velthuis-te Wierik EJ, Meijer P, Kluft C, Van der Berg H. Beneficial effect of a moderately energy-restricted diet on fibrinolytic factors in non obese men.  Metabolism. 1995;  44 1548-1552
• 29 Mertens I, Van Gaal LF. Obesity, haemostasis and the fibrinolytic system.  Obes Rev. 2002;  3 85-101
• 30 Brown NJ, Kumar S, Painter CA, Vaughan DE. Ace-inhibition versus angiotensin type I receptor antagonism. Differential effects on PAI-1 over time.  Hypertension. 2002;  40 859-865
• 31 Vague P, Juan-Vague I, Alessi MC, Badier C, Valadier J. Metformin decreases the high plasminogen activator inhibitor capacity, plasma insulin and triglycerides levels in non diabetic obese subjects.  Thromb Haemost. 1987;  57 326-328
• 32 Brown NJ, Agirbasli MA, Vaughan DE. Comparative effect of angiotensin converting enzyme inhibition and angiotensin II type I receptor antagonism on plasma fibrinolytic balance in humans.  Hypertension. 1999;  34 285-290
• 33 Alessi MC, Juhan-Vague I, Declerck PJ, Collen D. Molecular forms of plasminogen activator 1 (PAI-1) and tissue plasminogen activator (tPA) in human plasma.  Thromb Res. 1991;  62 275-285

Correspondence