Comparison of the Effects of Losartan Vs. Ramipril on Several Adipocytokines and Vascular Remodeling Biomarkers

COMMENTARY

Comparison of the effects of losartan vs.ramipril on several adipocytokines and vascular remodeling biomarkers

Junji Kobayashi, Tohru Noguchi, Atsushi Nohara and Hiroshi Mabuchi

Hypertension Research (2011) 34, 52–54; doi:10.1038/hr.2010.209; published online 25 November 2010

ngiotensin II receptor antagonists, also resistin, visfatin, vaspin) and vascular remo- treatment mainly through visceral fat mass A known as angiotensin receptor blockers deling biomarkers (matrix metalloproteinase- reduction. In rats, visceral fat accumulation is (ARBs), AT1-receptor antagonists or sartans, 2 (MMP-2) and MMP-9), whereas ramipril suppressed by telmisartan treatment.7 Telmi- block the activation of angiotensin II AT1 had no effect on any of these parameters sartan also modulates adipocyte size and fat receptors. ARBs directly cause vasodilatation, (Figure 1), although those two drugs reduced accumulation, resulting in protection against reduce secretion of vasopressin, and reduce blood pressure to comparable levels. diet-induced visceral obesity. It is also the production and secretion of aldosterone. Several investigators have reported that likely that the increased expression of Angiotensin-converting enzyme (ACE) inhi- losartan treatment increased total serum mitochondrial energy expenditure genes in bitors block the conversion of angiotensin I to adiponectin and high-molecular-weight adi- skeletal muscle is the mechanism by which angiotensin II and inhibit the breakdown of ponectin in IFG/IGT3 or hypertensive telmisartan decreases visceral fat accumula- bradykinin, resulting in physiological benefits subjects.4 Telmisartan was also demonstrated tion, as previously shown in rat models. that confer cardioprotective and renoprotec- to increase serum adiponectin levels.1 In For the association between ramipril treat- tive properties. contrast, another study showed that 8 weeks ment and plasma adiponectin, on the other Both ARBs and ACE inhibitors are classes of telmisartan treatment had a neutral effect hand, previous findings are conflicting. ofdrugsfrequentlyusedforthetreatment on insulin resistance, as assessed by home- One study performed in a randomized, of hypertension in daily clinical practice. ostasis model assessment-insulin resistance in double-blind, placebo-controlled cross-over They have protective effects on the heart hypertensive subjects with metabolic syndrome. manner showed that 10 mg of ramipril, and kidney and also lower blood pressure as So what is the potential mechanism by 16 mg of candesartan or combination therapy well as improve insulin sensitivity. which these ARBs increased adiponectin increased plasma adiponectin levels when There are a number of studies on the levels? Is this directly related to AT1 receptor compared with baseline values.8 Another effects of either ARBs or ACE inhibitors on block? The most conceivable explanation for study has shown that 9-week treatment with metabolic parameters, cytokines or cardiovas- this is peroxisome proliferator-activated 10 mg of ramipril did not cause significant cular biomarkers.1 However, there are very receptor (PPAR) activation by these ARBs. changes in adiponectin levels in patients with few, if any, studies directly comparing the A subset of ARBs, including losartan, induce type 2 diabetes. effects of ARBs with those of ACE inhibitors the activity of PPAR by partial agonism.5 Derosa et al.2 also investigated the effects of on metabolic parameters. Of note, this activation was independent of losartan vs. ramipril treatment on several In the current issue of Hypertension AT1R expression and therefore not related to other metabolic parameters and vascular Research, Derosa et al.2 describe a study in AT1R-blocking properties.5 PPAR functions remodeling biomarkers. To the best of our which they recruited 228 Caucasian hyper- as a transcriptional regulator in adipose knowledge, there appears to be no previous tensive subjects (115 males and 113 females) tissue, where it regulates multiple genes report on the association of losartan and/or in a double-blind clinical trial. The authors involved in lipid and glucose metabolism. In ramipril treatment with changes in RBP-4, found that 14 months of treatment with the case of telmisartan, our group and others6 visfatin or vaspin. Also, there are very few losartan improved a wide range of metabolic have shown that telmisartan treatment pro- reports, if any, on the effect of treatment with parameters (M value and levels of adiponec- duced significant reductions in visceral fat these compounds on serum resistin levels. tin, retinol-binding protein-4 (RBP-4), areas but not in subcutaneous areas evaluated A small crossover study by a Norwegian by computed tomography in Japanese sub- group composed of 23 hypertensive patients Professor J Kobayashi, T Noguchi, A Nohara and jects with metabolic syndrome. As plasma showed that there was no significant differ- H Mabuchi are at the Department of Lipidology, adiponectin level is inversely associated with ence in blood levels of resistin (11.7±1.0 vs. Kanazawa University Graduate School of Medical ± À1 Science, Kanazawa, Japan. visceral fat accumulation, we presumed 11.3 0.7 ng ml ) between treatment with E-mail: [email protected] that adiponectin increased after telmisartan amlodipine 10 mg and that with losartan Commentary 53

Adiponectin ↑ compared the effects of valsartan (4909 Visfatin↑ patients), valsartan plus captopril (4885 adipocytes Vaspin → Insulin patients) and captopril (4909 patients) on sensitivity↑ Resistin ↓ death from any cause in subjects with acute myocardial infarction who had already RBP-4 ↓ Losartan undergone conventional therapy. The authors concluded that valsartan is as effective as captopril in patients who are at high risk MMP-2 ↓ Plaque macrophages stabilization↑ for cardiovascular events after myocardial MMP-9 ↓ infarction. Thus, none of these three large- scale RCTs concluded that ARBs are superior to ACE inhibitors with respect to long-term Figure 1 Proposed effects of losartan therapy on adipocytokine and metalloproteinase production, mortality, incidence of cardiovascular disease as clarified in the study by Derosa et al.2 or new onset of diabetes. Are the observed favorable effects in the 100 mg+amlodipine 5 mg, respectively. As study was performed with a b1 receptor current study pharmacological class effects or RBP-4, visfatin, vaspin and resistin are closely antagonist rather than a placebo as control. specific to the drugs studied? As mentioned related to insulin resistance, the altered levels HOPE and DREAM are placebo-controlled earlier, certain ARBs may utilize mechanisms of these molecules along with adiponectin in RCTs for investigating the long-term out- involved in PPAR activation that are inde- the losartan group compared with the rami- comes of ramipril use, with the former utiliz- pendent of AT1 R-blocking properties. pril group in the current study suggest that ing cardiovascular events as end points and Indeed, Derosa et al.10 reported very recently losartan may have considerable advantages with the latter utilizing new-onset diabetes or a study comparing the effects of 1-year over ramipril in the prevention of athero- death as end points. The use of ramipril vs. treatment with 8 mg dayÀ1 candesartan or sclerotic disease or diabetes. The present placebo is associated with a 22% reduction in 10 mg dÀ1 olmesartan on various metabolic finding that losartan but not ramipril caused cardiovascular events without significant parameters related to insulin resistance. They a reduction in both MMP-2 and MMP-9 after reduction in new-onset diabetes. report that candesartan but not olmesartan 14 months (Po0.05) also suggests that losar- So what about head-to-head RCT compar- caused favorable changes in M-value, adipo- tan more effectively prevents the destabiliza- ing ARBs vs. ACE inhibitors? nectin, visfatin, RBP-4 and C-reactive tion of plaques, as expected, as MMPs are key There are several RCTs comparing ARBs protein, although comparable reductions enzymes involved in degrading the extracel- vs. ACE inhibitors in terms of mortality, were observed in blood pressure. These lular matrix. However, a previous report9 morbidity or cardiovascular events as end results suggest that the observed changes in showed that 10 mg once daily during points, but not the use of losartan vs. ramipril metabolic parameters may be due to com- 24 weeks of ramipril treatment reduced specifically. In the ONgoing Telmisartan pound-specific effects rather than class gene and protein expression of both MMP-2 Alone and in Combination with Ramipril effects. In the future, to compare head-to- and MMP-9. Global Endpoint Trial (ONTARGET), 25 620 head long-term outcomes, studies should To what degree does losartan or ramipril subjects from 730 centers in 40 countries were consider specific ARBs or ACE inhibitors prevent the incidence of cardiovascular dis- high-risk patients with coronary, peripheral, rather than broadly compare ARBs vs. ACE ease or the onset of diabetes? The Losartan or cerebrovascular disease or diabetes with inhibitors. Intervention for Endpoint Reduction (LIFE), end-organ damage. Patients were randomized the Heart Outcomes Prevention Evaluation to groups treated with 80 mg of telmisartan, (HOPE) and the Diabetes REduction Assess- 10 mg of ramipril or both drugs and followed ment with ramipril and rosiglitazone Medi- for 3.5–5.5 years. The authors concluded that cation (DREAM) studies are large-scale telmisartan was an equally effective alterna- 1 Chujo D, Yagi K, Asano A, Muramoto H, Sakai S, Ohnishi A, Shintaku-Kubota M, Mabuchi H, Yamagishi randomized control trials (RCTs) demon- tive to ramipril and that there is no additional M, Kobayashi J. Telmisartan treatment decreases strating the clinical outcome of using either advantage from the combination of full doses visceral fat accumulation and improves serum levels losartan or ramipril. of telmisartan and ramipril compared with of adiponectin and vascular inflammation markers in Japanese hypertensive patients. Hypertens Res 2007; LIFE is a trial comparing the effect of ramipril alone. The Optimal Trial in Myocar- 30: 1205–1210. losartan vs. atenolol, a selective b1 receptor dial Infarction with Angiotensin II Antagonist 2 Derosa G, Maffioli P, Ferrari I, Palumbo I, Randazzo S, Fogari E, D’Angelo A, Cicero AFG. Different actions antagonist, with regard to the incidence of Losartan (OPTIMAAL) is a trial involving of losartan and ramipril on adipose tissue activity cardiovascular mortality, fatal or nonfatal 5477 patients with confirmed acute myocar- and vascular remodeling biomarkers in hypertensive stroke, myocardial infarction or new-onset dial infarction and heart failure recruited patients. Hypertens Res 2011; 34: 145–151 3 Nishimura H, Sanaka T, Tanihata Y, Naito T, diabetes. The trial involved the recruitment from 329 centers in seven European coun- Higuchi C, Otsuka K. Losartan elevates the serum of 9193 hypertensive subjects with LVH. Main tries. Patients were randomly assigned and high-molecular weight-adiponectin isoform and outcomes are a 25% further reduction in titrated to a target dose of losartan (50 mg concurrently improves insulin sensitivity in patients with impaired glucose metabolism. Hypertens Res stroke and 25% reduction of new-onset once daily) or captopril (50 mg three times 2008; 31: 1611–1618. diabetes for losartan compared with atenolol, daily), with all-cause mortality as the primary 4 Uchida T, Shimizu M, Sakai Y, Nakano T, Hara K, Takebayashi K, Inoue T, Node K, Inukai T, Takayanagi without a significant difference in MI inci- end point. They concluded that ACE inhibi- K, Aso Y. Effects of losartan on serum total and dence between groups. It should be noted, tors should remain the first-choice treatment high-molecular weight adiponectin concentrations however, that LIFE did not necessarily in patients after complicated acute myocar- in hypertensive patients with metabolic syndrome. Metabolism 2008; 57: 1278–1285. demonstrate that long-term losartan therapy dial infarction. The VALsartan In Acute 5 Schupp M, Janke J, Clasen R, Unger T, Kintscher U. prevents the onset of diabetes because the myocardial iNfarcTion (VALIANT) study Angiotensin type 1 receptor blockers induce peroxisome

Hypertension Research Commentary 54

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