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Statins and Renin-Angiotensin System Inhibitor Combination Treatment To

Statins and Renin-Angiotensin System Inhibitor Combination Treatment To

Circulation Journal REVIEW Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp and Renin-Angiotensin System Inhibitor Combination Treatment to Prevent Cardiovascular Hae-Young Lee, MD, PhD; Ichiro Sakuma, MD, PhD; Sang-Hyun Ihm, MD, PhD; Choong-Won Goh, MD; Kwang Kon Koh, MD, PhD

Hypercholesterolemia and are common risk factors for (CVD). Updated guide- lines emphasize target reductions of overall cardiovascular risks. Experimental studies have shown reciprocal rela- tionships between resistance (IR) and . and hypertension have a synergistic deleterious effect on IR and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of and hypertension. Various strategies with different classes of anti- hypertensive to reach target goals have failed to reduce residual CVD risk further. Of interest, treating moderate elevations with low-dose statins in hypertensive patients reduced CVD risk by 35–40% further. Therefore, statins are important in reducing CVD risk. Unfortunately, therapy causes IR and increases the risk of type 2 mellitus. RAS inhibitors improve both endothelial dysfunction and IR. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of IR and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic effects on endothelial dysfunction and IR in addition to lowering cholesterol levels and pressure when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercho- lesterolemia, diabetes, metabolic syndrome, or obesity to prevent CVD. (Circ J 2014; 78: 281 – 287)

Key Words: Cardiovascular disease; Hypercholesterolemia; Hypertension; Renin-angiotensin system inhibitors; Statins

n the past, the goal of treating patients with hypertension proximately 26%; however, this prevalence doubles in the or hypercholesterolemia was merely to control numerical hypertensive population, reaching nearly 60%.6 Although it is I factors such as blood pressure (BP) or serum cholesterol not possible to provide a definite pathogenesis of hypertension- level alone; nowadays, it has changed. The updated guidelines hypercholesterolemia/ clustering, it is gaining target reductions in overall cardiovascular risk.1,2 Hypercholes- consensus that IR and endothelial dysfunction might play terolemia and hypertension are both associated with endothe- major roles.7,8 lial dysfunction and insulin resistance (IR) and their coexis- From 1988–1994 to 2005–2010, control of concomitant tence is a vicious cycle associated with an increased incidence hypertension and the low-density lipoprotein-cholesterol of cardiovascular events. Moreover, both risk factors are fre- (LDL-C) level rose from 5.0% to 30.7%. By multivariable lo- quently prevail together.3,4 Indeed, more than 60% of hyper- gistic regression, factors associated with concomitant hyper- tensive patients were consistently hypercholesterolemic in the tension, LDL-C, and non-high-density lipoprotein-cholesterol United States National Health and Nutrition Examination Sur- control were statin therapy (10.7) and antihypertensive (3.32) veys 1988–2010.5 More importantly, the prevalence of dyslip- medications, and ≥2 healthcare visits/year (1.90), whereas age idemia increased parallel to BP. In the prehypertensive range, (0.77/10-year increase), black race (0.59), Hispanic ethnicity prevalence was similar to that of the general population, ap- (0.62), cardiovascular disease (CVD) (0.44), and diabetes mel-

Received December 9, 2013; accepted December 12, 2013; released online January 8, 2014 Division of Cardiology, Seoul National University College of Medicine, Seoul (H.-Y.L.); Division of Cardiology, College of Medicine, The Catholic University of Korea, Seoul (S.-H.I.); Department of Cardiology, Sanggyepaik Hospital, Inje University, Seoul (C.-W.G.); Division of Cardiology, Gachon University Gil Hospital, Incheon (K.K.K.); Gachon Cardiovascular Research Institute, Incheon (K.K.K.), Korea; and Cardiovascular Medicine, Hokko Memorial Clinic, Sapporo (I.S.), Japan We presented part of this work at the American Association 2012 Scientific Session, November 4, 2012, Los Angeles, CA, USA Mailing address: Kwang Kon Koh, MD, PhD, FACC, Professor of Medicine, Director, Vascular Medicine and Atherosclerosis Unit, Division of Cardiology, Gachon University Gil Hospital, 1198 Kuwol-dong, Namdong-gu, Incheon 405-760, South Korea. E-mail: kwangk@ gilhospital.com ISSN-1346-9843 doi: 10.1253/circj.CJ-13-1494 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Circulation Journal Vol.78, February 2014 282 LEE HY et al.

Figure 1. Differential effects of antihypertensive on insulin sensitivity. Ramipril and candesartan therapies signifi- cantly increased levels to a greater extent than atenolol or thiazide. therapy significantly increased adi- ponectin levels to a greater extent than atenolol. Ramipril and candesartan therapies significantly increased insulin sensitivity [as assessed by the Quantitative Insulin-Sensitivity Check Index (QUICKI)] to a greater extent than atenolol or thiazide. Standard error of the mean is identified by the bars. Pl, ; At, atenolol; Am, amlodipine; Th, thiazide; Ra, ramipril; Ca, candesartan. (Re- produced with permission from Koh et al.24)

litus (DM) (0.54) were inhibiting factors. Interestingly, 69.3% comes,15 recently published hypertension guidelines state that of hypertensive hypercholesterolemic patients failed to be con- , β-blockers, calcium antagonists, angiotensin-con- comitantly controlled in 2005–2010.5 Various strategies to verting inhibitors (ACEIs) and angiotensin-receptor reduce residual CVD risk in hypertensive patients include blockers (ARBs) are equally recommendable for the initiation treating BP to lower target goals and using different classes of and maintenance of antihypertensive treatment.16 However, it antihypertensive medications; however still considerable re- is also widely accepted that there are substantial differing ef- sidual risks remains. In contrast, controlling hypercholesterol- fects on insulin sensitivity among the various classes of anti- emia in hypertensive patients by statins is very effective in hypertensive agents. The Antihypertensive and Lipid-Lower- reducing residual CVD risk by 35–40%.1 Therefore, statins are ing Treatment to Prevent Heart Attack Trial (ALLHAT), a of paramount importance in reducing CVD risk.2 clinical outcome trial in 42,418 high-risk patients with hyper- However, IR and the risk of type 2 DM have recently be- tension, which compared 3 classes of antihypertensive agents come problematic with statin therapy.9 In contrast, statin-based as initial therapy of hypertension, showed an increased inci- combination treatment with renin-angiotensin-aldosterone sys- dence of DM among -treated patients.17 Diuretic treat- tem (RAS) blockade has additive effects to control BP, lipid ment resulted in 4–6 mg/dl higher fasting plasma glucose lev- profiles, endothelial dysfunction and IR by both distinct and els, causing 17% increased incidence of DM compared with interrelated mechanisms,10–12 which may explain positive out- other agents.18 Hypokalemia associated with thiazide diuretics comes of recent clinical trials. Here, we review the role of IR is suggested to be the main mechanism of IR.19 β-blockers tend in hypertension-hypercholesterolemia/dyslipidemia clustering to increase body weight and cause IR, facilitating new-onset and suggest a strategy for achieving maximal additive effect DM.20 It is still unclear why β-blockers impair insulin sensi- with statin-based combination treatment to prevent CVD and tivity; however, peripheral vasoconstriction by traditional DM. β-blockers such as atenolol might limit glucose transportation to muscle, a major glucose-utilizing organ, thus causing de- 21 Insulin Resistance Associated With creased glucose . In contrast, new vasodilating β-blockers such as nebivolol and carvedilol are associated with Antihypertensive more favorable effects on glucose and lipid profiles than non- IR plays a pivotal role in hypertension, hypercholesterolemia/ vasodilating β-blockers.22,23 dyslipidemia, and atherosclerosis, and thus is present in most In contrast, RAS inhibitors such as ACEIs and ARBs po- patients with these . Approximately half of hyperten- tentially improve insulin sensitivity in hypertensive patients.24 sive individuals are in the hyperinsulinemic category,13 and up The RAS also has multiple effects in the central nervous sys- to three-quarters of people with type 2 DM have hypertension.14 tem, , , and adipose tissue that may inter- The prevalence of dyslipidemia is more than double in hyper- fere with insulin action. Thus, RAS dysregulation may con- tensive patients compared with the normotensive population.6 tribute to the evolution of IR, and conversely, RAS blockade Although meta-analyses occasionally suggest superiority of may potentially help prevent new-onset DM. RAS blockade 1 class of antihypertensive agents over another for some out- may have direct effects that augment insulin-stimulated glu-

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Figure 2. Differential effect of lipophilic and hydrophilic statins on insulin sensitivity. Lipophilic significantly decreased plasma adiponectin levels and insulin sensitivity when compared with baseline. In contrast, significantly increased plasma adiponectin levels and insulin sensitivity when compared with baseline. Moreover, these effects of pravastatin were sig- nificant when compared with placebo and simvastatin. Standard error of the mean is identified by the bars. Pl, placebo; P40, pravastatin 40 mg; QUICKI, Quantitative Insulin-Sensitivity Check Index; S20, simvastatin 20 mg. (Reproduced with permission from Koh et al.43)

cose uptake, promote adipogenesis,25 and induce peroxisome that ARBs reverse endothelial dysfunction and reduce oxidant proliferator-activated receptor-γ activity that promotes dif- stress and inflammatory cytokines, suggesting that ARBs have ferentiation of adipocytes.26 In ALLHAT, patients treated with antiatherogenic effects in hypertensive patients. the ACEI, lisinopril, experienced lower plasma glucose and total cholesterol levels compared with a diuretic.18 Meta-anal- yses data suggest that ACEIs and ARBs are associated with Effects of Statin Therapy on IR reductions in the incidence of new-onset DM by 27% and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc- 23%, respectively, and by 25% in a pooled analysis.27 We tase inhibitors (statins) are effective in lowering cholesterol compared the vascular and metabolic effects of antihyperten- and decreasing cardiovascular morbidity and mortality.2,33 sive drugs in hypertensive patients. Atenolol, amlodipine, and Statins have pleiotropic effects that go beyond lowering the candesartan therapies significantly reduced systolic BP when cholesterol level per se.10–12,34 For example, statins improve compared with ramipril. Atenolol and thiazide therapies in- endothelial-dependent , increase the bioavailabil- creased levels to a greater extent than either ity of (NO), and reduce the levels of endothelin-1 ramipril or candesartan therapy alone. Ramipril and candesar- (a potent vasoconstrictor).34,35 Moreover, statins reverse the tan therapies improved flow-mediated dilation and increased elevated BP response to angiotensin II infusion, accompanied adiponectin levels and insulin sensitivity measured by QUICKI by decreased AT1 receptor density.36 (Quantitative Insulin-Sensitivity Check Index, a surrogate Interestingly, high-dose statins have an off-target effect; for measure of insulin sensitivity) to a greater extent than atenolol example, worsening insulin sensitivity that may be uncomfort- or thiazide therapies alone (Figure 1).24 able when using statins to reduce overall morbidity and mor- Another important benefit of RAS inhibitors is that they tality.9,37,38 Indeed, lipophilic and hydrophilic statins have could attenuate the vascular complications associated with IR. markedly different effects on IR in many studies.9,38–40 Lipo- In the milieu of IR, the cardiovascular system is sensitized to philic statins, particularly at high doses, cause unfavorable the adverse trophic effects of RAS, which is evidenced by the effects, reducing insulin secretion and aggravating IR.41 Lipo- frequent occurrence of diffuse vascular disease and left ven- philic statins inhibit synthesis of isoprenoid and suppress ubi- tricular hypertrophy in diabetic patients, even when the lipid quinone () biosynthesis, which might delay and BP levels are normal. High insulin levels stimulate the ATP synthesis by pancreatic β-cells, leading to impaired insu- angiotensin II type 1 (AT1) receptor, which activates the RAS28 lin secretion.9 It is also possible that lipophilic statins are taken and also the cardiac sympathetic .29 In vessels, up by the brain and fat tissue where they may have unfavor- angiotensin II promotes superoxide anion generation and endo- able pleiotropic effects including secondary actions on the thelial dysfunction.30 Angiotensin II activates nuclear transcrip- regulation of insulin secretion and exacerbation of IR. In tion factor (NF-κB) induced by oxidative stress, mediated by contrast, a hydrophilic statin, pravastatin, improves insulin the AT1 receptor.31 In our previous study, candesartan signifi- sensitivity and increases circulating adiponectin levels in hu- cantly improved flow-mediated vasodilation and reduced plas- mans, which may have beneficial metabolic effects as well as ma levels of oxidant stress, and markers of , he- reduce atherogenesis.9 mostasis, independent of BP reduction.32 This finding showed We reported that high-dose simvastatin reduced adiponectin

Circulation Journal Vol.78, February 2014 284 LEE HY et al.

Figure 3. Dose-dependent adverse effects of lipophilic statins in insulin sensitivity. Hypercholesterolemic patients receiving the higher dose of developed higher fasting insulin levels and incidence of IR when compared with patients receiving the lower dose or placebo. Standard error of the mean is identified by the bars. QUICKI, Quantitative Insulin-Sensitivity Check Index. (Reproduced with permission from Koh et al.44)

Figure 4. Synergistic effect of statins and renin-angiotensin system (RAS) inhibitors on insulin sensitivity. In 48 hypercholesterol- emic patients, both pravastatin 40 mg and valsartan 160 mg increased plasma adiponectin levels, reduced fasting insulin levels, and increased insulin sensitivity relative to baseline measurements. When pravastatin was combined with valsartan, the response increased in an additive manner when compared with monotherapy alone. Median values (A,B) or mean with SEM (C) are pro- vided. QUICKI, Quantitative Insulin-Sensitivity Check Index. (Reproduced with permission from Koh et al.60)

levels and insulin sensitivity in hypercholesterolemic pa- lowering doses (Figure 2).43 Our group also reported that hy- tients.42 In a comparison study of simvastatin and pravastatin, percholesterolemic patients receiving high-dose atorvastatin simvastatin (20 mg) significantly increased fasting insulin lev- (80 mg) had a higher incidence of IR with higher fasting insu- els and decreased plasma adiponectin levels and insulin sensi- lin and glycated hemoglobin HbA1c levels when compared tivity, whereas pravastatin (40 mg) treatment did not signifi- with those taking the low dose (10 mg) or placebo, suggesting cantly change insulin levels but significantly increased plasma that high-dose statin therapy may have greater adverse effects adiponectin levels and insulin sensitivity at equivalent lipid- on glucose homeostasis than low-dose therapy (Figure 3).44

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Figure 5. Synergistic effect of statins and renin-angiotensin system (RAS) inhibitors in insulin resistance (IR) and endothelial dysfunction. Dysregulation of the RAS contributes to the pathogenesis of atherosclerosis. Angiotensin II binds to angiotensin II type I receptor (AT1R) resulting in enzymatic production of oxygen-derived free radicals. Free fatty acids (FFA) also promote oxygen-derived free radicals generation in vascular endothelial cells and smooth muscle cells. This leads to dissociation of in- hibitory factor, IκB with subsequent activation of nuclear transcription factor, NF-κB, which stimulates expression of proinflamma- tory genes, chemokines, and cytokines. Importantly, elevated levels of FFA associated with IR, obesity, diabetes mellitus, and the metabolic syndrome cause endothelial dysfunction by activating innate immune inflammatory pathways upstream of NF-κB. Thus, inflammation and oxidative stress contribute to endothelial dysfunction and IR while endothelial dysfunction and IR promote oxida- tive stress and inflammation. There is a reciprocal relationship between IR and endothelial dysfunction. Statins downregulate the expression of the AT1R via reducing low-density lipoprotein-cholesterol levels. Krüppel-like factor 2 (KLF2) is implicated as a key molecule maintaining endothelial function. High-glucose-induced, FOXO1-mediated KLF2 suppression was reversed by statin therapy. Further, experimental studies have shown cross-talk between hypercholesterolemia and RAS at multiple steps. Accord- ingly, combined therapy with statins and RAS inhibitors shows additive/synergistic beneficial effects on endothelial dysfunction and IR when compared with monotherapy in patients with cardiovascular risk factors by both distinct and interrelated mechanisms. ACEI, angiotensin-converting ; ARB, angiotensin-receptor blocker; CRP, C-reactive protein; eNOS, endothelial ; ICAM, intercellular adhesion molecule; MCP, monocyte chemotactic protein; TNF, tumor necrosis factor. (Modified from Koh et al.53,61–67)

Rosuvastatin is less hydrophilic than pravastatin but increased tion and oxidative stress contribute to endothelial dysfunction the incidence of type 2 DM in a large .45 We re- and IR, while endothelial dysfunction and IR promote oxida- cently reported that hypercholesterolemic patients receiving tive stress and inflammation.8,49,50 There is a reciprocal rela- 10 mg had worsened insulin sensitivity and glu- tionships between IR and endothelial dysfunction. In this re- cose control during the 8 weeks than when compared with spect, reversing IR is another important part of hypertension placebo.46 treatment, together with BP control. Of note, statins and RAS inhibitors have the potential to Statin Combined With RAS Inhibitor Therapy to exert synergistic effects on both endothelial function and insu- lin sensitivity. Statins improve endothelial function via stimu- Maximize Cardiovascular Protection lation of endothelial NO synthase (eNOS) activity and mediate Endothelial dysfunction and IR play crucial roles in the patho- antioxidant effects that result in enhanced NO bioactivi- genesis of atherosclerosis. A positive correlation between IR ty.34,51,52 impairs endothelial function whereas and endothelial function was also reported in obese hyperten- statins reversed endothelial dysfunction in both in vitro and in sive subjects.47 Importantly, elevated levels of free fatty acids vivo studies using a type 2 DM animal model, OLETF rats.53 associated with IR, obesity, DM, and the metabolic syndrome In addition, hypercholesterolemic rabbits display enhanced cause endothelial dysfunction by activating innate immune vascular expression of AT1 receptors, which mediate increased inflammatory pathways upstream of NF-κB.48 Thus, inflamma- activity of angiotensin II, thus increasing BP.54 Statins reverse

Circulation Journal Vol.78, February 2014 286 LEE HY et al. the BP-elevating response to angiotensin II infusion by de- of print]. creasing AT1 receptor density.36 Conversely, RAS inhibitors 3. Lim S, Shin H, Song JH, Kwak SH, Kang SM, Won Yoon J, et al. also improve endothelial function through potentiating shear- Increasing prevalence of metabolic syndrome in Korea: The Korean National Health and Nutrition Examination Survey for 1998 – 2007. stress induced NO production via modulation of eNOS phos- Diabetes Care 2011; 34: 1323 – 1328. phorylation.55 4. Jee SH, Jo J. Linkage of epidemiologic evidence with the clinical Indeed, in -E null mice fed with a high-cho- aspects of metabolic syndrome. Korean Circ J 2012; 42: 371 – 378. lesterol , neither valsartan nor had any effect on 5. Egan BM, Li J, Qanungo S, Wolfman TE. Blood pressure and cho- lesterol control in hypertensive hypercholesterolemic patients: Na- the BP or cholesterol level. 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Han SH, Quon MJ, Koh KK. Reciprocal relationships between ab- ACEI, ramipril, had beneficial additive effects on endothelial normal metabolic parameters and endothelial dysfunction. Cur Opin 11,58 function and insulin sensitivity in patients with type 2 DM. Lipidol 2007; 18: 58 – 65. In type 2 DM patients, atorvastatin combined with irbesartan 9. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of dis- treatment showed additive effects over either monotherapy.59 tinct statins. Atherosclerosis 2011; 215: 1 – 8. Recently, we observed that pravastatin combined with valsar- 10. Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, et al. Additive beneficial effects of losartan combined with simvastatin in tan therapy increased plasma adiponectin level, lowered the the treatment of hypercholesterolemic, hypertensive patients. 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