statins and renin-angiotensin system inhibitor combination … · 1 class of antihypertensive...

Circulation Journal Vol.78, February 2014

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

n the past, the goal of treating patients with hypertension or hypercholesterolemia was merely to control numerical factors such as blood pressure (BP) or serum cholesterol

level alone; nowadays, it has changed. The updated guidelines target reductions in overall cardiovascular risk.1,2 Hypercholes-terolemia and hypertension are both associated with endothe-lial dysfunction and insulin resistance (IR) and their coexis-tence is a vicious cycle associated with an increased incidence of cardiovascular events. Moreover, both risk factors are fre-quently prevail together.3,4 Indeed, more than 60% of hyper-tensive patients were consistently hypercholesterolemic in the United States National Health and Nutrition Examination Sur-veys 1988–2010.5 More importantly, the prevalence of dyslip-idemia increased parallel to BP. In the prehypertensive range, prevalence was similar to that of the general population, ap-

proximately 26%; however, this prevalence doubles in the hypertensive population, reaching nearly 60%.6 Although it is not possible to provide a definite pathogenesis of hypertension-hypercholesterolemia/dyslipidemia clustering, it is gaining consensus that IR and endothelial dysfunction might play major roles.7,8

From 1988–1994 to 2005–2010, control of concomitant hypertension and the low-density lipoprotein-cholesterol (LDL-C) level rose from 5.0% to 30.7%. By multivariable lo-gistic regression, factors associated with concomitant hyper-tension, LDL-C, and non-high-density lipoprotein-cholesterol control were statin therapy (10.7) and antihypertensive (3.32) medications, and ≥2 healthcare visits/year (1.90), whereas age (0.77/10-year increase), black race (0.59), Hispanic ethnicity (0.62), cardiovascular disease (CVD) (0.44), and diabetes mel-

I

Received December 9, 2013; accepted December 12, 2013; released online January 8, 2014Division 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 Heart Association 2012 Scientific Session, November 4, 2012, Los Angeles, CA, USAMailing 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: [email protected]

ISSN-1346-9843 doi: 10.1253/circj.CJ-13-1494All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Statins and Renin-Angiotensin System Inhibitor Combination Treatment to Prevent

Cardiovascular DiseaseHae-Young Lee, MD, PhD; Ichiro Sakuma, MD, PhD; Sang-Hyun Ihm, MD, PhD;

Choong-Won Goh, MD; Kwang Kon Koh, MD, PhD

Hypercholesterolemia and hypertension are common risk factors for cardiovascular disease (CVD). Updated guide-lines emphasize target reductions of overall cardiovascular risks. Experimental studies have shown reciprocal rela-tionships between insulin resistance (IR) and endothelial dysfunction. Hypercholesterolemia and hypertension have a synergistic deleterious effect on IR and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis and hypertension. Various strategies with different classes of anti-hypertensive medications to reach target goals have failed to reduce residual CVD risk further. Of interest, treating moderate cholesterol elevations with low-dose statins in hypertensive patients reduced CVD risk by 35–40% further. Therefore, statins are important in reducing CVD risk. Unfortunately, statin therapy causes IR and increases the risk of type 2 diabetes 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 blood 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

REVIEW


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comes,15 recently published hypertension guidelines state that diuretics, β-blockers, calcium antagonists, angiotensin-con-verting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) are equally recommendable for the initiation and maintenance of antihypertensive treatment.16 However, it is also widely accepted that there are substantial differing ef-fects on insulin sensitivity among the various classes of anti-hypertensive agents. The Antihypertensive and Lipid-Lower-ing Treatment to Prevent Heart Attack Trial (ALLHAT), a clinical outcome trial in 42,418 high-risk patients with hyper-tension, which compared 3 classes of antihypertensive agents as initial therapy of hypertension, showed an increased inci-dence of DM among diuretic-treated patients.17 Diuretic treat-ment resulted in 4–6 mg/dl higher fasting plasma glucose lev-els, causing 17% increased incidence of DM compared with other agents.18 Hypokalemia associated with thiazide diuretics is suggested to be the main mechanism of IR.19 β-blockers tend to increase body weight and cause IR, facilitating new-onset DM.20 It is still unclear why β-blockers impair insulin sensi-tivity; however, peripheral vasoconstriction by traditional β-blockers such as atenolol might limit glucose transportation to muscle, a major glucose-utilizing organ, thus causing de-creased glucose metabolism.21 In contrast, new vasodilating β-blockers such as nebivolol and carvedilol are associated with more favorable effects on glucose and lipid profiles than non-vasodilating β-blockers.22,23

In contrast, RAS inhibitors such as ACEIs and ARBs po-tentially improve insulin sensitivity in hypertensive patients.24 The RAS also has multiple effects in the central nervous sys-tem, skeletal muscle, liver, and adipose tissue that may inter-fere with insulin action. Thus, RAS dysregulation may con-tribute to the evolution of IR, and conversely, RAS blockade may potentially help prevent new-onset DM. RAS blockade may have direct effects that augment insulin-stimulated glu-

litus (DM) (0.54) were inhibiting factors. Interestingly, 69.3% of hypertensive hypercholesterolemic patients failed to be con-comitantly controlled in 2005–2010.5 Various strategies to reduce residual CVD risk in hypertensive patients include treating BP to lower target goals and using different classes of antihypertensive medications; however still considerable re-sidual risks remains. In contrast, controlling hypercholesterol-emia in hypertensive patients by statins is very effective in reducing residual CVD risk by 35–40%.1 Therefore, statins are of paramount importance in reducing CVD risk.2

However, IR and the risk of type 2 DM have recently be-come problematic with statin therapy.9 In contrast, statin-based combination treatment with renin-angiotensin-aldosterone sys-tem (RAS) blockade has additive effects to control BP, lipid profiles, endothelial dysfunction and IR by both distinct and interrelated mechanisms,10–12 which may explain positive out-comes of recent clinical trials. Here, we review the role of IR in hypertension-hypercholesterolemia/dyslipidemia clustering and suggest a strategy for achieving maximal additive effect with statin-based combination treatment to prevent CVD and DM.

Insulin Resistance Associated With Antihypertensive Drugs

IR plays a pivotal role in hypertension, hypercholesterolemia/dyslipidemia, and atherosclerosis, and thus is present in most patients with these diseases. Approximately half of hyperten-sive individuals are in the hyperinsulinemic category,13 and up to three-quarters of people with type 2 DM have hypertension.14 The prevalence of dyslipidemia is more than double in hyper-tensive patients compared with the normotensive population.6

Although meta-analyses occasionally suggest superiority of 1 class of antihypertensive agents over another for some out-

Figure 1. Differential effects of antihypertensive medication on insulin sensitivity. Ramipril and candesartan therapies signifi-cantly increased adiponectin levels to a greater extent than atenolol or thiazide. Amlodipine 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, placebo; At, atenolol; Am, amlodipine; Th, thiazide; Ra, ramipril; Ca, candesartan. (Re-produced with permission from Koh et al.24)


283Statin-Based Combination Therapy for CVD

that ARBs reverse endothelial dysfunction and reduce oxidant stress and inflammatory cytokines, suggesting that ARBs have antiatherogenic effects in hypertensive patients.

Effects of Statin Therapy on IR3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-tase inhibitors (statins) are effective in lowering cholesterol and decreasing cardiovascular morbidity and mortality.2,33 Statins have pleiotropic effects that go beyond lowering the cholesterol level per se.10–12,34 For example, statins improve endothelial-dependent vasodilation, increase the bioavailabil-ity of nitric oxide (NO), and reduce the levels of endothelin-1 (a potent vasoconstrictor).34,35 Moreover, statins reverse the elevated BP response to angiotensin II infusion, accompanied by decreased AT1 receptor density.36

Interestingly, high-dose statins have an off-target effect; for example, worsening insulin sensitivity that may be uncomfort-able when using statins to reduce overall morbidity and mor-tality.9,37,38 Indeed, lipophilic and hydrophilic statins have markedly different effects on IR in many studies.9,38–40 Lipo-philic statins, particularly at high doses, cause unfavorable effects, reducing insulin secretion and aggravating IR.41 Lipo-philic statins inhibit synthesis of isoprenoid and suppress ubi-quinone (coenzyme Q10) biosynthesis, which might delay ATP synthesis by pancreatic β-cells, leading to impaired insu-lin secretion.9 It is also possible that lipophilic statins are taken up by the brain and fat tissue where they may have unfavor-able pleiotropic effects including secondary actions on the regulation of insulin secretion and exacerbation of IR. In contrast, a hydrophilic statin, pravastatin, improves insulin sensitivity and increases circulating adiponectin levels in hu-mans, which may have beneficial metabolic effects as well as reduce atherogenesis.9

We reported that high-dose simvastatin reduced adiponectin

cose uptake, promote adipogenesis,25 and induce peroxisome proliferator-activated receptor-γ activity that promotes dif-ferentiation of adipocytes.26 In ALLHAT, patients treated with 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 reductions in the incidence of new-onset DM by 27% and 23%, respectively, and by 25% in a pooled analysis.27 We compared the vascular and metabolic effects of antihyperten-sive drugs in hypertensive patients. Atenolol, amlodipine, and candesartan therapies significantly reduced systolic BP when compared with ramipril. Atenolol and thiazide therapies in-creased triglycerides levels to a greater extent than either ramipril or candesartan therapy alone. Ramipril and candesar-tan therapies improved flow-mediated dilation and increased adiponectin levels and insulin sensitivity measured by QUICKI (Quantitative Insulin-Sensitivity Check Index, a surrogate measure of insulin sensitivity) to a greater extent than atenolol or thiazide therapies alone (Figure 1).24

Another important benefit of RAS inhibitors is that they could attenuate the vascular complications associated with IR. In the milieu of IR, the cardiovascular system is sensitized to the adverse trophic effects of RAS, which is evidenced by the frequent occurrence of diffuse vascular disease and left ven-tricular hypertrophy in diabetic patients, even when the lipid and BP levels are normal. High insulin levels stimulate the angiotensin II type 1 (AT1) receptor, which activates the RAS28 and also the cardiac sympathetic nervous system.29 In vessels, angiotensin II promotes superoxide anion generation and endo-thelial dysfunction.30 Angiotensin II activates nuclear transcrip-tion factor (NF-κB) induced by oxidative stress, mediated by the AT1 receptor.31 In our previous study, candesartan signifi-cantly improved flow-mediated vasodilation and reduced plas-ma levels of oxidant stress, and markers of inflammation, he-mostasis, independent of BP reduction.32 This finding showed

Figure 2. Differential effect of lipophilic and hydrophilic statins on insulin sensitivity. Lipophilic simvastatin significantly decreased plasma adiponectin levels and insulin sensitivity when compared with baseline. In contrast, pravastatin 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)


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lowering doses (Figure 2).43 Our group also reported that hy-percholesterolemic patients receiving high-dose atorvastatin (80 mg) had a higher incidence of IR with higher fasting insu-lin and glycated hemoglobin HbA1c levels when compared with those taking the low dose (10 mg) or placebo, suggesting that high-dose statin therapy may have greater adverse effects on glucose homeostasis than low-dose therapy (Figure 3).44

levels and insulin sensitivity in hypercholesterolemic pa-tients.42 In a comparison study of simvastatin and pravastatin, simvastatin (20 mg) significantly increased fasting insulin lev-els and decreased plasma adiponectin levels and insulin sensi-tivity, whereas pravastatin (40 mg) treatment did not signifi-cantly change insulin levels but significantly increased plasma adiponectin levels and insulin sensitivity at equivalent lipid-

Figure 3. Dose-dependent adverse effects of lipophilic statins in insulin sensitivity. Hypercholesterolemic patients receiving the higher dose of atorvastatin 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)



tion and oxidative stress contribute to endothelial dysfunction and IR, while endothelial dysfunction and IR promote oxida-tive stress and inflammation.8,49,50 There is a reciprocal rela-tionships between IR and endothelial dysfunction. In this re-spect, reversing IR is another important part of hypertension treatment, together with BP control.

Of note, statins and RAS inhibitors have the potential to exert synergistic effects on both endothelial function and insu-lin sensitivity. Statins improve endothelial function via stimu-lation of endothelial NO synthase (eNOS) activity and mediate antioxidant effects that result in enhanced NO bioactivi-ty.34,51,52 Hyperglycemia impairs endothelial function whereas statins reversed endothelial dysfunction in both in vitro and in vivo studies using a type 2 DM animal model, OLETF rats.53 In addition, hypercholesterolemic rabbits display enhanced vascular expression of AT1 receptors, which mediate increased activity of angiotensin II, thus increasing BP.54 Statins reverse

Rosuvastatin is less hydrophilic than pravastatin but increased the incidence of type 2 DM in a large clinical trial.45 We re-cently reported that hypercholesterolemic patients receiving rosuvastatin 10 mg had worsened insulin sensitivity and glu-cose control during the 8 weeks than when compared with placebo.46

Statin Combined With RAS Inhibitor Therapy to Maximize Cardiovascular Protection

Endothelial dysfunction and IR play crucial roles in the patho-genesis of atherosclerosis. A positive correlation between IR and endothelial function was also reported in obese hyperten-sive subjects.47 Importantly, elevated levels of free fatty acids associated with IR, obesity, DM, and the metabolic syndrome cause endothelial dysfunction by activating innate immune inflammatory pathways upstream of NF-κB.48 Thus, inflamma-

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 enzyme inhibitor; ARB, angiotensin-receptor blocker; CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; ICAM, intercellular adhesion molecule; MCP, monocyte chemotactic protein; TNF, tumor necrosis factor. (Modified from Koh et al.53,61–67)


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of print]. 3. Lim S, Shin H, Song JH, Kwak SH, Kang SM, Won Yoon J, et al.

Increasing prevalence of metabolic syndrome in Korea: The Korean National Health and Nutrition Examination Survey for 1998 – 2007. Diabetes Care 2011; 34: 1323 – 1328.

4. Jee SH, Jo J. Linkage of epidemiologic evidence with the clinical aspects of metabolic syndrome. Korean Circ J 2012; 42: 371 – 378.

5. Egan BM, Li J, Qanungo S, Wolfman TE. Blood pressure and cho-lesterol control in hypertensive hypercholesterolemic patients: Na-tional Health and Nutrition Examination Surveys 1988–2010. Circu-lation 2013; 128: 29 – 41.

6. Lee SR, Cha MJ, Kang DY, Oh KC, Shin DH, Lee HY. Increased prevalence of metabolic syndrome among hypertensive population: Ten years’ trend of the korean national health and nutrition examina-tion survey. Int J Cardiol 2013; 166: 633 – 639.

7. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350 – 357.

8. Han SH, Quon MJ, Koh KK. Reciprocal relationships between ab-normal metabolic parameters and endothelial dysfunction. Cur Opin Lipidol 2007; 18: 58 – 65.

9. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of dis-tinct statins. Atherosclerosis 2011; 215: 1 – 8.

10. Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, et al. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circu-lation 2004; 110: 3687 – 3692.

11. Koh KK, Quon MJ, Han SH, Ahn JY, Jin DK, Kim HS, et al. Vas-cular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. Hypertension 2005; 45: 1088 – 1093.

12. Joo SJ. Anti-inflammatory effects of statins beyond cholesterol low-ering. Korean Circ J 2012; 42: 592 – 594.

13. Zavaroni I, Mazza S, Dall’Aglio E, Gasparini P, Passeri M, Reaven GM. Prevalence of hyperinsulinaemia in patients with high blood pressure. J Intern Med 1992; 231: 235 – 240.

14. Kaplan NM. Management of hypertension in patients with type 2 diabetes mellitus: Guidelines based on current evidence. Ann Intern Med 2001; 135: 1079 – 1083.

15. van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: A meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012; 33: 2088 – 2097.

16. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hy-pertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281 – 1357.

17. ALLHat Officers, Coordinators for the ALLHAT Collaborative Re-search Group The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hyperten-sive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981 – 2997.

18. Wright JT Jr, Probstfield JL, Cushman WC, Pressel SL, Cutler JA, Davis BR, et al. ALLHAT findings revisited in the context of subse-quent analyses, other trials, and meta-analyses. Arch Intern Med 2009; 169: 832 – 842.

19. Shafi T, Appel LJ, Miller ER 3rd, Klag MJ, Parekh RS. Changes in serum potassium mediate thiazide-induced diabetes. Hypertension 2008; 52: 1022 – 1029.

20. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihy-pertensive drugs: A network meta-analysis. Lancet 2007; 369: 201 – 207.

21. Fonseca VA. Effects of beta-blockers on glucose and lipid metabo-lism. Curr Med Res Opin 2010; 26: 615 – 629.

22. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: A randomized controlled trial. JAMA 2004; 292: 2227 – 2236.

23. Celik T, Iyisoy A, Kursaklioglu H, Kardesoglu E, Kilic S, Turhan H, et al. Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble p-selectin levels in hypertensive patients. J Hypertens 2006; 24: 591 – 596.

24. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Koh Y, et al. Distinct vascular and metabolic effects of different classes of anti-hyperten-sive drugs. Int J Cardiol 2010; 140: 73 – 81.

the BP-elevating response to angiotensin II infusion by de-creasing AT1 receptor density.36 Conversely, RAS inhibitors also improve endothelial function through potentiating shear-stress induced NO production via modulation of eNOS phos-phorylation.55

Indeed, in apolipoprotein-E null mice fed with a high-cho-lesterol diet, neither valsartan nor fluvastatin had any effect on the BP or cholesterol level. However, combined therapy with both drugs significantly decreased plaque area and lipid depo-sition after 10 weeks, compared with either monotherapy.56 We reported vascular and metabolic responses to treatment with statin and RAS inhibitor alone or in combination in hyperten-sive, hypercholesterolemic patients: simvastatin combined with losartan improved endothelial function and insulin sensitivity in these subjects.10,57 In another study, statin combined with the ACEI, ramipril, had beneficial additive effects on endothelial function and insulin sensitivity in patients with type 2 DM.11,58 In type 2 DM patients, atorvastatin combined with irbesartan treatment showed additive effects over either monotherapy.59 Recently, we observed that pravastatin combined with valsar-tan therapy increased plasma adiponectin level, lowered the fasting insulin level, and improved insulin sensitivity in an additive manner when compared with monotherapy alone in a hypertensive population (Figure 4).60

ConclusionsHypercholesterolemia and hypertension share a common pathophysiology such as endothelial dysfunction and IR, and both are the most common risk factors of CVD. Indeed, more than 60% of hypertensive patients are hypercholesterolemic. Various strategies to reduce residual CVD risk in hypertensive patients include lower goals for BP and using different classes of antihypertensive medications, but the results have not great-ly changed. However, treating moderate cholesterol elevations with low-dose statins reduces CVD by 35–40%. Unfortu-nately, statin therapy causes IR and increases the risk of type 2 DM. On the other hand, RAS inhibitors improve both endo-thelial dysfunction and IR in addition to BP lowering. Of inter-est, cross-talk between hypercholesterolemia and RAS exists at multiple steps of IR and endothelial dysfunction. Combined therapy with statins and RAS inhibitors demonstrates syner-gistic effects on endothelial function and insulin sensitivity in addition to lowering cholesterol levels and BP when compared with either monotherapy in patients with cardiovascular risk factors. This is mediated by both distinct and interrelated mech-anisms (Figure 5).52,61–66 Therefore, there is a strong scientific rationale for recommending combination therapy to treat or prevent atherosclerosis and coronary artery disease.

In summary, combined therapy with statins and RAS inhibi-tors may be important in the development of optimal manage-ment strategies to prevent CVD in patients with hypertension, hypercholesterolemia, DM, metabolic syndrome, or obesity.

References 1. Go AS, Bauman M, Coleman King SM, Fonarow GC, Lawrence W,

Williams KA, et al. An effective approach to high blood pressure control: A Science Advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. J Am Coll Cardiol 2013 November 12, doi:10.1016/j.jacc.2013.11.007 [Epub ahead of print].

2. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013, November 12, doi:10.1161/01.cir.0000437738.63853.7a [E-pub ahead



insulin to stimulate skeletal muscle blood flow in obese man: A novel mechanism for insulin resistance. J Clin Invest 1990; 85: 1844 – 1852.

48. Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr Diabetes Rep 2003; 3: 279 – 288.

49. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relation-ships between insulin resistance and endothelial dysfunction: Mo-lecular and pathophysiological mechanisms. Circulation 2006; 113: 1888 – 1904.

50. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocrine Rev 2007; 28: 463 – 491.

51. Koh KK, Han SH, Oh PC, Shin EK, Quon MJ. Combination therapy for treatment or prevention of atherosclerosis: Focus on the lipid-RAAS interaction. Atherosclerosis 2010; 209: 307 – 313.

52. Lee BS, Choi JY, Kim JY, Han SH, Park JE. Simvastatin and losar-tan differentially and synergistically inhibit atherosclerosis in apoli-poprotein E(-/-) mice. Korean Circ J 2012; 42: 543 – 550.

53. Lee HY, Youn SW, Cho HJ, Kwon YW, Lee SW, Kim SJ, et al. Foxo1 impairs whereas statin protects endothelial function in diabe-tes through reciprocal regulation of Kruppel-like factor 2. Cardio-vasc Res 2013; 97: 143 – 152.

54. Nickenig G, Sachinidis A, Michaelsen F, Bohm M, Seewald S, Vetter H. Upregulation of vascular angiotensin ii receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circula-tion 1997; 95: 473 – 478.

55. Oyama N, Yagita Y, Sasaki T, Omura-Matsuoka E, Terasaki Y, Sugiyama Y, et al. An angiotensin II type 1 receptor blocker can preserve endothelial function and attenuate brain ischemic damage in spontaneously hypertensive rats. J Neurosci Res 2010; 88: 2889 – 2898.

56. Li Z, Iwai M, Wu L, Liu HW, Chen R, Jinno T, et al. Fluvastatin enhances the inhibitory effects of a selective at1 receptor blocker, valsartan, on atherosclerosis. Hypertension 2004; 44: 758 – 763.

57. Han SH, Koh KK, Quon MJ, Lee Y, Shin EK. The effects of simv-astatin, losartan, and combined therapy on soluble CD40 ligand in hypercholesterolemic, hypertensive patients. Atherosclerosis 2007; 190: 205 – 211.

58. Koh KK, Quon MJ, Han SH, Ahn JY, Lee Y, Shin EK. Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1+2 in patients with type 2 diabetes. Atherosclerosis 2007; 194: 230 – 237.

59. Ceriello A, Assaloni R, Da Ros R, Maier A, Piconi L, Quagliaro L, et al. Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflam-mation in type 2 diabetic patients. Circulation 2005; 111: 2518 – 2524.

60. Koh KK, Lim S, Choi H, Lee Y, Han SH, Lee K, et al. Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular pheno-types beyond that of monotherapy with either drug in patients with primary hypercholesterolemia. Diabetes 2013; 62: 3547 – 3552.

61. Koh KK, Han SH, Quon MJ. Inflammatory markers and the meta-bolic syndrome: Insights from therapeutic interventions. J Am Coll Cardiol 2005; 46: 1978 – 1985.

62. Han SH, Quon MJ, Kim JA, Koh KK. Adiponectin and cardiovascu-lar disease: Response to therapeutic interventions. J Am Coll Car-diol 2007; 49: 531 – 538.

63. Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: Response to therapeutic interventions. Circulation 2008; 117: 3238 – 3249.

64. Koh KK, Quon MJ. Targeting converging therapeutic pathways to overcome hypertension. Int J Cardiol 2009; 132: 297 – 299.

65. Lim S, Despres JP, Koh KK. Prevention of atherosclerosis in over-weight/obese patients: In need of novel multi-targeted approaches. Cir J 2011; 75: 1019 – 1027.

66. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important consid-erations in choosing specific statin treatments to reduce overall mor-bidity and mortality. Int J Cardiol 2013; 167: 1696 – 1702.

67. Lim S, Sakuma I, Quon MJ, Koh KK. Differential metabolic actions of specific statins: Clinical and therapeutic considerations. Antioxid Redox Signal 2013 September 24, doi:10.1089/ars.2013.5531 [Epub ahead of print].

25. Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hyper-tension 2002; 40: 609 – 611.

26. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated recep-tor-gamma activity. Circulation 2004; 109: 2054 – 2057.

27. Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr. Angiotensin-convert-ing enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: A meta-analysis of randomized clinical trials. J Am Coll Cardiol 2005; 46: 821 – 826.

28. Tuck ML, Bounoua F, Eslami P, Nyby MD, Eggena P, Corry DB. Insulin stimulates endogenous angiotensin ii production via a mito-gen-activated protein kinase pathway in vascular smooth muscle cells. J Hypertens 2004; 22: 1779 – 1785.

29. Weiss D, Kools JJ, Taylor WR. Angiotensin II-induced hypertension accelerates the development of atherosclerosis in ApoE-deficient mice. Circulation 2001; 103: 448 – 454.

30. Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, Harrison DG. Role of superoxide in angiotensin II-induced but not catechol-amine-induced hypertension. Circulation 1997; 95: 588 – 593.

31. Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion mole-cule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol 2000; 20: 645 – 651.

32. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, et al. Pleio-tropic effects of angiotensin ii receptor blocker in hypertensive pa-tients. J Am Coll Cardiol 2003; 42: 905 – 910.

33. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treat-ment Panel III). JAMA 2001; 285: 2486 – 2497.

34. Koh KK. Effects of statins on vascular wall: Vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000; 47: 648 – 657.

35. Koh KK, Son JW, Ahn JY, Jin DK, Kim HS, Choi YM, et al. Vas-cular effects of diet and statin in hypercholesterolemic patients. Int J Cardiol 2004; 95: 185 – 191.

36. Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M. Statin-sensitive dysregulated at1 receptor function and density in hypercholesterolemic men. Circulation 1999; 100: 2131 – 2134.

37. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with mod-erate-dose statin therapy: A meta-analysis. JAMA 2011; 305: 2556 – 2564.

38. Koh KK, Lim S, Sakuma I, Quon MJ. Caveats to aggressive lower-ing of lipids by specific statins. Int J Cardiol 2012; 154: 97 – 101.

39. Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of l-type Ca2+ channels in rat islet beta-cells. Br J Pharmacol 1999; 126: 1205 – 1213.

40. Kanda M, Satoh K, Ichihara K. Effects of atorvastatin and pravas-tatin on glucose tolerance in diabetic rats mildly induced by strepto-zotocin. Biol Pharmaceut Bull 2003; 26: 1681 – 1684.

41. Chamberlain LH. Inhibition of isoprenoid biosynthesis causes insu-lin resistance in 3t3-l1 adipocytes. FEBS Lett 2001; 507: 357 – 361.

42. Koh KK, Quon MJ, Han SH, Lee Y, Ahn JY, Kim SJ, et al. Simvas-tatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes Care 2008; 31: 776 – 782.

43. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Park JB, et al. Differ-ential metabolic effects of pravastatin and simvastatin in hypercho-lesterolemic patients. Atherosclerosis 2009; 204: 483 – 490.

44. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hyper-cholesterolemic patients. J Am Coll Cardiol 2010; 55: 1209 – 1216.

45. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195 – 2207.

46. Koh KK, Quon MJ, Sakuma I, Han SH, Choi H, Lee K, et al. Dif-ferential metabolic effects of rosuvastatin and pravastatin in hyper-cholesterolemic patients. Int J Cardiol 2013; 166: 509 – 515.

47. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of

statins and renin-angiotensin system inhibitor combination … · 1 class of antihypertensive...

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