Renin–angiotensin system inhibitor and statins combination therapeutics – what have we learnt?

Abstract

Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin–angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events 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, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD.

Keywords:

• cardiovascular disease
• hypercholesterolemia
• hypertension
• renin–angiotensin system inhibitors
• statins

1. Introduction

Risk factors of cardiovascular disease (CVD) are prevalent and patients often have two or more risk factors. The prevalence of hypertension or hypercholesterolemia is higher than other risk factors. The new USA guidelines released last year target reducing overall cardiovascular risks [1,2]. Atherosclerosis plays a pivotal role in the pathogenesis of CVD. Endothelial dysfunction and insulin resistance contribute to the pathogenesis of atherosclerosis. Hypercholesterolemia and hypertension are both associated with endothelial dysfunction and insulin resistance and their coexistence is a vicious cycle associated with an increased incidence of CVD.

Statins prevent CVD by lowering low-density lipoprotein (LDL)-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects [3,4]. Recently published hypertension guidelines state that diuretics, beta-blockers, calcium antagonists, ACE inhibitors and angiotensin II type I (AT₁) receptor blockers (ARBs) are equally recommendable for the initiation and maintenance of antihypertensive treatment. However, there is a substantially different impact on insulin sensitivity among various classes of antihypertensive drugs despite similar blood pressure reduction [5]. On the other hand, renin–angiotensin system (RAS) is involved in many steps of atherosclerosis. Angiotensin II promotes superoxide anion generation and endothelial dysfunction. Angiotensin II activates NF-κB induced by oxidative stress, mediated by AT₁ receptor [6]. We have reported that candesartan significantly improved flow-mediated vasodilation and reduced biomarkers of oxidant stress, inflammation and hemostasis in patients with hypertension, independent of blood pressure reduction [7].

On the other hand, we have demonstrated that statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus in patients over a decade [8,9]. Interestingly, we have observed that statin-based combination treatment with ACE inhibitors or ARBs compensates untoward effects of statins and has additive and/or synergistic effects in changing blood pressure, lipid profiles, endothelial dysfunction, inflammation, hemostasis and insulin resistance by both distinct and interrelated mechanisms [10-13] that may explain the positive outcomes in recent clinical trials [14,15]. Here, we discuss the promising treatment strategies of statins combination treatment with ACE inhibitors or ARBs in patients to prevent both CVD and diabetes mellitus.

2. Effects of statin therapy on insulin resistance

Statin therapy is very important in decreasing cardiovascular morbidity and mortality [2,6,13]. Surprisingly, high-dose statins cause off-target effects, for example, worsened insulin sensitivity [8,9]. It is still controversial whether lipophilic and hydrophilic statins have markedly different effects on insulin resistance. Lipophilic statins, particularly at high doses, cause the unfavorable effect of reducing insulin secretion and aggravating insulin resistance. Lipophilic statins inhibit the synthesis of isoprenoid and suppress ubiquinone (Coenzyme Q10) biosynthesis, which might delay ATP synthesis by pancreatic β-cells leading to impaired insulin secretion. It is also possible that lipophilic statins are taken up by the brain and fat tissue where they may cause unfavorable pleiotropic effects including secondary actions on the regulation of insulin secretion and exacerbation of insulin resistance. In contrast, the hydrophilic statin, pravastatin, improves insulin sensitivity and increases circulating adiponectin levels in humans that may have beneficial metabolic effects as well as atherogenesis reduction [13].

Rosuvastatin is less hydrophilic than pravastatin. We have demonstrated that rosuvastatin treatment significantly increased fasting insulin levels, decreased plasma adiponectin levels and worsened insulin sensitivity and glucose control, while pravastatin treatment showed opposite effects in hypercholesterolemic patients [16]. However, diabetes related to statin use has not been demonstrated to increase cardiovascular events. Nonetheless, we should keep in mind that the long-term adverse effects of new-onset diabetes mellitus might generate a relative increase in deaths. Indeed, a recent large-scale randomized clinical trial has confirmed this speculation. Compared with placebo, rosuvastatin treatment increased the incidence of diabetes mellitus by 28% in individuals with one or more risk factors for diabetes, but reduced the cardiovascular event by 39%. By contrast, in individuals with no major diabetes risk factors, rosuvastatin treatment did not cause diabetes mellitus and reduced the cardiovascular event by 52%: 13% more than the former group [17].

3. Insulin resistance associated with ACE inhibitors or ARBs

Insulin resistance plays a pivotal role in hypertension, hypercholesterolemia and atherosclerosis. About half of hypertensive individuals belong to hyperinsulinemic category and up to three fourths of people with type 2 diabetes have hypertension. The prevalence of dyslipidemia is more than double in hypertensive patients compared with normotensive population [6].

Compared with other antihypertensive drugs, ACE inhibitors and ARBs potentially improve insulin sensitivity in hypertensive patients [5]. RAS also has multiple effects in the central nervous system, skeletal muscle, liver and adipose tissue that may interfere with insulin action. Thus, RAS dysregulation may contribute to the evolution of insulin resistance, and conversely, RAS blockades may potentially help prevent new-onset diabetes. Indeed, RAS blockades have direct effects to augment insulin-stimulated glucose uptake, promote adipogenesis and induce peroxisome proliferator-activated receptor-γ activity that promotes differentiation of adipocytes [6]. Meta-analyses data suggest that ACE inhibitors and ARBs were associated with reductions in the incidence of new-onset diabetes by 27 and 23%, respectively, and by 25% in the pooled analysis [18].

Another important benefit of RAS inhibitors is that they could attenuate vascular complication associated with insulin resistance. In the milieu of insulin resistance, 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 ventricular hypertrophy in diabetic patients, even when the lipid and blood pressure levels are normal. High insulin levels stimulate AT₁ receptor, which activates RAS and also activates the cardiac sympathetic nervous system [6]. Accordingly, ACE inhibitors and ARBs reverse the endothelial dysfunction and reduce oxidant stress and inflammatory cytokines, suggesting that ACE inhibitors and ARBs have anti-atherogenic effects in hypertensive patients.

4. Statins combined with ACE inhibitors or ARB therapy to maximize cardiovascular protection

Endothelial dysfunction and insulin resistance play crucial roles in the pathogenesis of atherosclerosis. Importantly, elevated levels of free fatty acids associated with insulin resistance, 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 insulin resistance while endothelial dysfunction and insulin resistance promote oxidative stress and inflammation [6,13].

Of note, experimental and clinical studies demonstrated a cross-talk between hypercholesterolemia and RAS at multiple steps. Hypercholesterolemic rabbits display enhanced vascular expression of AT₁ receptors that mediate increased activity of angiotensin II, thus increasing blood pressure [19]. Statins reversed blood pressure–elevating response to angiotensin II infusion by decreasing AT₁ receptor density [20]. Therefore, statins and ACE inhibitors or ARBs may have potential to exert additive/synergistic beneficial effects in both endothelial function and insulin sensitivity when compared with monotherapy in patients with cardiovascular risk factors by both distinct and interrelated mechanisms [6,10-13,21]. We reported additive vascular and metabolic effects of statin and ACE inhibitor or ARB combination therapies in patients, compared with monotherapy alone [10,11]. Recently, we observed that pravastatin combined with valsartan therapy increased plasma adiponectin, lowered fasting insulin levels and improved insulin sensitivity in an additive manner when compared with monotherapy alone in hypertensive population [12].

Indeed, large-scale clinical studies assessed the ‘synergy’ of statins and ACE inhibitors in reducing vascular events in patients with coronary heart disease during the 3-year follow-up. The statin and ACE inhibitor combination reduces cardiovascular events more than a statin alone and considerably more than an ACE inhibitor alone [14]. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques [15].

5. Expert opinion

From 1988 – 1994 to 2005 – 2010, control of concomitant hypertension and LDL-cholesterol rose from 5.0 – 30.7%. By multivariable logistic regression, the most contributing factors associated with concomitant hypertension, LDL-cholesterol and non-high-density lipoprotein cholesterol control were statin (10.7) and antihypertensive (3.32) medications. Of note, 69.3% among hypertensive hypercholesterolemic patients failed to be concomitantly controlled in 2005 – 2010 [22]. It should be noted that various strategies to reduce residual CVD risk in hypertensive patients using different classes of antihypertensive medications reduced CVD risk only by 20 – 25% [1]; however, controlling hypercholesterolemia in hypertensive patients by statins reduced residual CVD risk by 35 – 40% [2]. These data suggest that effective treatment of both hypertension and hypercholesterolemia would reduce CVD risk by ≥ 50%. Thus, statins are paramount of importance in reducing CVD risk [2].

As we discussed before, there is strong scientific rationale from experimental and clinical studies to support that statins combined with ACE inhibitor or ARB therapy would maximize cardiovascular protection in high-risk patients. Hypercholesterolemia and hypertension share common pathophysiology such as endothelial dysfunction and insulin resistance, and both are most common risk factors of CVD. Indeed, > 60% of hypertensives are hypercholesterolemic. Alternate classes of antihypertensive medications in hypertensive patients do not substantially reduce residual CVD risk. However, treating moderate cholesterol elevations with low-dose statins reduces CVD by 35 – 40%. Therefore, statins are very important, but statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. On the other hand, ACE inhibitors or ARBs improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Of interest, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. Combined therapy with statins and ACE inhibitors or ARBs demonstrates additive/synergistic beneficial effects on endothelial function and insulin sensitivity in addition to lowering both cholesterol levels and blood pressure when compared with either monotherapy in patients with cardiovascular risk factors. This is mediated by both distinct and interrelated mechanisms. Therefore, there is a strong scientific rationale for recommending statins combined with ACE inhibitor or ARB therapy to treat or prevent CVD in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity.

Acknowledgments

Part of this work was presented at the American Heart Association 2014 Scientific Session, November 18, 2014, Chicago, Il, USA.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.