Korean Circ J.  2017 Jul;47(4):432-439. 10.4070/kcj.2016.0406.

Combining Potent Statin Therapy with Other Drugs to Optimize Simultaneous Cardiovascular and Metabolic Benefits while Minimizing Adverse Events

• Koh KK
• Sakuma I
• Shimada K
• Hayashi T
• Quon MJ

• KMID: 2392877
• DOI: http://doi.org/10.4070/kcj.2016.0406

Abstract

Hypercholesterolemia and hypertension are among the most important risk factors for cardiovascular (CV) disease. They are also important contributors to metabolic diseases including diabetes that further increase CV risk. Updated guidelines emphasize targeted reduction of overall CV risks but do not explicitly incorporate potential adverse metabolic outcomes that also influence CV health. Hypercholesterolemia and hypertension have synergistic deleterious effects on interrelated insulin resistance and endothelial dysfunction. Dysregulation of the renin-angiotensin system is an important pathophysiological mechanism linking insulin resistance and endothelial dysfunction to atherogenesis. Statins are the reference standard treatment to prevent CV disease in patients with hypercholesterolemia. Statins work best for secondary CV prevention. Unfortunately, most statin therapies dose-dependently cause insulin resistance, increase new onset diabetes risk and exacerbate existing type 2 diabetes mellitus. Pravastatin is often too weak to achieve target low-density lipoprotein cholesterol levels despite having beneficial metabolic actions. Renin-angiotensin system inhibitors improve both endothelial dysfunction and insulin resistance in addition to controlling blood pressure. In this regard, combined statin-based and renin-angiotensin system (RAS) inhibitor therapies demonstrate additive/synergistic beneficial effects on endothelial dysfunction, insulin resistance, and other metabolic parameters in addition to lowering both cholesterol levels and blood pressure. This combined therapy simultaneously reduces CV events when compared to either drug type used as monotherapy. This is mediated by both separate and interrelated mechanisms. Therefore, statin-based therapy combined with RAS inhibitors is important for developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity. This combined therapy can help prevent or treat CV disease while minimizing adverse metabolic consequences.

Keyword

Hypercholesterolemia; Hypertension; Statins; Renin-angiotensin system inhibitors; Cardiovascular disease

MeSH Terms

Atherosclerosis
Blood Pressure
Cardiovascular Diseases
Cholesterol
Diabetes Mellitus, Type 2
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors*
Hypercholesterolemia
Hypertension
Insulin Resistance
Lipoproteins
Metabolic Diseases
Obesity
Pravastatin
Renin-Angiotensin System
Risk Factors
Cholesterol
Lipoproteins
Pravastatin

Figure

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  Fig. 1 Synergistic effect of statins and angiotensin-receptor blocker on insulin sensitivity. In 48 hypercholesterolemic patients, both pravastatin 40 mg and valsartan 160 mg increased plasma adiponectin levels, reduced fasting insulin levels, and increased insulin sensitivity (QUICKI) relative to baseline measurements. When pravastatin was combined with valsartan, their response increased in an additive manner when compared with monotherapy alone. Median values (adiponectin) or mean with SEM (QUICKI) are provided. Modified from Koh et al.17) QUICKI: quantitative insulin sensitivity check index, SEM: standard error of the mean. ANOVA: analysis of variance.

• 

  Fig. 2 Synergistic effect of statins and ACEIs or ARBs for insulin resistance and endothelial dysfunction. Dysregulation of the RAS contributes to the pathogenesis of atherosclerosis. Angiotensin II binds to AT1R resulting in enzymatic production of oxygen-derived free radicals. FFA also promote oxygenderived free radical generation in vascular endothelial cells and smooth muscle cells. This leads to dissociation of inhibitory factor with subsequent activation of NF-κB which stimulates expression of proinflammatory genes, chemokines, and cytokines. Importantly, elevated levels of FFA 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. These have shown the reciprocal relationships between insulin resistance and endothelial dysfunction. Statins down-regulate the expression of AT1R via reducing lowering low-density lipoprotein-cholesterol levels. KLF2 is implicated as a key molecule maintaining endothelial function. High glucose-induced, FOXO1-mediated KLF2 suppression was reversed by statin treatment. Further, experimental studies have shown a cross-talk between hypercholesterolemia and RAS at multiple steps. Accordingly, combined therapy with statins and RAS inhibitors show additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance when compared with monotherapy in patients with cardiovascular risk factors by both distinct and interrelated mechanisms. Reproduced with permission from Koh et al.8)9)35)36)37) ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin-receptor blocker, FFA: free fatty acids, MCP: monocyte chemotactic protein, TNF: tumor necrosis factor, ICAM: intercellular adhesion molecule, PAI: plasminogen activator inhibitor, CRP: C-reactive protein, AT1R: angiotensin II type I receptor, IKKB: inhibitor of nuclear factor kappa B kinase subunit, NADH/NADPH: nicotinamide dehydrogenase/nicotinamide diphosphate dehydrogenase, FOXO1: forkhead box protein O1, Rac1: Ras-related C3 botulinum toxin substrate 1, KLF2: Kruppel-like factor 2, RAS: renin-angiotensin system, NF-κB: nuclear transcription factor, eNOS: endothelial nitric oxide synthase.

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