Longevity Medicine Strategies for Cardiovascular Disease: Closing the Statin Gap in Endothelial Dysfunction and Insulin Resistance Naturally, with L-Arginine and Citrulline: Part I

by Lara Pizzorno, MDiv, MA, LMT


Despite their efficacy in lowering cholesterol, statins remain ineffective for the primary or secondary prevention of myocardial infarction (MI) in two-thirds of patients, and cardiovascular disease (CVD) remains the #1 cause of death in the U.S. A key reason for statins’ failure to reduce MI incidence is that they ameliorate neither endothelial dysfunction, nor its corollary, hypertension. Additionally, statins do not impact insulin resistance, a major contributing factor to CVD as well as diabetes, which itself quadruples risk for CVD. Statins’ lack of efficacy against these risk factors constitutes a treatment gap that results in high risk of morbidity notwithstanding low cholesterol levels—a gap that has now been connected to elevated levels of a recently identified CVD risk factor, asymmetric dimethylarginine, whose deleterious effects can be overcome by treatment with L-arginine, which has been shown to significantly improve endothelial function both alone and when added to statin therapy, particularly if accompanied by necessary co-factors, including tetrahydrobiopterin and the methylating factors, B6, B12 and folate. Part I of this review summarizes the latest research on L-arginine’s beneficial effects on nitric oxide production, endothelial function and insulin resistance. Part II reviews the research on the co-factors without which L-arginine supplementation may not only lack efficacy, but could promote CVD; improvement in CVD outcomes from combined statin and L-arginine therapy; and why L-citrulline may offer an even better option.

Part I: L-Arginine Closes the Statin Gap by Overcoming ADMA’s Promotion of Endothelial Dysfunction and Insulin Resistance


Despite widespread use of statins, cardiovascular disease remains the #1 cause of death in the U.S., afflicting 36.3% of the American population, including more than 38 million individuals ≥ 60.1 Albeit the most successful pharmacotherapy agents used to treat atherosclerosis, statins remain ineffective for the primary or secondary prevention of myocardial infarction (MI) in two-thirds of patients.2

A key reason for statins’ failure to reduce MI incidence is the fact that, in the majority of studies examining their impact, statins, although highly effective in lowering cholesterol, have failed to mitigate endothelial dysfunction, a risk factor for CVD-related mortality on a par with hypercholesterolemia.3 Recent studies indicate that brachial endothelial function, as reflected by flow-mediated vasodilation (FMD), actually has more powerful prognostic value for predicting future cardiac events than carotid artery plaque burden,4 and patients with high FMD have low cardiovascular event rates irrespective of their degree of carotid atheroma.5

Statins’ lack of efficacy against endothelial dysfunction and its corollary, hypertension, constitutes a gap in the treatment of CVD that results in high risk of morbidity notwithstanding low cholesterol levels – despite the fact that statins have been shown to upregulate gene expression of endothelial nitric oxide synthase (eNOS) [the enzyme responsible for the production of vasodilating endothelial nitric oxide (NO)].3 In a significant number of patients, a primary reason for the statin gap is elevated levels of a recently identified cardiovascular risk factor, asymmetric dimethylarginine (ADMA), an inhibitor of eNOS whose deleterious effects may be overcome by supplementation with an inexpensive, natural agent, L-arginine.

A second key reason for statins’ failure to prevent MI is that statins also have no impact on insulin resistance, which is most often related to obesity, especially abdominal obesity, and has been recognized as a major contributing factor to hypertension. In the Framingham study, each 10% gain in weight was associated with a 6.5 mm Hg increase in systolic blood pressure.6 The connection can be partly understood by noting that L-arginine levels are significantly lower, and ADMA levels higher, in individuals with impaired glucose tolerance/metabolic syndrome (MetS) and type 2 diabetes. 

It is important to note that this relationship between body fat and blood pressure is not restricted to the obese patient, but progressively worsens throughout the entire range of above normal body weight. A direct association between hypertension and body mass index (BMI) has been observed in cross-sectional and longitudinal population studies from early childhood to old age.7 A BMI of <25 is considered normal or healthy; a BMI of 26 to 28 increases risk of high blood pressure by 180%, and risk of insulin resistance by >1000%.8

In 2006, 66.7% of the adult population in the United States was overweight or obese, 34.6% had MetS (aka insulin resistance syndrome), and 5.9% had been diagnosed with type 2 diabetes.9 10 Since individuals with diabetes are two to four times more likely to develop CVD, recent increases in Americans’ BMI and the prevalence of MetS and type 2 diabetes are likely to sharply increase lifetime risk for CVD, which according to current statistics, is already 49% for men and 32% for women ≥age 40.11

Given this scenario, it is important to note that L-arginine levels are significantly lower in individuals with impaired glucose tolerance and type 2 diabetes,12 while levels of ADMA are not only increased in these populations,13 but correlate with other predictors of MetS, even in supposedly “healthy” young adults.14 This article reviews current research on L-arginine, a conditionally essential amino acid that has been shown to not only lower levels of AMDA and alleviate insulin resistance, two key CVD risk factors unaffected by statins, but to significantly improve functional medicine outcomes when added to statin therapy. 

Endothelial Function, L-arginine and the Nitric Oxide Pathway

The vascular endothelium plays a key role in cardiovascular physiology and pathophysiology, largely via processes dependent upon nitric oxide (NO).  An endothelium-derived vasoactive mediator, NO is formed from L-arginine by the constitutively expressed enzyme endothelial nitric oxide synthase (eNOS), which is activated by shear-stress of the flowing blood or agonists such as acetylcholine and bradykinin.15 3

In the vasculature, NO plays vital protective roles in a wide variety of regulatory mechanisms affecting vascular tone (NO aka endothelium-derived relaxing factor [EDRF] is the major mediator of endothelium-dependent vasodilation), vascular structure (NO inhibits proliferation of smooth muscle cells), and cell-to-cell interactions in blood vessels (NO protects blood vessels from thrombosis by inhibiting platelet aggregation and adhesion; prevents leukocyte adhesion to the vascular endothelium and leukocyte migration into the vascular wall; decreases endothelial permeability; inhibits LDL oxidation;  and reduces lipoprotein influx into the vascular wall).3

Impairment of the endothelial L-arginine/NO pathway is a common underlying mechanism through which major cardiovascular risk factors--including hypercholesterolemia, hypertension, smoking, diabetes mellitus, homocysteine, and vascular inflammation—mediate their deleterious effects on the vascular wall.3 16

Impairment of the Endothelial L-arginine/NO Pathway

Flowchart by John Morgenthaler

L-arginine Supplementation Significantly Improves Endothelial Function

In individuals with essential hypertension

It is estimated that 43 million people in the United States – ~24% of the adult population – have hypertension with essential or idiopathic hypertension accounting for 95% of all cases of hypertension.8 Oral L-arginine has been shown to improve endothelial dysfunction in patients with essential hypertension within 1.5 hours.17

In a prospective, randomized, double-blind trial, 35 patients (ranging in age from 57-69) with essential hypertension received either 6 grams L-arginine (18 subjects) or placebo (17 subjects). Patients were examined for flow-mediated endothelium-dependent dilatation of the brachial artery before and 1.5 hours after administration of L-arginine or placebo. L-Arginine resulted in significant improvement in FMD (median FMD increased from 1.7% to 5.9%), while placebo had virtually no effect (median FMD 3.0% vs. 3.1%).17

In individuals with compromised flow-mediated dilation

L-arginine benefits those most in need (those with the lowest FMD), which is not surprising since it restores NO production, thus normalizing endothelial function. A recent meta-analysis of 12 randomized, placebo-controlled trials involving 492 participants evaluated the effect of short-term (3 days to 6 months) L-arginine supplementation (3 to 24 grams/day) on endothelial function. L-arginine supplementation significantly increased FMD when baseline FMD levels were <7% but had no effect on FMD when baseline FMD was >7%.18

In individuals with chronic heart failure

L-arginine has been shown to induce beneficial effects on endothelial function in patients with chronic heart failure. Forty patients with severe chronic heart failure (left ventricular ejection fraction 19 +/- 9%) were randomized to an L-arginine group (8 grams/day), a training group with daily handgrip training (T), an L-arginine and T group, or an inactive control group (C). After four weeks, in response to administration of acetylcholine [an eNOS agonist] (30 microg/min), internal radial artery diameter increased 8.8 +/- 0.9% in the L-arginine group, 8.6 +/- 0.9% in the T group, and 12.0 +/- 0.3% in L-arginine and T group, compared to  group C (controls).19

In patients with impaired glucose tolerance (MetS) and type 2 diabetes

Patients with impaired glucose tolerance show a lessening in NO bioavailability that correlates with the degree of insulin resistance and is associated with increased endothelin-1 activity.  (Endothelin-1 is a vasoconstrictive peptide whose effects include activation of smooth muscle cell mitogenesis, leukocyte adhesion, and monocyte chemotaxis, all of which contribute to the initiation and progression of the atherosclerotic process.20 21 ) L-arginine supplementation, most likely due to its effect of restoring the balance between NO and endothelin-1, has been shown to improve insulin sensitivity and endothelial function in lean and in obese individuals with insulin-resistant type 2 diabetes mellitus.22

In a study involving obese type 2 diabetic patients, 33 individuals were placed on a hypocaloric diet along with an exercise training program for 21 days. In addition, they were randomly divided into two groups, the first of which also received L-arginine (8.3 grams/day), while the second group was given placebo.22 L-Arginine treatment not only caused a more rapid improvement in fasting glucose levels, which were almost normalized within 3 weeks, but also a normalization of postprandial glucose levels, a result of special interest in relation to CVD since recent studies have found that management of postprandial blood glucose levels may influence microvascular and possibly cardiovascular risk in patients with type 2 diabetes.22

L-arginine reverses the age-associated impairment in FMD and endothelial function

Of particular interest for anti-aging and longevity medicine, L-arginine reverses the normally-observed age-associated impairment of endothelial function. A negative correlation has been noted between aging and peak coronary blood flow response to the endothelium-dependent vasodilator acetylcholine—a negative correlation that is lost after L-arginine infusion, suggesting that aging selectively impairs endothelium-dependent coronary microvascular function and that this impairment can be restored by L-arginine administration.23

Aging also correlates with impairment of FMD of the brachial artery and a reduction in vascular NO bioavailability, particularly in elderly individuals with cardiovascular disease. However, even in healthy elders, aging is associated with progressive endothelial dysfunction. In a prospective, double-blind, randomized crossover trial, 12 healthy older subjects (age 73.8 +/- 2.7 years) took L-arginine (8 grams/bid) or placebo for 14 days each, separated by a wash-out period of 14 days. L-Arginine significantly improved FMD (from 3.88 =/- 0.18 at base line to 5.7 +/- 1.2%), whereas placebo had no effect.24

L-arginine may benefit men with erectile dysfunction

Although little is known about how effective L-arginine will be for men with erectile dysfunction or which subset of men would most likely be helped, preliminary research suggests that some men may benefit. Elevated ADMA is commonly seen in erectile dysfunction, (ED), and ED is commonly associated with other conditions affecting the vasculature in aging men, including ischemic heart disease, peripheral vascular disease, hypertension, atherosclerosis, hyperlipidemia, stroke, and diabetes mellitus.29

In a controlled clinical trial, 50 patients with ED were given 5 grams L-arginine daily or placebo for 6 weeks. Nine of 29 patients taking L-arginine (31%), but only two of 17 patients taking placebo (11.7%), reported significant subjective improvement of sexual function, although all objective variables (complete physical examination including an assessment of bulbocavernosus reflex and penile haemodynamics) remained unchanged. All 9 patients who experienced a subjective improvement in sexual performance had initially had a low urinary nitrate and nitrate (NOx) level, which had doubled at the end of the study, indicating improved NO production secondary to L-arginine treatment.25

L-arginine may further facilitate erections in men with severe ED using sildenafil (Viagra) or its analogues tadalafil (Cialis), and vardenafil (Levitra). In a study involving 40 men between 50 and 60 years old with insulin-dependent diabetes and ED, those given L-arginine, propionyl-L-carnitine, and nicotinic acid daily, along with vardenafil 20 mg twice weekly, for 12 weeks, experienced better FMD and erectile function (estimated with the International Index of Erectile Function questionnaire) than those receiving only vardenafil.26

Sildenafil and its analogues improve ED via a different, albeit NO-related, mechanism of action than L-arginine. These drugs are potent and selective inhibitors of cGMP specific phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum. Since their molecular structure is similar to that of cGMP, sildenafil and analogs act as a competitive binding agent of PDE-5 in the corpus cavernosum, which raises cGMP levels when the NO/cGMP system is activated in the penis, resulting in improved erections. Sildenafil (under the name Revatio) has also been approved since 2005 for the treatment of pulmonary arterial hypertension. Sildenafil relaxes the arterial wall, decreasing pulmonary arterial resistance and pressure, which lessens the workload on the right ventricle of the heart, improving symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, however, the PDE-5 inhibitors act selectively in both these areas without inducing vasodilation in other areas of the body. L-arginine promotes vasodilation systemically.

Impairment of the Endothelial L-arginine/NO Pathway

Flowchart by John Morgenthaler

Primary Mechanisms through which L-arginine Improves Endothelial Function27

Antagonizes ADMA 

Most likely, the key mechanism behind both the occurrence of endothelial dysfunction and the beneficial effects of supplemental L-arginine in restoring healthy endothelial function is that L-arginine antagonizes asymmetric dimethylarginine (ADMA), a naturally occurring amino acid found in plasma and various tissues that is an endogenous inhibitor of NO synthase (NOS). By blocking endothelial NOS (eNOS), and therefore NO production from L-arginine in the vasculature, ADMA induces endothelial dysfunction, which contributes to the initiation and progression of CVD.28 Concentrations of ADMA normally seen in pathophysiological conditions (3-15 micromol/L)inhibit NO production.29

Elevated ADMA levels may explain the "L-arginine paradox": the observation that L-arginine supplementation improves NO-mediated vascular functions in vivo, although the enzyme kinetics of eNOS have been determined in vitro, and the data show that physiological plasma L-arginine concentrations are in a range about 25-fold higher than the Michaelis-Menten constant (KM) of endothelial NO synthase in vitro – a range that should enable full activity of the enzyme in the presence of physiological, low ADMA levels.

In the presence of elevated levels of ADMA, however, NOS is inhibited and the conversion of L-arginine to NO is impaired, resulting in decreased biological actions of NO. Under such circumstances, boosting the concentration of L-arginine, NOS’ natural substrate, by dietary supplementation may normalizes the L-arginine/AMDA ratio,28  and restore NO production to near-normal levels.30,31 Normally, the L-arginine/ADMA ratio is in the range of 50:1 to 100:1, given a range of L-arginine levels between 50 and 100 μmol/L, and ADMA concentrations between 0.3 and 0.7 μmol/L.3

Circulating levels of ADMA are elevated in association with virtually all traditional CVD risk factors and indicators of established CVD. Elevated AMDA levels are associated with low brachial FMD; insulin resistance/the MetS, diabetes; elevated CRP, VCCAM-1, elevated coronary artery calcium score; hypercholesterolemia, hypertriglyceridemia, hyperhomocystinemia; essential hypertension, unstable angina, peripheral arterial disease, congestive heart failure, renal failure, and aging. Evidence for a causal relationship between increased ADMA levels and endothelial dysfunction has been demonstrated in many of these conditions.28 32 33

In normotensive insulin resistant subjects, ADMA plasma concentrations correlate with insulin resistance independently of other CVD risk factors, being higher in obese, insulin-resistant women than in obese, insulin-sensitive women, and decreasing when weight loss results in improved insulin sensitivity.28

In numerous prospective clinical trials, plasma ADMA has been found to be a significant, independent predictor of CV events and mortality, even after controlling for CVD risk factors. Elevated ADMA is associated with a three-fold increased risk of future severe cardiovascular events and mortality in patients undergoing hemodialysis; a four-fold increased risk for acute coronary events in clinically healthy, nonsmoking men; and in humans with no underlying cardiovascular disease who are undergoing intensive care unit treatment, ADMA is a marker of mortality risk.34 As these trials have also revealed that ADMA levels vary in patients previously regarded as having a similar CVD risk profile, they suggest that plasma ADMA levels may be used to identify individuals at increased risk for a major cardiovascular event, e.g., individuals in the “statin gap.”28

Counteracts the negative effects of oxidized LDL cholesterol on endothelial-mediated vasodilation:

Oxidized LDL impairs endothelium dependent vasodilatation via numerous mechanisms including decreasing transport of L-arginine into cells, increasing superoxide (O2-) production, and inhibiting eNOS and NO activity. Specifically, in regards to eNOS, the presence of oxidized LDL leads to the activation and upregulation of the enzyme arginase II, which competes with NOS for L-arginine as a substrate. Not only does this result in impaired NO production, but it also causes increased production of reactive oxygen species (ROS) by NOS. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms unrelated to NO production, including polyamine-dependent vascular smooth muscle proliferation and collagen synthesis. Provision of supplemental L-arginine and antioxidants reverses all these effects.16 35 36

Increases insulin secretion

Insulin secretion promotes not only vasodilation, but decreased platelet aggregation and blood viscosity.37 38 Since the vasodilation produced by L-arginine can be prevented by octreotide, a somatostatin analogue that inhibits insulin release, it has been proposed that L-arginine’s stimulation of insulin release, rather than its enhancement of NO production, is responsible for its cardiovascular benefits.39  It has also recently been proposed that insulin resistance is primarily due to ADMA’s inhibition of the neuronal isoform of NOS (nNOS), while the simultaneously observed atherosclerosis is a consequence of ADMA’s inhibition of endothelial NOS (eNOS); thus ADMA—whose effects can be greatly ameliorated by L-arginine supplementation—is thought to be the molecule responsible for the coexistence of these two conditions.40 41

Maintains muscle mass while decreasing visceral obesity and inflammation in type 2 diabetics

Normally, a hypocaloric diet results in a loss of an equivalent amount of fat mass and fat-free (muscle) mass, although exercise helps preserve fat-free mass. In the study discussed immediately above, the addition of L-arginine to exercise caused a further muscle-saving effect, nearly abolishing the loss in fat-free mass and inducing greater reduction in fat mass. Furthermore, a twofold decrement in waist circumference occurred when L-arginine was added to the hypocaloric diet and exercise, suggesting L-arginine specifically decreased visceral obesity. These findings confirmed previous results in studies of Zucker diabetic fatty rats in which L-arginine therapy was found to increase expression of key genes responsible for fatty acid and glucose oxidation in adipose tissue.42 

L-arginine also lowered levels of adipokines (pro-inflammatory cytokines released by adipose tissue), while enhancing levels of adiponectin (a hormone secreted by adipose tissue that improves insulin sensitivity and triglyceride clearance, and protects against endothelial dysfunction).43 

A similar earlier study of 33 middle-aged patients with chronic heart failure, visceral obesity and MetS-associated type 2 diabetes also produced highly beneficial results. Subjects were not receiving any medication other than diet for their diabetes; statins were withdrawn one week before trial onset. Standard treatments for hypertension (angiotensin-converting enzyme inhibitors and β-blockers) were matched in L-arginine and placebo groups. Subjects were put on a hypocaloric diet (1,000 kcal/day) and a 3-week exercise program (a 45-minute twice daily exercise session 5 days/week). L-arginine plasma levels increased significantly in L-arginine group (from 81.8 ± 12.3 to 131.8 ± 16.5 µmol/l); no increase was seen in the placebo group.

After 21 days, both L-arginine and placebo therapy caused significant loss in whole body weight and fat mass; however, in the L-arginine group, fat mass accounted for 100% of the total weight loss, whereas in the placebo group, fat mass comprised 57% while fat-free mass accounted for 43% of total weight loss. The same research group had previously demonstrated that 3 weeks of a similar hypocaloric diet treatment without exercise training resulted in a 51% decrease of fat mass and a 49% decrease of fat-free mass. These data collectively indicate that L-arginine promotes VAT loss while sparing lean body mass.44


Statins alone are ineffective for the primary or secondary prevention of MI in two-thirds of patients because they do not improve endothelial dysfunction, its corollary hypertension, or insulin resistance. Particularly in individuals in whom the ratio of ADMA: L-arginine is elevated, supplementation with L-arginine restores NO production, improving endothelial function, while also improving insulin sensitivity.  Not only does L-arginine improve insulin sensitivity, but it specifically promotes loss of visceral adipose tissue while saving muscle mass—effects that greatly lessen adipokine-related inflammation, a key factor in the downward spiral to CVD associated with type 2 diabetes. Despite these benefits, L-arginine may actually promote CVD in individuals with an atheromatous or highly inflammatory phenotype. Part II of this review explains why and what to do to optimize the benefits, while avoiding the potential dangers, of L-arginine therapy. 

Read Part II: Key Considerations When Prescribing L-arginine: Maximizing Efficacy, Preventing Harm

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