Dietary carbohydrate restriction improves insulin sensitivity, blood pressure, microvascular function, and cellular adhesion markers in individuals taking statins☆
Introduction
Statins, by inhibiting hydroxy-methyl-glutaryl coenzyme A reductase, effectively decrease low-density lipoprotein cholesterol (LDL-C) concentrations and markedly reduce cardiovascular events [1]. Statins also exert beneficial cardiovascular effects independent of cholesterol lowering [1], [2]. These pleiotropic effects of statins have been proposed as key properties to reduce cardiovascular morbidity and mortality and include improvement of vascular endothelial function (VEF), increased stability of atherosclerotic plaques, and decreased oxidative stress and inflammation [2]. Impaired VEF is regarded as the earliest identifiable event in the progression of atherosclerotic cardiovascular disease (CVD) [3].
Carbohydrate restricted diets (CRD) have been shown to be more effective than low-fat diets for improving atherogenic dyslipidemia and other metabolic syndrome characteristics (reviewed in [4]), but the specific mechanism(s) by which these effects occur remains unclear. Well formulated very-low carbohydrate diets result in a fundamental shift in cellular energy provision to reliance on predominately fatty acids and ketones, with a concomitant reduction in glycolytic flux. The shift in metabolic fuel partitioning, along with recent data showing significant reductions in circulating levels of saturated fatty acids and anti-inflammatory effects [5], indicates that very-low carbohydrate diets work through diverse and complex mechanistic pathways. Nevertheless, there is good reason to speculate that these “mechanisms” differ between statins and very-low carbohydrate diets, and thus the benefits of combined treatments could be additive, at least for some cardio-metabolic risk markers.
We previously showed that a CRD, compared with a low-fat diet, ameliorates markers associated with metabolic syndrome and cardiovascular risk, including impairment of postprandial VEF [6]. Furthermore, a CRD reduced several inflammatory and cellular adhesion molecules compared to an isocaloric low-fat diet in overweight individuals with atherogenic dyslipidemia [5]. The beneficial effects of a very-low carbohydrate diet on inflammation may be mediated, in part, by increases in circulating ketones which in addition to their role as providing fuel also suppress oxidative stress through epigenetic mechanisms [7]. As inflammation-induced oxidative stress potentially mediates endothelial dysfunction in middle-aged and older adults [8], a very low-carbohydrate diet may lead to improvements in VEF by reducing oxidative stress [9] and inflammation [5].
Lifestyle and pharmacological therapies aim to reduce the progression of CVD and associated risk factors, while combined therapies may further aid in risk reduction. While statin therapy is an increasingly common option to decrease cardiometabolic risk, it is likely that optimal results will be achieved if drug therapy is combined with appropriate dietary intervention. The combined impact of statin therapy with carbohydrate restriction has not been investigated previously. Therefore, the objective of the present study was to examine the metabolic and vascular effects of implementing a CRD in individuals who had achieved a lowered LDL-C by statin treatment. We hypothesized that a CRD would improve lipid profiles and insulin sensitivity, reduce blood pressure, decrease circulating inflammatory and cellular adhesion molecules, and augment VEF as measured non-invasively by brachial artery flow mediated dilation (FMD), which predicts future cardiovascular events [10] and correlates with coronary artery endothelial function [11], and forearm blood flow (FBF).
Section snippets
Study population
Interested participants completed a comprehensive screening visit including a fasting blood draw, and a series of medical, physical activity, and nutritional history questionnaires. Participants were required to be taking a stable dose of statin medication as prescribed by their personal physician for at least 4 weeks prior to the screening visit and documented that they never or rarely missed a dose. They also refrained from taking any known lipid-lowering supplements (eg, omega-3 fatty acids,
Participant characteristics (Table 1)
Participants had been taking a statin for various lengths of time (mean ± SD = 3.7 ± 2.8 years, range = 8 months-14 years) and the doses varied (range = 5-80 mg/d, mode = 40 mg/d). Ten participants were prescribed simvastatin medication, including four who were taking simvastatin combined with ezetimibe. The remaining participants took atorvastatin (n = 4), rosuvastatin (n = 4), fluvastatin (n = 1), pravastatin (n = 1), or lovastatin (n = 1). The average potency of statin used by the
Discussion
This is the first study to our knowledge that has specifically examined how a low-carbohydrate diet affects intermediate risk factors in individuals who successfully lowered their LDL-C with statins. In accordance with our hypothesis, we observed that habitual statin users who were previously following a low-fat diet responded favorably to a CRD as evidenced by improvements in insulin resistance, serum adhesion molecules, blood pressure, and resistance vessel VEF. Maintenance of FMD and
Acknowledgments
Daniel Friedenreich, Juan Carlos Aristizibal and Dina Lajoie are thanked for their assistance with the study intervention. Analysis of CRP was generously performed by colleagues at the Department of Laboratory Medicine at Boston Children's Hospital. Funding for this study came from internal University research support and research incentive accounts belonging to JSV. The authors state no conflicts of interest.
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Author Contributions: KDB, EEQ, and BRK contributed to study conception and design, acquisition of data, and analysis and interpretation of data. KDB, EEQ, and BRK performed the analysis of insulin and cellular adhesion and inflammatory biomarkers. EEQ and BRK performed the analysis of ketones. BMV and DMK assisted with data acquisition and analysis. MLF, RLS, CMM, WJK, and JSV contributed to study conception and design and analysis and interpretation of data. KDB and JSV performed the statistical analyses and wrote the manuscript with assistance from EEQ, BRK, BMV, DMK, MLF, RLS, CMM, WJK All authors read and approved the final manuscript. JSV has primary responsibility for the final content of the manuscript.