Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials1–3 Liana C Del Gobbo,4* Michael C Falk,5 Robin Feldman,5 Kara Lewis,5 and Dariush Mozaffarian4 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and 5Life Sciences Research Organization, Bethesda, MD ABSTRACT Background: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. Objectives: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged $18 y without prevalent CVD. Design: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger’s and Begg’s tests. Results: Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (24.7 mg/dL; 95% CI: 25.3, 24.0 mg/dL), LDL cholesterol (24.8 mg/dL; 95% CI: 25.5, 24.2 mg/dL), ApoB (23.7 mg/dL; 95% CI: 25.2, 22.3 mg/dL), and triglycerides (22.2 mg/dL; 95% CI: 23.8, 20.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity , 0.001 each); stronger effects were observed for $60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (211.5 mg/dL; 95% CI: 216.2, 26.8 mg/dL) than in healthy populations (22.5 mg/dL; 95% CI: 24.7, 20.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. Conclusions: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. Am J Clin Nutr 2015;102:1347–56. Keywords: INTRODUCTION Accumulating evidence from prospective observational studies and a large clinical trial suggests that nut intake lowers the risk of cardiovascular disease (CVD)6 (1, 2). Tree nuts are rich in unsaturated fats, soluble fiber, antioxidants, and phytosterols (3), which separately or together may produce beneficial effects on serum lipids, blood pressure, and inflammation (4, 5). Prior meta-analyses of controlled trials have shown that tree nut intake lowers total and LDL cholesterol (6–8). However, effects of nut consumption on other key CVD risk factors, including specific lipoproteins, blood pressure, and inflammation, are not established. In addition, 2 of these prior meta-analyses evaluated only one type of nuts—almonds (6) (n = 5 trials) and walnuts (7) (n = 13 trials)— and potential effects of other tree nuts remain unclear. Furthermore, previous analyses (6–9) have not standardized pooled effects to a common dose or tested for nonlinearity of dose-responses, preventing conclusions about the magnitude of effects for a given intake of nuts or potential for nonlinear effects. Therefore, key questions remain on the major cardiovascular mechanisms influenced by tree nuts, on whether some types of nuts are preferential for improving risk, and on dose-response relations of these effects. To address these knowledge gaps, we performed a systematic review and meta-analysis of controlled interventional trials to 1 Supported by National Heart, Lung, and Blood Institute grant R01HL085710-07. 2 The International Tree Nut Council (ITNC) had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 3 Supplemental Tables 1–4, Supplemental Figures 1–10, and Supplemental Material are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org. *To whom correspondence should be addressed. E-mail: . 6 Abbreviations used: ApoB, apolipoprotein B; CRP, C-reactive protein; CVD, cardiovascular disease. Received March 11, 2015. Accepted for publication September 23, 2015. First published online November 11, 2015; doi: 10.3945/ajcn.115.110965. Am J Clin Nutr 2015;102:1347–56. Printed in USA. Ó 2015 American Society for Nutrition nuts, cholesterol, lipids, apolipoprotein, cardiovascular 1347 1348 DEL GOBBO ET AL. examine the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, pine nuts, and Brazil nuts) on major CVD risk factors, including blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), lipoproteins [apolipoprotein A1, apolipoprotein (ApoB), and apolipoprotein B100], blood pressure (systolic and diastolic), and inflammation (C-reactive protein, CRP) in adults aged $18 y without prevalent CVD. We hypothesized that tree nuts would lower concentrations of LDL cholesterol and its primary lipoprotein, ApoB. As a secondary hypothesis, we evaluated potential differences in effects by nut type. METHODS We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (10) during all stages of implementation, analysis, and reporting of this meta-analysis. A review protocol has not been published. Eligibility criteria We searched for all published controlled trials that reported the effect of tree nut consumption on blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), lipoproteins (apolipoprotein A1, ApoB, and apolipoprotein B100), blood pressure (systolic and diastolic), or inflammation (CRP). We did not include body weight or adiposity as outcomes because a metaanalysis of nut intake and body weight was recently reported (11). Trials had to be controlled but could be randomized or nonrandomized (with plans to evaluate only randomized tri (...truncated)