Re: Meta-analysis Finds Cocoa Flavanols Can Improve Both Lipid Metabolism and Insulin Resistance

Cocoa (Theobroma cacao, Malvaceae) Flavanols Cardiometabolic Diseases Biomarkers Systematic Review/Meta-analysis Date: 04-14-2017 HC# 031761-566 Lin X, Zhang I, Li A, et al. Cocoa flavanol intake and biomarkers for cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials. J Nutr. November 2016;146(11):2325-2333. Cardiometabolic diseases, such as cardiovascular disease and diabetes, are worldwide health concerns. Previous studies have shown that the consumption of chocolate (Theobroma cacao, Malvaceae) reduces the risk of cardiovascular disease, hypertension, metabolic syndrome, and diabetes. Chocolate, cocoa, or their flavanol compounds may also attenuate blood pressure according to numerous prior randomized clinical trials (RCTs). This systematic review and meta-analysis compiled and analyzed results from RCTs to determine whether consumption of cocoa flavanols impacted markers of cardiometabolic health; also addressed were impacts of study design, participant characteristics, and dosage. The databases PubMed, Web of Science, and Cochrane Central Register of Controlled Trials were searched for clinical trials reported in English that were published from January 1965 to December 2015. Search terms included "cacao," "cocoa," "chocolate," "clinical trial," "controlled clinical trial," and "RCT." RCTs that had a group consuming cocoa products, chocolate, or cocoa flavanols; a placebo group; and measurements of markers of cardiometabolic health at baseline and endpoint were screened for possible inclusion. Those studies that were not RCTs; did not include a placebo group; did not use cocoa products, chocolate, or cocoa flavanols; assessed cardiometabolic health markers more than one week after treatment; included cocoa flavanol dosage at < 100 mg/day; had pregnant women, children, or adolescents as participants; or did not include endpoint results were not considered. From a total of 326 publications, 19 RCTs were analyzed with 1131 participants. Authors noted study details, participant parameters, and outcome assessments. Study risk of bias was measured using Cochrane Collaboration's tool; this is informed by criteria such as random sequence generation, allocation concealment, and others. Risk was rated as low, unclear, or high. RCTs reported an average participant age of 30-71 years. Dosage of cocoa flavanols was 166-2110 mg/day, and length of treatment was two to 52 weeks. Eleven RCTs were crossover studies, eight had a placebo-controlled parallel format, and 13 had participants with comorbidities. The risk of performance bias was deemed low for seven RCTs, and of the six studies that reported details on blinding of outcome assessment, one RCT was considered to have a high risk of bias. Two RCTs had missing outcome data, and a high risk of bias was also assigned to two RCTs due to low compliance or other reasons. In those consuming cocoa flavanols, compared with the placebo groups, triglyceride concentrations were significantly decreased (weighted mean difference [WMD], −0.10 mmol/L; 95% confidence intervals [CI], −0.16 mmol/L, −0.04 mmol/L; P < 0.001) and high-density lipoprotein (HDL) cholesterol concentrations increased significantly (WMD, 0.06 mmol/L; 95% CI, 0.02 mmol/L, 0.09 mmol/L; P < 0.001). Also, fasting insulin concentrations in those treated with cocoa flavanols were significantly decreased as compared with the placebo groups (WMD, −2.33 µIU/ml; 95% CI, −3.47 µIU/ml, −1.19 µIU/ml; P < 0.001). This was also seen with the homeostatic model assessment–insulin resistance (HOMA-IR) results, where a decrease indicates improved insulin sensitivity (WMD, −0.93; 95% CI, −1.31, −0.55; P < 0.001). The quantitative insulin sensitivity check index (QUICKI; higher values indicate improved insulin sensitivity) significantly increased in those consuming cocoa flavanols as compared with placebo groups (WMD, 0.03; 95% CI, 0.01, 0.05; P = 0.01). This was also seen with the insulin sensitivity index (WMD, 2.54; 95% CI, 0.63, 4.44; P = 0.01). C-reactive protein (a marker of inflammation) was significantly decreased in those consuming cocoa flavanols as compared to those consuming placebo (WMD, −0.83 mg/dl; 95% CI, −0.88 mg/dl, −0.77 mg/dl; P < 0.001). A significant increase in vascular cell adhesion molecule 1 (a possible indicator of vascular stress) also was observed (WMD, 85.6 ng/mL; 95% CI, 16.0 ng/mL, 155 ng/mL; P = 0.02). Oxidative stress markers were unaffected. There was no impact of participant age or sex, study duration or format, or form of cocoa flavanols on lipid metabolism or insulin resistance; however, a dosage of < 200 mg/day was significantly correlated with higher HDL cholesterol concentrations (P < 0.001). The dosage of ≥ 200 and < 600 mg/day resulted in significantly decreased fasting glucose (P < 0.001) and elevated HDL cholesterol (P = 0.001). A dosage of ≥ 600 mg/day was associated with significantly decreased fasting insulin (P = 0.004). This meta-analysis suggests that the consumption of cocoa flavanols can impact both lipid metabolism and insulin resistance. These results agree with certain previous studies. The authors mention that flavanols are associated with multiple cellular mechanisms, including beneficial effects on the vasculature, insulin secretion, and glucose uptake. Discussed limitations include variations in the number of studies reporting certain outcomes, small sample sizes in certain RCTs, and differing treatment duration, among others. The authors call for further RCTs that target the clinical relevance of potential cocoa flavanol impact on cardiometabolic markers. This study was supported by the National Institutes of Health (Bethesda, Maryland); American Heart Association (Dallas, Texas); Mars Symbioscience (Germantown, Maryland); National Heart, Lung, and Blood Institute (Bethesda, Maryland); and Pfizer (New York, New York). Three of the authors (Manson, Sesso, and Wang) received support from Mars Symbioscience for an investigator-initiated clinical trial testing cocoa flavanols. —Amy C. Keller, PhD