CVD remains the leading cause of mortality worldwide and obesity is a convinced risk factor for the pandemic of CVD. Slavin J. has reported the mechanism of the protective effect of whole grains in preventing CVD in 2003[25], including changing gut environment by dietary fiber, carbohydrate and short-chain fatty acid, being rich in antioxidants and regulating glucose metabolism and insulin response. With the uncovering of this mechanism, whole grains are recommended in 2003 edition of Australia dietary guidelines[26]. In 2013 edition, guideline emphasized that at least 4 to 6 serves of grain food, mostly whole grains, per day is recommended for adult, especially for people with high risk of CVD and obesity[27]. In our systematic review, we hypothesised that obese patients accepted whole grain diet intervention would have a greater improvement of CVD risk factors, including body weight, LDL-C concentration, systolic BP, waist circumference, CRP, insulin resistance index and BMI. However, compared to control group, we only observed a slightly greater reduction in body weight and LDL-C concentration. Whole grain diet group participants also had a greater reduction in CRP, although the heterogenity among studies is relatively large.
In order to investigate the source of heterogenity, subgroup analysis was conducted in three outcomes with positive results. For weight and LDL-C data, the subgroup whose participants suffer another chronic disease besides obesity, such as type 2 diabetes, abnormal plasma cholesterol, explain more significant results. Specially, these comorbidities are in accord with the diagnosis criteria of metabolic syndrome (MetS). As defined by the US National Heart, Lung and Blood Institute and American Heart Association Consensus Statement, MetS can be diagnosed when patients have at least 3 among 4 risk factors, which include abdominal obesity [waist circumference > 102 cm (men) or > 88 cm (women)], high triglycerides ( ≥ 150 mg/dL), low- and high-density lipoprotein cholesterol [fasting serum HDL cholesterol > 40 mg/dL (men) or > 50 mg/dL (women)], high blood pressure [BP ≥130/≥85 mmHg], and elevated fasting blood glucose (≥ 100 mg/dL)[28]. Metabolic syndrome was reported as an important contributor for CVD incidence and mortality, as well as all-cause mortality. Previous studies demonstrated that whole grain diet can greatly reverse the process of MetS, lowers postprandial plasma insulin and several cholesterol levels[29–32]. To a certain extent, our results are in line with these suggestions and also show that whole grain diet has more significant effects on patients combined with one or two chronic metabolic disorder.
Another factor appeared through subgroup analysis is well-organized study design. Studies included in this review with positive results are in common with high quality of intervention monitoring. One effective method was giving educational lessons or standard 7-day cyclical menu before intervention period or during the visits, which is named as “centralized intervention”[33,34]. Some studies also supervised participants’ diet, suggesting them to provide a 4-d diet record for each visit in a specific nutrition clinic. Professional dieticians were recruited to assess these diet records and to decide whether participants’ diet should be adjusted according to study design [35,36]. Precise baseline information collection is also emphasized in these studies, which introduce a run-in period before the intervention period. In run-in period, participants in both groups were asked to replace their habitual grain products with refined grain only to eliminate the influences from their habitual diet[35,36]. Structured run-in period is confirmed as an important element in clinical trial design, especially for medicine development. Run-in strategy is usually used to vanish prior treatment and has no magnify effect on realistic intervention effect[37,38]. The duration of run-in period is still controversial and in our review this period was designed as 4 to 6 weeks, unequally.
Discrepancies among studies may also be caused by variety of whole grain diet intervention. In our review, the interventions covered barley, oat, wheat, rye and quinoa, and few studies only gave ambiguous definition. Previous studies have showed differences when considering the types of whole grain diet. In a 6-week randomized trial, Suhr J et al reported that compared with refined wheat, whole grain rye, but not wholegrain wheat, lowers body weight and fat mass significantly[39]. In a meta-analysis, Liangkui Li group investigated the effect of buckwheat on improving CVD risk factors in both human and animals. In human, compared with control group, the glucose metabolism, total cholesterol and triglycerides were significantly improved following buckwheat intervention [differences in blood glucose: 0.85 mmol/L (95% CI: 1.31, 0.39), total cholesterol: 0.50 mmol/L (95% CI: 0.80, 0.20) and triglycerides: 0.25 mmol/L (95% CI: 0.49, 0.02)]. In animals, only triglycerides and total cholesterol show slight differences with high heterogenity[40]. However, in another trial regarding quinoa conducted by Liangkui Li group, they suggested that quinoa consumption can regulate glucose response, while only has minimal effects on other CVD risk biomarkers[41]. As a result, the discrepancies among studies in this review is reasonable, and further subgroup analysis focused the same type of whole grain diet should be conducted.
Interestingly, we found few studies introduced a biomarker, Plasma alkylresorcinols, to quantify the intake of whole grain diet, which can be used to adjusting the indeed effectiveness of whole grain, especially for wheat, rye and barley[42–44]. Alkylresorcinols are a short-half-life phenolic lipid compound abundant in out layer of whole wheat, rye and barley as homologues with odd-numbered hydrocarbon side chains[42,45]. Although its half-life is estimated as about 5 hours, single plasma alkylresorcinols is proved to be reliable biomarker for long-term whole grain food consumption[46]. Concentration of alkylresorcinol is also reported to be a sensitive indicator, whose concentrations were correlated with WG intake and could be used to distinguish between low- and high-WG consumers. And it is also suggested that there was no difference whether alkylresorcinol concentration is expressed as “nmol/mmol total lipids” or “nmol/L”, which means the concentration of alkylresorcinol is not influenced by lipid distribution[47]. In summary, concentration of alkylresorcinol might be a reliable biomarker in evaluating the effect of whole grain diet in later studies.