We searched MEDLINE (between 1966 and 2007) and the Cochrane Library Central Registry of Controlled Trials (between 1984 and 2007) for relevant publications using the following medical subject heading terms: diabetes and (food or diet). We examined reference lists of those publications to identify additional studies suitable for our purpose. We restricted the search to randomized controlled trials published in English. We searched for studies of the effects of two kinds of prescribed diets differing according to proportions of carbohydrate and fat under conditions that the prescribed total energy and protein intake did not differ significantly between groups of patients with type 2 diabetes. Trials in patients with type 1 diabetes were excluded. We designated one diet as the LFHC diet, which was defined as having a relatively high C/F ratio, and the other as the HFLC diet, which had a relatively low C/F ratio. As shown in detail in , in examining these studies, we found that the C/F ratio ranged from 0.60 to 1.56 for the HFLC diets and from 1.67 to 7.30 for the LFHC diets.
Descriptive statistics of studies included in the meta-analysis
Among the studies identified, we included only randomized controlled trials with measurements of fasting plasma glucose (FPG) and fasting insulin and intervention periods of ≥1 week. Both parallel-group and crossover designs were included. Studies that included an intervention with a change in the content or quality of carbohydrate such as an increase in fiber and whole grains were excluded because such diets are high in fiber, which in itself ameliorates glycemia and lipemia regardless of changes in the C/F ratio (3
). Studies of very-low-calorie or enteral (not oral) diets and those in which the dosage of hypoglycemic agents was changed during the intervention period were also excluded. One of three reviewers extracted all studies that met the eligibility criteria, and a second reviewed all extracted data. When necessary, disagreement was resolved by discussion with a third author.
Extracted data included features of the study design (i.e., crossover or parallel design and presence of a washout period), intervention periods, characteristics of patients (mean age, BMI, percent men, and percent those using hypoglycemia agents). Other extracted data regarded the characteristics of each diet, such as macronutrient composition; a weight-loss diet, which was defined as caloric restriction resulting in weight reduction; a weight-maintenance diet, which was defined by a weight change of ≤1 kg during the intervention period, and a monounsaturated fat (MUFA) diet within the HFLC-diet group, which was defined as the addition of MUFA to the HFLC diet. We also extracted baseline and final means and statistical dispersions of each group for the following metabolic profiles: A1C, FPG, fasting insulin, total cholesterol, fasting triglycerides, LDL cholesterol, HDL cholesterol, and 2-h postprandial levels of glucose and insulin. If VLDL cholesterol but not triglyceride data were provided, the triglyceride value was calculated by multiplying VLDL cholesterol × 5 according to the Friedewald formula (5
). Also, if HbA1
but not A1C data were provided, A1C was estimated by the relation between HbA1
and A1C concentrations according to the methodology of Kilpatrick et al. (6
). If necessary, measures of means and dispersion were approximated from figures in the articles using an image scanner (CanoScan LiDE 500F [resolution 600 dpi]; Canon, Tokyo, Japan). Study quality was assessed according to the scale described by Jadad et al. (7
), with each included trial evaluated according to randomization, double blinding, withdrawals, and dropouts.
The effect on each metabolic profile, which is expressed as the mean difference between LFHC- and HFLC-diet groups in individual studies, was calculated by subtracting the change from baseline to final values in the HFLC-diet group from that in the LFHC-diet group. The SE of the change from baseline values was directly extracted from the reported data or estimated from the SEs of the baseline and final values in the LFHC- and HFLC-diet groups, assuming a correlation of 0.5 between the baseline and final measures within each group, according to the formula of Follmann et al. (8
), as follows:
We chose the percent change from baseline values because the mean baseline and final values in patients in each study were highly skewed. To estimate percent change, we divided each change from baseline values and its SE by the baseline value. When no baseline value was reported, as in some crossover studies, we summarized the intervention effect by the ratio of the difference in final values between LFHC- and HFLC-diet groups to the final value in the HFLC-diet group and assumed that the baseline SE was equal to the final SE. This method of estimating percent change has limitations, especially in studies without washout periods. Therefore, we performed a sensitivity analysis to examine the effect of these studies on the results.
All percent changes were firstly pooled with a fixed-effects model (9
). For each outcome measure, influence analysis was conducted to detect an outlier (i.e., a single estimate with an extreme result), which influenced overall outcome. Study heterogeneity was statistically assessed by Q
). If heterogeneity was significant, the percent changes were secondarily re-pooled with a random-effects model (9
). Publication bias was assessed using two formal methods: Begg's test (10
) and Egger's test (11
). The trim-and-fill technique (12
) was used to investigate the impact of any suggested bias.
We also calculated the weighted mean difference (WMD) in individual trials by multiplying each percent change by the inverse of its SE squared. We ecologically examined the mutual association among each metabolic effect of the LFHC diet compared with the HFLC diet by Spearman's correlation analyses among WMDs.
To investigate the effect of study characteristics, stratified analyses were performed for the following possible confounders: study design (i.e., whether each trial used a crossover design and, if so, whether the trial had a washout period or data on baseline values), intervention period (<4 vs. ≥4 weeks), percent the study of female sex (<50 or ≥50%), mean age (<55 vs. ≥55 years), BMI (<28 vs. ≥28 kg/m2), percentage using hypoglycemia agents (zero vs. above zero), C/F ratio in the LFHC (>3 vs. ≤3) and HFLC (>1 vs. ≤1) groups, prescription of the MUFA diet (yes vs. no), and prescription of a weight-loss or weight-maintenance diet. We additionally conducted linear multivariable regression analyses to determine whether the characteristics of the patients were independent predictors that influenced the effect of the LFHC diet versus that of the HFLC diet. In this analysis, age, BMI, and the carbohydrate proportion in the LFHC and HFLC diets were entered as continuous variables. A P value of ≤0.05 was considered statistically significant. All analyses were performed with STATA software version 10 (STATA Corporation, College Station, TX).