We believe that this analysis represents the most comprehensive meta-analysis of the data presented as quantiles of GI and/or GL. However, we were unable to include 2 studies in this analysis because of the expression of results as either the substitution of low GI carbohydrates for SFAs, rather than dietary GI analysis, or the incremental association of dietary GI with CHD rather than quantile presentation (ie, CHD risk per 5 GI unit increments). These studies indicated that in Danish47
and Black American44
men, positive benefits for cardiovascular events were seen related to consumption of lower GI foods. We demonstrated an overall increased relative risk of CHD of 11% in the comparison of the highest versus lowest quantile of GI and a 27% increased relative risk of CHD for the highest versus the lowest quantile of GL. The effect was seen only in women with 26% increased relative risk of CHD for GI and 55% for GL.
The sex difference in the CHD response to the glycemic index was unexpected and may be the result of the larger total number of subjects in the female cohorts (n=177 887, CHD events=4260) than in the male cohorts (n=63 049, CHD events=2680) and our inability to include 2 studies, 1 from Denmark47
and 1 from the United States,44
both of which demonstrated adverse effects of high GI foods or diets on CHD outcomes in men. Furthermore, the 1 study43
of men in the present analysis that showed a near-significant deleterious effect of low-GI diets was also responsible for the heterogeneity in the analysis. This study differed from the other studies of men in several respects. The proportion (54%) of smokers was almost twice that of the other studies, and BMI was somewhat lower (25.3 versus 26.1 kg/m2
); men with lower BMIs have been shown to be less susceptible to the effects of GI on CHD risk.48
There may also be another potential explanation for the difference between men and women, possibly a result of differences in diet reporting. For example, if women report more precisely, there would be less measurement error and hence better power. In addition, there may be more homogeneity (insufficient heterogeneity) in the diets of men and therefore a lack of the necessary power to detect potentially important relationships between dietary GI/GL and CHD risk in men.
Despite these reservations there are reasons why women may be potentially more vulnerable to high glycemic index diets. Part of the protection that women have from CHD may be related to their high HDL-C levels.49,50
Higher glycemic index diets tend to reduce circulating HDL-C concentrations and thus disproportionately increase CHD risk in women, especially when postmenopausal.51
At the same time, high-GI diets may raise TG levels,52
which may also carry more risk for CHD in women than in men.53,54
Other factors that in general may contribute to the increased CHD risk with high-GI diets are blood pressure and CRP, both of which may be raised by high-GI diets.52,55
Conversely, acarbose, the α-glucosidase inhibitor that converts dietary carbohydrate to a low glycemic index form, has been shown to prevent hypertension and CHD events in the STOP NIDDM trial.56
The link between low GI and GL diets and lower CHD risk is also substantiated by randomized clinical trials (RCTs) assessing the effects of dietary strategies low in GI and GL with low saturated fat content. A systematic review of such RCTs in overweight and obese subjects found that replacing refined carbohydrates with low-GI complex carbohydrates conferred more beneficial effects on CHD lipid risk factors when compared with complex starchy carbohydrates with higher GI.57
There has also been emerging evidence on the positive effects of low-GI diets on CHD risk factors such as oxidative damage58
in overweight/obese and type 2 diabetic individuals, respectively. In addition, meta-analyses of low-GI RCTs have shown beneficial effects on body weight and lipid profiles in obese and overweight subjects21
as well as on glycemic control in type 2 diabetic subjects.59
The current studies do not suggest a latency effect of GI or GL on CHD risk. Because no studies have a time frame shorter than 6 years, it is not possible to determine whether the effect is early, possibly from alterations in clotting factors,60
or later due to reduction in the rate of atheroma formation secondary to oxidative damage.61
An earlier meta-analysis that assessed the effect of dietary GI on several health outcomes including diabetes, CHD, and cancer also concluded that low-GI diets were protective for diabetes, CHD, and colon and breast cancers.62
However, only 2 studies28,29
were available to assess CHD outcome at the time of that analysis.
In general, the glycemic index and glycemic load data were in agreement, although the magnitude of the CHD risk was greater based on the difference between the extreme quantiles of glycemic load. In the overall GL extreme quantile analysis there was significant heterogeneity that became nonsignificant when either the Grau et al43
or the Sieri et al33
reports on women were removed. The Grau et al43
report was visually an outlier on the publication bias funnel plot, which could potentially be a result of the difference in the analytical approach, using restricted cubic splines in Grau et al,43
compared with the methods of analyses used in other reports. We could not find an explanation for the heterogeneity in the overall GL analysis due to the Sieri et al33
report on women.
The weaknesses of the present study include the limited number of studies, the inability to include potentially relevant studies44,47
because of lack of necessary data, and the heterogeneity in the overall analyses, especially in the likely underpowered analyses of men. Another inherent limitation of observational analyses is the potential problem for residual confounding as well as the possibility of overadjusting, which remains an area of debate in epidemiology.63
Perhaps, the most common limitation in meta-analyses of dietary studies is the combination of dietary data collected using multiple instruments. Although no change was found in our overall conclusions with post hoc sensitivity analyses removing the 429,35,43
reports with food diaries and interviews, because of the time frame of published reports, the GI and GL data were still compiled from various data sources. As such, our findings should be considered with caution, and further studies should be undertaken to allow sufficient power for subgroup analyses of dietary data sources.
Although the reports included men and women from Holland,29,31,36
and the United States,28,34
the majority of the population was white, limiting the racial diversity of this meta-analysis. However, it is noteworthy that our systematic review captured a report on African American men that, although not included because of lack of necessary data (ie, quantile analyses), showed that a 5-unit increase in GI conferred a 16% increase in CHD risk.44
Further studies are required with a wider range of ethnic groups and more racial diversity both in women and especially in men because cohorts of men were likely underpowered.
The strength of our study included the use of random-effects models to allow assessment of heterogeneity to guide the sensitivity analyses. We further believe that our systematic review was strengthened by our efforts to acquire as much data as possible by contacting all study authors to include all relevant studies in our analyses.