The present meta-analysis has quantitatively assessed the associations of dietary GL and GI with risk of CHD, stroke, and stroke-related mortality. Our results showed that gender significantly modified the effects of dietary GL and GI on CHD risk, and high dietary GL and GI are positively associated with increased CHD risk in women but not in men. The harmful influence of high dietary GL is more evident in overweight and obese subjects. In addition, high GL level was associated with 19% increased risk for stroke, while high GI level was not associated with stroke and stroke-related mortality.
It has been recognized that diet plays a major role in decreasing risk of cardiovascular diseases. Dietary GI and dietary GL are used to evaluate the glycemic properties of the diet. The first findings were reported from the Nurses Health Study where high dietary GL was observed to be associated with the risk of CHD 
and later with hemorrhagic stroke 
, and these associations were the most evident in overweight women in both studies. Later, similar findings for CVD risk have been reported in several 
, but not all studies 
. This meta-analysis of 12 prospective cohort studies supported that high dietary GL and GI are significantly associated with increased risk of CHD in women but not in men. This gender difference may be explained by the evidence that high GL and GI diets induce a more unfavorable cardiovascular risk profile in women than in men, such as dyslipidemia 
and poor glycemic control 
Stratified meta-analysis by BMI indicated that among overweight and obese subjects, body weight may serve as an effect modifier in the association of high dietary GL with increased risk of CHD. The increasing demand of insulin in response to a high glycemic diet may exacerbate insulin resistance and lipid dysfunction in subjects with higher BMI 
, thus leading to a higher risk for developing CHD. Because of the varied BMI cut-off points across studies, however, further researches are needed to confirm the influence by body weight. The best way to investigate the influence of covariates, such as gender and the patients’ weight, is to perform a meta-analysis with studies’ individual data.
Our systematic review showed that high dietary GL, but not dietary GI, was associated with increased risk of stroke. The harmful effects were more pronounced for GL than for GI, which is expected as GL describes both quality and quantity of carbohydrates while GI represents only quality. Dietary GL is likely to be associated with more infusion of circulating glucose and higher postprandial insulin levels. One concern is that the relationship between GI or GL and stroke risk may be somewhat attenuated by combining ischemic stroke and hemorrhagic stroke in our analysis, because of the distinct pathogenesis of the 2 subtypes. High GI and GL diets can lead to endothelial impairment and vessel dysfunction mediated by the formation of advanced glycation end products, glycemia-induced oxidative stress, and inflammation 
, and these changes may contribute to higher risk of stroke. Although ischemic stroke and hemorrhagic stroke also share common risk factors, such as hypertension, dyslipidemia, and atherosclerosis, large prospective cohort studies are needed to better understand the possible different effects of dietary GI and GL on risk of stroke and subtypes.
Several limitations should be considered carefully in the present meta-analysis. First, as in any observational study, our results could be influenced by differences in other factors. The diet patterns and dietary contributors to the GL vary in different populations. For example, white bread and potatoes are major contributors to the dietary GL in both the United States 
and Sweden 
. Cereal fiber intake such as crisp bread and whole-grain bread are substantially higher in the Swedish men than women in the Nurses’ Health Study 
. While in Asian populations, white rice is the major contributor to the dietary GL, but with a low intake of fiber 
. Second, because the exposure levels of the highest and lowest categories varied between studies, this difference may obscure the associations; nevertheless, our additional analysis that changed the exposures as continuous variables showed a consistent dose-response relationship between dietary GL and the risk of CHD. Among the included studies, only the Nurses’ Health Study had repeated dietary assessment during the follow-up period 
, while the others had a single dietary measurement. Misclassification of exposure to dietary GI and GL due to errors in completing the food-frequency questionnaire or changes in diet habits may have obscured the associations.
Third, even when conducted thoroughly, systematic reviews and meta-analysis are not immune to bias, including publication bias, small-study effect, and between-study heterogeneity. Some novel methods 
have been developed to avoid the correlation between the natural log of odds ratio (InOR) or relative risk (InRR) and its standard error (and hence false-positive test results); however, most assessments of potential publication bias are indirect, rely on some assumptions, and usually require a large number of studies (at least 30 for sufficient power). In addition, between-study heterogeneity can lead to funnel plot asymmetry. There are several sources of the potential heterogeneity across studies, including poor methodological quality in study design, execution or analysis, and small studies targeting at high risk groups for whom the intervention may be most beneficial. In our meta-analysis, the test of heterogeneity using the Cochran Q test and the I2
statistics showed no significant between-study heterogeneity, and there is little evidence of the publication bias as suggested by the Egger’s test. Nevertheless, even though the tests for publication bias are not significant, it is still very likely that negative studies are under published. Study registries with detailed knowledge of which studies have been published and which are unpublished would then be necessary to test publication bias accurately.
Finally, the use of dietary GI and GL is criticized for limited applicability in nutritional counseling and in the selection of foods to prevent and treat cardiovascular diseases. However, nutrition guidelines in western countries such as United States and Australia have currently recommended labeling foods with a symbol of their GI value, suggesting that it is applicable in public health recommendations.
In summary, our meta-analysis of all relevant prospective studies indicates that high dietary GI and GL are associated with increased risk of CHD in women but not in men, and the association was more pronounced between dietary GL and CHD, particularly in the overweight and obese subjects. High dietary GL was associated with increased risk of stroke. Clinical trials that aimed to evaluate the effect of reducing dietary GI or GL on the development of cardiovascular events should be performed in specific population.