In general, if two factors have a positive or no multiplicative interaction, they have a positive interaction in the addition model; if two factors have a negative multiplication interaction, they may have a positive, a negative or no interaction in the addition model. That is, the negative multiplicative interaction cannot prove whether the two factors have biological interactions. In this way, the results of the multiplicative interaction model and additive interaction model in our study are essentially consistent with each other in the nature of biological interactions. Namely, the combination of DM and HT can significantly increase the risk of cardio-cerebrovascular diseases compared with their existence alone, but no interaction effects were observed in our study between them on cardio-cerebrovascular diseases. The increased risk may be attributed to a simple superposition of the two.
As far as we concerned, only a few studies focused on the combined effect of DM and HT on cardio-cerebrovascular diseases[2, 13, 14, 15, 19, 20, 21]. Nevertheless, there were still 2 papers[14, 21] among this studied the independent and combined effects of the two variables but did not further study the interaction effect. They respectively are: Gang Hu found that HT and type 2 DM increased the CHD risk independently, and their combination increased the risk dramatically, particularly in women. Neda Zafari found that the risk of CHD and stroke was different between HT and DM. The risk of CHD and stroke in DM combined with HT was higher than that in DM and higher than that in HT. The interaction effect was not analyzed in both studies. That is, only 5 papers studied the interaction effect of DM and HT on cardio-cerebrovascular diaseases[2, 13, 15, 19, 20].
Yun Ju Lai conducted a cross-sectional survey of community elderly people aged 65 and above in Shipai, Taiwan. The results showed that there were sex differences in the interaction between DM and HT on stroke. DM and HT had synergistic additive interactions (SI = 3.16, 95% CI: 1.35–7.39) but only in elderly women. However, that study had the following shortcomings: a) the study population was over 65 years old, which makes the extrapolation of conclusions limited; and b) only the additive interaction was studied, while the multiplication interaction was not explored. Although Rothman thought that the evaluation of biological interactions should be based on an additive scale rather than a multiplicative scale, there is still controversy regarding which interaction model is more in line with biological laws. And the Strengthening the Reporting of Observational Studies in Epidemiology statement suggests that both the results of additive and multiplicative interaction analyses should be reported when evaluating interactions. Most importantly, if there is truly an interaction between DM and HT on cardio-cerebrovascular diseases, the interaction effects should not be limited to women but equally exist in both sexes theoretically. Therefore, the possibility of a third-order interaction on cardio-cerebrovascular diseases of DM, HT and sex cannot be excluded According his study results. Cai Huan's small sample cross-sectional study found that DM and HT had synergistic interactions on the severity of stroke (severe stroke). However, the study used patients with moderate/medium-sized stroke rather than non-patients as controls and only adjusted for age and sex, not other common cardio-cerebrovascular risk factors such as smoking, drinking, diet, physical activity, or body mass index, which may have a large residual confounding effect. Shan Lu also conducted a cross-sectional survey of 11036 people aged 15 and above in Nanjing, China. And they found that there was no multiplicative interaction between DM and HT on myocardial infarction and stroke. In addition, Gang Hu’s further study found that the interaction terms of HT and DM on both stroke incidence and stroke mortality were not statistically significant, indicating that these two factors operated independently for stroke risk. However, that conclusion was also based on only the results of the multiplicative model. Zhan Yiqiang evaluated the interaction between DM and HT on cardio-cerebrovascular diseases. The results showed that HT and DM had additive interactions on cardiovascular diseases but had no interaction on stroke. That study was the most comparative with our study, but the diagnostic criteria of DM included both DM detected by blood sampling on the spot and self-reported DM of the respondents. The nonuniform standards might bring qualitative differences between on-site measurements of DM and self-reported DM; for example, self-reported diabetic patients with negative measured DM might pay more attention to health management than those with positive present DM on the spot whose status of HT and even cardio-cerebrovascular diseases might be worse than that of the former. In that way, the direction and intensity of the interaction effect might be covered due to sample selection bias. In addition, other cardio-cerebrovascular diseases other than stroke and coronary heart disease were widely included in that study, which might be responsible for the difference in results.DM combined with HT increased the risk of cardio-cerebrovascular diseases, but it seems to be too early to say that DM and HT had an interactive effect on cardio-cerebrovascular diseases because no interaction effects were found in our study, whether by the multiplication model or the additive model.
Although there were no interaction effects found between DM and HT on the prevalence of cardio-cerebrovascular diseases, we still need to attach great importance to them because the risk of cardio-cerebrovascular diseases in DM combined with HT sharply increased almost two- to four-fold in our study when the two cardio-cerebrovascular risk factors emerged simultaneously. It was reported that DM and HT share common patient behavioral factors and pathophysiological pathways. These pathways interact and influence each other and may even lead to a vicious cycle. HT and DM are components of the metabolic process of metabolic syndrome. Therefore, they may develop one after the other in the same individual. Cardio-cerebrovascular disease is related to multiple risk factors. The risk of occurrence depends not only on the severity of a certain risk factor but also on the number of risk factors possessed by the individual.Jonathan N found that DM and systemic hypertension(SHT) each have adverse effects on left ventricular structure and function, and the combination of DM and SHT results in the greatest degree of left ventricular hypertrophy, myocardial dysfunction, and arterial stiffness. Cesare Russo found that HT and DM are independently associated with impaired left ventricular diastolic function, independent of the effect of overweight/obesity and other covariates. Their coexistence resulted in a worse effect on left ventricular diastolic mechanics and was associated with higher left ventricular filling pressures than either condition alone. DM and HT are both risk factors for atherosclerosis and play roles in the formation and aggravation of endothelial and smooth muscle function. In basic research, the combination of DM and HT can promote endothelial cell dysfunction. The dysfunction of endothelial cells may be a change in the early stage of atherosclerosis. Both DM and HT can promote the generation of oxygen-derived free radicals, thus damaging endothelial function. When DM and HT coexist, endothelial cell function further decreases, and smooth muscle function is also impaired. In addition, the superposition of DM and HT can promote monocyte adhesion to endothelial cells, thus increasing the production of vascular superoxide and the expression of monocyte chemoattractant protein-1, leading to atherosclerosis and subsequent cardio-cerebrovascular diseases. Therefore, the risk of cardio-cerebrovascular outcomes in patients with DM and HT is increased, which is biologically reasonable.
Based on the high risk of cardio-cerebrovascular diseases in patients with DM complicated with HT, it is an urgent problem to strengthen the health management of patients with DM complicated with HT in order to prevent the occurrence and progression of cardio-cerebrovascular diseases.
This study was a large-scale population cross-sectional study with 14422 participants. The cardio-cerebrovascular diseases evaluated in our study included two major cardio-cerebrovascular diseases, namely, CHD and stroke, and their comorbidity. Both the results of the multiplicative interaction and additive interaction were reported, and the results were consistent, which provided strong support for the main conclusion; that is, DM and HT do not have interaction effects on cardio-cerebrovascular diseases. In addition, five main risk factors for cardio-cerebrovascular diseases, including sex, age, smoking, drinking and physical exercise, were adjusted, thus excluding the influence of mixed factors. However, there are still some limitations in this study: a) the information about the disease was provided by the investigators themselves, and recall bias cannot be avoided; and b) the occurrence order of DM, HT and cardio-cerebrovascular diseases is unknown, so a causal relationship cannot be determined, which is a common feature of cross-sectional studies.
Strengths And Limitations
This is the first community-based cross-sectional study exploring the interaction effects of diabetes and hypertension on cardio-cerebrovascular diseases with a large-scale population of 14422 participants. Both the results of the multiplicative interaction and additive interaction were analyzed and reported, and the results were consistent, which provided strong support for the main conclusion. The multivariable logistical regression models in this study were adjusted for five recognized cardio-cerebrovascular risk factors including sex, age, smoking, drinking and physical exercise, which greatly improved the reliability of the results.This study adopted cross-sectional design, which precluded causal correlations.The information about the disease was provided by the investigators themselves, and recall bias cannot be avoided.