Association of alcohol consumption with all-cause mortality, new-onset stroke, and coronary heart disease in patients with abnormal glucose metabolism—Findings from a 10-year follow-up of the REACTION study

1 INTRODUCTION

The past 30 years have seen a growing trend of diabetes mellitus (DM) and prediabetes in China. The prevalence of DM in Chinese adults was 4.5% in urban areas and 1.8% in rural areas in 2002, while it rose to 11.2% in 2015–2017. Furthermore, in 2010, 493.4 million adults (50.1% of the total population in China) had prediabetes.¹ DM and diabetic complications pose a great threat to human health. So far, population-based longitudinal studies have consistently suggested that type 2 diabetes mellitus (T2DM) is associated with risk of total cardiovascular disease (CVD), mainly coronary heart disease (CHD) and stroke.^{2, 3} Thus, prevention and treatment of DM are particularly important. It is well-known that healthy lifestyles are significant for patients with DM and prediabetes. The relationship between alcohol consumption and CVD mortality has raised concern worldwide. In the Global Burden of Disease (GBD) Study from 2019, alcohol use is the ninth leading risk factor for morbidity and mortality.⁴ Several studies have reported that light-to-moderate alcohol consumption in the general population was associated with a decrease in CHD^{5, 6} and all-cause mortality.^7-9 In contrast, some studies indicated that low to moderate alcohol consumption had no cardioprotective effect on Chinese and Indians,^{10, 11} and regular alcohol intake increased all-cause mortality.¹² For patients with DM, the effect of alcohol consumption on health outcomes remains controversial. In the ADVANCE study, moderate alcohol use, particularly wine consumption, was associated with reduced risks of cardiovascular events and all-cause mortality in patients with T2DM.¹³ The ACCORD trial suggested that moderate alcohol consumption was associated with hypertension and might elevate cardiovascular risks.¹⁴ Recently, a cross-sectional study in China indicated that drinking 1–3 days per week or daily was negatively related to stroke.¹⁵ There is still a lack of long-term longitudinal studies in China about the impact of alcohol consumption on health outcomes, including all-cause mortality, stroke, and CHD in patients with abnormal glucose metabolism including DM and prediabetes. The frequency and quantity of alcohol consumption need to be considered in such studies. This paper aims to investigate the association between alcohol consumption and all-cause mortality, stroke, and CHD in patients with abnormal glucose metabolism to provide them with guidance for alcohol consumption.

2 METHODS

3 RESULTS

3.4 Association of baseline risk factors with 10-year outcomes

Increased age (RR 1.085, 95% CI [1.063, 1.106]), history of hypertension (1.536 [1.088, 2.169]), elevated HbA1c (1.279 [1.154, 1.417]), and creatinine (1.009 [1.004, 1.015]) were associated with all-cause mortality (Figure 1A). Increased age (1.046 [1.029, 1.063]), history of hypertension (1.660 [1.238, 2.225]), and history of CHD (1.451 [1.046, 2.012]) were associated with new-onset stroke (Figure 1B). Female gender (1.354 [1.009, 1.818]) was associated with new-onset CHD, while moderate-intensity activities (0.683 [0.473, 0.987]) and higher HDL-C (0.516 [0.305, 0.874]) were associated with a lower risk of CHD (Figure 1C).

4 DISCUSSION

To our knowledge, this is the first long-term observational study focusing on the association between alcohol consumption and CVD and all-cause mortality in China. We conducted a 10-year longitudinal study on Chinese people with abnormal glucose metabolism and suggested the impact of alcohol consumption on health outcomes. We found that compared with never drinking, occasional drinking was more significantly associated with a reduced risk of all-cause mortality, with an RR of 0.50 (95% CI [0.252, 0.993]) in fully adjusted models. Furthermore, compared with light consumption, heavy alcohol consumption was more significantly associated with increased new-onset stroke (RR 2.503, 95% CI [1.138, 5.506]). No significant association was found between alcohol consumption and new-onset CHD. Age, history of hypertension, HbA1c, and creatinine levels were positively associated with all-cause mortality. Age, history of hypertension and CHD were positively associated with new-onset stroke. Female gender was associated with increased new-onset CHD, while moderate-intensity activities and higher HDL-C were associated with a lower risk of CHD.

On the one hand, we chose the population with glucose metabolism disorders because the guidelines for diabetes provided few instructions on alcohol consumption. Most previous studies have shown that drinking was harmful for individuals with diabetes, and we often instructed them to limit alcohol consumption. On the other hand, the impact of alcohol consumption on health outcomes, especially mortality, stroke, and CHD, was still controversial. In the present longitudinal study, we sought to determine whether alcohol consumption was harmful and how much alcohol consumption was appropriate for people with abnormal glucose metabolism.

The ADVANCE study¹³ was conducted in 20 European countries. However, alcohol consumption in Asia was significantly lower than in European countries. Therefore, the results of the ADVANCE study may only be specific to Europeans and had no reference value for studies on Chinese people. In addition, the analyses were based on alcohol consumption at the time of randomization in the ADVANCE trial, so the actual alcohol consumption might be disturbed by the grouping. In a Danish cross-sectional study,²⁰ among people with diabetes, high alcohol consumption (>21 drinks/week for men and >14 drinks/week for women) was more significantly associated with a lower odds ratio of myocardial infarction and stroke compared to low alcohol consumption, but this finding is only specific to men. Another cross-sectional study suggested that low-to-moderate alcohol intake seemed to be associated with reduced prevalence of acute coronary syndrome (ACS), whereas high alcohol consumption was associated with increased levels of lipids and blood pressure and increased risk of ACS.²¹ Our study analyzed the impact of alcohol consumption on all-cause mortality, stroke, and CHD based on a longitudinal observation. The results are more reliable than those in cross-sectional studies. The different results of various studies can be attributed to genetic variations and differences in ethnic origin, and the definition and grouping of alcohol consumption.

The mechanisms of the adverse effects of heavy alcohol consumption on stroke are as follows: Excessive alcohol intake may elevate the level of blood pressure and TG in people with diabetes,²² resulting in cerebrovascular diseases.²³ Furthermore, heavy alcohol consumption adversely affects brain structure and function, causing atrophy of the hippocampus and cerebellum.²⁴ A previous study found that there was a dose–response relationship between alcohol consumption and lower extremity arterial disease in patients with diabetes.²⁵ It was also reported that alcohol intake was positively correlated with peripheral atherosclerotic plaque volume,²⁶ suggesting that heavy consumption may result in macrovascular diseases. Recently, it was reported that alcohol-induced imbalances in the symbiotic relationship between the host and the gut microbiota could lead to the development and progression of CVD.²⁷ In the present study, we also found that occasional drinking could more significantly decrease all-cause mortality compared with never drinking, indicating that drinking less than once a week may have a positive effect on health outcomes. However, no association was found between light or moderate alcohol consumption and the outcomes. One of the reasons is that the major cases of new-onset CHD in our study were female, and most of them drank less alcohol than males. It was reported that light-to-moderate alcohol intake may augment insulin sensitivity, raise HDL-C, suppress inflammation, raise adiponectin, and improve endothelial function.^{28, 29} Additionally, angiogenic effects of moderate alcohol consumption were concomitant with other beneficial cardio-protective effects, including improved microvascular reactivity, endothelial function, and myocardial perfusion in the ischemic regions of the myocardium.^{30, 31}

The present study has several limitations. First, the follow-up outcomes were obtained from the service system, and the data might not be accurate. The information on alcohol consumption was self-reported, and recall bias could exist. Second, we did not take abstainers into consideration. Instead, we calculated the amount of alcohol consumed as long as the subject drank. Third, subjects with T2DM and prediabetes were not analyzed separately, so we could not know whether the association between alcohol consumption and health outcomes was the same in these two cases. In the future, we will expand the population size, collect more information and clinical data, and refine the grouping. Forth, because we acquired the outcomes 10 years after baseline, we could not know the changes in alcohol consumption over time and the baseline variables that could change with time. We will focus on the effect of time on the association and get relatively complete clinical data in future work. In addition, in-depth studies will be conducted to investigate the essential association between alcohol consumption and CHD, stroke, and other outcomes.

5 CONCLUSION

This study demonstrates the association between alcohol consumption and health outcomes of patients with abnormal glucose metabolism in China. Occasional drinking (less than once a week) decreases all-cause mortality, while heavy alcohol consumption (≥30 g/day for men and ≥15 g/day for women) increases the prevalence of stroke. Heavy alcohol consumption causes CVD, while occasional or light alcohol consumption improves the detrimental outcomes. Patients with abnormal glucose metabolism should avoid heavy alcohol intake, but they should not be prevented from occasional or light alcohol consumption. In addition, it is crucial for them to control blood glucose and blood pressure and keep performing physical activities.

AUTHOR CONTRIBUTIONS

Y.L., G.W., and X.G. contributed to the conception and design of the study. Y.G., X.X., G.W., F.L. and Y.L. conducted the baseline investigation of this study. M.C. and F.L. collected the events of the 10-year follow-up. Y.G. organized the database. X.X. performed the statistical analysis. M.C. wrote the first draft of the manuscript. X.G. revised the manuscript. F.L. gave diet and exercise introductions to patients with diabetes and prediabetes. All authors contributed to manuscript revision and read and approved the submitted version.

FUNDING INFORMATION

This study was funded by the Department of Science and Technology of Jilin Province (China) (20210303001SF and 20170623005TC) and Finance Department of Jilin Province (China) (JLSWSRCZX2021-075).

CONFLICT OF INTEREST STATEMENT

Mengzhao Cui, Fei Li, Xiaokun Gang, Yuan Gao, Xianchao Xiao, Gang Wang, Yujia Liu, and Guixia Wang declare that they have no conflict of interest.