Chewing Betel Quid and the Risk of Metabolic Disease, Cardiovascular Disease, and All-Cause Mortality: A Meta-Analysis

and All-Cause Mortality: A Meta- Analysis. PLoS ONE 8(8): e70679. doi:10.1371/journal.pone.0070679 Chewing Betel Quid and the Risk of Metabolic Disease, Cardiovascular Disease, and All-Cause Mortality: A Meta- Analysis Tomohide Yamada 0 Kazuo Hara 0 Takashi Kadowaki 0 Antony Bayer, Cardiff University, United Kingdom 0 Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo , Tokyo , Japan Background: Betel nut (Areca nut) is the fruit of the Areca catechu tree. Approximately 700 million individuals regularly chew betel nut (or betel quid) worldwide and it is a known risk factor for oral cancer and esophageal cancer. We performed a meta-analysis to assess the influence of chewing betel quid on metabolic diseases, cardiovascular disease, and all-cause mortality. Methodology/Principal Findings: We searched Medline, Cochrane Library, Web of Science, and Science Direct for pertinent articles (including the references) published between 1951 and 2013. The adjusted relative risk (RR) and 95% confidence interval were calculated using the random effect model. Sex was used as an independent category for comparison. Results: Of 580 potentially relevant studies, 17 studies from Asia (5 cohort studies and 12 case-control studies) covering 388,134 subjects (range: 94 to 97,244) were selected. Seven studies (N = 121,585) showed significant dose-response relationships between betel quid consumption and the risk of events. According to pooled analysis, the adjusted RR of betel quid chewers vs. non-chewers was 1.47 (P,0.001) for obesity (N = 30,623), 1.51 (P = 0.01) for metabolic syndrome (N = 23,291), 1.47 (P,0.001) for diabetes (N = 51,412), 1.45 (P = 0.06) for hypertension (N = 89,051), 1.2 (P = 0.02) for cardiovascular disease (N = 201,488), and 1.21 (P = 0.02) for all-cause mortality (N = 179,582). Conclusion/Significance: Betel quid chewing is associated with an increased risk of metabolic disease, cardiovascular disease, and all-cause mortality. Thus, in addition to preventing oral cancer, stopping betel quid use could be a valuable public health measure for metabolic diseases that are showing a rapid increase in South-East Asia and the Western Pacific. - Obesity has rapidly become a modern epidemic, with one billion people worldwide being either overweight or obese [1]. In particular, abdominal obesity is associated with insulin resistance that often leads to type 2 diabetes mellitus. Insulin resistance, its associated hyperinsulinemia and hyperglycemia, and the cytokines produced by adipose tissue (adipokines) can also provoke vascular endothelial dysfunction, dyslipidemia, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease (CVD) [2,3]. In Asia, the prevalence of obesity, diabetes, and metabolic disease has increased rapidly in recent years, partly as a result of rapid socioeconomic development [4,5]. Asia already has 60% of the worlds diabetic population and diabetes is increasing more rapidly in Asia than anywhere else [6]. Such metabolic diseases have a crucial influence on public health, since a modest increase in the risk of morbidity and mortality [7] translates into a substantial social burden, so prevention of these diseases is extremely important. Betel nut (Areca nut) is the fruit of the Areca catechu tree, which grows in Asia, the tropical Pacific region, and parts of east Africa. It is a major ingredient of betel quid (BQ), which generally consists of areca nut, betel leaf, catechu, slaked lime, and sometimes tobacco [8]. Chewing BQ is common in Central Asian, South Asian, and South-east Asian countries, including Bangladesh, China, India, Pakistan, Philippines, Sri Lanka, Taiwan, and Vietnam [9]. In fact, it has been estimated that 700 million individuals (approximately 10% of the worlds population) chew BQ regularly and it is thought to be the fourth most commonly used psychoactive substance in the world [10]. There are four main arecal alkaloids (arecoline, arecaidine, guvacine, and guvacoline) in betel nut, with arecoline being the main component. These alkaloids bind to GABA receptors in the brain to trigger psychoactive effects such as a sensation of alertness and well-being, but also dizziness [11,12]. The nitrosated compounds that form when these alkaloids are exposed to gastric acid in the presence of nitrates released by oral bacteria are carcinogenic, and are also similar in structure to various nitrosamines that are well known to be diabetogenic [11]. In fact, the WHO International Agency for Research on Cancer Monograph Working Group has reported that chewing BQ is a known risk factor for oral cancer and esophageal cancer [13]. It was recently proposed that there is an association between inflammatory oral conditions and systemic disorders [14]. Numerous studies have shown that chewing BQ is associated with the risk of various systemic diseases (including metabolic disease, cardiovascular disease, and all-cause mortality), as well as oral diseases, and have generally identified a positive association, although its magnitude has varied [1531]. Thus, clarifying the relationship between chewing BQ and metabolic disease may be important for the development of preventive strategies. Accordingly, we performed a meta-analysis to confirm the influence of chewing BQ on metabolic disease, cardiovascular disease, and all-cause mortality. Searches To identify observational studies that had investigated the association between chewing BQ and metabolic disease, cardiovascular disease, and/or all-cause mortality, the electronic databases of Medline, Cochrane Library, Web of Science, and Science Direct were searched from January 1, 1951 until January 30, 2013 using the following key words: (areca nut OR betel nut OR betel quid) AND (mortality OR hypertension OR metabolic OR diabetes OR obesity OR dyslipidemia OR coronary OR heart OR cardiovascular disease). Reference lists of the articles thus identified were also reviewed. Selection Initial screening was based on study titles or abstracts, while subsequent detailed screening employed full-text review. Cohort studies, case-control studies, and cross-sectional studies that assessed the relation between chewing BQ and metabolic disease (obesity, metabolic syndrome, diabetes, hypertension, and dyslipidemia), cardiovascular disease, and all-cause mortality were eligible for inclusion if the following criteria were met: 1) the full text of the report was published in English; 2) the influence of chewing BQ on the relative risk (risk ratio, hazard ratio, or odds ratio) of events was reported with confidence intervals; and 3) the definitions of events were reported. Assessment of Validity To assess the validity of the studies thus identified, each report was appraised with reference to the STROBE statement (an established checklist of items that should be included in articles reporting observational (...truncated)