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Nitrates and nitrites are used as food additives in processed meats. They are also commonly ingested from water and several foods. Evidence suggests a beneficial role of dietary nitrites and nitrates in lowering blood pressure. However, associations between exposure to nitrites and nitrates from natural sources and food additives, separately, and risks of hypertension and cardiovascular disease (CVD) have not been investigated. We aimed to study these associations in the French population based prospective cohort NutriNet-Santé. Overall, 104,817 adults were included. Associations between exposure to nitrites and nitrates (evaluated using repeated dietary records, linked to a food composition database accounting for commercial brands of industrial products) and risks of hypertension and cardiovascular disease were assessed using multivariable Cox proportional hazard models. During follow-up, 3810 incident cases of hypertension were ascertained, and 2075 cases of CVD, 1004 of cerebrovascular diseases and 1079 or coronary heart diseases were diagnosed. Participants with higher exposure to nitrites from food additives and specifically those highly exposed to sodium nitrite (e250) had a higher hypertension risk compared with those who are not exposed to nitrites from food additives (HR = 1.19 (95% CI 1.08-1.31), P = 0.002, and 1.19 (95% CI 1.07-1.31), P = 0.002, P < 0.001), respectively). There was no evidence for an association between total nitrites or nitrites from natural sources, or dietary nitrates with hypertension risk (all P-values>0.3). There was no evidence for associations between dietary nitrites, or nitrates with risks of cardiovascular, cerebrovascular or coronary heart diseases (all P-values>0.2). In conclusion, we found that higher exposure to nitrites from food additives was associated with higher risk of hypertension. Our results do not support a potential protective association between dietary nitrites or nitrates and cardiovascular outcomes. Key messages • These results provide additional evidence in the context of current discussions about updating regulations on the use of nitrites as food additives. • Our findings do not support any protective impact of nitrites and nitrates on cardiovascular health.

Background Artificial sweeteners are widely used today by the food industry as sugar alternatives. Potential adverse effects of these food additives on cardiovascular disease (CVD) have been suggested in experimental studies, but data from studies involving humans remain very limited. Previous cohorts have focused on artificially sweetened beverages. Our objective was to study the associations between artificial sweeteners from all dietary sources, overall and by molecule (aspartame, acesulfame-potassium and sucralose), and risk of CVDs (overall, coronary heart and cerebrovascular). Methods The study included 103,388 participants of the web-based NutriNet-Santé cohort (2009-2021). Artificial sweetener intakes were assessed using repeated 24h dietary records including names and brands of industrial products consumed. Multi-adjusted Cox proportional hazard models were performed. Exposure to artificial sweeteners were coded as 3-category variables: non-consumers, lower consumers (artificial sweetener intake below the sex-specific median) and higher consumers (above the sex-specific median). Results Compared to non-consumers, higher consumers of total artificial sweeteners had increased risk for CVD (n = 1502 incident cases, HR = 1.17 [1.01-1.35], P-trend=0.04) and more specifically cerebrovascular diseases (n = 777, HR = 1.34 [1.10-1.62], P = 0.004). Higher consumption of aspartame was associated with increased cerebrovascular diseases (HR = 1.29 [1.03-1.60], P = 0.01). Higher consumption of acesulfame-K was associated with a higher risk of CVD (HR = 1.24 [1.04-1.47], P = 0.02) and cerebrovascular diseases (HR = 1.29 [1.02-1.64], P = 0.1). No association was detected for coronary heart diseases (n = 730 incident cases). Conclusions These findings suggest a direct association between higher artificial sweetener consumption and increased CVD risk, in particular cerebrovascular. These results provide key novel information for the ongoing re-evaluation of sweeteners by the European Food Safety Authority. Key messages • In this large-scale prospective cohort (n = 103,388), artificial sweeteners (especially aspartame and acesulfame-K) were associated with increased risks of cardiovascular and cerebrovascular diseases. • These results provide key insights to feed EFSA’s expertise for the ongoing risk assessment of artificial sweeteners.

Nitrates and nitrites occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives. The epidemiological evidence linking exposure to nitrites/nitrates with type-2 diabetes (T2D) risk is scarce. We aimed to study these associations in a large population based prospective cohort study. Overall, 104,168 adults from the French NutriNet-Santé cohort study (median follow-up time 6.7 years) were included. Associations between intakes of nitrites and nitrates (evaluated using repeated 24h dietary records, linked to a comprehensive food composition database and accounting for details of commercial names/brands of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During follow-up, 969 incident T2D cases were ascertained. Total nitrites and nitrites from natural sources were both positively associated with higher T2D risk (HRtertile 3 vs.1=1.29 (95% CI 1.06-1.56), Ptrend=0.004, and 1.27 (95% CI 1.05-1.54), Ptrend=0.01, respectively). Participants with higher exposure to nitrites from food additives (i.e. above the sex-specific median), and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to food additive nitrites (HRtertile 3 vs.1=1.58 (95% CI 1.28-1.94), Ptrend0.4). In this large prospective cohort, a higher dietary exposure to nitrites (from both natural sources and food additives) was associated with higher T2D risk. These results provide additional evidence in the context of current discussions about updating regulations on the use of nitrites as food additives. Key messages • A high exposure to dietary nitrites (from both natural and food additive sources) is associated with an increased risk of type-2 diabetes. • These findings support further regulations concerning the use of nitrites as food additives in processed meats.