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Abstract Context The functional status of organs, such as the liver, involved in IGF-1 signaling pathways influences circulating levels of IGF-1 and hence its relationship to risk of chronic disease and mortality, yet this has received limited attention. Objective To examine the relationship between IGF-1 and risk of morbidity and mortality from cancer, cardiovascular diseases (CVD), and all causes, accounting for liver function. Methods This study was a case-cohort design nested within EPIC-Heidelberg. IGF-1 was measured in 7461 stored serum samples collected from 1994 to 1998. Median follow-up for incident mortality events was 17.5 years. The case-cohort included a subcohort of 1810 men and 1890 women, in addition to 1668 incident cases of cancer (623 breast, 577 prostate, 202 lung, and 268 colorectal), and 1428 cases of CVD (707 myocardial infarctions and 723 strokes) and 2441 cases of death. Results Higher IGF-1 levels showed direct associations with risks of breast (1.25; 95% CI [1.06-1.47]) and prostate (1.31; [1.09-1.57]) cancers. Restricted cubic splines plots and models including IGF-1 as quintiles revealed a U-shaped relationship between the biomarker and mortality. Participants with the lowest and the highest levels of IGF-1 experienced higher hazards of mortality from cancer, CVD, and all causes. The U-shaped form of the relationship persisted but was attenuated in analyses including only participants without any indications of liver dysfunction. Conclusion This large population-based prospective study showed that both individuals with lowest and highest levels of circulating IGF-1 were at increased risk of deaths from cancer, CVD, and all causes. For individuals with low IGF-1, the excess risks of death were more pronounced among individuals with liver cancer and cirrhosis but were also present among individuals without elevated liver enzymes.

This first paper in a three-part Lancet Series combines narrative and systematic reviews with original analyses and meta-analyses to assess three hypotheses concerning a dietary pattern based on ultra-processed foods. The first hypothesis—that this pattern is globally displacing long-established diets centred on whole foods and their culinary preparation as dishes and meals—is supported by decades of national food intake and purchase surveys, and recent global sales data. The second—that this pattern results in deterioration of diet quality, especially in relation to chronic disease prevention—is confirmed by national food intake surveys, large cohorts, and interventional studies showing gross nutrient imbalances; overeating driven by high energy density, hyper-palatability, soft texture, and disrupted food matrices; reduced intake of health-protective phytochemicals; and increased intake of toxic compounds, endocrine disruptors, and potentially harmful classes and mixtures of food additives. The third and final hypothesis—that this pattern increases the risk of multiple diet-related chronic diseases through various mechanisms—is substantiated by more than 100 prospective studies, meta-analyses, randomised controlled trials, and mechanistic studies, covering adverse outcomes across nearly all organ systems. The totality of the evidence supports the thesis that displacement of long-established dietary patterns by ultra-processed foods is a key driver of the escalating global burden of multiple diet-related chronic diseases. Two companion papers in this Series specify policy actions and wider public health strategies to promote, protect, and support diets based on fresh and minimally processed foods and prevent their displacement by ultra-processed foods.

Background: The food industry uses artificial sweeteners in a wide range of foods and beverages, as alternatives to added sugars for which deleterious effects on several chronic diseases are now well established. The safety of these food additives is debated, with conflicting findings regarding their role in the etiology of various diseases. In particular, their carcinogenicity has been suggested by several experimental studies but robust epidemiological evidence is lacking. Thus, our objective was to investigate the associations between artificial sweetener intakes (total from all dietary sources, and most frequently consumed ones: aspartame E951, acesulfame-K E950 and sucralose E955) and cancer risk (overall and by site).Methods and findings: Overall, 102,865 adults from the French population-based cohort NutriNet-Santé (2009-2021) were included (median follow-up time=7.8y). Dietary intakes and consumption of sweeteners was obtained by repeated 24h-dietary records including brand names of industrial products. Associations between sweeteners and cancer incidence were assessed by Cox hazard models, notably adjusted for age, sex, education, physical activity, smoking, body mass index, height, weight-gain during follow-up, diabetes, family history of cancer, baseline intakes of energy, alcohol, sodium, saturated fatty acids, fibre, sugar, whole-grain foods and dairy products.Compared to non-consumers, higher consumers of total artificial sweeteners (i.e. above the median exposure in consumers) had higher risk of overall cancer (n=3358 cases, Hazard Ratio=1.13, 95% confidence interval=1.03 to 1.25, P-trend=0.002). In particular, aspartame (HR=1.15 (1.03 to 1.28) P=0.002) and acesulfame-K (HR=1.13 (1.01 to 1.26 P=0.007) were associated with increased cancer risk. Higher risks were also observed for breast cancer (n=979 cases, HR=1.22 (1.01 to 1.48) P=0.036 for aspartame) and obesity-related cancers (n=2023 cases, HR=1.13 (1.00 to 1.28) P=0.036 for total artificial sweeteners and HR=1.15 (1.01 to 1.32) P=0.026 for aspartame).Limitations of this study include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.Conclusions: In this large cohort study, artificial sweeteners (especially aspartame and acesulfame-K), which are used in many food and beverage brands worldwide, were associated with increased cancer risk. These findings provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally.

Daily eating/fasting cycles synchronise circadian peripheral clocks, involved in the regulation of the cardiovascular system. However, the associations of daily meal and fasting timing with cardiovascular disease (CVD) incidence remain unclear. We used data from 103,389 adults in the NutriNet-Santé study. Meal timing and number of eating occasions were estimated from repeated 24 h dietary records. We built multivariable Cox proportional-hazards models to examine their association with the risk of CVD, coronary heart disease and cerebrovascular disease. In this study, having a later first meal (later than 9AM compared to earlier than 8AM) and last meal of the day (later than 9PM compared to earlier than 8PM) was associated with a higher risk of cardiovascular outcomes, especially among women. Our results suggest a potential benefit of adopting earlier eating timing patterns, and coupling a longer nighttime fasting period with an early last meal, rather than breakfast skipping, in CVD prevention. The relation between daily meal and fasting timing with cardiovascular disease incidence remains unclear. Here, authors show that a later daily meal timing is associated with increased cardiovascular disease risk, especially in women. This study suggests that adopting earlier daily eating patterns may be beneficial for cardiovascular prevention.

Background Nitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives, mainly in processed meats, to increase shelf life and to avoid bacterial growth. Experimental studies suggested both benefits and harmful effects of nitrites and nitrates exposure on type 2 diabetes (T2D) onset, but epidemiological and clinical data are lacking. We aimed to study these associations in a large population-based prospective cohort study, distinguishing foods and water-originated nitrites/nitrates from those from food additives. Methods and findings Overall, 104,168 adults from the French NutriNet-Santé cohort study (2009 to 2021, 79.1% female, mean age [SD] = 42.7 [14.5]) were included. Associations between self-reported exposure to nitrites and nitrates (evaluated using repeated 24-h dietary records, linked to a comprehensive food composition database and accounting for commercial names/brands details 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 a median follow-up duration of 7.3 years (interquartile range: [3.2; 10.1] years), 969 incident T2D cases were ascertained. Total nitrites and foods and water-originated nitrites were both positively associated with a higher T2D risk (HR tertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), P trend = 0.009 and 1.26 (95% CI 1.03 to 1.54), P trend = 0.02, respectively). Participants with higher exposure to additives-originated nitrites (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 additives-originated nitrites (HR higher consumers vs. non-consumers = 1.53 (95% CI 1.24 to 1.88), P trend < 0.001 and 1.54 (95% CI 1.26 to 1.90), P trend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all P trend = 0.7). No causal link can be established from this observational study. Main limitations include possible exposure measurement errors and the lack of validation versus specific nitrites/nitrates biomarkers; potential selection bias linked to the healthier behaviors of the cohort’s participants compared to the general population; potential residual confounding linked to the observational design, as well as a self-reported, yet cross-checked, case ascertainment. Conclusions The findings of this large prospective cohort did not support any potential benefits for dietary nitrites and nitrates. They suggested that a higher exposure to both foods and water-originated and additives-originated nitrites was associated with higher T2D risk in the NutriNet-Santé cohort. This study provides a new piece of evidence in the context of current debates about updating regulations to limit the use of nitrites as food additives. The results need to be replicated in other populations. Trial registration ClinicalTrials.gov NCT03335644 ( https://clinicaltrials.gov/ct2/show/NCT03335644 )

Evidence on the impact of ultra-processed food (UPF) intake on diet quality among cancer survivors remains limited. This study examined UPF consumption and nutrient intake adequacy among cancer survivors in Lebanon. In this cross-sectional study, adult cancer survivors in remission for at least three months were recruited from two medical centers. Dietary intake was assessed using a validated food frequency questionnaire (FFQ), and food items were categorized according to the NOVA classification. Nutrient adequacy ratio (NAR) and mean adequacy ratio (MAR) were calculated. Participant characteristics, nutrient adequacy, and macronutrient intakes were compared across UPF quartiles using Chi-square tests, and ANOVA. Logistic regression was performed to identify predictors of nutrient inadequacy. The study included 268 participants (mean age: 59 years; 83% female). UPF accounted for 8 ± 7% of total food weight and 17.5 ± 11% of energy intake. Most participants did not meet requirements for potassium (95%), vitamin A (87%), and vitamin D (99%) with mean intakes of 2,527 ± 1236 mg, 350 ± 175 Retinol Activity Equivalents, and 0.8 ± 1.2 µg, respectively. Higher UPF intake was significantly associated with higher energy ( p  < 0.001), carbohydrate ( p  < 0.001), protein ( p  = 0.017), fat ( p  < 0.001), and saturated fat intake ( p  < 0.001), and with lower vitamin C adequacy ( p  = 0.02). In multivariable analysis, higher education predicted lower odds of nutrient inadequacy (AOR = 0.26, 95% CI: 0.1–0.65, p  = 0.004), while UPF intake did not. Despite the relatively low UPF contribution, significant micronutrient inadequacies were observed among cancer survivors. These findings underscore the importance of integrating dietary counseling into cancer care to address nutrient gaps and promote healthier food choices.

To assess the prospective association of two diet quality scores based on the Nova food classification with BMI gain. The NutriNet-Brasil cohort is an ongoing web-based prospective study with continuous recruitment of participants aged ≥ 18 years since January 2020. A short 24-h dietary recall screener including 'yes/no' questions about the consumption of whole plant foods (WPF) and ultra-processed foods (UPF) was completed by participants at baseline. The Nova-WPF and the Nova-UPF scores were computed by adding up positive responses regarding the consumption of thirty-three varieties of WPF and twenty-three varieties of UPF, respectively. Participants reported their height at baseline and their weight at both baseline and after approximately 15 months of follow-up. A 15-month BMI (kg/m ) increase of ≥5 % was coded as BMI gain. Brazil. 9551 participants from the NutriNet-Brasil cohort. Increasing quintiles of the Nova-UPF score were linearly associated with higher risk of BMI gain (relative risk Q5/Q1 = 1·34; 95 % CI 1·15, 1·56), whereas increasing quintiles of the Nova-WPF score were linearly associated with lower risk (relative risk Q5/Q1 = 0·80; 95 % CI 0·69, 0·94). We identified a moderate inverse correlation between the two scores (-0·33) and a partial mediating effect of the alternative score: 15 % for the total effect of the Nova-UPF score and 25 % for the total effect of the Nova-WPF score. The Nova-UPF and Nova-WPF scores are independently associated with mid-term BMI gain further justifying their use in diet quality monitoring systems.

Mixtures of food additives are daily consumed worldwide by billions of people. So far, safety assessments have been performed substance by substance due to lack of data on the effect of multiexposure to combinations of additives. Our objective was to identify most common food additive mixtures, and investigate their associations with type 2 diabetes incidence in a large prospective cohort. Participants (n = 108,643, mean follow-up =  7.7 years (standard deviation (SD) =  4.6), age =  42.5 years (SD =  14.6), 79.2% women) were adults from the French NutriNet-Santé cohort (2009-2023). Dietary intakes were assessed using repeated 24h-dietary records, including industrial food brands. Exposure to food additives was evaluated through multiple food composition databases and laboratory assays. Mixtures were identified through nonnegative matrix factorization (NMF), and associations with type 2 diabetes incidence were assessed using Cox models adjusted for potential socio-demographic, anthropometric, lifestyle and dietary confounders. A total of 1,131 participants were diagnosed with type 2 diabetes. Two out of the five identified food additive mixtures were associated with higher type 2 diabetes incidence: the first mixture included modified starches, pectin, guar gum, carrageenan, polyphosphates, potassium sorbates, curcumin, and xanthan gum (hazard ratio (HR)per an increment of 1SD of the NMF mixture score = 1.08 [1.02, 1.15], p = 0.006), and the other mixture included citric acid, sodium citrates, phosphoric acid, sulphite ammonia caramel, acesulfame-K, aspartame, sucralose, arabic gum, malic acid, carnauba wax, paprika extract, anthocyanins, guar gum, and pectin (HR = 1.13 [1.08,1.18], p < 0.001). No association was detected for the three remaining mixtures: HR =  0.98 [0.91, 1.06], p = 0.67; HR =  1.02 [0.94, 1.10], p = 0.68; and HR =  0.99 [0.92, 1.07], p = 0.78. Several synergistic and antagonist interactions between food additives were detected in exploratory analyses. Residual confounding as well as exposure or outcome misclassifications cannot be entirely ruled out and causality cannot be established based on this single observational study. This study revealed positive associations between exposure to two widely consumed food additive mixtures and higher type 2 diabetes incidence. Further experimental research is needed to depict underlying mechanisms, including potential synergistic/antagonist effects. These findings suggest that a combination of food additives may be of interest to consider in safety assessments, and they support public health recommendations to limit nonessential additives. The NutriNet-Santé cohort is registered at clinicaltrials.gov (NCT03335644). https://clinicaltrials.gov/study/NCT03335644.

Experimental studies suggested potential adverse effects of preservative food additives, but epidemiological data are lacking. We aim to investigate associations between exposure to these compounds and type 2 diabetes incidence in the NutriNet-Santé prospective cohort (n = 108,723; 79.2%women; mean age=42.5 (SD = 14.6); France, 2009-2023). Dietary intakes are assessed using repeated 24h-dietary records. Exposure is evaluated through multiple composition databases and ad-hoc laboratory assays in food matrices. Associations between cumulative exposures to preservatives and diabetes incidence are characterised using multi-adjusted Cox models. The sum of total preservatives encompasses 58 substances. Among those, 17 are consumed by at least 10% of the study population and thus individually investigated. Thirteen (12 after multiple test correction) widely used individual preservatives are associated with higher diabetes incidence (n=1131cases): potassium sorbate, potassium metabisulfite, sodium nitrite, acetic, citric and phosphoric acids, sodium acetates, calcium propionate, sodium ascorbate, alpha-tocopherol, sodium erythorbate, and rosemary extracts. These findings call for their safety re-evaluation and support recommendations to favour fresh and minimally processed foods without superfluous additives. Trial registration: The NutriNet-Santé cohort is registered at clinicaltrials.gov (NCT03335644). Exposure to twelve widely used preservative food additives are associated with a higher incidence of type 2 diabetes in the French NutriNet-Santé cohort of 108,723 adults, supporting recommendations to favour fresh and minimally processed foods

Objective: To compare the initial and the updated versions of the front-pf-pack label Nutri-Score (related to the nutritional content) with the NOVA classification (related to the degree of food processing) at the food level. Design: Using the OpenFoodFacts database -129,950 food products-, we assessed the complementarity between the Nutri-Score (initial and updated) with the NOVA classification through a correspondence analysis. Contingency tables between the two classification systems were used. Settings: The food offer in France. Participants: Not applicable Results: With both versions (i.e. initial and updated) of the Nutri-Score, the majority of ultra-processed products received medium to poor Nutri-Score ratings (between 77.9% and 87.5% of ultra-processed products depending on the version of the algorithm). Overall, the update of the Nutri-Score algorithm led to a reduction in the number of products rated A and B and an increase in the number of products rated D or E for all NOVA categories, with unprocessed foods being the least impacted (-3.8 percentage points (-5.2%) rated A or B and +1.3 percentage points (+12.9%) rated D or E) and ultra-processed foods the most impacted (-9.8 percentage points (-43.4%) rated A or B and +7.8 percentage points (+14.1%) rated D or E). Among ultra-processed foods rated favourably with the initial Nutri-Score, artificially-sweetened beverages, sweetened plant-based drinks and bread products were the most penalized categories by the revision of Nutri-Score while low-sugar flavoured waters, fruit and legume preparations were the least affected. Conclusion: These results indicate that the update of the Nutri-Score reinforces its coherence with the NOVA classification, even though both systems measure two distinct health dimensions at the food level.