Artificial Sweeteners and Risk of Type 2 Diabetes in the Prospective NutriNet-Santé Cohort

Abstract

Objective: To study the relationships between artificial sweeteners, accounting for all dietary sources (total and by type of artificial sweetener) and risk of type 2 diabetes (T2D), in a large-scale prospective cohort.

Research design and methods: The analyses included 105,588 participants from the web-based NutriNet-Santé study (France, 2009-2022; mean age 42.5 ± 14.6 years, 79.2% women). Repeated 24-h dietary records, including brands and commercial names of industrial products, merged with qualitative and quantitative food additive composition data, enabled artificial sweetener intakes to be accurately assessed from all dietary sources. Associations between artificial sweeteners (total, aspartame, acesulfame potassium [K], and sucralose) and T2D were investigated using Cox proportional hazard models adjusted for potential confounders, including weight variation during follow-up.

Results: During a median follow-up of 9.1 years (946,650 person-years, 972 incident T2D), compared with nonconsumers, higher consumers of artificial sweeteners (i.e., above the sex-specific medians of 16.4 mg/day in men and 18.5 mg/day in women) had higher risks of developing T2D (hazard ratio [HR] 1.69; 95% CI 1.45-1.97; P-trend <0.001). Positive associations were also observed for individual artificial sweeteners: aspartame (HR 1.63 [95% CI 1.38-1.93], P-trend <0.001), acesulfame-K (HR 1.70 [1.42-2.04], P-trend <0.001), and sucralose (HR 1.34 [1.07-1.69], P-trend = 0.013).

Conclusions: Potential for reverse causality cannot be eliminated; however, many sensitivity analyses were computed to limit this and other potential biases. These findings of positive associations between artificial sweetener intakes and increased T2D risk strengthen the evidence that these additives may not be safe sugar alternatives. This study provides important insights in the context of on-going reevaluation of artificial sweeteners by health authorities worldwide.

Graphical abstract

Figure 1

Association between total artificial sweeteners, aspartame, acesulfame-K, and sucralose intakes and T2D risk, NutriNet-Santé cohort, France, 2009-2022 (N = 105,588). Median follow-up time was 9.13 years (946,650 person-years). Multivariable Cox proportional hazard models were adjusted for (main model) age (time scale), sex, BMI (continuous, kg/m²), mean percentage of weight change per year of follow-up (continuous), physical activity (categorical IPAQ variable: high, moderate, low, missing value), smoking status (categorical: never, former, current smokers), number of smoked cigarettes in pack-years (continuous), educational level (categorical: less than high school degree, <2 years after high school degree, ≥2 years after high school degree), family history of diabetes in first-degree relatives (categorical: yes, no), prevalence of cardiovascular disease (categorical: yes, no), prevalence of hypertension (categorical: yes, no), prevalence of dyslipidemia (categorical: yes, no), number of 24-h dietary records (continuous), energy intake without alcohol (continuous variable: kcal/day), daily intakes (continuous, g/day) of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, red and processed meat, and dairy products. In addition, all models were mutually adjusted for artificial sweetener intake other than the one studied. Sex specific cutoffs among consumers were 16.4 mg/day in men and 18.5 mg/day in women for total artificial sweeteners, 13.3 mg/day in men and 15.0 mg/day in women for aspartame, 5.05 mg/day in men and 5.40 mg/day in women for acesulfame-K, and 3.44 mg/day in men and 3.30 mg/day in women for sucralose.

Figure 2

Dose-response associations between artificial sweetener intakes and T2D, NutriNet-Santé, France, 2009-2022 (N =105,588). Median follow-up time was 9.13 years (946,650 person-years). Multivariable Cox proportional hazard models were adjusted for (main model) age (time scale), sex, BMI (continuous, kg/m²), mean percentage of weight-change per year of follow-up (continuous), physical activity (categorical IPAQ variable: high, moderate, low, missing value), smoking status (categorical: never, former, current smokers), number of smoked cigarettes in pack-years (continuous), educational level (categorical: less than high school degree, <2 years after high school degree, ≥2 years after high school degree), family history of diabetes in first-degree relatives (categorical: yes, no), prevalence of cardiovascular disease (categorical: yes, no), prevalence of hypertension (categorical: yes, no), prevalence of dyslipidemia (categorical: yes, no), number of 24h dietary records (continuous), energy intake without alcohol (continuous variable: kcal/day), daily intakes (continuous, g/day) of alcohol, sodium, saturated fatty acids, fiber, sugar, fruits and vegetables, red and processed meat, and dairy products. In addition, all models were mutually adjusted for artificial sweetener intake other than the one studied. Restricted cubic splines functions with the SAS macro were developed by Desquilbet and Mariotti (1).