The Effects of Aspartame on Glucose, Insulin, and Appetite-Regulating Hormone Responses in Humans: Systematic Review and Meta-Analyses

Abstract

Aspartame (L-α-aspartyl-L-phenylalanine methyl ester) has been implicated in increased risk of several chronic health conditions, yet underlying mechanisms remain unclear. The objective of this work was to systematically identify and summarize all controlled intervention studies investigating the effects of aspartame consumption on glucose, insulin, and appetite-related hormone responses. Five academic databases, 4 trial registries, and additional resources were searched until June 2024. Search hits were screened, in duplicate, for intervention studies of aspartame compared with comparator, which assessed glucose, insulin, and/or any other appetite-regulating hormone. Results were tabulated, and meta-analyses run where ≥10 studies with similar methodology were found. Risk of bias (RoB) was assessed using RoB-2. Certainty of the evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation. One hundred one articles were identified, detailing 100 experiments: 79 acute (≤1 d), 8 medium term (2-30 d), and 13 long term (>30 d). Experiments involved healthy adults, individuals with aspartame sensitivity, and individuals with compromised glucose metabolism, varied widely in aspartame provision and comparator/s, and although almost all assessed glucose and/or insulin responses, few experiments investigated other appetite-regulating hormones. Meta-analyses (acute cross-over studies) revealed few effects of aspartame on blood glucose/insulin compared with vehicle or low-calorie sweeteners (LCS), and lower blood glucose/insulin concentrations compared with sugars, other carbohydrates, or other nutritive elements. Over the medium term and longterm, few effects of aspartame were found, and high heterogeneity between studies remained. Similar effects were found in other populations, and other outcomes, with few adverse events. RoB assessments suggested "some concerns" for the majority of studies. The certainty of the evidence for all outcomes in all populations was judged to be "very low." Our findings suggest little to no effects of aspartame consumption on glucose metabolism over the short term or the long term. Further studies over the long term, assessing a range of appetite-regulating hormones and comparing aspartame with other LCS, would be of value. This study was registered in PROSPERO as CRD42024540781 on April 29, 2024.

Keywords: E951; adverse events; appetite; appetite-regulating hormones; aspartame; energy intake; glucose; insulin; low-calorie sweeteners; nonnutritive sweeteners.

FIGURE 1

PRISMA diagram. ∗ Includes article record not found (n = 7), full study article not available (n = 11), and article not retrieved due to copyright (n = 1). ∗∗ Where data on aspartame use was unavailable or unclear, clarification was sought from authors. Studies were only included if authors responded by the September 30, 2024, with confirmation of aspartame use. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

FIGURE 2

Forest plot for meta-analysis 1 investigating the effects of aspartame administered alone on glucose responses in healthy individuals (cross-over studies). Individual studies are represented by the blue boxes; combined effects are represented by the diamonds. The x-axis demonstrates the effect size, in standard deviations, as calculated using Hedges’ adjusted g. Studies on the 0 line demonstrate no differences between aspartame and comparator, studies to the right of the 0 line demonstrate greater responses to aspartame, studies to the left of the 0 line demonstrate reduced responses to aspartame / increased responses to comparator. CHO, carbohydrate. GI: Glycaemic Index; REML: restricted Maximum Likelihood.

FIGURE 3

Forest plot for meta-analysis 3 investigating the effects of aspartame administered alone on insulin responses in healthy individuals (cross-over studies). Individual studies are represented by the blue boxes; combined effects are represented by the diamonds. The x-axis demonstrates the effect size, in standard deviations, as calculated using Hedges’ adjusted g. Studies on the 0 line demonstrate no differences between aspartame and comparator, studies to the right of the 0 line demonstrate greater responses to aspartame, studies to the left of the 0 line demonstrate reduced responses to aspartame / increased responses to comparator. CHO, carbohydrate. GI: Glycaemic Index; REML: restricted Maximum Likelihood.