Background: There has been an emerging concern that non-nutritive sweeteners (NNS) can increase the risk of cardiometabolic disease. Much of the attention has focused on acute metabolic and endocrine responses to NNS. To examine whether these mechanisms are operational under real-world scenarios, we conducted a systematic review and network meta-analysis of acute trials comparing the effects of non-nutritive sweetened beverages (NNS beverages) with water and sugar-sweetened beverages (SSBs) in humans.
Methods: MEDLINE, EMBASE, and The Cochrane Library were searched through to January 15, 2022. We included acute, single-exposure, randomized, and non-randomized, clinical trials in humans, regardless of health status. Three patterns of intake were examined: (1) uncoupling interventions, where NNS beverages were consumed alone without added energy or nutrients; (2) coupling interventions, where NNS beverages were consumed together with added energy and nutrients as carbohydrates; and (3) delayed coupling interventions, where NNS beverages were consumed as a preload prior to added energy and nutrients as carbohydrates. The primary outcome was a 2 h incremental area under the curve (iAUC) for blood glucose concentration. Secondary outcomes included 2 h iAUC for insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), ghrelin, leptin, and glucagon concentrations. Network meta-analysis and confidence in the network meta-analysis (CINeMA) were conducted in R-studio and CINeMA, respectively.
Results: Thirty-six trials involving 472 predominantly healthy participants were included. Trials examined a variety of single NNS (acesulfame potassium, aspartame, cyclamate, saccharin, stevia, and sucralose) and NNS blends (acesulfame potassium + aspartame, acesulfame potassium + sucralose, acesulfame potassium + aspartame + cyclamate, and acesulfame potassium + aspartame + sucralose), along with matched water/unsweetened controls and SSBs sweetened with various caloric sugars (glucose, sucrose, and fructose). In uncoupling interventions, NNS beverages (single or blends) had no effect on postprandial glucose, insulin, GLP-1, GIP, PYY, ghrelin, and glucagon responses similar to water controls (generally, low to moderate confidence), whereas SSBs sweetened with caloric sugars (glucose and sucrose) increased postprandial glucose, insulin, GLP-1, and GIP responses with no differences in postprandial ghrelin and glucagon responses (generally, low to moderate confidence). In coupling and delayed coupling interventions, NNS beverages had no postprandial glucose and endocrine effects similar to controls (generally, low to moderate confidence).
Conclusions: The available evidence suggests that NNS beverages sweetened with single or blends of NNS have no acute metabolic and endocrine effects, similar to water. These findings provide support for NNS beverages as an alternative replacement strategy for SSBs in the acute postprandial setting.
The systematic review and network meta-analysis by Zhang and colleagues confirms that beverages with low/no calorie sweeteners have no effect on postprandial glucose levels and endocrine responses, similar to water, whereas sugar-sweetened beverages increase glycaemic responses.
A total of 25 studies containing data for 36 acute feeding trials of beverages involving 472 participants met the criteria for inclusion in this systematic review. The study compared the effect of beverages sweetened with single or blends of low/no calorie sweeteners, under different intake patterns (i.e., when consumed alone, or as a preload or together with an additional source of energy/ carbohydrates) to water or sugar-sweetened beverages. The main outcome of interest was effects on postprandial glucose levels and secondary outcomes involved endocrine responses including insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), ghrelin, leptin, and glucagon levels.
When consumed alone, beverages with single or blends of low/no calorie sweeteners had no effect on postprandial glucose, insulin, GLP-1, GIP, PYY, ghrelin, and glucagon responses, similar to water, whereas sugar-sweetened beverages increased postprandial glucose, insulin, GLP-1, and GIP responses. The results were similar when beverages with low/no calorie sweeteners were consumed together with additional energy/ carbohydrates, or when they were consumed as a preload prior to food. The confidence in the estimates was assessed as generally moderate to high for postprandial glucose and insulin, and low to moderate for the remaining outcomes.
These findings are in line with previous systematic reviews of randomised controlled trials (RCTs) showing a neutral effect of low/no calorie sweeteners on acute glucose and insulin responses, similar to water and contrary to effects of sugar-sweetened beverages.