Comment on Lee et al. Relation of Change or Substitution of Low- and No-Calorie Sweetened Beverages With Cardiometabolic Outcomes: A Systematic Review and Meta-analysis of Prospective Cohort Studies. Diabetes Care 2022;45:1917–1930

With interest we read the article in Diabetes Care from Lee et al. (1), who performed a systematic review and meta-analysis of prospective cohort studies and showed that substitution of low- and no-calorie sweetened beverages for sugar-sweetened beverages was associated with a lower cardiometabolic risk. Although the authors carefully attempted to mitigate the influence of residual confounding, they deservedly conclude that they were most likely unable to exclude both unmeasured and measured residual confounding (1).

Mendelian randomization (MR) is a powerful approach to study the lifelong effects of an exposure of interest on outcomes, independent of the disruptive effects of confounders. We recently studied a common variant in the gene encoding ketohexokinase (KHK) (2). KHK catalyzes the phosphorylation of fructose, the main caloric constituent of sugar-sweetened beverages. Impaired KHK function results in reduced fructose metabolism and, eventually, urinary fructose excretion (2). We showed that the rs2304681 minor A allele, a common missense variant in KHK, was associated with greater urinary fructose excretion and protection from colorectal cancer (2).

To gain more insight into the causal association between dietary fructose and cardiometabolic outcomes, we studied the association between the rs2304681 minor A allele and cardiometabolic disease by using publicly available databases.

We found that the rs2304681 minor A allele was associated with lower intrahepatic lipid content, assessed by magnetic resonance imaging in the UK Biobank cohort (β −0.028 ± 0.008, n = 36,703) (3). Protective effects were also observed for the risk of type 2 diabetes in the combined Asian Genetic Epidemiology Network (AGEN) and European Diabetes and Mental Health Adaptive Notification Tracking and Evaluation (DIAMANTE) trial cohorts (fixed-effects meta-analysis odds ratio [OR] 0.985, 95% CI 0.975, 0.994, n = 1,331,670) (4), the risk of hypertension in the UK Biobank cohort (OR 0.988, 95% CI 0.976, 0.999, n = 440,285) (3), and the risk of myocardial infarction for the combined Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) and UK Biobank cohorts (fixed-effects meta-analysis OR 0.976, 95% CI 0.961, 0.992, n = 583,191) (3,5).

We subsequently conducted two-sample MR analyses (TwoSampleMR package in R). The previously reported association between the rs2304681 minor A allele and (log₁₀-transformed) urinary fructose (2) was used as exposure and the hitherto-reported associations between the rs2304681 minor A allele and cardiometabolic disease were used as outcomes. We found that genetically proxied impaired fructose metabolism protects from intrahepatic lipid accumulation (Wald ratio −0.63, 95% CI −0.98, −0.28, P < 0.001), type 2 diabetes (Wald ratio −0.35, 95% CI −0.57, −0.13, P = 0.002), hypertension (Wald ratio −0.28, 95% CI −0.55, −0.01, P = 0.040), and myocardial infarction (Wald ratio −0.54, 95% CI −0.90, −0.19, P = 0.003).

Our findings suggest that fructose per se has harmful cardiometabolic effects and, therefore, support and substantiate the conclusions of Lee et al. (1) on the use of water or low- and no-calorie sweetened beverages as a health strategy to reduce the intake of sugar-sweetened beverages.