**Conflict of interest**

*Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

reduces cells levels of tetrahydrofolate, which is a cofactor in nucleotide synthesis. The cancer drug Methotrexate inhibits dihydrofolate reductase which generates tetrahydrofolate, therefore histidine supplementation could act synergistically with methotrexate in killing cancer cells [123]. Increasing arginine in mice was found to

All of these example diets with glucose and specific amino acids suggest a cancer patient on a high fat/low carb/low protein diet with NNS's could have better outcomes than if on a normal diet.. While NNS's could increase adherence to such diets it is not currently known if such a diet would be any better than intermittent fasting for cancer patients [95, 98, 105, 127–130], and in fact intermittent fasting has been

NNS's have been shown to increase death, though studies have varied largely in the magnitude of the effect. In 2018 Mulle et al. found NNS's to cause more deaths than natural sugar. The study was done with a 451,743 cohort from across 10 European countries. Participants were fairly healthy and excluded if they had preexisting conditions (cancer, heart disease, stroke, or diabetes at baseline), with a mean (SD) age of 50.8 (9.8) years. The participants were mostly women (71.1%). Participants that consumed 2 or more glasses per day of total soft drinks (with NNS's or sugar beverages, compared to <1 glass per month) died earlier (hazard ratio [HR], 1.17; 95% CI, 1.11–1.22; P < .001). Sugar-sweetened soft drinks only had a HR of 1.08 (95% CI, 1.01–1.16; P = .004), compared to NNS's with a HR of 1.26 (95% CI, 1.16–1.35; P < .001). While NNS's seemed to increase participants risk of deaths from circulatory diseases (HR, 1.52; 95% CI, 1.30–1.78; P < .001), sugar-sweetened soft drinks increased deaths from digestive diseases (HR, 1.59; 95% CI, 1.24–2.05; P < .001) [121]. Some studies have found aspartame to be carcinogenic in large animal studies with rats [131, 132] and mice [131, 133] (many animals per sex and group of exposure, numerous dose levels tested, and with observation extending to death) [134]. In 2012 a prospective epidemiological study showed diet soda with aspartame to increase risk of non-Hodgkin's lymphoma and multiple myeloma in men [135]. Some have theorized that increased aspartame consumption could be linked to an increase in brain tumors [136], but a later study looking at almost half a million people between 50 and 71 years of age found there to be no link between aspartame and either hematopoietic or brain cancer [137]. However, a metaanalysis of 22 studies found aspartame to not cause cancer while looking at low, medium, and high doses in rodents, however it is worth noting that the odds ratio had an extraordinarily large range from 0.115 to 3.500 [138]. While case control studies have found an increased risk of cancer, such as a relative risk (RR) 1.3 for bladder cancer from heavy sweetener consumption, the same study found heavy coffee consumption (50 cups/week) had a RR of 1.4 for bladder cancer [34, 139]. While cancer can result in death, and therefore has large negative effects on Quality of Life Year calculations (QALYs), the data does not suggest NNS's increased cancer risk as much as other

increase T-cell activation and T-cell mediated antitumor response [126].

shown in analysis to have the best adherence of common diets.

diseases, such as circulatory disease and metabolic syndromes.

While the continually growing list of NNS's still have many unanswered questions regarding their biological effect in humans, the knowledge we are gaining about each NNS continues to grow as well. Sucralose is now known to become acylated and accumulate in fat tissue. Future studies with sucralose could require long wash out periods, and consumers could expect a delay in biological changes if they removed sucralose from their diet. Aspartame holds a preferential spot among the major NSS's in that it is quickly broken down when consumed so less

**52**

**3. Conclusions**

The authors declare no conflict of interest.

## **Appendices and nomenclature**


#### *Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

