Fructose‐Containing Sugars Do Not Raise Blood Pressure or Uric Acid at Normal Levels of Human Consumption

The article by Angelopoulos and colleagues1 published in this month's issue of The Journal of Clinical Hypertension brings to the forefront the continued debate regarding the role of dietary sweeteners in health and disease, specifically that of fructose and its relationship with hypertension. The study consisted of 268 weight‐stable, normotensive individuals (blood pressure [BP] <140/90 mm Hg) whose BP and uric acid measurements were followed before and after 10 weeks of consuming one of four sugar‐sweetened milk beverages, each containing a single sweetener (high‐fructose corn syrup, fructose, glucose, and sucrose) at a particular percentage of calories for weight maintenance. At the end of the 10 weeks there was a significant reduction in both systolic and diastolic BP with no change in uric acid levels despite an average 2‐pound weight gain. However, the BP was not measured using 24‐hour ambulatory BP monitoring. Energy intake increased by 12.1%, with increased protein intake but decreased fat intake.

Dietary sweeteners are logical research targets as a cause of chronic disease considering that rates of hypertension, obesity, and overall metabolic disturbances have escalated over the past decades, an effect that parallels increased added sugar consumption.2 Of all the sweeteners, fructose is touted to be most detrimental since it is metabolized differently than other monosaccharides: (1) it is poorly absorbed in the intestine; (2) it does not stimulate insulin secretion; (3) it provides a rapid substrate for synthesis of lipids in the liver; (4) it can elevate uric acid levels; and (5) it may stimulate the endogenous production of inflammatory, glycated products.2, 3

Based on existing published literature, the results from this study are not entirely unexpected: the participants were normotensive at recruitment and were asked to consume a sweetened milk beverage. Milk peptides have been shown to reduce BP in some clinical trials and meta‐analyses.4

The authors suggested that the amount of sweetener was reflective of a “normal level of consumption.” This is a significant point, as the level of dietary fructose has been shown to be deterministic in its metabolic effects. As Livesey5 stated, “Fructose is proving to have bidirectional effects. At moderate or high doses, an effect on any one marker may be absent or even the opposite of that observed at very high or excessive doses.” Research indicates that higher‐than‐normal daily intake (≥100–200 g/d) of fructose intake may lead to a host of metabolic changes, including hyperuricemia.5, 6, 7, 8 Most recently, Jayalath and colleagues9 reported no association of fructose consumption with the incidence of hypertension in a systematic review and meta‐analysis of three prospective cohort studies (n=37,375 men and 185,855 women). While they found no effect of fructose at average levels of consumption over time, a positive association was identified with high intakes of fructose.

In the 9% fructose group in the Angelopoulos study, participants received about 50 g of fructose, which has been classified by Livesey and Taylor10 as “moderate” intake. One pear contains about 11 g of fructose.11 Thus, if we consider that general nutritional guidelines advocate 2 to 3 servings of fruit per day, and the amount of 11 g is used as an average, 22 g to 33 g of fructose might be what could be considered acceptable, a number that comes in less than what Angelopoulos and colleagues studied. In contrast to fruit, a 12‐ounce soft drink has between 16.3 g (cola) and 22.4 g (lemon‐lime) fructose.11 Le and associates6 demonstrated that acute consumption of 24 ounces of high‐fructose corn syrup–sweetened beverages (an estimated average of 40 g of fructose per day) led to significant changes in metabolic biomarkers in healthy men and women, such as systolic BP and serum uric acid compared with a sucrose‐sweetened beverage. Although not tested head‐to‐head, it would seem that the overall nutritional composition of the fructose‐containing food might be extremely relevant, considering that 24 ounces of a soft drink may not differ much in fructose content from the overall amount ingested from daily fruit intake, yet different metabolic results may be seen.

High‐fructose corn syrup intake is thought to be particularly concerning because of the potential for its relatively excessive intake from soft drinks and sugar‐sweetened beverages.12 Brown and colleagues7 demonstrated that consumption of sugar‐sweetened beverages, even at one serving per day, led to significantly greater BP levels. In the study by Angelopoulos and associates, all sweeteners were consumed within a milk beverage rather than in a soft drink. The fact that participants were given milk may have been significant as dairy products contain naturally occurring angiotensin‐converting enzyme‐inhibitory peptides.4 Also, milk is high in a number of other nutrients that could favorably alter BP, such as potassium, calcium, magnesium, and vitamin D. Moreover, as noted above, there was a significant increase in dietary protein in all four study groups compared with their baseline intake, which may have been a favorable influence on BP regulation.13

It may also be relevant to examine the total calories consumed. Angelopoulos and colleagues had participants consume the amount of sugar‐sweetened milk at the level of weight maintenance. It is plausible that different results for fructose (or any sweetener) may have been obtained with calorie excess. However, it would remain debatable whether the sweetener or overnutrition was the true culprit. Johnston and colleagues14 found no difference between high‐fructose and high‐glucose diets on liver enzymes in healthy overweight men who consumed an isocaloric diet; however, hypercaloric consumption led to significant changes in liver triglycerides and serum liver enzymes. No difference was found between the groups. It might have been worthwhile for Angelopoulos and colleagues to report whether there were any other changes over the 10 weeks that may lead to hypertension, including dyslipidemia (especially hypertriglyceridemia), dysglycemia, insulin resistance, abnormal liver function tests, inflammatory markers such as high‐sensitivity C‐reactive protein, or flow‐mediated vasodilation. It is conceivable that individuals susceptible to gout and those with hereditary fructose intolerance (and gradations thereof) may have a more pronounced effect to even moderate levels of dietary fructose.3 Using data from the large, prospective, Nurses’ Health Study, Choi and coworkers15 found that women who consumed one serving per day of a sugar‐sweetened soda had a 74% higher risk of incident gout, with greater rates seen with increasing intake of fructose.

Aside from the inclusion of dairy and higher protein in the diet, it would be valuable to examine the dietary pattern of the participants in greater complexity to fully assess the complex role of food bioactives on BP. It is well accepted that dietary patterns such as the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets are comprised of several nutrients and antioxidants that can positively impact BP. For example, as mentioned previously, minerals such as calcium, magnesium, sodium, and potassium all have a significant effect on BP, as do select vitamins such as vitamin D. The thousands of phytonutrients in plant‐based foods, such as flavonoids, nitrates, and isoflavones, fulfil essential functions for cardiovascular health. Thus, a full evaluation of the participants’ dietary pattern is warranted to have a complete understanding of the dynamic interplay of nutrients on BP regulation in these patients.

Finally, hypertension is a lifestyle‐initiated disease characterized by inflammation, oxidative stress, and immune dysfunction, which is induced by multiple causes, including poor diet, lack of physical activity, obesity, and heightened stress.16 Rather than focus research on one nutrient (such as an isolated sweetener), which is always difficult to truly extract from other dietary changes that occur (such as the increased calories, protein, carbohydrate, and decreased fat in this study), a better understanding of the development of hypertension can be best comprehended by bringing in the whole context of diet and lifestyle combined. It is well‐known that various dietary approaches, physical activity, and stress management practices can help reduce risk for developing hypertension. Therefore, any detrimental effect of fructose or other sweeteners might be negated or lessened in the context of healthy lifestyle patterns. It would have been helpful to have more detailed information of the participants’ lifestyle in the study by Angelopoulos and colleagues so that it could be deduced whether there might have been a positive influence of these factors. While participants seemed to be rather “healthy” according to the entrance criteria, except for being on the low end of the overweight body mass index, it would have been helpful to document whether they were taking any medications, as this variable could have changed any response to fructose and provided input on their general health.

Overall, this is a valuable study with several salient takeaways. It will be important for future studies to investigate whether qualitatively different fructose‐containing foods, for example, sugar‐sweetened beverages vs fruit, provoke different responses in BP in acute and chronic settings. Fructose by itself may not be the sole issue. The bigger issue might be whether the fructose‐containing food is nutrient dense, how much of it is eaten, for how long of a duration, and in what dietary pattern context. Furthermore, lifestyle factors need to be accounted for in order to obtain a complete picture of all the variables involved in BP.