New question marks over the safety of diet soda have arisen following a study linking intake of artificially sweetened beverages to both stroke and dementia.

The study, published online in Stroke on April 20, showed that consumption of one can of diet soda or more each day was associated with a three times increased risk for stroke and dementia over a 10-year follow-up period compared with individuals who drank no artificially sweetened beverages.

"There are many studies now suggesting detrimental effects of sugary beverages, but I think we also need to consider the possibility that diet drinks may not be healthy alternatives," lead author, Matthew P. Pase, PhD, Boston University School of Medicine, Massachusetts, told Medscape Medical News.

"We can't show cause and effect in this study as it is observational in design, but given the popularity of diet drinks we desperately need more research on this question."

He is not yet recommending against diet beverages based on this study, he added, "but I would urge caution — especially to those individuals who consume multiple diet drinks daily. I believe we need to rethink the place of these drinks."

It is possible that the observation could be due to reverse causality, he noted. "It is not clear whether the diet sodas are causing stroke and dementia or whether unhealthy people gravitate more towards these drinks than healthier people.

"If you already have cardiovascular risk factors, you are likely to have been advised to lower your sugar intake and so may move away from sugary beverages to diet drinks," Dr Pase said. "We did find that a higher intake of diet soda was linked to diabetes at baseline, but again we don't know which came first. Did the diet drinks increase the risk of developing diabetes, or did diabetic patients choose diet drinks as they have to limit their sugar intake?"

The link between diet drinks and dementia became nonsignificant when adjusted for vascular risk factors. Dr Pase suggested this could be because the association may be mediated through vascular risk factors — artificial sweeteners could be increasing vascular risk factors. "Or it could just be that people with vascular risk factors drink more diet sodas, which is perfectly possible as they could have been advised to cut down on sugar."

The link with ischemic stroke was still there in all models after adjustment for all other risk factors.

Sugar-sweetened beverages were not associated with stroke or dementia risk, but the authors say this should not be taken as evidence that sugary drinks are safe.

"There are many other studies suggesting harmful effects of sugar-sweetened drinks, and we did not have large enough numbers of people consuming sugary drinks in our current study for reliable information on this," Dr Pase said. "We had much larger numbers of individuals reporting intake of artificially sweetened drinks."

Another study by the same group, published online in Alzheimer's and Dementia on March 5, shows a link between consumption of both sugar-sweetened and artificially sweetened beverages and reduction in brain volume in a middle-aged cohort. In the cross-sectional study, the sugary drinks, which included both soda and fruit juice, were also associated with worse episodic memory.

"Greater intake of total sugary beverages, fruit juice, and soft drinks were all associated with characteristics of preclinical Alzheimer's disease," the authors concluded. "Additional studies are warranted to confirm our findings and evaluate if sugary beverages are associated longitudinally with worsening of subclinical Alzheimer's disease and with incident Alzheimer's disease."

Commenting on these studies for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association, said, "Both studies are difficult to interpret — the conclusions are a bit different to one another — but epidemiological data is messy."

Still, he added, "These two papers should certainly sound warning bells, but neither are suggesting we can take just one simple step of cutting out sodas and or juice to reduce our risk of stroke or dementia. We must look at the whole picture of diet and exercise, of which this is just one very small piece."

It's a better idea to skip both and just drink water. Dr Keith Fargo It's a better idea to skip both and just drink water.

"Of the two papers, it is easier to grasp that high sugar intake is not doing good things to the brain, but there is growing evidence in the literature that diet drinks are not necessarily the panacea that some once might have believed them to be," Dr Fargo noted.

"We can't say from this data that that someone who drinks a few diet [beverages] will have a significantly higher risk of dementia. It's all just speculation. The best thing we can do is conduct further studies to find out more. The health recommendations are unlikely to be simple, but perhaps it may not be the best idea to replace a sugary beverage with an artificially sweetened drink. It's a better idea to skip both and just drink water."

In the study published in Stroke, researchers analyzed data from the Framingham Heart Study Offspring cohort on intake of sugar sweetened and artificially sweetened beverages and the incidence of a first stroke or diagnosis of dementia.

The stroke cohort included 2888 participants older than age 45 years (average age, 62 years) and the dementia cohort included 1484 participants older than age 60 years (average age, 69 years).

All participants had completed regular food intake questionnaires. For the current study, researchers focused on beverage intake from 1991 to 2001 and the occurrence of stroke or dementia in the following 10 years.

There were 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer's disease).

Results showed that after adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk for ischemic stroke, all-cause dementia, and Alzheimer's disease dementia.

When the researchers compared daily cumulative intake to 0 beverages per week (reference), the hazard ratios were 2.96 (95% confidence interval [CI], 1.26 - 6.97) for ischemic stroke and 2.89 (95% CI, 1.18 - 7.07) for Alzheimer's disease.

On the diet drink results, he said, "We found that people who drank at least one can of diet soda each day had a 3 times increased risk of stroke and dementia than those not drinking any such beverages."

He noted that lower intakes (between 1 and 6 drinks a week) were still associated with stroke but not dementia.

Sugar-sweetened beverages were not associated with stroke or dementia.

In addition to the smaller numbers on sugary beverages, there was also the possibility that more of those who drank sugar-sweetened beverages may have died of heart disease during the study period and would therefore not be included in the stroke and dementia endpoints, he said.

Dr Pase said it is not known how diet soda could be causing harm, but there some data suggest that artificial sweeteners may predispose toward weight gain.

"Animal studies have shown that rats given artificial sweeteners gain weight more than rats given an identical diet without artificial sweeteners," he said. "These artificial sweeteners have also been linked to a change in the composition of gut bacteria and the development of glucose intolerance. There is some data on this in humans too, but it is much more difficult in humans to show cause and effect."

He added: "There is the possibility that the association of sweetness and calories becomes uncoupled in the brain when we consume artificial sweeteners. The brain is conditioned to expect calories when it senses a sweet taste, but if this doesn't happen maybe people tend to overcompensate with other sweet food."

Markers of Preclinical Alzheimer's

In the study published in Alzheimer's and Dementia, the researchers, again led by Dr Pase, used Framingham data to look at possible links between sugar-sweetened and artificially sweetened beverage intake and results of neuropsychological (n = 4276) and MRI (n = 3846) markers of preclinical Alzheimer's disease.

They found that greater consumption of total sugary beverages was associated with lower total brain volume and lower memory scores. Relative to no intake, the difference in total brain volume associated with consuming 1 to 2 or more than 2 sugary beverages per day was equivalent to 1.6 and 2.0 years of brain aging, respectively, and the difference in memory scores was equivalent to 5.8 and 11.0 years of brain aging, respectively.

Higher diet soft drink intake was associated with smaller total brain volume and poorer performance on one of the neuropsychological tests.

In an editorial accompanying the study published in Stroke, and addressing the results with the diet drinks, Heike Wersching, MD, University of Munster, Germany, and Hannah Gardener, ScD, and Ralph L. Sacco, MD, University of Miami Miller School of Medicine, Florida, reiterate that whether the observed associations between artificially sweetened beverages and stroke and dementia are causal or reflect reverse causation bias is difficult to elucidate, and further studies are needed.

They suggest that future epidemiologic studies could include requirements for data on previous weight fluctuations, dieting behavior, changes in sweetened/artificially sweetened beverage consumption over time, and reasons for choosing artificially sweetened beverages.

Both sugar-sweetened and artificially sweetened soft drinks may be hard on the brain. Wersching et al Both sugar-sweetened and artificially sweetened soft drinks may be hard on the brain.

"The work by Pase et al highly encourages further discussion and more research into this question, for even small causal effects would have tremendous effects on public health due to the popularity of both artificially sweetened and sugar sweetened beverage consumption," they conclude.

They add that the current body of literature is inconclusive about the causal nature of the associations between artificially sweetened beverage consumption and risk for stroke, dementia, diabetes mellitus, and the metabolic syndrome.

The growing number of epidemiologic studies showing strong associations between frequent consumption of artificially sweetened beverages and vascular outcomes, however, suggests that it may not be reasonable to substitute or promote these drinks as healthier alternatives to sugary drinks.

"Both sugar-sweetened and artificially sweetened soft drinks may be hard on the brain," they conclude.

The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute and by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. Dr Pase is funded by the National Health and Medical Research Council. The authors have disclosed no relevant financial relationships. Dr Sacco received a National Institutes of Health grant for the Northern Manhattan Study. Dr Gardener is also funded by the National Institutes of Health for her work on the Northern Manhattan Study. Dr Wersching has disclosed no relevant financial relationships.

Stroke. Published online April 20, 2017. Abstract, Editorial

Alzheimer's & Dementia. Published online March 5, 2017. Abstract

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