Increased risk of CV outcomes and all-cause mortality with diet drinks in postmenopausal women
Artificially Sweetened Beverages and Stroke, Coronary Heart Disease, and All-Cause Mortality in the Women’s Health InitiativeLiterature - Mossavar-Rahmani Y, Kamensky V, Manson JE et al. - Stroke 2019; 50: DOI: 10.1161/STROKEAHA.118.023100
Introduction and methods
The effect of sugar-sweetened beverages (SSBs) on CVD risk has been well documented [1-3], while data on artificially sweetened beverages (ASBs) are limited. A previous Women’s Health Initiative (WHI) study showed an association between consumption of ≥2 servings of ASBs per day and a 30% increase in composite CVD events and all-cause mortality, and a 50% increase in CVD death after controlling for CVD risk factors . However, data on the effect of ASB consumption on CVD events remain controversial. ASB consumption was associated with increased risk of stroke and dementia, and of CV events (stroke, MI, vascular death) in the Framingham Offspring cohort study [5,6] and the Northern Manhattan Study , respectively, whereas it was not associated with higher risk of coronary heart disease (CHD) in the Nurses’ Health Study .
This prospective study (n=81.714) therefore assessed the association between ASBs and ischemic and hemorrhagic stroke separately, CHD, and all-cause mortality in postmenopausal U.S. women from the WHI Observational Study (WHI-OS). The study also evaluated the association of ASBs with subtypes of ischemic stroke.
The WHI-OS was a multicenter longitudinal study including 93.676 postmenopausal women aged 50 to 79 years at baseline who enrolled during 1993 to 1998. Eligible participants completed a follow-up visit 3 years after baseline, during which they were asked about their ASB consumption, and ethnicity, lifestyle and risk factor variables were assessed. Intake of ASB was categorized as: never or <1 per week (reference), 1-4 per week, 5-7 per week, or ≥2 per day. Mean follow-up after year 3 visit was 11.9 years.
Outcomes were overall stroke, ischemic stroke, hemorrhagic stroke, and ischemic stroke subtypes (large artery atherosclerosis, cardio-embolism, and small artery occlusion [SAO]), CHD and all-cause mortality. Overall stroke included fatal and non-fatal stroke. CHD included non-fatal MI and CHD death.
ASBs and risk of stroke, CHD and all-cause mortality
- After multivariable adjustment, participants with highest intake of ASBs (≥2 per day) had significantly higher risk of fatal and non-fatal stroke (HR: 1.23, 95%CI: 1.02-1.47), ischemic stroke (HR: 1.31, 95%CI: 1.06-1.63), fatal and non-fatal CHD (HR: 1.29, 95%CI: 1.11-1.51) and all-cause mortality (HR: 1.16, 95%CI: 1.07-1.26), compared to the reference group (never or <1 per week), but not of hemorrhagic stroke. Exclusion of women with CVD or diabetes gave similar results.
ASBs, BMI, race/ethnicity, and risk of outcomes
- There was no clear pattern of association between consumption of ASBs and outcomes across BMI groups, however, participants with a BMI ≥30 in the highest category of ASBs had an increased risk of ischemic stroke (HR: 2.03, 95%CI: 1.38-2.98, P-trend=0.002) and those with BMI<30 had an increased risk of all-cause mortality (HR: 1.24, 95%CI: 1.04-1.47, P-trend=0.117), compared to the reference group.
- Intake of ≥2 ASBs per day was significantly associated with higher risk of ischemic stroke among blacks (HR: 3.93, 95%CI: 1.87-8.26), compared to the reference group, but not among white or other race/ethnic groups.
- There was a significant interaction between black race and risk of all stroke (P-interaction=0.0006) and ischemic stroke (P-interaction=0.002) in those with highest ASB consumption, compared to the reference group.
ASBs and subtypes of ischemic stroke
- After multivariable adjustment, those with ≥2 ASBs per day had an increased risk of SAO (HR: 1.81, 95%CI: 1.18-2.80), which was even higher after exclusion of patients with diabetes mellitus or CVD (HR: 2.44, 95%CI: 1.47-4.04, P-trend=0.001). This result remained similar when stratifying participants by non-hypertensives and hypertensives (HR: 2.45, 95%CI: 1.09-5.50, P=0.030 and HR: 2.38, 95%CI: 1.25-4.55, P=0.009, respectively).
This retrospective study of postmenopausal women showed an association between self-reported consumption of ≥2 ASBs per day and higher risk of fatal and non-fatal stroke, ischemic stroke, CHD, and all-cause mortality. A new finding was the increased risk of SAO with higher consumption of ASBs. However, there might be residual confounding due to the observational study design. More research is needed on ASBs in relation to stroke and other outcomes, and on specific ASBs, to guide clinical recommendations.
The AHA advised short-term replacement of SSBs with beverages containing low-calorie sweeteners, including ASBs, as effective and realistic approach to calorie reduction and weight loss in some adults. Gardener and Elkind  emphasize that although data on negative health effects of low-calorie non-nutritive sweeteners is increasing, ‘these studies assessed ASB consumption as single entity despite the possibility of heterogenous effects on cardiometabolic health across an increasing variety of artificial sweeteners’. More research is therefore needed on effects of different artificial sweeteners.
Frequent consumption of ASBs during mid- and late life has been associated with vascular events in various observational studies. There may, however, be heterogeneity among adults who consume ASBs: there are people who have consumed SSBs daily during their adult years and switched to ASBs in an obese, prediabetic state, while other consumed ASBs for decades as part of an overall healthy nutrient-dense diet, and still others rarely consumed SSBs and only incorporated ASBs into their diet later in life to reduce calorie intake and to lose weight. Assessing vascular disease risk in these various subsets of ASB consumers may elucidate the potential causal nature of the associations.
Interesting results were obtained with analyses stratifying for BMI, including increased incidence of stroke with highest ASB consumption among the obese and increased risk of all-cause mortality with highest ASB consumption in people with normal weight or overweight. It might be that frequent ASB consumers have started this habit as the result of diabetes mellitus or CVD, or that ASB consumption leads to weight gain as a mediating pathway, indicating reverse causality of the increased risk for frequent ASB consumers.
Limitations of the current study that are stressed by the authors are: the lack of repeated ASB evaluations, and assessment of data on ASB consumption history and weight fluctuations. Since ‘a single assessment of ASB consumption may not always reflect long-term exposure’, long-term prospective epidemiological studies with repeated dietary assessment are needed to elucidate this bias, characterize individual soda consumption trends in a population, and relate these to patterns of metabolic risk factors and incident vascular events.
Gardener and Elkin conclude that ASB consumption is high and ‘until we have more evidence to better understand who, if anyone, benefits from consumption of ASB, we should emphasize water as the healthiest substitute for SSBs. If ASB consumption is used to wean off SSBs, it should be viewed as a time-limited intermediate in the transition to water and other healthier beverages.’