Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis

Introduction

Some dietary guidelines have focused on lowering saturated and trans fat but not total fat or overall macronutrient composition.^1,2 Other guidelines continue to recommend lowering total fat (<30% of energy from fat) in exchange for higher carbohydrate intake.³ In practice, however, low carbohydrate diets that exchange carbohydrates for a greater intake of protein or fat have gained substantial popularity because of their ability to induce short-term weight loss,^4–7 despite incomplete and conflicting data regarding their long-term effects on health outcomes.^8–12 Results from meta-analyses that included several large cohort studies in North America and Europe have suggested an association between increased mortality and low carbohydrate intake.^8–12 However, the 2017 Prospective Urban Rural Epidemiology (PURE) study, of individuals from 18 countries across five continents (n=135 335, median follow up 7·4 years, 5796 deaths), reported that high carbohydrate intake was associated with increased risk of mortality.¹³ These data were interpreted as being contrary to previous work in the field, prompting calls for revisions to current nutrition guidelines.^13,14 It is important to note, however, that most studies have reported mortality risk based on quantiles of carbohydrate intake that are specific to the populations studied. Thus, the effects of carbohydrate intake can depend on the internal reference range for a given population. Furthermore, most analyses of carbohydrate intake have not accounted for the potential effects of specific food sources (ie, animal-based versus plant-based) that are used to replace carbohydrate intake in low carbohydrate intake settings.

Given the need for more evidence to help guide recommendations regarding optimal carbohydrate intake, we did a population-based study of overall carbohydrate consumption, allowing for the possibility of non-linear relationships. Specifically, we investigated the association of carbohydrate intake with mortality and residual lifespan in a large bi-racial cohort of adults living in four US communities, and then combined these mortality data with previous data as part of a meta-analysis to contextualise our findings. We then studied whether the replacement of carbohydrate for animal-based or plant-based sources of fat and protein modified any observed associations.

Methods

Results

Baseline characteristics of the ARIC study population, according to quantiles of percentage energy from carbohydrate intake, are shown in table 1. Mean carbohydrate intake was 48·9% (SD 9·4). Participants who consumed a relatively low percentage of total energy from carbohydrates (ie, participants in the lowest quantiles) were more likely to be young, male, a self-reported race other than black, college graduates, have high body-mass index, exercise less during leisure time, have high household income, smoke cigarettes, and have diabetes. Overall, mean consumption of energy from animal fat and protein was higher than from plant fat and protein across all carbohydrate quantiles (table 1). Participants in the lowest carbohydrate quantile had higher average consumption of animal fat and protein and lower average consumption of plant protein and dietary fibre than participants in the other quantiles. Plant fat and total energy intake had reverse U-shaped or J-shaped relationships across carbohydrate quantiles: participants in both the first and fifth quantile had lower mean plant-derived fats and calorie consumption compared with those in the intermediate quantiles (table 1). Prevalence of hypertension was similar across carbohydrate quantiles. There was no significant difference in weight gain at 3-year or 6-year timepoints across carbohydrate quantiles (table 1).

The median length of follow-up was 25 years, during which there were 6283 deaths. The highest risk of mortality was observed in participants with the lowest carbohydrate consumption, in both unadjusted and adjusted models (p<0·001; figure 1; appendix p 8). However, the relationship between carbohydrate consumption and risk of mortality was significantly nonlinear (p<0·001), resulting in a U-shaped association, with the lowest observed risk associated with carbohydrate consumption of 50–55% (figure 1). There were corresponding significant differences in mean residual lifespan based on carbohydrate intake (appendix p 2). For example, we estimated that a 50-year-old participant with intake of less than 30% of energy from carbohydrate would have a projected life expectancy of 29·1 years, compared with 33·1 years for a participant who consumed 50–55% of energy from carbohydrate (difference 4·0 years [95% CI 2·6, 5·3]). Similarly, we estimated that a 50-year-old participant with high carbohydrate intake (>65% of energy from carbohydrate) would have a projected life expectancy of 32·0 years, compared with 33·1 years for a participant who consumed 50–55% of energy from carbohydrate (difference 1·1 years [0·1, 2·0]). We did a sensitivity analysis using 50–60% energy from carbohydrate as the comparison group, with similar findings (data not shown). The association of overall carbohydrate intake with cardiovascular and non-cardiovascular mortality is shown in the appendix (pp 3, 4). There were similar results when we used dietary information from Visit 1 and Visit 3 in the sensitivity analysis (appendix pp 5, 6).

We updated a meta-analysis¹² published in 2012, by identifying two additional studies that had since been published and that met inclusion criteria, using previously defined methods;^13,24 we also added results from ARIC because they met previously defined inclusion criteria¹² (table 2). Including data from the ARIC cohort, there were 432 179 participants in eight cohort studies investigating carbohydrate intake, with 40 181 (9·3%) deaths reported. Because there was significantly lower consumption of carbohydrate in European and North American regions compared with Asian countries, low-income countries, and multinational cohorts (p<0·001), studies fell into two categories in the meta-analysis: North American and European studies (mean carbohydrate intake approximately 50%) that compared low carbohydrate diets with primarily moderate carbohydrate consumption as the reference (figure 2A), and Asian and multinational studies (mean carbohydrate intake approximately 61%) that compared high carbohydrate consumption with moderate carbohydrate consumption as the reference (figure 2B; table 2). The association between carbohydrate consumption and mortality was dependent on the range of carbohydrate intake. Figure 2 illustrates the significantly increased risk of all-cause mortality among participants with low carbohydrate versus moderate carbohydrate consumption (pooled HR 1·20, 95% CI 1·09–1·32; p<0·0001). This relationship remained significant if the ARIC study was excluded from the analysis (1·31, 1·07–1·58; p=0·007). High carbohydrate consumption was associated with a significantly higher risk of all-cause mortality compared with moderate carbohydrate consumption (1·23, 1·11–1·36; p<0·0001; figure 2).

The ARIC and PURE studies were the only two cohorts for which data were published or available about the continuous percentage of energy from carbohydrate. Figure 3 shows the overlapping and continuous relationship between percentage of energy from carbohydrate intake and mortality in these cohorts. By comparison with ARIC, the PURE study¹³ assessed participants primarily at the high end of the overall range of percentage of energy from carbohydrate consumption (figures 2, 3). However, the associations between primarily high carbohydrate intake and mortality in the PURE study still fell within the confidence intervals of those observed in ARIC (figure 3).

To explore the association between mortality and the source of fat and protein alternatives to carbohydrate intake, we compared studies that assessed animal-based and plant-based scores, which represented increasing substitution of animal-based or plant-based fat and protein for carbohydrate intake (table 2). Baseline characteristics of the ARIC study population, according to animal-based or plant-based low carbohydrate diet scores, are shown in the appendix (pp 9–11). The plant-based low carbohydrate dietary score was associated with higher average intake of vegetables but lower fruit intake (appendix p 11). By contrast, the animal-based low carbohydrate dietary score was associated with lower average intake of both fruit and vegetables (appendix pp 9, 10). Both low carbohydrate diets were associated with higher fat intake in exchange for carbohydrate, although the plant-based low carbohydrate diet had higher average polyunsaturated fat and lower saturated fat intake compared with the animal-based low carbohydrate diet (appendix pp 9–11). Overall, total protein intake was higher in the animal-based diet (appendix p 9). We determined the five foods that differed most significantly between the highest and lowest quantiles of animal-based and plant-based low carbohydrate dietary score. The animal-based low carbohydrate diet had more servings per day than did higher carbohydrate diets of beef, pork, and lamb as the main dish; beef, pork, and lamb as a side dish; chicken with the skin on; chicken with the skin off; and cheese (appendix p 10). The plant-based low carbohydrate diet had more servings per day of nuts, peanut butter, dark or grain breads, chocolate, and white bread than did higher carbohydrate diets (appendix p 11). Both low carbohydrate diets were lower in average regular soft drink intake (appendix pp 10, 11). In the ARIC cohort and in meta-analysis, increased consumption of animal-based protein and fat instead of carbohydrate was associated with a significant increase in all-cause mortality (p<0·0001; table 3). Alternatively, increased consumption of plant-based protein and fat instead of carbohydrate was associated with a significant decrease in all-cause mortality (p<0·0001; table 3). The animal and plant-based findings were consistent for cardiovascular and non-cardiovascular mortality (appendix pp 3, 4). Sensitivity analysis of plant-specific and animal-specific findings, using dietary information from Visit 1 and Visit 3, yielded similar results (appendix pp 6, 7). Similarly, in the meta-analysis, mortality increased when animal-derived fat and protein were substituted for carbohydrate, and decreased when these substitutions were plant-based (table 3). In the post-hoc sensitivity analysis, we assessed all meta-analyses using a fixedeffects model, with similar findings. Additionally, to minimise the likelihood of reverse causation, we did a sensitivity analysis whereby individuals with cardiovascular disease, diabetes, or cancer at baseline were excluded from the analyses. These post-hoc analyses also yielded similar results.

Discussion

In a large cohort of adults living in four diverse US communities, with more than two decades of follow-up, mid-life dietary patterns marked by both low carbohydrate (<40% of energy from carbohydrate) and high carbohydrate (>70% of energy from carbohydrate) consumption were associated with increased mortality risk and shorter residual lifespan, with minimum risk observed with 50–55% of energy from carbohydrate. These findings reflect a U-shaped relationship between carbohydrate intake and mortality, and were corroborated by data from other North American, European, Asian and multinational cohorts, combined as part of a meta-analysis. However, low carbohydrate dietary patterns that replaced energy from carbohydrate with energy from animal-derived protein or fat were associated with greater risk. However, this association was reversed when energy from carbohydrate was replaced with plant-derived protein or fat.

In this study, the association of carbohydrate intake with mortality was dependent on the range of carbohydrate intake. The range of carbohydrate intake differs by geographical and socioeconomic factors; percentage of energy from carbohydrates have been lower in North American and European cohort studies (mean values generally ≤50%) than in Asian or multinational cohorts, which are largely comprised of low-income and middle-income countries (mean values >60%). Overall, there was a U-shaped relationship between carbohydrate intake and mortality, but the North American and European cohorts primarily represented the left side of the U-shaped curve whereas Asian and less economically advanced nations (as included in the PURE study) represented the right side of the curve. North American and European cohort studies have compared true low carbohydrate dietary patterns (in terms of absolute value of <40% of total energy intake) and consistently found a modest yet significantly increased relative risk of all-cause death when compared with the highest quantile (generally still falling in a moderate carbohydrate range of 40–70%). The NIPPON DATA80²⁴ and PURE¹³ studies represent the right side of the curve for absolute intake of percentage of energy from carbohydrate, and consistently show a modest yet significantly decreased relative risk of all-cause death when comparing moderate (45–55% of total energy) to the highest quantile (>70% of total energy).

Findings from this study suggest that previous analyses of carbohydrate intake that focused on quantiles of consumption and then searched for a trend across those quantiles seem to have overlooked valuable information. Using the carbohydrate intake data continuously provides more granular information and allowed us to identify a more U-shaped relationship between carbohydrate consumption and risk, which might otherwise not have been evident. Continuous data have not been published for North American or European cohorts; several previous studies only showed a linear relationship,^8,10,11 whereas others that reported quantiles were suggestive of U-shaped or J-shaped relationships.^9,24 The relationship between dietary carbohydrate and mortality was reported as a continuous relationship in the PURE study, with intake ranging primarily from moderate to high carbohydrate, but still fell within the confidence intervals of what we observed in ARIC, with intake ranging primarily from low to moderate carbohydrate, further supporting a U-shaped relationship between carbohydrate intake and mortality. Although this study included quantile-based analyses to the extent that previous work has used such analyses, and we illustrate how the ARIC data fit in that context, the continuous analyses probably reflect a much closer representation of the true relationship between carbohydrate intake and mortality.

To further examine the potential effects of protein and fat sources supplanting carbohydrate intake, we investigated animal-based and plant-based diets in the ARIC cohort. We found that low carbohydrate dietary patterns favouring animal-derived protein and fat sources were associated with higher mortality, in accordance with results from the Nurses’ Health Study and Health Professionals Follow up Study.⁹ However, low carbohydrate diets that favoured plant-derived protein and fat intake were associated with lower mortality, also consistent with previous results.^9,24 These data suggest that the source of the protein and fat substituted for carbohydrates in the diet might notably modify the relationship between carbohydrate intake and mortality. Previous work has shown a less consistent relationship between overall carbohydrate intake and cardiovascular death by comparison with all-cause mortality.¹² However, in our analysis, when carbohydrate is substituted for higher animal fat or protein intake it is associated with both higher cardiovascular and non-cardiovascular death, whereas plant-based substitutions are associated with both lower cardiovascular and non-cardiovascular death, indicating that food source could be an important consideration for both causes of mortality.

There are several possible explanations for our main findings. Low carbohydrate diets have tended to result in lower intake of vegetables, fruits, and grains and increased intakes of protein from animal sources,^23,25–27 as observed in the ARIC cohort, which has been associated with higher mortality. It is likely that different amounts of bioactive dietary components in low carbohydrate versus balanced diets, such as branched-chain amino acids, fatty acids, fibre, phytochemicals, haem iron, and vitamins and minerals are involved.²⁸ Long-term effects of a low carbohydrate diet with typically low plant and increased animal protein and fat consumption have been hypothesised to stimulate inflammatory pathways, biological ageing, and oxidative stress. On the other end of the spectrum, high carbohydrate diets, which are common in Asian and less economically advantaged nations, tend to be high in refined carbohydrates, such as white rice; these types of diets might reflect poor food quality^13,24 and confer a chronically high glycaemic load that can lead to negative metabolic consequences.²⁹

There are limitations to this study that merit consideration. This study represents observational data and is not a clinical trial; however, randomised trials of low carbohydrate diets on mortality are not practical because of the long duration of study required. Another limitation of this study is that diet was only assessed at two time intervals, spanning a 6-year period, and dietary patterns could change during 25 years. However, because participants are able to increase or decrease their consumption of carbohydrates during the course of follow-up, any dietary changes that occur after the described assessments would be expected to attenuate any observed associations. Our conclusions about animal fat and protein might have less generalisability to Asian cultures, which often feature very high carbohydrate consumption but with a primary meat source that is often from fish. In fact, the plant score calculated in the Japanese cohort, NIPPON DATA80,²⁴ included fish as a source of protein as well. Hence, animal scores reported here are composed largely of beef, pork, and fowl, in addition to fish. An additional limitation is that the international data¹³ about very high carbohydrate intakes, largely derived from China, are, on average, higher than the national data,³⁰ for unclear reasons. However, the advantage of these data is that they include multi-racial and ethnic groups across a spectrum of socioeconomic groups, and they are representative of many high quality cohorts. Given the relatively small number of individuals adhering to low carbohydrate diets with mainly plant-based protein and fat sources of macronutrients, this study could not definitively examine the relative benefits of this diet compared with other dietary patterns. Our study focused on general carbohydrate intake, which represents a heterogeneous group of dietary components. Any number and combination of dietary components could have been considered and adjusted for in this analysis; therefore, some confounders might have been unadjusted for. Ideally, it would be preferable to do an individual-level meta-analysis in a collaborative effort that would have allowed for consistent adjustment for confounders in pooled analysis. Finally, some degree of measurement error is unavoidable for all dietary assessment methods, and the absolute intakes need to be interpreted cautiously.

Our findings suggest a negative long-term association between life expectancy and both low carbohydrate and high carbohydrate diets when food sources are not taken into account. These data also provide further evidence that animal-based low carbohydrate diets should be discouraged. Alternatively, when restricting carbohydrate intake, replacement of carbohydrates with predominantly plant-based fats and proteins could be considered as a long-term approach to promote healthy ageing.

Supplementary Material