Abstract
Little is known about the long-term association between low-carbohydrate diets (LCDs) and mortality. We evaluated the link between LCD and overall or cause-specific mortality using both individual data and pooled prospective studies. Data on diets from the National Health and Nutrition Examination Survey (NHANES; 1999–2010) were analyzed. Multivariable Cox proportional hazards were applied to determine the hazard ratios and 95% confidence intervals (CIs) for mortality for each quartile of the LCD score, with the lowest quartile (Q1—with the highest carbohydrates intake) used as reference. We used adjusted Cox regression to determine the risk ratio (RR) and 95% CI, as well as random effects models and generic inverse variance methods to synthesize quantitative and pooled data, followed by a leave-one-out method for sensitivity analysis. Overall, 24 825 participants from NHANES study were included (mean follow-up 6.4 years). After adjustment, participants with the lowest carbohydrates intake (quartile 4 of LCD) had the highest risk of overall (32%), cardiovascular disease (CVD) (50%), cerebrovascular (51%), and cancer (36%) mortality. In the same model, the association between LCD and overall mortality was stronger in the non-obese (48%) than in the obese (19%) participants. Findings on pooled data of nine prospective cohort studies with 462 934 participants (mean follow-up 16.1 years) indicated a positive association between LCD and overall (RR 1.22, 95% CI 1.06–1.39, P < 0.001, I² = 8.6), CVD (RR 1.13, 95% CI 1.02–1.24, P < 0.001, I² = 11.2), and cancer mortality (RR 1.08, 95% CI 1.01–1.14, P = 0.02, I² = 10.3). These findings were robust in sensitivity analyses. Our study suggests a potentially unfavourable association of LCD with overall and cause-specific mortality, based on both new analyses of an established cohort and by pooling previous cohort studies. Given the nature of the study, causality cannot be proven; we cannot rule out residual bias. Nevertheless, further studies are needed to extend these important findings, which if confirmed, may suggest a need to rethink recommendations for LCD in clinical practice.
Generated Summary
This study, published in the European Heart Journal, is a population-based cohort study and meta-analysis that examines the association between low-carbohydrate diets (LCDs) and all-cause and cause-specific mortality. The research utilized data from the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010 and included 24,825 participants. The study further synthesized findings by pooling data from nine prospective cohort studies, encompassing a total of 462,934 participants. The primary objective was to evaluate the relationship between LCDs and mortality, specifically examining overall mortality and deaths related to cardiovascular disease (CVD), stroke, and cancer. The methodology involved multivariable Cox proportional hazards models to determine hazard ratios and 95% confidence intervals for mortality across different quartiles of LCD scores. The study also employed random effects models and generic inverse variance methods for synthesizing quantitative and pooled data, followed by leave-one-out sensitivity analyses. The research aimed to provide comprehensive evidence on the controversial role of LCDs and their impact on public health.
Key Findings & Statistics
- NHANES Study: Overall, 24,825 participants were included, with a mean age of 47.6 years, comprising 48.6% men and 51.4% women.
- Age and LCD Quartiles: There was a significant, but not linear, age difference between quartiles of LCD (P<0.001).
- Gender Distribution in LCD Quartiles: From the first to the third quartile of LCD, women were the majority, while the highest quartile of LCD had more males (males: 56.4% vs. females: 43.6%, P<0.001).
- Mortality during Follow-up: During the follow-up period of 144 months, 3432 total deaths were recorded, including 827 cancer deaths, 709 heart disease deaths, and 228 cerebrovascular disease deaths.
- Overall Mortality Risk (LCD Quartiles): Participants in the top quartile (Q4) of LCD had the highest risk of overall mortality [Q2: 1.11 (1.02–1.96), Q3: 1.23 (1.11–1.43), Q4: 1.42 (1.27-1.96), P < 0.001].
- Overall Mortality Risk (Adjusted for Confounding): After adjustment for additional factors, participants in the top quartile (Q4) had a 32% higher chance of overall mortality [Q2: 1.09 (1.02–1.64), Q3: 1.19 (1.09–1.82), Q4: 1.32 (1.14–2.01), P<0.001].
- CVD and Cerebrovascular Mortality (LCD): In the second model, participants in the top quartile (Q4) of LCD had 50 and 51% higher risk of CVD and cerebrovascular mortality, respectively, compared with the first reference quartile (Q1).
- Cancer Mortality (LCD): Participants in the top quartile (Q4) of LCD had the highest risk of overall cancer mortality [Model 1 (52%) and Model 2 (36%)].
- LC/HP Diet and Mortality: A significant positive association was found between LC/HP diets and overall mortality [RR 1.16, 1.07-1.26, P<0.001].
- LC/HP Diet and CVD Mortality: A positive correlation between LC/HP and CVD mortality (RR 1.35, 1.07-1.69, P < 0.001).
- Meta-analysis Results: The study revealed a significant positive association between LCD and overall mortality (RR 1.22, 1.06-1.39, P < 0.001, n = 8 studies).
- LCD and CVD Mortality: A significant association between LCD score and CVD mortality was observed (RR 1.13, 1.02-1.24, P<0.001, n = 6 studies).
- LCD and Cancer Mortality: Similar results were observed for LCD score and risk of cancer mortality (RR 1.08, 1.01-1.14, P = 0.02, n = 3 studies).
Other Important Findings
- The study found that the association between LCD and overall mortality was stronger in non-obese participants than in obese participants.
- The meta-analysis indicated a positive association between LC/HP diets and overall mortality, CVD, cerebrovascular, and cancer mortality.
- The findings on pooled data of nine prospective cohort studies indicated a positive association between LCD and overall mortality (RR 1.22, 95% CI 1.06–1.39, P < 0.001, I² = 8.6), CVD (RR 1.13, 95% CI 1.02–1.24, P < 0.001, I² = 11.2), and cancer mortality (RR 1.08, 95% CI 1.01–1.14, P = 0.02, I² = 10.3).
- The link between LCD and overall mortality was stronger for older participants.
Limitations Noted in the Document
- Causality cannot be proven due to the nature of the study.
- The study cannot rule out residual bias.
- The study acknowledges the limitations of observational data.
- Reporting of dietary intake relies on participant recall, which is subject to error.
- The study did not have information on the dietary intake of participants during the follow-up which might have had an impact on the final results.
- Recall bias cannot be overcome as in similar studies.
- Reverse causality or residual confounding may potentially explain some findings.
Conclusion
The study suggests a potentially unfavorable association of LCD with overall and cause-specific mortality, based on both new analyses of an established cohort and by pooling previous cohort studies. The findings support a potentially adverse association of LCD and LC/HP diet with overall mortality, CVD, cerebrovascular, and cancer mortality. These results appeared robust to adjustment for potential confounding factors. Given the nature of the study, causality cannot be proven; we cannot rule out residual bias. The authors note that further studies are needed to extend these important findings, which if confirmed, may suggest a need to rethink recommendations for LCD in clinical practice. The study highlights an unfavorable association of LCD with overall and cause specific mortality, based on both individual data and pooling previous cohort studies. The study indicates that higher whole grain consumption was associated with lower total (by 9%) and CVD mortality (by 15%), independently of other dietary and lifestyle factors. Given the fact that long-term LCDs may well be associated with greater long-term harm, it might be important to consider whether we should routinely recommend such diets in clinical practice for weight loss until further higher quality studies evaluate this issue in greater detail. Other dietary patterns that have been associated with both short-term weight loss and long-term benefits (such as low-fat diets, with plentiful fibre) may be preferable.
IFFS Team Summary
- 24k Subjects from the NHANES (National Health and Nutrition Examination Survey)
- followed mean of 6.4 years
- followed mean of 6.4 years
- Adjusted using two models, second model may be over adjusted, since it includes adjustment for waist circumference, BMI, hypertension, diabetes, cholesterol
- Mortality rates in highest quartile, vs lower, with respect to low carb index (Quartile 4 consumed lowest carbs) (Using model 2 adjustment)
- Total RR = 1.32
- Cancer RR = 1.35
- CVD RR = 1.51
- Cerebrovascular disease RR = 1.50
- Total RR = 1.32
- Cancer RR = 1.35
- CVD RR = 1.51
- Cerebrovascular disease RR = 1.50
- Adjusted for
- Model 1: age, gender, race, education, marital status, poverty to income ratio, total energy intake, physical activity, smoking, and alcohol consumption; in model
- Model 2: Adjusted for age, sex, gender, education, marital status, poverty to income ratio, total energy intake, physical activity, smoking, alcohol consumption, body mass index and waist circumference, hypertension, serum total cholesterol and diabetes
- Model 2 results displayed above
- Model 1: age, gender, race, education, marital status, poverty to income ratio, total energy intake, physical activity, smoking, and alcohol consumption; in model
- Model 2: Adjusted for age, sex, gender, education, marital status, poverty to income ratio, total energy intake, physical activity, smoking, alcohol consumption, body mass index and waist circumference, hypertension, serum total cholesterol and diabetes
- Model 2 results displayed above
- Results were incremental from first to 4th quartiles
- Stronger in model 1 More marked in Model 1 adjustments
- Stronger in model 1 More marked in Model 1 adjustments
- Also a meta analysis of of 462K individuals and total of 45K deaths
- Mean duration of 16.1 years, and high variability
- Low carb diet had RR of 1.22 for Overall Mortality RR of 1.13 for CVD Mortality
- Mean duration of 16.1 years, and high variability
- Low carb diet had
- RR of 1.22 for Overall Mortality
- RR of 1.13 for CVD Mortality
- RR of 1.22 for Overall Mortality
- RR of 1.13 for CVD Mortality
- Despite potential short term weight loss and other benefits, low carb diets may be associated with long term harm