Study Questions: What is the long-term association between low-carbohydrate diets and all-cause and cause-specific mortality?

Methods: Data from the National Health and Nutrition Examination Survey (NHANES; 1999–2010) were used for this analysis. In addition, a pooled analysis of nine studies was completed. Multivariable Cox proportional hazards were applied to determine the hazard ratios (HRs) and 95% conﬁdence intervals (CIs) for mortality for each quartile of the low-carbohydrate diet score, with the lowest quartile (Q1 – with the highest carbohydrate intake) used as reference. Adjusted Cox regression was used 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.

Results: For the NHANES study, 24,825 participants with a mean follow-up of 6.4 years were included in the present analysis. Participants were a mean age of 47.6 years, and 51.4% were women. During follow-up, 3,432 total deaths occurred, including 827 cancer deaths, 709 heart disease deaths, and 228 cerebrovascular disease deaths. After adjustment 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, participants with the lowest carbohydrate intake (Q4) had the highest risk of overall mortality (HR, 1.32; 95% CI, 1.14-2.01) compared to the highest carbohydrate intake group (Q1). Coronary heart disease mortality (HR, 1.52; 95% CI, 1.19-1.91), cerebrovascular disease mortality (HR, 1.50; 95% CI, 1.12-2.31), and cancer (HR, 1.35; 95% CI, 1.06-1.69) were also higher for the lowest carbohydrate intake group compared to those in the highest carbohydrate intake group. A similar pattern was observed when quartiles of low-carbohydrate, high-protein diets were examined. The association between low-carbohydrate diets and overall mortality was also stronger in the nonobese (48%) than in the obese (19%) participants. For the systematic review/meta-analysis, pooled data of nine prospective cohort studies with 462,934 participants was included in the present analysis. Mean follow-up was 16.1 years. Low-carbohydrate diets were associated with an increased risk for overall mortality (RR, 1.22; 95% CI, 1.06-1.39; p < 0.001; I2 = 8.6). A similar pattern was observed for cardiovascular disease mortality (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). A similar pattern was observed for low-carbohydrate, high-protein diets.

Conclusions: The investigators concluded that these data suggest a potentially unfavorable association of low-carbohydrate diets with overall and cause-speciﬁc mortality.

Perspective: This study provides new data on the long-term associations of dietary patterns low in carbohydrates. As the authors note, observational studies have limitations including recall bias and residual confounding. Unfortunately, the investigators also did not have information on diet patterns during follow-up. Carbohydrate quality (such as amounts of refined carbohydrates consumed) may play a factor in these associations observed. Given this information, recommendations for a healthy diet consistent with a Mediterranean dietary pattern appear to be a sound recommendation for patients.

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention, Vascular Medicine, Diet

Keywords: Carbohydrates, Cerebrovascular Disorders, Coronary Disease, Diet, Carbohydrate-Restricted, Diet, Diet, Mediterranean, Mortality, Neoplasms, Obesity, Primary Prevention