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Low-Carbohydrate Diets and All-Cause and Cause-Specific Mortality: Two Cohort Studies

Teresa T. Fung, ScD; Rob M. van Dam, PhD; Susan E. Hankinson, ScD; Meir Stampfer, MD, DrPH; Walter C. Willett, MD, DrPH; and Frank B. Hu, MD, PhD
[+] Article, Author, and Disclosure Information

From Simmons College, Harvard School of Public Health, Boston, Massachusetts, and National University of Singapore, Singapore.

Acknowledgment: The authors thank Dr. Tricia Y. Li for statistical and programming support.

Grant Support: By the National Institutes of Health (grants CA87969, HL60712, and CA95589).

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0297.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Fung (e-mail, teresa.fung@simmons.edu).

Requests for Single Reprints: Teresa T. Fung, ScD, Department of Nutrition, Simmons College, 300 The Fenway, Boston, MA 02115; e-mail, teresa.fung@simmons.edu.

Current Author Addresses: Dr. Fung: Department of Nutrition, Simmons College, 300 The Fenway, Boston, MA 02115.

Dr. van Dam: Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597.

Dr. Hankinson: Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115.

Dr. Stampfer: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.

Drs. Willett and Hu: Department of Nutrition, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.

Author Contributions: Conception and design: T.T. Fung, R.M. van Dam, F.B. Hu.

Analysis and interpretation of the data: T.T. Fung, R.M. van Dam, S.E. Hankinson, M. Stampfer, F.B. Hu.

Drafting of the article: T.T. Fung.

Critical revision of the article for important intellectual content: T.T. Fung, R.M. van Dam, S.E. Hankinson, M. Stampfer, W.C. Willett, F.B. Hu.

Final approval of the article: T.T. Fung, R.M. van Dam, S.E. Hankinson, M. Stampfer, F.B. Hu.

Statistical expertise: R.M. van Dam.

Obtaining of funding: T.T. Fung, F.B. Hu.

Administrative, technical, or logistic support: W.C. Willett, F.B. Hu.

Collection and assembly of data: S.E. Hankinson, F.B. Hu.

Ann Intern Med. 2010;153(5):289-298. doi:10.7326/0003-4819-153-5-201009070-00003
Text Size: A A A

Background: Data on the long-term association between low-carbohydrate diets and mortality are sparse.

Objective: To examine the association of low-carbohydrate diets with mortality during 26 years of follow-up in women and 20 years in men.

Design: Prospective cohort study of women and men who were followed from 1980 (women) or 1986 (men) until 2006. Low-carbohydrate diets, either animal-based (emphasizing animal sources of fat and protein) or vegetable-based (emphasizing vegetable sources of fat and protein), were computed from several validated food-frequency questionnaires assessed during follow-up.

Setting: Nurses' Health Study and Health Professionals' Follow-up Study.

Participants: 85 168 women (aged 34 to 59 years at baseline) and 44 548 men (aged 40 to 75 years at baseline) without heart disease, cancer, or diabetes.

Measurements: Investigators documented 12 555 deaths (2458 cardiovascular-related and 5780 cancer-related) in women and 8678 deaths (2746 cardiovascular-related and 2960 cancer-related) in men.

Results: The overall low-carbohydrate score was associated with a modest increase in overall mortality in a pooled analysis (hazard ratio [HR] comparing extreme deciles, 1.12 [95% CI, 1.01 to 1.24]; P for trend = 0.136). The animal low-carbohydrate score was associated with higher all-cause mortality (pooled HR comparing extreme deciles, 1.23 [CI, 1.11 to 1.37]; P for trend = 0.051), cardiovascular mortality (corresponding HR, 1.14 [CI, 1.01 to 1.29]; P for trend = 0.029), and cancer mortality (corresponding HR, 1.28 [CI, 1.02 to 1.60]; P for trend = 0.089). In contrast, a higher vegetable low-carbohydrate score was associated with lower all-cause mortality (HR, 0.80 [CI, 0.75 to 0.85]; P for trend ≤ 0.001) and cardiovascular mortality (HR, 0.77 [CI, 0.68 to 0.87]; P for trend < 0.001).

Limitations: Diet and lifestyle characteristics were assessed with some degree of error. Sensitivity analyses indicated that results were probably not substantively affected by residual confounding or an unmeasured confounder. Participants were not a representative sample of the U.S. population.

Conclusion: A low-carbohydrate diet based on animal sources was associated with higher all-cause mortality in both men and women, whereas a vegetable-based low-carbohydrate diet was associated with lower all-cause and cardiovascular disease mortality rates.

Primary Funding Source: National Institutes of Health.


Grahic Jump Location
Timeline for the 2 cohorts.

The arrows indicate time points at which food-frequency questionnaires were sent.

Grahic Jump Location




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Submit a Comment/Letter
The Meat of the Diet-Mortality Matter
Posted on September 10, 2010
Sean C. Lucan, MD, MPH, MS
Montefiore Medical Center / Albert Einstein College of Medicine
Conflict of Interest: None Declared

Congratulations to Fung et al for their article on low-carbohydrate diets and mortality(1). The authors used prospective cohort designs to show that animal-based diets are associated with premature mortality, whereas plant-based diets are associated with longevity. These findings are consistent with previous studies suggesting cancer prevention and cardiovascular benefits from various components of plant-derived foods like fruits, vegetables, whole grains, and nuts (e.g. vitamins, minerals, fiber, antioxidants, phytochemicals, mono- and poly-unsaturated fats), and health detriments from various components of animal-derived foods like meat and dairy (e.g. saturated fat, cholesterol, heme iron, and animal protein)(2, 3).

I applaud the authors for evaluating overall dietary patterns rather than individual food components. After all, people eat foods (in the context of other foods), not food components (in isolation from each other).

Yet while dietary patterns are important, understanding possible mechanisms is also important, as is appreciating heterogeneity within broader food categories. The categorization proposed by Fung et al ("animal-based" vs. "plant-based") is a decided step forward from other studies that have examined the diet-mortality question(4, 5). Unfortunately, not all plant-derived foods and animal-derived foods are created equal though, and it is likely that critical differences are lost using even this more-specific categorization.

For instance, do low-carb eaters who choose salmon (lower saturated fat, higher omega-3s) live longer than those who choose beef ? Among beef eaters, do consumers of "pastured" (potentially higher omega-3s, lower antibiotics and hormones) outlive those who eat industrially-raised beef from factory farms? For produce, does "organic" (fewer synthetic fertilizers and pesticides, potentially higher vitamins) promote longevity more than "conventional"? Do people who boil (losing water-soluble nutrients) do worse than those who steam; and do people who grill (coating their meat in heterocyclic amines) die earlier than those who bake? If people eat broccoli with their steak, does one food undo the effects of the other? What if young "mostly-steak eaters" convert to "mostly- broccoli eaters" later in life? ... and then convert back? Many questions remain.

In response to Fung et al's article, editorialists call for "a large- scale clinical trial"(6). While trial data might clarify causality questions, a trial addressing even a few of the critical questions raised above would not be feasible. Still, as other kinds of evidence mount towards more definitive understanding, we should recognize that despite seeming controversy, science-based dietary advice has changed relatively little in more than a half century(7); it still probably makes sense to eat your veggies and avoid red meat (opinions of Atkins-supported editorialist notwithstanding(6)).


1. Fung TT, van Dam RM, Hankinson SE, Stampfer M, Willett WC, Hu FB. Low-carbohydrate diets and all-cause and cause-specific mortality: two cohort studies. Ann Intern Med. 2010;153(5):289-98.

2. Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114(1):82-96.

3. Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC. Diet, nutrition and the prevention of cancer. Public Health Nutr. 2004;7(1A):187-200.

4. Trichopoulou A, Psaltopoulou T, Orfanos P, Hsieh CC, Trichopoulos D. Low-carbohydrate-high-protein diet and long-term survival in a general population cohort. Eur J Clin Nutr. 2007;61(5):575-81.

5. Lagiou P, Sandin S, Weiderpass E, Lagiou A, Mucci L, Trichopoulos D, et al. Low carbohydrate-high protein diet and mortality in a cohort of Swedish women. J Intern Med. 2007;261(4):366-74.

6. Yancy WS, Jr., Maciejewski ML, Schulman KA. Animal, vegetable, or ... Clinical trial? Ann Intern Med. 2010;153(5):337-9.

7. Nestle M. Food politics : how the food industry influences nutrition and health. Rev. and expanded ed. Berkeley: University of California Press; 2007.

Conflict of Interest:

None declared

Re:The Meat of the Diet-Mortality Matter
Posted on September 15, 2010
Charles P. Rippey
No Affiliation
Conflict of Interest: None Declared

Of crucial importance is the quality of the fat. Is it from grass fed aminals and free of growth hormones and anti-biotics, or were the animals fed on corn and soy products raised using chemical fertillizers? Was the oil in its pure form or had it been subject to processing such as hydrogenation or heating that causes oxidation? Were any deadly trans-fats included? The conclusions of the study lose a great deal of credibility since none of these factors were considered.

Conflict of Interest:

None declared

Re:The Meat of the Diet-Mortality Matter
Posted on September 29, 2010
Eric C Anderson
Conflict of Interest: None Declared

Just look at protein by quintile More protein = Shorter Life

Look at refined + 'Whole Grain' Grain = Shorter life

Evan sugar intake by quintile or fat intake by quintile does not decrease life as much as higher quintiles of protein intake or grain intake.

Refined grain intake is much grater than 'whole grain' in the western world. Plus we did not see whole grain eaters 200 years ago live longer lives nor do we see 3rd world whole grain eaters all live to 120 years.

The grain does not increase health and longevity. Feed a pig 50% pig chow and 50% whole grain mix and see the health results and lifespan versus 50% pig chow and 50% simple carbohydrate C3H8O3 Glycerol.

We need to relook at optimal protein and grain intake for older persons and let the data not opinion be the guide. The cost in shorter life and increased medical cost is too much to let guesses and outdated opinion inform or misinform diet selections for older persons.

Conflict of Interest:

None declared

The Truths & Tribulations of Trials
Posted on October 5, 2010
Bert A. Govig
McGill University
Conflict of Interest: None Declared

Thanks to Dr Fung and her team for their cohort reports on dietary patterns and mortality (ref 1), and Drs Yancy, Maciejewski and Schulman for their astute editorial insights (ref 2) about the state of nutrition research in general and on the question that Fung et al seek to answer.

Nutrition repeatedly proves itself to be amongst the most complex of health related phenomena. In a retrospective editorial concerning the Woman's Health Initiative, Walter Willett succinctly notes that the shortcomings of the WHI were "not the result of inexperienced investigators: these trials were conducted by our very best research teams who invested enormous efforts to achieve their goals." (ref 3) Observational studies carry their own well-known shortcomings, and it is clear that it will take a full set of imperfect tools (observational studies and trials) to decipher the truth from the tea leaves in nutrition research.

There is some good news on the diet trials front. The food supply is becoming increasingly standardized. For example, trans fat, an omnipresent and difficult to measure (by history) food additive, and perhaps the most important dietary confounder in recent diet research, is rapidly disappearing from the North American food supply. Eliminating this toxin will also remove a lot of noise in dietary research, and make it easier to detect differences in dietary patterns that matter most to the research community.

The DASH diet trial (ref 4) has also taught us lessons in conducting dietary trials. Furnishing the food, as they did in this study, simplifies and improves diet measurement, and allows us to address efficacy head on. This is an expensive proposition, but there are host of institutional settings where the food is already being provided. Prisons and chronic care facilities come to mind. This is not a new idea, and it harks back to the Finnish Mental Hospital Study conducted in 1979 (ref 5). This trial had its own issues, but demonstrated the feasibility of research in such settings. Are such settings acceptable venues for research in 2010? Only if there is true equipoise over the dietary patterns in question. The debates highlighted over the past ten years confirm the certitude of our uncertainty.


1. Fung TT, van Dam RM, Hankinson SE, Stampfer M, Willett WC, Hu FB. Low-carbohydrate diets and all-cause and cause-specific mortality: two cohort studies. Ann Intern Med. Sep 7 2010;153(5):289-298.

2. Yancy WS, Jr., Westman EC, McDuffie JR, et al. A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Intern Med. Jan 25 2010;170(2):136-145.

3. Willett WC. The WHI joins MRFIT: a revealing look beneath the covers. Am J Clin Nutr. Apr 2010;91(4):829-830.

4. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. Apr 17 1997;336(16):1117-1124.

5. Turpeinen O, Karvonen MJ, Pekkarinen M, Miettinen M, Elosuo R, Paavilainen E. Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study. Int J Epidemiol. Jun 1979;8(2):99-118.

Conflict of Interest:

None declared

Defining Dietary Outcomes Based upon End Organ Damage.
Posted on November 18, 2010
Richard M. Fleming
No Affiliation
Conflict of Interest: None Declared

Our congratulations to Fung, et al, regarding their analysis of outcome data based upon low-carbohydrate diets and actual disease statees. Of greatest importance is the recognition that there is a difference between low-carbohydrate diets based upon animal versus vegetable sources. The data is clear that independent of what happens to weight, which is controlled by caloric1 intake, the bigger picture has to do with how does saturated2-4 fat (different between animal and vegetable sources) influence surrogate markers of heart disease as well as actual heart disease itself. Death is certainly a "hard" end-point which can be measured and as demonstrated required 26 years of follow up in women and 20 years in men. Today, there is considerable debate over the effects of low-carbohydrate diets and their effect on heart disease. Despite the current data presented by the authors, it is clear that positions have not changed5 based upon retrospective data analysis. We conclude, therefore, that a prospective study looking at cardiac end organ disease is called for. Problems with non-invasive evaluation of ischemia has recently been corrected by looking at sestamibi redistribution6-8 which can not only provide "quantitative" measurements of physiologic disease; but, can be used for "anatomic" evaluation of disease (FHRWW) as discussed by our studies6,7.


1. Fleming RM. Caloric intake, not carbohydrate or fat consumption, determines weight loss. Am J Med 2003;114:78.

2. Fleming RM, Boyd L, Forster M. Reversing Heart Disease in the New Millennium - The Fleming Unified Theory, Angiology 2000;51(10):617-629.

3. Fleming, RM. The Effect of High Protein Diets on Coronary Blood Flow. Angiology 2000;51(10):817-826.

4. Fleming RM. The Effect of High, Moderate and Low Fat Diets On Weight Loss and Cardiovascular Disease Risk Factors. Preventive Cardiology 2002;V(III):110-118. [http://www.medscape.com/viewarticle/438769]

5. "Kill or cure? Atkins diet debated in diabetes." By Lisa Nainggolan. Theheart.org, October 18, 2010. http://www.theheart.org/article/1137677.do#comments

6. Fleming RM, Harrington GM, Baqir R, Jay S, Sridevi Challapalli, Avery K, Green J. The Evolution of Nuclear Cardiology takes Us Back to the Beginning to Develop Today's "New Standard of Care" for Cardiac Imaging: How Quantifying Regional Radioactive Counts at 5 and 60 Minutes Post-Stress Unmasks Hidden Ischemia. Methodist DeBakey Cardiovascular Journal (MDCVJ) 2009;5(3):42-48.

7. Fleming RM, Harrington GM, Baqir R, Jay S, Challapalli S, Avery K, Green J. Renewed Application of an Old Method Improves Detection of Coronary Ischemia. A Higher Standard of Care. Federal Practitioner 2010;27:22-31.

8. Sheikine Y, Berman DS, Di Carli MF. Technetium-99m-sestamibi redistribution after exercise stress test. Identified by a novel cardiac gamma camera: Two case reports. Clin Cardiol 2010;33:E39-E45.

Conflict of Interest:

None declared

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