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Editorials |

Animal, Vegetable, or … Clinical Trial?

William S. Yancy Jr., MD, MHS; Matthew L. Maciejewski, PhD; and Kevin A. Schulman, MD
[+] Article and Author Information

From Veterans Affairs Medical Center and Duke University Medical Center, Durham, NC 27705.


Disclaimer: This material is the result of work supported with resources and the use of facilities at the Veterans Affairs Medical Center in Durham, North Carolina. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.

Grant Support: Dr. Yancy has received research grants from the Robert C. Atkins Foundation.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1774.

Requests for Single Reprints: William S. Yancy Jr., MD, MHS, Veterans Affairs Medical Center (152), 508 Fulton Street, Durham, NC 27705; e-mail, yancy006@mc.duke.edu.

Current Author Addresses: Drs. Yancy and Maciejewski: Veterans Affairs Medical Center, Mailstop 152, 508 Fulton Street, Durham, NC 27705.

Dr. Schulman: Center for Clinical and Genetic Economics, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.


Ann Intern Med. 2010;153(5):337-339. doi:10.7326/0003-4819-153-5-201009070-00009
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Several clinical trials in the past 10 years have demonstrated that a low-carbohydrate, high-fat, high-protein diet is at least as effective as a calorie-restricted, high-carbohydrate, low-fat diet for weight loss and improvement of risk factors (blood pressure, serum lipid levels, and glycemia) (13). These clinical trial results conflict with older observational studies that linked dietary fat with poor health outcomes. Newer observational studies and systematic reviews, however, have absolved fat (with the exception of trans fat) as a detriment to health, and some have implicated refined sugars and starches instead (48).

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Observational studies vs randomized trials
Posted on September 20, 2010
Teresa T. Fung
Simmons College
Conflict of Interest: None Declared

In the Editorial that accompanied our paper on low carbohydrate diets and mortality (1), Yancy et al. raised methodological issues to cast doubts on the value of observational studies as well as criticisms specific to our paper. These include unmeasured confounding, measurement errors, and discrepant results from observational studies and randomized clinical trials.

In this study, we addressed the potential influence of unmeasured confounders by a sensitivity analysis that tests the robustness of the results (2). As stated in the paper, the unmeasured confounder would have to have a relative risk of 2.0 and a high prevalence in order to render our results non-significant. As strong predictors of major causes of mortality were adjusted in our analyses, it is unlikely that we have missed unmeasured confounders that have such a strong influence on our results.

Although there is no perfect method to assess diet, we used multiple approaches to addressing measurement errors. In particular, we used repeated measures of diet to reduce random variations and to represent long-term diets. We also corrected for random and systematic errors in the analyses (3). Contrary to the Yancy, consumption of animal fats and protein was substantially higher in the highest decile of the animal than in the vegetable low carbohydrate score (animal protein 18.5% vs 12.7% energy, animal fat 26.3% vs 17.2% energy).

The editorial greatly exaggerated the discrepancies in the results from observational studies and randomized clinical trials. In the case of hormone replacement therapy, the findings on nearly all endpoints except coronary heart disease (CHD) are consistent between the Nurses' Health Study and Women's Health Initiative; these include stroke, pulmonary embolism, diabetes, hip fracture, colorectal cancer, and breast cancer (4). The discrepant results for CHD are probably explained by different age of HRT initiation and short-term vs. long-term effects of HRT, in practice HRT is usually started near the time of menopause whereas in the WHI women as old as 70 years were started on HRT (5). Also, in the Nurses' Health Study total fat intake was not associated with various health outcomes including breast cancer, CHD, and body weight; these results are actually consistent with those in the Women's Health Initiative. The editorial also referred to an inverse association between the animal low carbohydrate score and coronary heart disease in our previous paper (6). However, that association was weak (RR=0.94) and not statistically significant with no suggestion of any trend. Although randomized trials of dietary changes for cardiovascular disease and cancer prevention are theoretically desirable, they can easily be likely to be misleading because of inadequate duration and poor adherence, which is likely to worsen with longer follow-up (7). Soberingly, although smoking is the most important modifiable risk factor for cancer and cardiovascular disease, randomized trials of smoking cessation have consistently shown no benefit for cancer, cardiovascular disease, or total mortality.

References

1. Yancy WDJ, Maciejewski ML, Schulman KA. Animal, vegetable, or ...clinical trial? Annals of Internal Medicine. 2010;153:337-9.

2. Lin DY, Psaty BM, Kronmal RA. Assessing the sensitivity of regression results to unmeasured confounders in observational studies. Biometrics. 1998;54:948-63.

3. Spiegelman D, McDermott A, Rosner BA. Regression calibration method for correcting measurement-error bias in nutritional epidemiology. American Journal of Clinical Nutrition. 1997;65 (suppl):1179s-86s.

4. Grodstein F, Clarkson TB, Manson JE. Understanding the Divergent Data on Postmenopausal Hormone Therapy. New England Journal of Medicine. 2003;348:645-50.

5. Mendelsohn ME, Karas RH. HRT and the young at heart. New England Journal of Medicine. 2007;356:2639-41.

6. Halton TL, Willett WC, Liu S, Manson JE, Albert CM, Rexrode K, Hu FB. Low-Carbohydrate-Diet Score and the Risk of Coronary Heart Disease in Women. New England Journal of Medicine. 2006;355:1991-2002.

7. Willett WC. The WHI joins MRFIT: a revealing look beneath the covers. American Journal of Clinical Nutrition. 2010;91:829-30.

Conflict of Interest:

None declared

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