This study compares the effects of very low-carbohydrate and very low-fat diets on body weight in free-living obese patients over a year’s time and examines whether genetic or metabolic factors can predict the response to the different diets.

Understanding the role of diet composition on human health and disease over periods of time longer than a few months requires that participants be “free-living” — eating their own food, housed in their own homes, going about their lives as usual. The longer the study lasts and the greater the number of participants, the more researchers can learn about the health risks and benefits of a diet, but the less control they retain over what and how much the subjects actually eat. This study attempts to maximize what we can learn about diets of different macronutrient compositions in a free-living environment, while piloting technologies and methodologies that will be necessary for future studies that will increase significantly the number of participants and the duration of the study itself.

This study compares the role of dietary fat and carbohydrates on body weight and on the risk factors for obesity-related chronic diseases in 600 free-living overweight and obese subjects. Unlike previous studies of its kind, the trial is designed to assure that participants randomized to the different diets actually eat those diets for the duration of the study. It starts by maximizing the difference between the fat and carbohydrate content of the two diets and then applies an intense program of counseling and monitoring to achieve far better adherence to the assigned diets than previous studies. Smart phone applications will be piloted to further improve adherence. Metabolic measures and gene analyses will help determine whether differences in blood sugar control and genetic factors predict the participants’ response to the diets. This study should be able to document, for the first time ever, what happens when free-living participants maintain compliance with a very-low-fat diet and a very-low-carbohydrate diet for an entire year.

Effect of macronutrient composition on weight loss and chronic disease risk with maximum divergence between diets in a free-living setting

Experiments that impose strict control over food intake in a controlled environment are necessary to reliably test hypotheses about causal relationships between diet, body fat and metabolic effects. However, to understand the role of diet composition on human physiology in the real world, in large populations, and over periods of time longer than a few months, participants must be “free-living,” thus ceding control of the subjects’ ultimate dietary choices to the subjects themselves. The longer the duration of the study and the greater the number of participants, the less control researchers retain over what and how much the subjects ultimately eat.

This study is designed to test two very different dietary interventions in free-living subjects to elucidate the role of fat and carbohydrates on body fat and chronic disease risk factors. It expands on work by Gardner et al. reported in JAMA in 2007 – “Comparison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and Related Risk Factors Among Overweight Premenopausal Women” (commonly referred to as the “A TO Z” study). In this previous study, which compared four diets varying in macronutrient content, Gardner et al. reported that consumption of fat and carbohydrates converged over time toward a single common diet similar to the subjects’ pre-study diets. By the end of the year-long study, only the subjects assigned the two diets most divergent in fat and carbohydrate (the Atkins diet and the Ornish diet) differed substantially in their intake of these macronutrients. The difference between these two groups in the A TO Z study remains one of the best examples of dietary differentiation in a free-living study, and the A TO Z study is currently the most read study on nutrition in JAMA.

An important observation in the A TO Z study was the significant individual variation in weight loss and metabolic response (e.g., decrease in blood pressure, improvement in cardiovascular biomarkers) among subjects. A post-hoc analysis revealed two findings. First, the subjects who had the best outcomes on the lowest-carbohydrate diets were more insulin resistant at the beginning of the study, while those who had the best outcome on the lowest-fat diets had been the least insulin resistant. Second, three genetic markers (single nucleotide polymorphisms or “SNPs”) seemed to predict subject response to the different diets.

This study is designed to maximize both the difference between the carbohydrate-restricted and fat-restricted dietary interventions and subjects’ compliance to the diets as the study progresses. While previous studies documented what happens when free-living participants are instructed to consume a particular dietary intervention for one or two years, this study is designed to document what happens when free-living participants actually do consume a particular dietary intervention for that length of time. This study will also test the hypothesis that insulin resistance and genetic predisposition (based on SNPs) predicts response to different dietary patterns. This study represents the largest free-living human experiment ever conducted to test the therapeutic efficacy of low-fat versus low-carbohydrate diets.

For more information about this study go to Diet X Genotype Study


Stanford University School of Medicine, Stanford, California, 94305


Christopher Gardner, Ph.D. (Principal investigator)
Abby King, M.D., Ph.D.
John Ioannidis, Ph.D.
Robert Haile, Dr.P.H.
Manisha Desai, Ph.D.
Julie Parsonnet, M.D.
Tracey McLaughlin, M.D.
Holden Maecker, Ph.D.


Christopher Gardner

Christopher Gardner, Ph.D.
Stanford Prevention Research Center,
Stanford University School of Medicine

Christopher Gardner is a Professor of Medicine at Stanford University, where he is renowned for his work in nutrition and obesity, particularly through the use of human randomized trials. He received his Ph.D. from the University of California, Berkeley, in nutrition science in 1993. Dr. Gardner’s “A TO Z” study, published in Journal of the American Medical Association (JAMA) in 2007, is widely considered one of the landmark trials in the field and was recently listed by JAMA as the most-read article in the field. At Stanford, Dr. Gardner leads initiatives to bring together scholars from all seven of Stanford’s schools to address the complex web of factors influencing production, distribution, and consumption of food. He has led four annual Stanford Food Summits (2010-2013) and is working with a team of scholars to craft an undergraduate program in Food Systems. He also directs Stanford’s Nutritional Studies Program, and serves as a Director of a National Institutes of Health postdoctoral training program. Dr. Gardner recently served two terms on the American Heart Association’s Nutrition Committee, and currently serves on the Scientific Advisory Board of the Culinary Institute of America.