In people with metabolically unhealthy obesity, losing weight on a very-low-carbohydrate ketogenic diet improved liver health more than on a Mediterranean or very-low-fat plant-forward diet, a randomized clinical trial showed.

Many trials have shown that people with obesity can lose weight and improve their metabolic health on different kinds of diets, and that adherence is a key factor in how much weight is lost, said lead author Max C. Petersen, MD, PhD, an endocrinologist at the Center for Human Nutrition, Washington University School of Medicine, St. Louis. “What has not been clear is whether different diets produce different metabolic effects if the same amount of weight is lost,” he told Medscape Medical News.

The question has taken on even more relevance now that GLP-1s are used widely for obesity, added senior author Samuel Klein, MD, also of the Center for Human Nutrition. “While they’ve had a dramatic effect in treating people with obesity by helping them lose large amounts of weight, whether diet composition itself has benefits beyond weight loss alone is not known,” he said.

Their trial identified multiple benefits to the liver from the ketogenic diet compared with the two other diets. Patients showed greater improvement in intrahepatic triglyceride content, hepatic insulin sensitivity, and glycated hemoglobin.

“These benefits to liver health were exciting, but what was unexpected was that the ketogenic diet group didn’t experience any of the downsides that commonly discourage clinicians from recommending a diet high in saturated fat and cholesterol,” Petersen noted. “The sensitivity of muscle tissue to insulin improved by a similar amount with all three diets, and blood cholesterol profiles were similar across all diets, as well.”

The study was published online in Cell Metabolism.

‘Many Who Try It Will Not Continue’

The researchers randomized 55 adults with metabolically unhealthy obesity, defined as obesity plus prediabetes and hepatic steatosis, to a very-low-carbohydrate ketogenic diet (4% of energy from carbohydrates), a Mediterranean diet (50% from carbohydrates), or a very-low-fat plant-forward diet (70% from carbohydrates).

All food was provided as prepared entrées and snacks, and participants met weekly with a dietitian. Metabolic testing was conducted before and after weight loss of about 10% of body weight.

Forty-two participants (nine women and five men in each group) completed the study and were included in the analysis. Participants’ mean age was 43 years and mean BMI at baseline was 38.9. Weight loss was matched across groups at roughly 10% of the starting body weight, achieved over 4-5 months, followed by 3-4 weeks of weight maintenance before repeat testing.

The researchers found that skeletal muscle insulin sensitivity, measured during a hyperinsulinemic-euglycemic clamp, increased by about 50% in all three groups. However, hepatic insulin sensitivity increased two-to-three times more in the ketogenic group than in the Mediterranean or plant-forward groups.

Intrahepatic triglyceride content fell by 67% in the ketogenic group compared with 45% in each of the other two groups. Hepatic de novo lipogenesis and glycated hemoglobin also decreased more with the ketogenic diet.

Other findings included similar decreases (about 72%) in body fat and fat-free mass in the three diet groups; decreases in fasting plasma glucose, fasting plasma insulin, and the homeostasis model assessment of insulin resistance after weight loss in all groups, but with a greater decrease in the ketogenic diet group; and decreases in glycated hemoglobin after weight loss in the ketogenic and very-low-fat plant-forward diet groups, with a greater decrease in the ketogenic diet group.

In addition, prediabetes remitted in 50% of participants in the ketogenic group compared with 29% in the Mediterranean group and 7% in the plant-forward group. There were no differences among groups in low-density lipoprotein cholesterol, apolipoprotein B, or 24-hour plasma triglyceride concentrations.

As noted, despite deriving 23% of its energy from saturated fat, the ketogenic diet did not worsen skeletal muscle insulin sensitivity or blood lipid profiles relative to the other diets.

No serious adverse events occurred, and no participant withdrew because of an adverse event.

Petersen cautioned that the findings describe what happens when people strictly follow one of three diets for months, not what happens when a diet is simply recommended in clinic. “Not all people with metabolically unhealthy obesity will want to adopt a very-low-carbohydrate ketogenic diet, and many who try it will not continue it for long,” he said.

The diet studied was very restrictive, with under 5% of energy from carbohydrates, and therefore, the results might not have been the same on a high-fat diet without severe carbohydrate restriction, he said. Furthermore, the findings might not have been the same for people with obesity who are more metabolically healthy.

“For people who need to lose weight to reverse their prediabetes and fatty liver, any diet that reduces energy intake will work, whether high-carb, high-fat, or balanced,” Petersen said. “However, pound-for-pound, liver health may improve most on a very-low-carb ketogenic diet.”

Overall, Klein said “diet composition should be considered part of the therapeutic strategy in treating people with obesity and concomitant prediabetes and liver disease.”

‘Hypothesis-Generating, Not Definitive’

Commenting on the study for Medscape Medical News, William S. Yancy Jr, MD, MHS, director of the Duke Lifestyle and Weight Management Center, Durham, North Carolina, said it confirms many points from previous trials of low-carbohydrate eating, but has “two notable attributes. It used a more highly controlled design than most previous studies by providing food to the participants rather than the participants buying and preparing their own food. And it had a more comprehensive and rigorous evaluation of the health benefits that occur.”

However, “the main concern is also an attribute,” he noted. “By actually providing meals to participants, we get a more confident look at the changes that occur in the body when people are very adherent to a certain eating pattern. On the other hand, it is more difficult for people to stick with an eating plan when buying and preparing their own meals.”

Yancy said he’d like to see the diets tested alongside newer obesity medications. Given that GLP1 medications have shown notable benefits to prediabetes and fatty liver disease, he said, “it would be very interesting to see a study of these diet approaches in combination with medication.”

Esther López-García, PhD, lecturer and researcher in preventive medicine and public health at the Autonomous University of Madrid in Madrid, Spain, noted that the study “does not address the major issue with high-fat diets, which relates to their quality. It is not the same to follow a diet consisting mainly of foods high in unhealthy fats — such as those found in high-fat meats and processed foods — as it is to follow a diet comprised of foods high in healthy fats, such as those found in olive oil and oily fish.” 

Furthermore, she said, “high-carbohydrate diets may include healthy foods, such as whole grains, fruit and vegetables, and pulses, but they may also include foods that provide sugars — which are low-quality carbohydrates — such as sugary drinks or industrially produced pastries.”

“The Spanish dietary guidelines recommend a diet that includes a moderate-to-high intake of healthy fats and a similarly moderate-to-high intake of healthy carbohydrates (adjusting the ratio depending on individual preferences or circumstances), alongside a moderate intake of animal protein and a high intake of plant-based protein,” she said. “This combination appears to be the most balanced for preventing disease in the general population.”

This study was supported by grants from the National Institutes of Health and support from the Foundation for Barnes-Jewish Hospital. Klein reported receiving scientific advisory board fees from AbbVie, 89Bio, and Boehringer Ingelheim; an investigator-initiated grant from Merck; and support for an industry-initiated multi-center clinical trial from Viking Therapeutics. Petersen declared having no competing interests. Yancy declared having no relevant competing interests. Lopez-Garcia did not respond to a request for any conflicts of interest. 

Marilynn Larkin, MA, is an award-winning medical writer and editor based in New York City whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.