Diabetes, Endocrine, Gastrointestinal Health, Metabolic Syndrome

Effect of diet macronutrient content on the cardiometabolic response to weight loss: A randomized clinical trial  

In this 2026 randomized clinical trial, researchers compared three different dietary approaches in adults with metabolically unhealthy obesity, defined by obesity, prediabetes, and hepatic steatosis. Participants were randomized to a very-low-carbohydrate ketogenic diet, a Mediterranean diet, or a very-low-fat, plant-forward diet. All food was provided, and adherence exceeded 95%. The diets supplied approximately 4%, 50%, and 70% of energy from carbohydrate, respectively.

Of 55 randomized participants, 42 completed the study, with 14 in each group. Participants had a mean age of 43 years and BMI of 38.9 kg/m². Rather than comparing outcomes after a fixed period, researchers repeated detailed metabolic testing once participants had achieved approximately 10% weight loss, which took about five months across groups. This matched weight loss allowed the researchers to examine whether diet composition influenced metabolic improvements beyond the effects of weight loss itself.

Results/Key Findings

• All three diets produced approximately 10% weight loss and improved several cardiometabolic measures, including skeletal muscle insulin sensitivity.
• The ketogenic diet produced greater reductions in liver fat, hepatic insulin sensitivity, endogenous glucose production, and hepatic de novo lipogenesis than the Mediterranean or very-low-fat diet.
• Whole-body insulin sensitivity improved across all groups, with a greater improvement on the ketogenic diet than the Mediterranean diet.
• Prediabetes remission occurred in 50% of the ketogenic group, compared with 29% of the Mediterranean group and 7% of the very-low-fat group.
• Twenty-four-hour insulin concentrations decreased by 74% with the ketogenic diet, compared with 44% and 27% with the Mediterranean and very-low-fat diets, respectively.
• Despite providing 23% of energy from saturated fat, the ketogenic diet produced similar changes in total cholesterol, LDL cholesterol, apolipoprotein B, and blood pressure to the other diets.
•  Although all three diets lowered fasting triglycerides, the ketogenic diet group experienced the largest reduction.

Conclusion

The authors concluded that dietary macronutrient composition can modify the metabolic benefits of moderate weight loss. While all three diets improved metabolic health, weight loss achieved with a very-low-carbohydrate ketogenic diet produced greater benefits for several outcomes, particularly hepatic insulin sensitivity and liver metabolism.