Background
Obesity remains a significant global health challenge, prompting ongoing research into effective dietary strategies for weight loss. While the Mediterranean diet (MedDiet) is well-established for its cardiovascular and metabolic benefits, there is limited data comparing it with emerging alternative diets that vary in carbohydrate content and eating patterns. This study aimed to assess the weight loss effects of three dietary interventions with different ketogenic potentials—a very-low carbohydrate ketogenic diet (KD), time-restricted eating (TRE), and modified alternate-day fasting (mADF)—compared to a calorie-restricted MedDiet in adults with obesity.
Methods
This was a three-month, parallel-arm randomized clinical trial involving 160 adults diagnosed with obesity. Participants were randomly assigned to one of five groups: control group following a calorie-restricted Mediterranean diet (MedDiet), ketogenic diet (KD), early time-restricted eating (eTRE), late time-restricted eating (lTRE), or modified alternate-day fasting (mADF). Each diet was carefully calorie-restricted to ensure comparability. The primary endpoint was the difference in weight loss from baseline to three months between the MedDiet group and each of the other four dietary interventions. Secondary outcomes included changes in body mass index (BMI), body composition parameters such as fat and lean mass, and cardiometabolic risk markers including blood lipids and glucose metabolism.
Results
The average age of participants was 45.7 years (standard deviation 10.7), with 70.6% being female. Out of 160 participants, 140 completed the study protocol. Significant weight loss differences were observed when comparing the KD, mADF, and lTRE groups to the MedDiet control group. Specifically, the ketogenic diet group lost an average of 3.78 kg more than controls (95% confidence interval [CI]: -5.65 to -1.91 kg), the mADF group lost 3.14 kg more (95% CI: -4.98 to -1.30 kg), and the late TRE group lost 2.27 kg more (95% CI: -4.13 to -0.40 kg). The early TRE group showed a non-significant difference, losing 1.22 kg more than controls (95% CI: -3.07 to 0.64 kg). Secondary outcomes also favored these three interventions with improvements in BMI, body fat percentage, and some cardiometabolic risk factors.
Discussion
The study provides evidence that calorie-restricted ketogenic diet, modified alternate-day fasting, and late time-restricted eating are more effective for short-term weight loss in adults with obesity than a calorie-restricted Mediterranean diet. The ketogenic diet’s low carbohydrate intake likely promotes fat oxidation and ketone production, contributing to greater weight loss. Modified alternate-day fasting induces intermittent calorie restriction, which may enhance metabolic flexibility and fat loss. Late time-restricted eating, which concentrates food intake to a specific window later in the day, also showed significant benefits, possibly related to circadian rhythm alignment and improved metabolic regulation.
Early time-restricted eating did not show significant weight loss benefits compared to the MedDiet in this study, suggesting timing of the eating window may influence outcomes, but further research is needed.
Clinical Implications and Future Directions
These findings support the utility of alternative dietary approaches beyond the traditional Mediterranean diet for obesity management, particularly when calorie intake is controlled. However, longer-term studies are essential to evaluate the sustainability, adherence, and long-term safety of ketogenic diets, alternate-day fasting, and time-restricted eating compared to Mediterranean diets. Additionally, patient preferences, lifestyle compatibility, and potential metabolic effects should guide personalized dietary recommendations.
Healthcare providers should consider these evidence-based options when counseling patients with obesity, while monitoring for possible side effects and nutritional adequacy.
Trial Registration
This trial was registered at ClinicalTrials.gov with identifier NCT04453150.
Reference
Martínez-Montoro JI, Bandera B, Gutiérrez-Bedmar M, Gómez-Pérez AM, Macías-González M, Moreno-Indias I, Tinahones FJ. Effect of a ketogenic diet, time-restricted eating, or alternate-day fasting on weight loss in adults with obesity: a randomized clinical trial. BMC Med. 2025 Jul 1;23(1):368. doi: 10.1186/s12916-025-04182-z. PMID: 40598397; PMCID: PMC12220164.
