Efficacy and safety of a very low-calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

XIAO Yanmei ,  XUE Kun , DANG Zhengyi , WANG Menghao , HE Gengsheng , GUO Hongwei

Department of Nutrition and Food Hygiene, School of Public Health, Fudan University, Shanghai 200032, P. R. China;

Corresponding author：

XUE Kun, Email: xuekun@shmu.edu.cn

Keywords：

Very low-calorie ketogenic diet; Obesity; Overweight; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202110090

Video：

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Objective To systematically review the efficacy and safety of a very low-calorie ketogenic diet (VLCKD) in patients who were overweight or obese. Methods From inception to August 2021, the electronic databases PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang Data, VIP, and CBM were searched for randomized controlled trials (RCTs) of VLCKD in patients with overweight or obesity. Two reviewers independently screened the literature, extracted data, and evaluated the risk of bias of the included studies. Then, meta-analysis was performed using Stata 16.0 software. Results A total of 5 RCTs involving 245 patients were included. Among patients with baseline body mass index (BMI) ≥30 kg/m², the meta-analysis showed that compared with the control group, VLCKD could significantly reduce the BMI (MD=−0.24, 95%CI −0.39 to −0.08, P<0.05), weight (MD=−7.00, 95%CI −10.48 to −3.53, P<0.05) and waist circumference (MD=−7.40, 95%CI −12.68 to −2.12, P<0.05) . The subgroup analysis results showed that compared with the control diet, VLCKD could significantly reduce the glucose (MD=−9.60, 95%CI −17.52 to −1.69, P<0.05), glycated hemoglobin (MD=−0.24, 95%CI −0.39 to −0.08, P<0.05), insulin resistance index (MD=−0.90, 95%CI −1.08 to −0.73, P<0.05) and triglycerides (MD=−41.42, 95%CI −53.78, −29.06, P<0.05) in patients with type 2 diabetes and with obesity or overweight. In patients with obesity or overweight, VLCKD could increase high-density lipoprotein cholesterol (MD=8.60, 95%CI 0.17 to 17.03, P<0.05) when the intervention lasted longer than 12 months. In patients with obesity or overweight, VLCKD had no effect on insulin, total cholesterol, low-density lipoprotein, urea, creatinine, or uric acid. Patients with VLCKD had a higher rate of adverse events than those in the control groups; however, there was no significant difference in the rate when the intervention lasted longer than 4 months. Conclusion The current evidence shows that VLCKD can reduce BMI, weight, and waist circumference and reduce fasting glucose, HbA₁c, insulin resistance index, and triglycerides among patients with type 2 diabetes and with obesity or overweight. However, VLCKD has no effect on insulin, total cholesterol, low-density lipoprotein, urea, creatinine, or uric acid. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： XIAO Yanmei, XUE Kun, DANG Zhengyi, WANG Menghao, HE Gengsheng, GUO Hongwei. Efficacy and safety of a very low-calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2022, 22(4): 403-410. doi: 10.7507/1672-2531.202110090 Copy

1.	Global BMI Mortality Collaboration None, Di Angelantonio E, Bhupathiraju ShN, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet, 2016, 388(10046): 776-786.
2.	NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19. 2 million participants. Lancet, 2016, 387(10026): 1377-1396.
3.	国家卫生健康委员会. 中国居民营养与慢性病状况报告(2020年). 营养学报, 2020, 42(6): 521.
4.	Pan XF, Wang L, Pan A. Epidemiology and determinants of obesity in China. Lancet Diabetes Endocrinol, 2021, 9(6): 373-392.
5.	Wang L, Zhou B, Zhao Z, et al. Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004-18. Lancet, 2021, 398(10294): 53-63.
6.	中国医疗保健国际交流促进会营养与代谢管理分会, 中国营养学会临床营养分会, 中华医学会糖尿病学分会, 等. 中国超重/肥胖医学营养治疗指南(2021). 中国医学前沿杂志(电子版), 2021, 13(11): 1-55.
7.	Hall KD, Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am, 2018, 102(1): 183-197.
8.	Field AE, Willett WC, Lissner L, et al. Dietary fat and weight gain among women in the Nurses' Health Study. Obesity, 2007, 15(4): 967-976.
9.	Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open, 2018, 3(2): 175-192.
10.	Chianese R, Coccurello R, Viggiano A, et al. Impact of dietary fats on brain functions. Curr Neuropharmacol, 2018, 16(7): 1059-1085.
11.	Gershuni VM, Yan SL, Medici V. Nutritional ketosis for weight management and reversal of metabolic syndrome. Curr Nutr Rep, 2018, 7(3): 97-106.
12.	Gibson AA, Seimon RV, Lee CM, et al. Do ketogenic diets really suppress appetite: a systematic review and meta-analysis. Obes Rev, 2015, 16(1): 64-76.
13.	Paoli A, Bosco G, Camporesi EM, et al. Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol, 2015, 6: 27.
14.	Nagy R. Dr. Atkins' diet revolution:a review. Va Med Mon (1918), 1974, 101(5): 383-385.
15.	Poorshiri B, Barzegar M, Tahmasebi S, et al. The efficacy comparison of classic ketogenic diet and modified Atkins diet in children with refractory epilepsy: a clinical trial. Acta Neurol Belg, 2021, 121(2): 483-487.
16.	Murphy NE, Carrigan CT, Margolis LM. High-fat ketogenic diets and physical performance: a systematic review. Adv Nutr, 2021, 12(1): 223-233.
17.	Bueno NB, de Melo IS, de Oliveira SL, et al. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss:a meta-analysis of randomised controlled trials. Br J Nutr, 2013, 110(7): 1178-1187.
18.	中华医学会儿科学分会神经学组, 中国抗癫痫协会, 中华儿科杂志编辑委员会. 生酮饮食疗法在癫痫及相关神经系统疾病中的应用专家共识. 中华儿科杂志, 2019, 57(11): 820-825.
19.	中国医师协会神经内科医师分会儿童神经专业委员会, 中华医学会儿科学分会神经学组. 生酮饮食治疗儿童癫痫性脑病循证指南. 中华实用儿科临床杂志, 2019, 34(12): 881-888.
20.	江波, 白文佩, 郁琦, 等. 生酮饮食干预多囊卵巢综合征中国专家共识(2018年版). 实用临床医药杂志, 2019, 23(1): 1-4.
21.	江波, 邹大进, 马向华, 等. 生酮饮食干预2型糖尿病中国专家共识(2019年版). 全科医学临床与教育, 2019, 17(4): 291-295.
22.	Trimboli P, Castellana M, Bellido D, et al. Confusion in the nomenclature of ketogenic diets blurs evidence. Rev Endocr Metab Disord, 2020, 21(1): 1-3.
23.	Caprio M, Infante M, Moriconi E, et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J Endocrinol Invest, 2019, 42(11): 1365-1386.
24.	Cunha GM, Guzman G, Correa De Mello LL, et al. Efficacy of a 2-month very low-calorie ketogenic diet (VLCKD) compared to a standard low-calorie diet in reducing visceral and liver fat accumulation in patients with obesity. Front Endocrinol (Lausanne), 2020, 11: 607.
25.	Perticone M, Maio R, Sciacqua A, et al. Ketogenic diet-induced weight loss is associated with an increase in vitamin D levels in obese adults. Molecules, 2019, 24(13): 2499.
26.	Goday A, Bellido D, Sajoux I, et al. Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus. Nutr Diabetes, 2016, 6(9): e230.
27.	Merra G, Miranda R, Barrucco S, et al. Very-low-calorie ketogenic diet with aminoacid supplement versus very low restricted-calorie diet for preserving muscle mass during weight loss: a pilot double-blind study. Eur Rev Med Pharmacol Sci, 2016, 20(12): 2613-2621.
28.	Moreno B, Bellido D, Sajoux I, et al. Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity. Endocrine, 2014, 47(3): 793-805.
29.	Bruci A, Tuccinardi D, Tozzi R, et al. Very Low-calorie ketogenic diet: a safe and effective tool for weight loss in patients with obesity and mild kidney failure. Nutrients, 2020, 12(2): 333.
30.	Moreno B, Crujeiras AB, Bellido D, et al. Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease. Endocrine, 2016, 54(3): 681-690.
31.	Tragni E, Vigna L, Ruscica M, et al. Reduction of cardio-metabolic risk and body weight through a multiphasic very-low calorie ketogenic diet program in women with overweight/obesity: a study in a real-world setting. Nutrients, 2021, 13(6): 1804.
32.	Michalczyk MM, Klonek G, Maszczyk A, et al. The effects of a low calorie ketogenic diet on glycaemic control variables in hyperinsulinemic overweight/obese females. Nutrients, 2020, 12(6): 1854.
33.	Castellana M, Conte E, Cignarelli A, et al. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord, 2020, 21(1): 5-16.
34.	Gomez-Arbelaez D, Crujeiras AB, Castro AI, et al. Acid-base safety during the course of a very low-calorie-ketogenic diet. Endocrine, 2017, 58(1): 81-90.
35.	Muscogiuri G, El Ghoch M, Colao A, et al. European guidelines for obesity management in adults with a very low-calorie ketogenic diet: a systematic review and meta-analysis. Obes Facts, 2021, 14(2): 222-245.
36.	Furth SL, Casey JC, Pyzik PL, et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol, 2000, 15(1-2): 125-128.
37.	Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med, 1993, 119(10): 1029-1035.
38.	苏绮璇, 侯小兵. 生酮饮食添加疗法对药物难治性癫痫儿童的疗效与生活质量的影响. 临床神经病学杂志, 2021, 34(1): 5-9.
39.	宁泽淑, 杨理明, 廖红梅, 等. 生酮饮食添加治疗儿童难治性癫痫的临床疗效及随访研究. 中国医师杂志, 2018, 20(11): 1676-1679.
40.	陈文杰, 秦炯. 生酮饮食疗法治疗儿童难治性癫痫作用机制研究进展. 中华实用儿科临床杂志, 2017, 32(24): 1912-1914.
41.	刘秀, 乔静敏, 秦英军, 等. 生酮饮食及限能平衡饮食对超重2型糖尿病患者身体状况的影响. 中国临床保健杂志, 2020, 23(6): 823-826.
42.	张营丽, 周艳华, 李卓, 等. 生酮饮食对阿尔茨海默病患者神经损伤及焦虑抑郁情绪的影响. 中国实用神经疾病杂志, 2021, 24(1): 49-53.
43.	周艳茹. 浅析生酮饮食法于体重管理中的应用. 当代体育科技, 2021, 11(16): 35-37.
44.	吴少彬, 岳文婧. 三种不同营养干预方式对肥胖患者减重及代谢的影响分析. 中国实用医药, 2020, 15(25): 189-191.

1. Global BMI Mortality Collaboration None, Di Angelantonio E, Bhupathiraju ShN, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet, 2016, 388(10046): 776-786.
2. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19. 2 million participants. Lancet, 2016, 387(10026): 1377-1396.
3. 国家卫生健康委员会. 中国居民营养与慢性病状况报告(2020年). 营养学报, 2020, 42(6): 521.
4. Pan XF, Wang L, Pan A. Epidemiology and determinants of obesity in China. Lancet Diabetes Endocrinol, 2021, 9(6): 373-392.
5. Wang L, Zhou B, Zhao Z, et al. Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004-18. Lancet, 2021, 398(10294): 53-63.
6. 中国医疗保健国际交流促进会营养与代谢管理分会, 中国营养学会临床营养分会, 中华医学会糖尿病学分会, 等. 中国超重/肥胖医学营养治疗指南(2021). 中国医学前沿杂志(电子版), 2021, 13(11): 1-55.
7. Hall KD, Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am, 2018, 102(1): 183-197.
8. Field AE, Willett WC, Lissner L, et al. Dietary fat and weight gain among women in the Nurses' Health Study. Obesity, 2007, 15(4): 967-976.
9. Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open, 2018, 3(2): 175-192.
10. Chianese R, Coccurello R, Viggiano A, et al. Impact of dietary fats on brain functions. Curr Neuropharmacol, 2018, 16(7): 1059-1085.
11. Gershuni VM, Yan SL, Medici V. Nutritional ketosis for weight management and reversal of metabolic syndrome. Curr Nutr Rep, 2018, 7(3): 97-106.
12. Gibson AA, Seimon RV, Lee CM, et al. Do ketogenic diets really suppress appetite: a systematic review and meta-analysis. Obes Rev, 2015, 16(1): 64-76.
13. Paoli A, Bosco G, Camporesi EM, et al. Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol, 2015, 6: 27.
14. Nagy R. Dr. Atkins' diet revolution:a review. Va Med Mon (1918), 1974, 101(5): 383-385.
15. Poorshiri B, Barzegar M, Tahmasebi S, et al. The efficacy comparison of classic ketogenic diet and modified Atkins diet in children with refractory epilepsy: a clinical trial. Acta Neurol Belg, 2021, 121(2): 483-487.
16. Murphy NE, Carrigan CT, Margolis LM. High-fat ketogenic diets and physical performance: a systematic review. Adv Nutr, 2021, 12(1): 223-233.
17. Bueno NB, de Melo IS, de Oliveira SL, et al. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss:a meta-analysis of randomised controlled trials. Br J Nutr, 2013, 110(7): 1178-1187.
18. 中华医学会儿科学分会神经学组, 中国抗癫痫协会, 中华儿科杂志编辑委员会. 生酮饮食疗法在癫痫及相关神经系统疾病中的应用专家共识. 中华儿科杂志, 2019, 57(11): 820-825.
19. 中国医师协会神经内科医师分会儿童神经专业委员会, 中华医学会儿科学分会神经学组. 生酮饮食治疗儿童癫痫性脑病循证指南. 中华实用儿科临床杂志, 2019, 34(12): 881-888.
20. 江波, 白文佩, 郁琦, 等. 生酮饮食干预多囊卵巢综合征中国专家共识(2018年版). 实用临床医药杂志, 2019, 23(1): 1-4.
21. 江波, 邹大进, 马向华, 等. 生酮饮食干预2型糖尿病中国专家共识(2019年版). 全科医学临床与教育, 2019, 17(4): 291-295.
22. Trimboli P, Castellana M, Bellido D, et al. Confusion in the nomenclature of ketogenic diets blurs evidence. Rev Endocr Metab Disord, 2020, 21(1): 1-3.
23. Caprio M, Infante M, Moriconi E, et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J Endocrinol Invest, 2019, 42(11): 1365-1386.
24. Cunha GM, Guzman G, Correa De Mello LL, et al. Efficacy of a 2-month very low-calorie ketogenic diet (VLCKD) compared to a standard low-calorie diet in reducing visceral and liver fat accumulation in patients with obesity. Front Endocrinol (Lausanne), 2020, 11: 607.
25. Perticone M, Maio R, Sciacqua A, et al. Ketogenic diet-induced weight loss is associated with an increase in vitamin D levels in obese adults. Molecules, 2019, 24(13): 2499.
26. Goday A, Bellido D, Sajoux I, et al. Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus. Nutr Diabetes, 2016, 6(9): e230.
27. Merra G, Miranda R, Barrucco S, et al. Very-low-calorie ketogenic diet with aminoacid supplement versus very low restricted-calorie diet for preserving muscle mass during weight loss: a pilot double-blind study. Eur Rev Med Pharmacol Sci, 2016, 20(12): 2613-2621.
28. Moreno B, Bellido D, Sajoux I, et al. Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity. Endocrine, 2014, 47(3): 793-805.
29. Bruci A, Tuccinardi D, Tozzi R, et al. Very Low-calorie ketogenic diet: a safe and effective tool for weight loss in patients with obesity and mild kidney failure. Nutrients, 2020, 12(2): 333.
30. Moreno B, Crujeiras AB, Bellido D, et al. Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease. Endocrine, 2016, 54(3): 681-690.
31. Tragni E, Vigna L, Ruscica M, et al. Reduction of cardio-metabolic risk and body weight through a multiphasic very-low calorie ketogenic diet program in women with overweight/obesity: a study in a real-world setting. Nutrients, 2021, 13(6): 1804.
32. Michalczyk MM, Klonek G, Maszczyk A, et al. The effects of a low calorie ketogenic diet on glycaemic control variables in hyperinsulinemic overweight/obese females. Nutrients, 2020, 12(6): 1854.
33. Castellana M, Conte E, Cignarelli A, et al. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord, 2020, 21(1): 5-16.
34. Gomez-Arbelaez D, Crujeiras AB, Castro AI, et al. Acid-base safety during the course of a very low-calorie-ketogenic diet. Endocrine, 2017, 58(1): 81-90.
35. Muscogiuri G, El Ghoch M, Colao A, et al. European guidelines for obesity management in adults with a very low-calorie ketogenic diet: a systematic review and meta-analysis. Obes Facts, 2021, 14(2): 222-245.
36. Furth SL, Casey JC, Pyzik PL, et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol, 2000, 15(1-2): 125-128.
37. Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med, 1993, 119(10): 1029-1035.
38. 苏绮璇, 侯小兵. 生酮饮食添加疗法对药物难治性癫痫儿童的疗效与生活质量的影响. 临床神经病学杂志, 2021, 34(1): 5-9.
39. 宁泽淑, 杨理明, 廖红梅, 等. 生酮饮食添加治疗儿童难治性癫痫的临床疗效及随访研究. 中国医师杂志, 2018, 20(11): 1676-1679.
40. 陈文杰, 秦炯. 生酮饮食疗法治疗儿童难治性癫痫作用机制研究进展. 中华实用儿科临床杂志, 2017, 32(24): 1912-1914.
41. 刘秀, 乔静敏, 秦英军, 等. 生酮饮食及限能平衡饮食对超重2型糖尿病患者身体状况的影响. 中国临床保健杂志, 2020, 23(6): 823-826.
42. 张营丽, 周艳华, 李卓, 等. 生酮饮食对阿尔茨海默病患者神经损伤及焦虑抑郁情绪的影响. 中国实用神经疾病杂志, 2021, 24(1): 49-53.
43. 周艳茹. 浅析生酮饮食法于体重管理中的应用. 当代体育科技, 2021, 11(16): 35-37.
44. 吴少彬, 岳文婧. 三种不同营养干预方式对肥胖患者减重及代谢的影响分析. 中国实用医药, 2020, 15(25): 189-191.

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Efficacy and safety of a very low-calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a meta-analysis

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