Mapping evidence and identifying risks: A systematic scoping review of meal replacements in type 2 diabetes

Table 1 Distribution of studies and participants according to geographical location

Country	Number of studies	Participants in meal replacement arm (n)	Ref.
Asia
China	7	465	[33,37,44,47,86,103,104]
India	4	303	[63,82,92,93]
Japan	1	119	[91]
Malaysia	3	193	[24,45,141]
Singapore	1	19	[85]
Indonesia	1	30	[117]
Taiwan	1	30	[46]
Thailand	2	172	[39,118]
Qatar	2	70	[40]
Oceania
Australia	9	396	[36,52,55,56,61,90,95,106,116]
New Zealand	1	20	[70]
America
Canada	4	514	[48,54,62,94]
United States	49	3301	[30,34,38,43,49,50,72-76,80,84,88,89,96,101,107,115,121,122]
Brazil	1	34	[100]
Europe
Czech Republic	1	22	[102]
Denmark	1	11	[83]
Germany	8	700	[57,64-68,81,120]
Greece	1	43	[59]
Italy	3	77	[32,41,97]
Netherlands	8	147	[28,31,42,87]
Spain	1	17	[29]
Sweden	2	392	[109,114]
Ireland	1	20	[113]
United Kingdom	21	1443	[18,35,51,58,60,69,71,77-79,99,105,106,108,110-112,119]

Table 2 Types, composition, dosage, and duration of meal replacement intervention for type 2 diabetes

Ref.	Country	Trial type & setting	Setting	Meal replacement arm (n)	Meal replacement type	Dosage/calorie	Combination	Length of intervention/follow up
Low calorie/energy MR (n = 35)
Rothberg et al[75]	United States	Observational study	Clinical	66	HMR®, Boston, MA, United States	TDR; 160-170 kcal per packet, total 800 kcal per day; > 160 kg additional 160-170 kcal/day per 23 kg	/	12 weeks
Tatti et al[41]	Italy	Non-randomised controlled trial	Clinical	38	Glucerna® SR, Abbott Nutrition	PMR; 206 calories per 230 mL for one main meal; Blend with low calorie frozen yoghurt into 250-270 kcal	/	12 weeks
Steven et al[51]	United Kingdom	Longitudinal study	Clinical	30	Optifast (Nestle Nutrition, Croydon, United Kingdom)	TDR; 3 shakes per day + 240 g non starchy vegetables; total Cal intake 624-700 kcal/day	/	8 weeks VLCD; + 24 weeks wight maintenance phase
Shantha et al[101]	United States	Cohort Study	Clinical	72	Calorie-restricted diet using meal replacements	1000 kcal/day energy deficit; Individualized	Behaviour modification plan; Aerobic and strength training	Individualized 3 months to 1.5 years
Astbury et al[35]	United Kingdom	Randomized controlled trial	Clinical	138	TDR with four formula products daily (LCD) provided by Cambridge Weight Plan United Kingdom	TDR; First 2 weeks, liquid MR. Week 3 onwards MR bars option; Energy intake comprised 810 kcal/day (3389 kJ/day)	/	8 weeks LCD, gradual food reintroduction, weekly behavioural support for 24 weeks - one MR is consumed per day
Baker et al[52];	Australia	Non-randomized case-control trial	Clinical	37	Optifast (Nestle Nutrition, Croydon, United Kingdom)	TDR; 3 sachets daily combined with serving of vegetable once daily (800 kcal/day)	After week 12, 8-week transition phase to calorie restriction diet based on Australian Commonwealth Scientific and Industrial Research Organization Total Wellbeing diet (1350 kcal) for another 4 weeks	12 weeks VLCD + 8 weeks transition to calorie restriction diet + 4 weeks 1350 kcal diet
Bishay[53]	Australia	RCT Protocol	Clinical	Not reported	Optifast (Nestle Nutrition, Croydon, United Kingdom)	TDR; 5-months of complete VLCD (820 kcal/day)	/	32 weeks
Bhatt et al[82]	India	Clinical Audit	Clinical	12	Protein formula (Prototal Whey)	TDR; 1000 kcal/day diet	/	12 weeks
Berk et al[42]	Netherlands	Randomized controlled trial	Clinical	64	Glucerna® SR, Abbott Nutrition	PMR; Replace breakfast and lunch; Light dinner for a combined 750 kcal/day	/	8 weeks + 12 weeks LCD reintroduction (1300 kcal/day)
Shiau et al[54]	Canada	Retrospective cohort study	Clinical	317	OPTIFAST® 900	TDR; 4 MR shakes per day for a total of 900 kcal per day	First 6 months - weekly diet session, behavioural and therapy; Next 6 months - optional monthly support session	BMI > 33 kg/m2 - 12 weeks of full MRs; BMI < 33 kg/m2 - 6 weeks of full MRs with option to increase to up to 12 weeks of full MRs; 5-week transition to maintenance diet
Cinkajzlová et al[102]	Czech Republic	Intervention study	Clinical	22	VLCD	2500 kJ per day	/	/
Taheri et al[40]	Qatar	Non-blinded, randomised controlled, parallel-group trial	Clinical	70	LCD from Cambridge Weight Plan	800 kcal; First 12 weeks: TDR supplemented by low-fat milk; Month 4 to month 6: PMR; Gradual introduction to three meal per day eating pattern	Individual dietetic and activity appointments. Unsupervised physical activity of at least 150 minutes per week	PHASE 1: 12 weeks LED + physical activity; PHASE 2: 12 weeks partial LED + physical activity; PHASE 3: 6 months own food, physical activity, and lifestyle change. PHASE 4: 12 months follow-up
Harder et al[83]	Denmark	Single arm study	Clinical	11	Nutriletts (NutriPharma, Oslo, Norway)	TDR; 850 kcal/day	/	8 weeks
Friedman et al[84]	United States	Proof-of-concept pilot study	Clinical	6	Nutrimed (Robard Corporation, Mount Laurel, NJ, United States)	PMR; 800 kcal/day	/	12 weeks
Lean and Leslie[77]	United Kingdom	RCT protocol	Clinical	Total N = 25	Counterweight Pro 800	TDR; Initial Total Diet Replacement phase (0-12 weeks); 825-853 kcal/day	Counter weight-Plus’ weight management programme; Structured food reintroduction (12-20 weeks).; -Replacing TDR with meals which contain 30% of energy from fat	20 weeks with initial 12 weeks TDR
Wong et al[103]	China	Randomized, non-blinded, single center trial	Clinical	Total N = 37	LED	PMR; Replace at least one meal with less than 300 kcal	/	24 weeks
Leader et al[55]	Australia	RCT	Clinical	36	Optifast VR	PMR; 1 or 2 PMR per day	/	12 months
Overl et al[104]	China	Conference paper; RCT	NA	Total N = 10	MR shakes	Three meal replacement shakes (600 kcal/day) for two 24-hour periods/week	/	12 weeks
Gulsin et al[69]	United Kingdom	Single-center, prospective, randomized, open-label, blinded end point trial with a nested case-control study	Clinical	24	Low energy MRP from Cambridge Weight Plan	TDR approximately 810 kcal/day (Cambridge Weight Plan)	/	12 weeks
Farrer and Golley[36]	Australia	Non-randomized intervention	Clinical	19	Optifast VLCD programme	Three phases of 4 weeks each: Intensive (3 Optifast VLCD per day, < 3360 kJ/day), Transition (2 Optifast VLCD per day, approximately 5040 kJ/day) and Maintenance (1 Optifast VLCD per day, approximately 5040 kJ/day); 12th week: Full normal meals were resumed to meet energy deficit requirements of 50% total energy	Traditional diabetes and weight management education	12 weeks
Sumithran and Proietto[56]	Australia	Case study	Clinical	1	Optifast VLCD	TDR; 5 months VLCD 3 times a day (1908 kJ); Transition phase 7 months: Two VLCD meals per day and one low fat meal per day	Daily exercise program; Weight control clinic	12 months
Rolland et al[105]	United Kingdom	Case study	Community	355	VLCD in the form of food packs (soups, shakes, textured meals and bars)	TDR; 550 kcal daily	Commercial weight-management programme (Lighter Life Total); Group support; Cognitive behaviour therapy	12 weeks
Dhindsa et al[71]	United Kingdom	Intervention	Clinical	44	VLCD Slimfast, liquid MR	PMR; 3 Slimfast MR per day; 750 cal	Follow-up phase (week 8 to week 52) with a standard low-calorie weight-maintenance diet	(1) 8 weeks of VLCD therapy; and (2) Follow-up phase (week 8 to week 52) with a standard low-calorie weight-maintenance diet
Khoo et al[85]	Singapore	Randomized Trial	Clinical	19	Liquid meal replacement (Kicstart, Pharmacy Health Solutions, Sydney, Australia)	PMR; Maximum 450 kcal, 0.8 g/kg ideal body weight of protein and one other small meal, for a total of approximately 900 kcal/day for 8 weeks	Switch to or continue high protein diet for the remaining 44 weeks	8 weeks LCD/52 weeks
Moriconi et al[97]	Italy	Retrospective study	Clinical	15	Very-low-calorie ketogenic diet (VLCKD) (Therascience, New Penta SRL or Pronokal Group)	First phase (45 days) TEI was < 800 kcal with 4/5 MR per day. Second phase (45 days), one and subsequently two replacement meals were replaced with conventional food	Caloric intake gradually increases; Full carb reintroduction - 6 months	Phase 1 - 45 days; Phase 2 - 45 days; Phase 3 - until 12 months
Tang and Lin[86]	China	RCT	Clinical	50	Fasting-mimicking diet (FMD) MR (Maide Technology Co., Ltd., Wuhan, China)	PMR; FMD MR from Monday to Friday in the second week of a month. Eat normally for the rest of the month. Energy for first day and the second to fifth days was 1196 and 805 kcal respectively	/	First 3 months - MR; Last month - normal diet
Maher et al[106]	Ireland	Case study	Clinical	1	Low-energy liquid diet	TDR; 1012 kcal per day with 2.2 L of semi-skimmed milk	/	8 weeks LELD; + 16 weeks of phased reintroduction of normal diet
Nori Janosz et al[34]	United States	Retrospective chart review	Clinical	33	LCD MR	PMR; 1000-1200 kcal/day	Behavioural treatment plan	At least 4 weeks
Storck et al[57]	Germany	Prospective, interventional study	Clinical	36	OPTIFAST® II Short program, Nestlé Health Science, Germany)	TDR; 5 sachets per day of 800 kcal for 6 weeks. 4-week refeeding phase.; Last 5 weeks, energy intake will be gradually increased to between 1200 and 1500 kcal	Standardized weight-loss program (OPTIFAST® II Short program, Nestlé Health Science, Germany); Weekly visit for exercise training. Diet counseling	12 weeks
Schwasinger-Schmidt et al[107]	United States	Retrospective analysis	Community	44	LCD in form of shakes, soups, cereal, and entrees	TDR; Consume at least five meal replacements with a minimum of 800 kcal per day	Weekly behavioural education classes	12 weeks
Steven and Taylor[58]	United Kingdom	Intervention study	Clinical	30	VLCD liquid MR (Optifast)	TDR; Replaced all meals with Optifast 624 kcal/day	Discontinued all diabetic medications	8 weeks
Redmon et al[72]	United States	RCT	Clinical	30	LCD MR (meal shakes or meal bars) (Slim Fast Foods Company)	PMR; Repetitive intermittent LCD weeks: LCD of 900-1300 kcal per day (220 kcal/serving, four to six servings daily) for 7 consecutive days every 2 months; On normal days, use one MR and one snack bar (120 kcal/snack bar) daily to replace one usual meal and snack to reach 500 to 1000 kcal per day reduction goal	Combination therapy group; Individual counseling by a registered dietitian; Individualized diet of 500-1000 kcal reduction in daily energy; Individualized exercise prescription	12 months
Lips et al[87]	Netherlands	Controlled nonrandomized observational trial	Clinical	12	Commercially available Prodimed (Prodimed Benelux BV, Val-Kenswaard, The Netherlands)	TDR; 4-5 sachets a day with 90 kcal each sachet, average 600 kcal/day	/	3 weeks
Elizabeth O Beale[76]	United States	RCT protocol	Clinical	15	TDR first 3 months; PMR 3-6 months; HMR70 Plus products; HMR Boston, MA, United States	Phase 1: TDR 3-months 1200-1400 cal diet. Phase 2: Regular meals and 1 MR/day. Phase 3: 6-month weight loss maintenance period with 1 MR/day	Usual care at Roybal Diabetes Management Clinic	12 months
Abi-Chahine et al[108]	United Kingdom	Abstract for poster presentation for a person-centred intervention study	Community	23	TDR	TDR of 800 kcal daily supplementation	Food reintroduction after 12 weeks; Culturally sensitive diet and lifestyle support through 26 e-learning modules	24 weeks
Rafey et al[113]	Ireland	Prospective observational cohort study	Clinical	20	Milk-based LELD	TDR; Week 1-8: Approximately 1200 kcal/day, or 130 g of carbohydrates and 40 g of fat intake per day. Week 9-16: Gradual reintroduction of low calorie meals.; Week 17-24: Stopped milk replacement and start fully isocaloric meal plan	/	24 weeks
Reynolds[70]	New Zealand	RCT protocol	Clinical	20	Cambridge Weight Plan products (VLED)	TDR; Consumption of 3-4 meal replacements per day providing approximately 3600 kJ/day	Structured programme with monthly visits for long-term weight loss maintenance	12 weeks
Scragg et al[112]	United Kingdom	RCT protocol	Clinical	254	Low-energy low-carbohydrate diet	TDR; 800-1000 kcal with a maximum of 40-60 g carbohydrate/day, compared to usual intake of 200-250 g	/	6 months
Tsompanaki et al[111]	United Kingdom	RCT protocol	Community	28	TDR with LED	TDR; LED with package of soups, shakes, bars (4 per day providing approximately 850 kcal/day) for first 12 weeks	Stepped food reintroduction starting from 12th weeks and weight maintenance phase	12 months
Shirmann[110]	United Kingdom	RCT protocol	Clinical	36	TDR with Low-calorie Diet Programme	TDR; approximately 850 cal per day through four TDR products daily for 12 weeks; Followed by a 6-week food reintroduction period and weight maintenance support for 8 months		12 weeks
Hocking et al[61]	United Kingdom	Single arm intervention trial	Clinical	155	TDR with LED; Optifast; Nestlé Health Science	TDR; 3 MRP per day (800 kcal per day). If BMI more than 40, 950 kcal per day	Dieitian visits every 2-4 weeks	13-week TDR; 8 weeks structured food reintroduction; 31-week supported weight maintainence
Ekberg[109]	Sweden	RCT Protocol	Not stated	286	Low Carb or low calorie diet	Not stated	/	15 months
Low glycemic index MR (n = 5)
Stenvers et al[28]	Netherlands	Randomized, controlled, cross over trial	Clinical	29	Glucerna SR (Abbott Nutrition)	PMR; Baseline breakfast intake mean 292 kcal	/	12 weeks
Foster et al[88]	United States	Randomized controlled trial	Clinical	50	Pre-packaged, Portion Controlled Diet (Nutrisystem D, Fort Washington, PA, United States)	PMR; Women approximately 1250 and men 1550 kcal per day, with approximately 55% of total energy from the packaged foods and 45% from supplemental grocery items	/	6 months
Boonyavarakul et al[39]	Thailand	Randomized controlled trial	Clinical	60	ONCE-PRO	PMR; Replace one meal per day to provide 30% of energy intake; Aim: 25-30 kcal/kg/day	/	12 weeks
Li et al[33]	China	randomized, open label, interventional study	Clinical	47	Multi-nutrient powdered supplements (LEHEL Company, Guangzhou, China)	PMR; Provides 346 kcal energy in place of breakfast	Diabetic health education organized by nutritionists every 2 weeks	12 weeks
Eliana and Pranoto[117]	Indonesia	Randomized, controlled, crossover, open-labelled study	Clinical	30	Carbohydrate mix-fortified liquid meal replacement nutrition (LMRN)	TDR; 4008 kcal	/	4 days × 2 (crossover)
Santen et al[89]	United States	Intervention Pilot study	Clinical	11	TDR with Nutrisystem®D® Meal Replacements, Nutrisystem Inc.	TDR; 1450 to 1550 kcal/day for men; 1200 to 1250 kcal/day for women	Telcare with glucometer, weighing scale and cloud data assessment.; Education sessions	6 months
Otten[114]	Sweden	RCT Protocol	Clinical	106	TDR	TDR for 850 kcal/day	Cognitive behavioural therapy programs through face to face or ehealth application	Total diet replacement for 3 months. Weight maintenance for 21 months
Anyiam et al[99]	United Kingdom	RT	Clinical	18	TDR VLCD; LighterLife® total meal replacement	TDR VLCD with less than 800 kilocalories per day	/	12 weeks
De Freitas et al[115]	United States	Case study	Clinical	1	TDR VLCD with a formula liquid diet meal replacement	TDR 800 kcal/day; Twelve weeks of VLCD were followed by 4 weeks of low-calorie diet (incorporating 3 meal replacements and 1 meal with ad libitum non-starchy vegetables)	/	16 weeks
Khoo et al[116]	AUS	Retrospective cohort study	Clinical	51	PMR with LCD	PMR Two meal replacement shakes plus a healthy meal	/	3 months PMR + 21 months reduced calorie meal
Diabetes Specific Formulas (n = 16)
Belcaro et al[32]	Italy	Single blinded RCT	Clinical	24	Glucaffect™ (Reliv Inc., Chesterfield, MO, United States)	PMR; Substitute up to two meals a day for 6 days a week. Dinner following regular choices	Personal Exercise Program with 60 minutes each day	8 weeks
Fonda et al[43]	United States	Prospective, 3-way, cross-over design	Clinical	18	Glucerna Weight Loss Shake, Slim-Fast Shake, and Ensure with Fiber Shake	Subjects consumed the meal replacement; beverages after an overnight fast, in random sequence on; different weeks, 1 week apart	/	1 week
Garvey et al[119]	United Kingdom	Multi-center, single arm, unblinded study	Clinical	147	/	PMR; Two meal replacement shakes and snack bars daily	Diet and lifestyle counseling	12 weeks + 12 weeks sustainability
Sun et al[37]	China	Unblinded, randomized, controlled clinical trial	Clinical	100	Glucerna SR (Abbot Nutrition)	PMR; Replace breakfast, providing 200 kcal	Weekly sessions on: Diet consultation; Review of blood glucose measurements	24 weeks
Peng et al[44]	China	RCT	Clinical	62	Glucerna SR (Abbot Nutrition)	PMR; Replacing breakfast providing 220.5 kcal	Lifestyle education; Individualized meal plan	4 weeks
Chee et al[45]	Malaysia	RCT	Clinical	115	Glucerna SR (Abbot Nutrition)	PMR; Structured low-calorie meal plan - 1200 or 1500 kcal/day; Normal foods + one or two diabetes-specific formula servings	tDNA group receives physical activity at least 150 minutes/week; Education using tDNA toolkit: Flipchart on healthy eating, 14-day meal plans, information on physical activity; Subgroup receives motivational interviewing or conventional interviewing	6 + 6 months follow-up
Patel[92]	India	RCT Protocol	Clinical	100	Prohance D Vanilla Flavour (Nutraveutical Product)	PMR; Once a day	/	12 weeks
Hwu[46]	Taiwan	RCT protocol	Clinical	30	Glucerna SR (Abbot Nutrition)	PMR; To replace one meal (breakfast) and one pre-sleep snack for 24 weeks	Diet plan with 500-800 kcal/day less than their estimated daily maintenance energy requirement	24 weeks
Bao[47]	China	Single-centre, Randomized, Open-label, Parallel Group Study Protocol	Clinical	66	Glucerna SR (Abbot Nutrition)	To replace breakfast	/	4 weeks
Lansink et al[31]	Netherlands	Randomized, controlled, double-blind, parallel-group study	Clinical	22	Diasip® (Nutricia N.V., Zoetermeer, The Netherlands)	PMR; Two 200 mL portions (200 kcal per portion) per day for 4 weeks, one for breakfast and one for snack in the afternoon or evening	/	4 weeks
Mottalib et al[30]	United States	A prospective, randomized, three-arm study	Clinical	72	DSNF	PMR; Group B and C - hypocaloric dietary plan (1500 kcal/day for women, 1800 kcal/day for men) with a commercially available DSNF (220 kcal/serving) 1-3 times per day	/	16 weeks
Otto et al[48]	Canada	Retrospective cohort study	Clinical	47	Glucerna SR (Abbot Nutrition)	PMR; 2 cans of Glucerna per day (230 kcal/serving as part of a 1200 to 1400 kcal diet)	/	At least 3 months
Yip et al[73]	United States	RCT	Clinical	41	Liquid MR preparation containing lactose, fructose, and sucrose (Slim-Fast; MR1); Liquid MR in which sucrose and fructose were replaced by nonsugar-containing glucose oligosaccharides (sugar-free Slim-Fast; MR2)	MR1 (Slim-Fast Foods, New York, NY, United States): 11 g lactose, 13 g fructose, 8.5 g sucrose, and 14 g protein. MR2: Identical to MR1, fructose and sucrose were replaced with equivalent levels of maltodextrins. (250 kcal each); Replaced their three meals with MRs for the first 5 days. Replaced two meals for remainder of the study	/	12 weeks
Mottalib et al[38]	United States	Cross-over, three-way and open-label clinical study	Clinical	22	Three types of meal replacement served on each visit on breakfast: Glucerna (Abbott Nutrition Inc., Columbus, OH, United States); Ultra Glucose Control (Metagenics Inc., Aliso Viejo, CA, United States); OM (Quaker Oats Co., Chicago, IL, United States)	PMR for breakfast; 200 kcal/meal	/	Three visits with crossover of different MR
Cheskin et al[80]	United States	Controlled clinical trial	Community	54	Medifast Plus for Diabetics (Medifast, Inc, Owings Mills, MD, United States)	PMR; 25% of energy calorie deficit at weight-loss-phase diet; 10% calorie deficit at weight-maintenance-phase diet. PCD group received 50% to 60% of their prescribed calories from meal replacements	An initial 34-week weight loss period, then PCD participants were rerandomized for 52-week maintenance phase to either 26 weeks of PCD followed by 26 weeks of Standard Diet (PCD1) or vice versa (PCD2)	34-week weight loss period and 52-week maintenance phase (86 weeks)
Mustad et al[49]	United States	Randomized, open-label, three-group parallel study design	Clinical	49	Glucerna Hunger Smart (Abbott Nutrition, Columbus, OH, United Sates)	PMR; One meal supplies 180 kcal. DSNS breakfast and afternoon snack (Bkfst/AS); DSNS breakfast and bedtime snack (Bkfst/PBS); Self-selected diets for 7 days, then MR for 7 days	/	7 SSD + 7 days MR
Lew et al[98]	Malaysia	RCT Protocol	Clinical	78	PMR with Diabetes specific meal replacement - Metabolic Sauver, Powerlife (M) Sdn Bhd, Kuala Lumpur, Malaysia	PMR for 5 days a week replacing 1 meal per day, providing 327 kcal per comsumption	Dietary Consultation	12 weeks intervention + 12 weeks follow up
Wichansawakun[118]	Thailand	RCT Protocol	Not stated	76	PMR with Diabetes specific meal replacement	Replace 1 meal per day based on weight based calculation at 25-30 kcal of energy per ideal body weight per day, and the ratio of carbohydrates to protein to fat is 45-50:20:30-35 of total energy	/	12 weeks
Dharmalingam et al[93]	India	RCT	Clinical	71	PMR with DSNS (Prohance-D® Vanilla flavored powder); (Sun Pharmaceutical Industries Limited, Mumbai, India)	One serving of DSNS used as breakfast/evening snack replacement, providing 16.8% of the recommended daily allowance (RDA) of protein, 454 kcal energy	Oviva Diabetes Remission Insulin (ODR-I) programme: Expert dietitian coaching; Oviva app (with a 12-month weight prediction chart); Capilar Blood Glucose meters; BodyTrace weight scales	12 weeks
Zagury et al[100]	Brazil	Randomized control crossover trial	Clinical	34	Glycemia targeted specialized supplement PMR; Nutren Control®, Nestle	Replaced breakfast to provide 208 kcal	/	7 days
Protein rich MR (n = 13)
Keogh and Clifton[90]	Australia	Randomized controlled trial	Community	60	Probiotec Formula WL (Probiotec Limited, Laverton North, VIC, Australia 3026)	PMR; 2 MR (880 kJ each) and low-fat evening meal per day first 12 weeks + at least 5 serves of fruit and vegetables/day (total approximately 5000 kJ); 1 MR for further 12 weeks	/	24 weeks
Navas-Carretero et al[29]	Spain	Single group, sequential, longitudinal design	Clinical	17	4 weeks Structured meal replacements: Breakfast, morning snack and afternoon snack, were exchanged by specific products, with a moderately high protein content and low glycemic index (55); Enerzona© (Equipe Enervit)	TDR; approximately 1800 kcal	/	4 + 4 weeks
Manjunath[63]	India	Randomized, Parallel Group, Multiple Arm Trial Protocol	Clinical	120	Almased Soya protein powder with yogurt	PMR; First 6 months, Almased substituting one major meal/day; Dosage will be defined individually according to body weight. Next 6 months, Almased (50 g/day) added to the diet before one meal	/	6 + 6 months follow-up
Kempf et al[64]	Germany	Proof of principle study	Clinical	22	Almased-Vitalkost; Almased-Wellness-GmbH, Bienenbüttel, Germany	First week, breakfast, lunch and dinner replaced with Almased (50 g per meal = 150 g per day = 2223 kJ) + 45 g oil (1717 kJ) + 750 mL vegetable juice (544 kJ), Total 4903 kJ per day. 2-4 week: Breakfast and dinner (1465 kJ) + regular lunch (2093 kJ) + 45 g oil, total 4600-5300 kJ; 5-12 week, only dinner is replaced with 50 g Almased	/	12 weeks
Kempf et al[65]	Germany	RCT	Clinical	Strict diet regime N = 37; Moderate group N = 43	Almased®, Almased-Wellness-GmbH, Germany	PMR; Strict diet group replaced three meals in week 1, two meals in weeks 2-4 and one meal in weeks 5-12 with 1 g PMR (Almased®) per kg normal body weight.; Moderate group replaced two meals in weeks 1-4 and one meal in weeks 5-12	/	12 weeks + 9 months follow up
Kempf et al[120]	Germany	Conference paper; RCT	Clinical	55	Protein-rich meal replacement	PMR	/	12 weeks
Martin et al[66]	Germany	RCT	Clinical	Stringent diet regime (n = 40); moderate diet regime (n = 37)	Almased-Vitalkost, Almased Wellness GmbH, Bienenbüttel, Germany	1st week: Replaced 3 main meals by 50 g PMR = 1100 kcal/day; 2-4th week: 2 meals were replaced, and a protein-rich lunch was allowed; 5-12th week: Only dinner was replaced.; Moderate Group: Replaced breakfast and dinner for 5 weeks and then only dinner during the next 7 weeks		12 weeks
Li et al[74]	United States	RCT	Clinical	46	SlimFast Food Company, Inc. West Palm Beach, FL 33401, United States	Replace 3 meals per day for first 5 days of the study. Replace 2 meals for three additional months. After three months, replace one to two meals per day with MR	/	12 months
Kempf et al[68]	Germany	Single-blind, active comparator, intervention study	Clinical	102	Almased-Vitalkost, Almased Wellness GmbH, Bienenbüttel, Germany	1st week: Replaced 3 main meals by 50 g PRMR = 1100 kcal/day; 2-4th week: 2 meals were replaced, and a low carb protein-rich lunch was allowed; 5-12th week: Only dinner was replaced	Weekly care calls (planned duration 20 minutes) from trained diabetes coaches. Received a weighing scale, and a step counter; TeLiPro group additionally received a blood glucose meter	12 weeks; 26 weeks and 56 weeks follow up without intervention
Shirai et al[91]	Japan	Randomized Trial	Clinical	119	Protein Sparing Formula Diet (Microdiet, Sunny Health Co. Ltd)	PMR; One pack of MR in the morning providing 240 kcal/meal; 2 conventional Japanese meal in noon and evening	/	24 weeks
Durrer et al[94]	Canada	RCT Protocol	Clinical	100	Commercial diet plan (Ideal Protein)	Commercial diet plan with pre-packaged foods used for two meals and one snack each day. The third meal prepared from lower-fat protein sources and low-carbohydrate vegetables.; Meal plan: 850-1100 kcal per day	/	12 weeks
Kempf et al[67]	Germany	RCT	Clinical	M: Moderate diet group 146; S: Stringent diet group 139	Almased-Vitalkost; Almased-Wellness-GmbH, Bienenbüttel, Germany	PMR; Contained 30.6 g carbohydrates and 1507 kJ (360 kcal) energy per 100 g powder	/	12 weeks of intervention, and 52 weeks of follow-up
Papakonstantinou et al[59]	Greece	Randomized, crossover Protocol	Clinical	17	Optifast by Novartis Hellas, S.A.C.I., Metamorfossi, Greece	PMR; Replaced breakfast and lunch and made up 26% of their energy intake	/	/
Low fat MR (n = 1)
Barbosa-Yañez et al[81]	Germany	randomized, parallel group, intervention study	Clinical	43	Flavoured meal replacement powder [MODIFAST® (OTC Siebenhandl GmbH) Ulm, Germany]	TDR; 1000-1200 kcal/day, and less than 30% of the total energy intake (E%) is fat; 200 g of raw or steamed vegetables	/	3 weeks of intensive low-fat diet, 49 weeks of eucaloric diet under DGE guidelines
MR + lifestyle intervention programme (n = 10)
Delahanty et al[121]	United States	Randomized, assessor-blinded, practice-based clinical trial	Clinical	69	Shakes, bars, and pre-packaged entrees	PMR; Use of meal replacements was recommended (but not supplied) for 1-2 meals per day starting in week 3 based on the Look AHEAD protocol. Meal replacement use was not formally tracked	Lifestyle intervention delivered by registered dietitian with 37 session identical contents in in-person and telephone arm.; Medical nutrition therapy participants were referred to a dietitian at their health center or preferred location as per usual care	12 months
Wycherley et al[95]	Australia	Randomized clinical trial	Community	37	KicStartä, Pharmacy Health Solutions, New SouthWales, Australia	PMR; High-protein, energy-restricted diet (5500 kJ/day)	A group of only diet. Another group of diet + exercise; Walking/jogging exercise programme comprising four to five exercise sessions per week	12 weeks
McDiarmid et al[60]	United Kingdom	RCT	Clinical	79	Optifast 820	TDR; 8 weeks of Optifast 820 kcal/3430 kJ formula diet, followed by 4 weeks of food reintroduction. Both groups were asked to complete 56 days during their active weight loss phase	After active weight loss phase, participants will be separated into two groups with CLED following a portion-controlled Mediterranean diet 7 days per week while ILED follows a MR diet for 1-2 days and portion-controlled Mediterranean diet for 5-6 days a week	12 months
Reynolds et al[122]	United States	RCT	Clinical	21	Pre-packaged entrees and low-calorie shakes (Health Management Resources, Boston, MA, United States)	PMR; Replace two meals with at least 1500 kcal per day	Placebo or Rosiglitazone 4 mg/day; Lifestyle programme with weekly behavioural education classes for 6 weeks then bi-weekly classes for remainder of the study	6 months
Hamdy and Carver[96]	United States	Intervention study	Clinical	85	BOOST Glucose Control (Nestlé HealthCare Nutrition, Inc., Minneapolis, MN, United States)	PMR; A meal plan with a 500-cal reduction rounded to the nearest 1200-, 1500-, or 1800-cal level	Weekly cognitive behavioural support; Weekly group education; Intensive and interactive diabetes medication adjustment; Individualized exercise plan	12 weeks
Pi-Sunyer et al[50]	United States	RCT	16 Clinical Centres	2496 (97.1%) ILI; 2463 (95.7%) DSE	4 meal replacements to choose: SlimFast (SlimFast Foods), Glucerna (Ross Laboratories), OPTIFAST (Novartis Nutrition) and HMR (HMR, Inc.)	First 3 weeks: Self-selected diet with energy goal for persons < 114 kg is 1200-1500 kcal/day and is 1500-1800 kcal/day for individuals ≥ 114 kg. First 6 months: Replace two meals and one snack a day with liquid shakes and meal bars (1200-1500 kcal/day); Months 7 onwards to year 4: Replace one meal and one snack per day; Calorie targets personalized based on participants weight loss goals	1 hour diabetes education class on first visit + Three group educational/social support sessions each year for 4 years; Physical activity + Behavioural techniques	Intensive intervention for first 4 years, with an average of 10.25 years follow up
Lean et al[18]	United Kingdom	RCT	Clinical	149	Counterweight-Plus MR	TDR phase using a low energy formula diet (825-853 kcal/day)	Counterweight-Plus weight management programme	Total diet replacement of 3-5 months with stepped food reintroduction of 2-8 weeks and long-term weight maintenance program until month 12
Sattar et al[78]	United Kingdom	RCT	Clinical	25	TDR with Low energy liquid formula diet (Counterweight Pro 800)	Initial Total Diet Replacement phase (3-5 months); A commercial micronutrient-replete 825-853 kcal/day LELD is provided (Counterweight Pro 800) to replace normal foods	Counterweight-Plus’ weight management programme; Structured food reintroduction (6-8 weeks)	3 months minimum
Marples et al[79]	United Kingdom	Intervention study/service evaluation	Clinical	37	Phased LED TDR and PMR with Counterweight TDR products	TDR phase: 825-853 kcal/day; Food reintroduction phase: Gradual reduction in the formula product and the incorporation of nutritionally dense and energy-restricted meals (360-400 cal per meal). Weight Loss Maintenance phase	Behhaviour change techniques	TDR phase: 12 weeks; Food reintroduction phase: 9 weeks; Weight Loss Maintenance phase: 31 weeks
Dasgupta et al[62]	United Kingdom and Canada	RCT protocol	Clinical	50	Phased TDR and PMR with Optifast products (Nestlé)	First 2 weeks: Optifast products (Nestlé), totalling 800-900 kcal/day (30% protein, 50% carbohydrate and 20% fat).; Week 3-12: PMR with 800-900 kcal daily on non-exercise days and an additional 150-200 kcal from meal replacement products on exercise days. Week 12-24: Maintainence phase, individualized meal plan	Exercise training	24 weeks: 12 weeks MR and 12 week maintainence

RCT: Randomized controlled trial; MR: Meal replacement; PMR: Partial meal replacement; TDR: Total diet replacement; LCD: Low calorie diet; VLCD: Very low calorie diet; LELD: Low energy liquid diet; TEI: Total energy intake; VLED: Weight Plan products; DSNF: Diabetes specific nutrition formula; BMI: Body mass index.

Table 3 Outcome of meal replacement on hemoglobin A1c, glucose, weight, other health status and adverse effects

Ref.	Year	HbA1c	Glucose	Weight (kg)	Lipid profile	Other health status	Adverse effects
Low calorie/energy MR (n = 32)
Rothberg et al[75]	2014	1R	/	1R	/	/	Not reported
Tatti et al[41]	2010	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; HDL - 2I	SBP - 1R; DBP - 1R	Not reported
Steven et al[51]	2016	1R	1R	1R	1R	Plasma insulin levels - 1R	Not reported
Shantha et al[101]	2012	1R	/	1R	/	/	Not reported
Astbury et al[35]	2018	1R	1R	1R	NC	HOMA-IR - 2I	Constipation (1 in 7), fatigue (1 in 12), Headache (1 in 17), dizziness (1 in 22)
Baker et al[52]	2011	/	/	1R	/	Plasma insulin levels - 1R	Not reported
Bhatt et al[82]	2017	1R	1R	1R	Triglycerides - 1R; HDL - NC; LDL - NC	/	Not reported
Berk et al[42]	2016	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; HDL - 2I; LDL - 1R; Non-HDL Cho - 1R	/	Not reported
Shiau et al[54]	2017	1R	/	1R	/	/	Not reported
Cinkajzlová et al[102]	2017	/	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; HDL - 2I; LDL - 1R	/	Not reported
Taheri et al[40]	2019	1R	/	1R	Total cholesterol - 2I; Triglycerides - 1R; HDL - 2I; LDL - 2I	Diabetes remission% - 1R; Quality of life - 2I	Dizziness, constipation and other gastrointestinal; symptoms, hair loss, and fatigue
Harder et al[83]	2003	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; LDL - 1R	/	Not reported
Friedman et al[84]	2013	1R	1R	1R	/	Serum creatinine, cystatin C and estimated glomerular filtration rate- 1R; Albuminuria - 1R	Elevations in BUN and serum creatinine early in the diet, resolved after reducing doses of antihypertensive medications
Lean and Leslie[77]	2017	1R	/	1R	/	/	Not reported
Leader et al[55]	2012	1R	/	1R	/	/	Not reported
Overl et al[104]	2017	1R	/	1R	/	/	Not reported
Gulsin et al[69]	2020	1R	/	1R	/	Blood pressure - 1R	Not reported
Farrer and Golley[36]	2013	1R	/	1R	Cholesterol - NC	/	Not reported
Sumithran and Proietto[56]	2008	1R	1R	1R	/	/	Not reported
Rolland et al[105]	2013	/	/	1R	/	/	Not reported
Dhindsa et al[71]	2003	1R	/	1R	1R	BP - 1R	Not reported
Khoo et al[85]	2011	/	1R	1R	LDL - 1R	Quantitative Insulin Sensitivity check - 2I	Not reported
Moriconi et al[97]	2021	1R	/	1R	Total cholesterol - 1R	SBP - 1R	Not reported
Tang and Lin[86]	2020	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; HDL - 2I; LDL - 1R	/	Not reported
Maher et al[106]	2019	1R	/	1R	/	/	Not reported
Nori Janosz et al[34]	2008	1R	NC	1R	/	/	Not reported
Storck et al[57]	2021	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R	WC - 1R; Liver profile - 1R; Insulin and HOMAIR - 2I	Constipation (n = 5)
Schwasinger-Schmidt et al[107]	2020	1R	1R	1R	/	/	Not reported
Steven and Taylor[58]	2015	1R	1R	1R	1R	/	Not reported
Redmon et al[72]	2003	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; LDL - 1R	/	Dry mouth; Constipation; Mild hypoglycemia
Lips et al[87]	2014	/	1R	1R	/	HOMA-IR - 1R	Not reported
Abi-Chahine et al[108]	2021	1R	/	1R	/	Quality of life - 2I	Not reported
Rafey et al[113]	2022	1R	/	/	/	Leptin - 1R; Adiponectin - 2I	Not reported
Hocking et al[61]	2023	1R	/	1R	/	/	Two serious adverse events - hypotension
Anyiam et al[99]	2023	/	/	R	/	/	/
De Freitas et al[115]	2023	R	R	R	Total cholesterol - R; Triglycerides - R; HDL - I; LDL - R	HOMA-IR - R	/
Khoo et al[116]	2023	1R	/	1R	/	/	/
Low Glycemic Index MR (n = 5)
Stenvers et al[28]	2014	NC	1R	NC	NC	/	Altered defecation pattern and/or flatulence - n = 8; Nausea - n = 1; Mild attack of gout - n = 1
Foster et al[88]	2013	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; HDL - 2I; LDL - 1R	BP - 1R	No related adverse effects
Boonyavarakul et al[39]	2018	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 2I; LDL - 1R	/	Not reported
Li et al[33]	2014	1R	NC	1R	/	/	Not reported
Eliana and Pranoto[117]	2018	/	1R	/	/	/	Vomiting - n = 1; Soft stools - n = 1
Santen et al[89]	2023	1R	/	1R	Total cholesterol - R	/	/
Diabetes specific formulas (n = 13)
Belcaro et al[32]	2009	1R	1R	1R	/	/	No adverse effects
Fonda et al[43]	2010	/	1R	/	/	/	Not reported
Garvey et al[119]	2006	1R	1R	1R	HDL-C - 2I	Insulin sensitivity - 2I; SBP and DBP - 1R; Quality of life - 2I	Not reported
Sun et al[37]	2008	1R	1R	1R	NC	/	Not reported
Peng et al[44]	2019	1R	1R	1R	Triglycerides - 1R	SBP - 2I; HOMA-IR - 2I	Not reported
Chee et al[45]	2017	1R	1R	1R	HDL - 2I; LDL - 1R	SBP - 1R	Not reported
Lansink et al[31]	2011	/	NC	1R	/	/	Low incidence and mild intensity of reported abdominal pain
Mottalib et al[30]	2018	1R	NC	1R	Total cholesterol - NC; HDL - 2I; LDL - NC	/	Not reported
Otto et al[48]	2009	1R	/	1R	/		Not reported
Yip et al[73]	2001	1R	1R	1R	Total cholesterol - 1R; LDL - 1R	Insulin levels - 1R	Not reported
Mottalib et al[38]	2016	/	1R	/	NC	/	Not reported
Cheskin et al[80]	2008	1R	1R	1R	HDL: 34 weeks - 2I; 86 weeks - 2I	SBP and DBP - 1R	Not reported
Mustad et al[49]	2020	/	1R	/	/	/	Not reported
Dharmalingam et al[93]	2022	1R	1R	1R	Total cholesterol - R; Triglycerides - R; HDL - I; LDL - I	/	No serious adverse events; Six mild adverse effects: Loss of appetite, stomach bloating, peripheral leg edema, burning micturition, and urinary retention
Zagury et al[100]	2022	/	1R	/	/	/	No serious adverse events. 4 participants (13%) had mild diarrhea and 3 participants (10%) had mild nausea
Protein rich MR (n = 10)
Keogh and Clifton[90]	2012	1R	1R	1R	Total cholesterol - 1R; Triglycerides - 1R; LDL - 1R	SBP and DBP - 1R	Not reported
Navas-Carretero et al[29]	2011	/	NC	1R	NC	/	Not reported
Kempf et al[64]	2014	1R	1R	1R	Triglycerides - 1R; HDL - 2I	/	Not reported
Kempf et al[65]	2014	/	/	1R	/	SBP and DBP - 1R	Not reported
Kempf et al[120]	2015	1R	/	1R	/	/	Not reported
Martin et al[66]	2014	1R	/	1R	/	/	Not reported
Li et al[74]	2005	1R	1R	1R	/	High-sensitivity C-reactive protein - 1R	Not reported
Kempf et al[68]	2017	1R	1R	1R	/	SBP - 1R; Quality of life and eating behaviour - 2I	Not reported
Shirai et al[91]	2013	1R	1R	1R	HDL - 2I	Insulin and HOMAIR - 1R; Leptin - 1R; Adiponectin - 2I; Lipoprotein lipase mass - 2I	Not reported
Kempf et al[67]	2018	1R	1R	1R	/	/	Not reported
Low fat MR (n = 1)
Barbosa-Yañez et al[81]	2018	1R	/	1R	1R	/	Not reported
MR + lifestyle intervention programme (n = 9)
Delahanty et al[121]	2020	1R	/	1R	/	/	Not reported
Wycherley et al[95]	2008	/	1R	1R	/	/	Not reported
Reynolds et al[122]	2002	1R	/	1R	Total cholesterol - 1R; LDL - 1R	WC- 1R; BP - 1R	Not reported
Hamdy and Carver[96]	2008	1R	/	1R	1R	/	Not reported
Pi-Sunyer et al[50]	2009	1R	1R	1R	Triglycerides - 1R; HDL - 2I	WC - 1R	Not reported
Lean et al[18]	2018	1R	/	1R	/	Quality of life - 2I	65% reported constipation, 57% reported sensitivity to cold and 53% reported headache
Sattar et al[78]	2023	R	R	1R	Total cholesterol - R; HDL - R	WC - R	/
McDiarmid et al[142]	2021	R	/	1R	/	/	/
Marples et al[79]	2022	1R	/	1R	Total cholesterol - R; Triglycerides - 1R; HDL - I; LDL - R	/	No serious adverse events were reported.; Mild side-effects: Constipation, diarrhoea, nausea, fatigue and feeling cold

¹Significant reduction.

²Significant increment.

I: Non-significant increment; R: Non-significant reduction; NC: No changes; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; HOMA-IR: Homeostatic model assessment of insulin resistance; WC: Waist Circumference; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HbA1c: Hemoglobin A1c.