The effect of meal replacements therapy on blood pressure and C-reactive protein: a systematic review and meta-analysis of randomized controlled trials

Abstract

Although some evidence shows the beneficial effects of meal replacement (MR) on blood pressure (BP) and inflammation as one of the main factors of cardiovascular disease, there are still no comprehensive findings in this field. Therefore, we investigate the effects of total and partial MRs on BP and C-reactive protein (CRP) in this comprehensive study and meta-analysis. In order to identify all randomized controlled trials that investigated the effects of MRs on BP and CRP levels, a systematic search was conducted in the original databases using predefined keywords. The pooled weighted mean difference (WMD) and 95% confidence intervals (CIs) were computed using the random-effects model. Forty studies were included in this article. The findings indicated significant reductions in systolic blood pressure (SBP) (WMD, −2.51 mmHg; 95% CI, −3.48 to −1.54; P < 0.001), diastolic blood pressure (DBP) (WMD, −1.43 mmHg; 95% CI, −2.02 to −0.85; P < 0.001), and CRP (WMD, −0.50 mg/L; 95% CI, −0.89 to −0.11; P = 0.012) levels following MR consumption compared to the control group. The findings obtained from the subgroup analysis showed that MRs cause a greater reduction in SBP in people over 50 years of age, and the duration of the intervention ≤ 24 weeks. Also, the subgroup analysis shows the greater effect of DBP and CRP, respectively, in the type of intervention with total meal replacement and less equal to 50 years. In conclusion, it appears that MR, along with other lifestyle factors, can lead to significant improvements in BP and CRP.

BACKGROUND

Cardiovascular disease (CVD) remains a major cause of death and long-term disability worldwide [1,2]. One of the prominent risk factors that significantly contributes to CVD and overall mortality on a global level is hypertension [3,4,5]. Over the span of nearly three decades, the prevalence of hypertension among individuals aged 30–79 years has experienced a 2-fold increase, with the number of affected women and men rising from 331 million women and 317 million men in 1990 to 626 million women and 652 million men in 2019 [6]. In light of these alarming statistics, research has shed light on the impact of hypertension on the lifetime susceptibility to CVD. A comprehensive study involving a substantial sample size of 1.25 million patients revealed that individuals diagnosed with hypertension exhibited a greater lifetime susceptibility to CVD compared to those without hypertension (63% vs. 46%) and, on average, experienced the onset of CVD 5 years earlier [7]. Additionally, understanding the role of inflammation in cardiovascular events is also crucial. Studies have demonstrated correlations between inflammation biomarkers, such as C-reactive protein (CRP), and the likelihood of future cardiovascular events [8,9].

Meanwhile, meal replacement (MR) products have become increasingly popular as a convenient and potentially effective dietary choice for achieving various health objectives. MRs are specially formulated food products designed to provide a controlled balance of macronutrients while replacing one or more daily meals, often used in weight management or clinical nutrition. Typically, MRs are low in fat and carbohydrates while being rich in protein, fiber, and essential vitamins and minerals to ensure adequate nutrition despite calorie restriction [10]. These products are commercially available in various forms, including shakes, bars, and powders, and are often prescribed as part of medically supervised dietary interventions for obesity, diabetes, and metabolic disorders [11]. The duration of MR prescription varies depending on individual health goals and clinical recommendations, ranging from short-term weight loss programs to longer-term maintenance phases [12]. The idea of substituting one or more daily meals with MRs has attracted attention due to its potential advantages in weight control [11,13,14]. Nevertheless, the advantages of MR are not solely confined to weight management. Findings regarding some parameters [13,14,15], which are related to cardiovascular disease, indicate that MR benefits encompass a broader scope.

This article aims to review the current literature regarding the effects of MRs, including partial meal replacement (PMR) and total meal replacement (TMR), on several cardiovascular risk factors. Particularly, we will focus on systolic blood pressure (SBP), diastolic blood pressure (DBP), and CRP levels. We will also perform subgroup analysis by considering the duration and type of intervention (PMR and TMR) as well as the mean age of participants. Furthermore, we will propose several hypotheses that may impact the effectiveness of MRs regarding blood pressure (BP) and CRP. Ultimately, we will emphasize the constraints of the current studies and propose potential avenues for future research.

METHODS

Search strategy

The parameters of this investigation were in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis criteria [16]. A comprehensive search was conducted in the PubMed/MEDLINE, Web of Science, Scopus, and Embase databases, with no limitations on language or timeframe, during the period ending in February 2024. Furthermore, the search encompassed relevant academic articles, as well as unpublished or unconventional sources of information. Embase Subject Headings and National Library of Medicine Medical Subject Headings were chosen to simplify searches in online databases. The reference lists of the collected publications and connected review papers were manually checked to identify any eligible trials that may have been missed.

Eligibility criteria

The procedure involved the identification and evaluation of pertinent publications, followed by the individual removal of duplicate articles by scrutinizing their titles, abstracts, or entire texts by 2 researchers. In the end, the papers were categorized according to the criteria that were previously set forth: 1) A randomized clinical trial methodology was implemented in the investigation. 2) The intervention entailed the recommendation of a specialized formula as a PMR (2 main meals or less) and TMR (all main meals) for individuals who were ≥ 18 years. SBP, DBP, and CRP were measured at baseline and post-intervention in both the intervention and control groups. 4) The intervention extends beyond 2 weeks. When reporting outcomes at multiple follow-up intervals, the research study utilized data from the most recent or longest follow-up period. Reviews and meta-analyses were excluded from the analysis, as were studies with duplicated data, studies with ambiguous or confusing information, studies with non-randomized trial designs, studies conducted on animals, and studies without a control group. The Population, Intervention, Comparison, Outcomes and Study criteria, which were employed to ascertain which studies were included and excluded, were as follows. Individuals who were 18 years of age or older comprised the sample population. The intervention that was being examined involved the provision of formula as a partial or complete diet substitution. Individuals who were administered either a standard diet or a control diet comprised the comparison group. SBP, DBP, and CRP comprise the variables under investigation in this investigation. The study design employed in the research investigation was randomized clinical trials.

Data extraction

The qualifying research was independently analyzed by the writers. Factors such as the initial author’s name, the study’s location, the year of publication, the number of participants in the intervention and control groups, demographic information about the participants (including the proportion of males, body mass index [BMI], age, and health status), the nature and length of the intervention, and the average and standard deviations (SDs) of the intended outcomes at the start, end, and/or changes between the start and end of the intervention were all collected.

Quality assessment

Using the most recent version of the Cochrane risk-of-bias tool for randomized trials (RoB 2), the trial’s methodological quality was evaluated [17]. A number of possible causes of bias were investigated and ranked by the study’s authors: insufficient outcome data, biased reporting, blinding of participants and staff, blinding of allocation concealment, blinding of volunteers and researchers, and random sequence formation. Each research was evaluated by two authors who separately determined the level of bias and labeled it as low, high, or uncertain. In order to reach a consensus, a third author was brought in to carefully address any disagreements. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) grading system to check how well this analytical study held up. An all-encompassing 10-point grading method that evaluates several factors impacting study quality is the GRADE checklist. There are a total of 7 distinct parts to the scale, and they are as follows: 1) bias risk; 2) precision; 3) heterogeneity; 4) directness; 5) publication bias; 6) funding bias; and 7) research design [18].

Data synthesis and statistical analysis

The STATA version 12.0 software was used to analyze the data. Also, by using Endnote, we were able to efficiently sort appropriate articles and eliminate duplicates. To determine the means and SDs [19,20], the data were subjected to a predetermined conversion procedure. In cases when standard deviations are unavailable, the following method was used to determine the change: A method to calculate the change in standard deviation is to first find the square root of the squared difference between the baseline and final standard deviations. Next, subtract twice the product of the correlation coefficients between the baseline and final standard deviations from the sum of the squared final standard deviation. This will give you the change in standard deviation. Once the standard error of the mean (SEM) is obtained, it can be converted to standard deviation using this formula: multiplying SEM by the square root of the number of participants in each group results in the SD. The results of the meta-analysis were examined using the random-effects model. In the normal inverse variance fashion, the research was weighted. The study used data from the longest length time point, which allowed for many exams to be included in the same research group. Using Q-statistics and I-squared (I²), we evaluated the heterogeneity of the studies. There were four categories for the heterogeneity according to the study: low, moderate, high, and insignificant. Values for I² ranged from 0% to 25% for the first level, 26% to 50% for the second, 51% to 75% for the third, and 76% to 100% for the fourth level [21]. A preplanned subgroup analysis was carried out to investigate potential factors contributing to heterogeneity. These factors included the average age of participants, the length of the intervention, and the kind of intervention. If we wanted to know how each study affected the mean difference, we ran a sensitivity analysis. We used the Egger’s test, a well-established statistical method, to assess the presence of publication bias [22].

RESULTS

Including exclusion criteria in the study selection process is shown in the flowchart (Fig. 1). A grand total of 2,095 items were generated by the electronic databases mentioned before. The remaining number of publications after deleting useless research was 1,474. The study excluded 1,385 articles that did not fulfill the inclusion criteria after reviewing their titles and abstracts. During the secondary screening step, a thorough full-text search method yielded 89 articles. The reasons stated above led to the cancellation of 49 investigations. issues such as a lack of control groups (n = 19), studies with designs that did not meet the inclusion criteria (n = 6), studies with inadequate data (n = 5), interventions lasting less than four weeks (n = 3), and the prescription of a non-formula diet substitution (n = 6) are all issues to consider. The quantitative meta-analysis comprised 40 publications, each with 43 treatment arms, that fulfilled the inclusion criteria.

Fig. 1. Flow chart of the study, including identification, screening, eligibility, and the final sample included.

Study characteristics

Table 1 displays the attributes of the combined articles [12,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. Table 1 reveals that a total of 10 studies were carried out in the Americas, 13 in Asia, 15 in Europe, and 2 in Australia. Furthermore, with the exception of one study that utilized a cross-over design, all the other publications were conducted in parallel. The papers analyzed in this study were published from 2000 to 2023. The follow-up interventions lasted between 8 and 144 weeks. Initially, the mean age and percentage of male participants ranged from 33 to 61.9 years and 0% to 100%, respectively. The average BMI at the initial stage ranged from 26.2 to 40.4 in the studies that were considered. In 6 studies, the majority of the MRs were administered as a complete MRs, while the remaining MRs were given to individuals in a partial MRs form. Our research indicates that all studies have exclusively focused on participants who are overweight or obese, with some of these individuals also having type 2 diabetes or metabolic syndrome.

Table 1. Characteristics of eligible studies.

Studies	Years	Country	Population	Mean age (yr)	Sex (male %)	Sample size of study		Follow up of intervention (wk)	Type of RCTs	Intervention group	Control group	Baseline of BMI (kg/m2)
						Intervention	Control
Kreider et al. [23]	2010	USA	Obese and apparently healthy women	41.4	0	40	37	34	Parallel	Participants in the MRP group replacing 2 meals per day with SK RTE cereal (SK Original, Kellogg Company, Battle Creek, MI, USA), 2/3 cc skim milk, and a serving of fruit + calorie restriction 500 kcal.	Supervised exercise program (SDE) consisted of a 1-week structured diet plan (1,200 kcal/day) during phase I, followed by a 9-week diet plan (1,600 kcal/day) during phase II.	33.5
Lean et al. [24]	2018	England	Remission of T2DM	52.9	59	149	149	48	Parallel	The total diet replacement (825–853 kcal/day formula diet for 3–5 months), stepped food reintroduction (2–8 weeks), and structured support for long-term weight loss maintenance.	Best-practice care by guidelines.	35.1
Armborst et al. [25]	2018	Germany	Overweight women	50.2	0	40	40	24	Parallel	The MR (phase 1 for 3 month)-group was advised to replace 2 of 3 daily meals with MRs and energy-restricted diet with a balanced variety of nutrient-dense food of approximately 1,200 kcal/day.	The control (phase 1 for 3 month) group was advised to follow a conventional energy restricted modified diet.	31.2
Davis et al. [12]	2010	USA	Obese adults	43	45.55	45	45	40	Parallel	The intervention diet plan (Medifast 5 & 1 plan) included 5 MRs (90–110 kcal/each), 5–7 oz lean protein, 1 1/2 cups of non-starchy vegetables, and up to 2 fat servings daily (providing 800–1,000 kcal).	Isocaloric food-based plan (FB) using guidelines from the USDA Food Guide Pyramid, both providing ~1,000 kcal per day.	38.5
Rock et al. [26]	2014	USA	Overweight or obese adults with type 2 diabetes	57.3	47.05	77	76	48	Parallel	Low carbohydrate diet: Three entrees and one to two snacks were provided for 7 days/week during the initial weight loss phase (months 1–6) and for 5 days/week during a transition and for 5 days/week during a transition one snack daily was provided, as de sired, during the maintenance phase (months 10–12) + weight loss program diet meal plans were reduced in energy relative to expenditure (typically 1,200–2,000 kcal/day).	Usual care: Consultation at baseline and at 6 months with a research dietician who provided print materials on dietary and physical activity guidelines for weight loss and weight loss maintenance.	36.2
										Low fat diet: Three entrees and one to two snacks were provided for 7 days/week during the initial weight loss phase (months 1–6) and for 5 days/week during a transition and for 5 days/week during a transition one snack daily was provided, as de sired, during the maintenance phase (months 10–12) + weight loss program diet meal plans were reduced in energy relative to expenditure (typically 1,200–2,000 kcal/day).
Metzner et al. [27]	2011	Germany	Overweight women	49.8	0	43	44	12	Parallel	Energy-restricted modified of approximately 1,200 kcal/day diet with MRs for weight control (the MR group was advised to replace two meals, i.e. breakfast and dinner, every day with 2 MR shakes, soups or bars).	Energy-restricted modified of approximately 1,200 kcal/day diet.	31.2
Guo et al. [28]	2018	China	Individuals with overweight and obesity	39.15	45.9	86	88	12	Parallel	The intervention group was advised to consume one liquid MR and 388 kcal in total energy at dinner time during the intervention.	The routine diet group (control group).	29.35
Shirai et al. [29]	2012	Japan	Obese type 2 diabetic patients	50.5	37	119	110	24	Parallel	Low-caloric diet with partial use of formula diet group (FD): one pack of formula diet (MicroDiet®, 240 kcal/pack) in place of one of three daily low-caloric meals.	Conventional low-caloric diet group.	30.8
Astbury et al. [30]	2018	UK	Obese adults	48	39	138	140	48	Parallel	Total MR dietary intervention: The TMR programme comprised weekly behavioural support for 12 weeks and monthly support for three months, with formula food products providing 810 kcal/day (3,389 kJ/day) as the sole food during the first eight weeks followed by reintroduction of food.	Usual care: Usual care comprised behavioural support for weight loss from a practice nurse and a diet programme with modest energy restriction.	37.2
Truby et al. [31]	2006	UK	Overweight and obese adults	38.9	NA	58	61	24	Parallel	The MR (Slim-Fast): Two MRs each day.	Usual care: Maintain current diet and exercise pattern.	32.2
Cheskin et al. [32]	2008	USA	Obese participants with T2DM	54.6	43.95	16	8	86	Parallel	Portion-controlled MR diet (PCD) using Medifast Plus: A 25% of energy calorie deficit was used to construct the weight-loss-phase diet, and a 10% calorie deficit (based on the new body weight after weight loss) was used to construct the weight-maintenance-phase diet.	Standard diet (SD): A 25% of energy calorie deficit was used to construct the weight-loss-phase diet, and a 10% calorie deficit (based on the new body weight after weight loss) was used to construct the weight-maintenance-phase diet.	35.3
Halle et al. [33]	2020	Germany	Patients with overweight or obesity and accompanied cardiovascular risk factors	50.5	37.05	308	155	52	Parallel	Liquid MR (INT): INT obtained a liquid MR substituting three meals/day (~1,200 kcal) within the first week. During weeks 2–4, participants replaced two meals/day and during weeks 5–26 only one meal/day was substituted (1,300–1,500 kcal/day).	Lifestyle intervention only.	31.6
Ard et al. [34]	2023	USA	Obese adults	47.15	17.55	110	107	52	Parallel	Partial or total MR programme (MRP; total for first 26 weeks included 5 MR servings per day [800 kcal], partial for the ensuing 26 weeks; calories were gradually increased to achieve weight stability and participants were advised to use 1 to 2 MR products daily during this time) with OPTIFAST.	Low-calorie food based (FB) dietary plan (the FB diet followed a modified version of the Diabetes Prevention Program prescribing a calorie-restricted diet [fat accounted for 25%–30% of total calories] reduced by 500–750 kcal below the estimated total energy expenditure).	38.4
Brown et al. [35]	2019	UK	Obese participants with T2DM	58.5	43.3	45	45	48	Parallel	Low-energy TDR intervention: participants commenced a 12-week TDR formula low-energy diet followed by 12 weeks of structured food reintroduction and then ongoing follow-up in combination with an energy deficit diet at 3-month intervals until 12 months.	Standardized dietetic care: Participants received behavioral support to aid lifestyle adherence and maintenance and were encouraged to undertake moderate exercise.	36.7
Xu et al. [36]	2012	China	Subjects with impaired glucose regulation	60.35	45.6	41	40	48	Parallel	The intervention group also received a daily MR and intensive lifestyle intervention to promote healthy eating habits during the first 3 months of the study, and follow-up visits performed monthly until the end of the 1-year study. It was used to replace breakfast food items.	The intensive lifestyle intervention.	26.8
Wadden et al. [37]	2018	USA	Obese adults	48	20	50	50	52	Parallel	IBP-liraglutide combined for 12 weeks with a 1,000- to 1,200-kcal/d meal-replacement diet that provided four servings daily of a liquid shake (health management resources, 160 kcal per shake) and an evening meal of a frozen food entrée (250–300 kcal).	IBP-liraglutide combined for 12 weeks.	38.8
Taheri et al. [38]	2020	Qatar	Early T2DM	42.1	73	70	77	48	Parallel	The intensive lifestyle intervention group: The intensive lifestyle intervention comprised a total diet replacement phase, in which participants were given formula low-energy diet MR products followed by gradual food reintroduction combined with physical activity support, and a weight loss maintenance phase, involving structured lifestyle support.	Usual medical care: Participants in the control group received usual diabetes care, which was based on clinical guidelines.	34.9
Chaiyasoot et al. [39]	2018	Thailand	Obese adults and metabolic syndrome	42.5	17	48	45	12	Parallel	LEI with partial MR: In this group were supplied with high-protein MR and instructed to replace two main meals daily with one sachet per meal (2 sachets per day), which were either breakfast, lunch or dinner throughout the 12-week period.	LEI.	34.6
Astbury et al. [40]	2021	UK	Obese Adults	50.8	44.8	96	83	12	Parallel	Total diet replacement: The intervention was TMR for 8 weeks, followed by food-reintroduction over 4 weeks. Behavioral support was provided weekly for 8 weeks, bi-weekly for the next 4 weeks, then monthly for 3 months after which no further support was provided.	The usual care (UC) group received dietary advice and behavioral support from a practice nurse for up to 3 months.	37.5
Siener et al. [41]	2022	Germany	Overweight Women	49	0	37	41	12	Parallel	Conventional energy-restricted modified diet (with a balanced selection of nutrient-dense foods at approximately 1,200 kcal per day) with MR (the MR group was advised to replace 2 of 3 meals per day with MR products).	Conventional energy-restricted modified diet (with a balanced selection of nutrient-dense foods at approximately 1,200 kcal per day).	31.7
Röhling et al. [42]	2020	Germany	Persons with prediabetes	52.5	29.1	96	45	52	Parallel	Lifestyle intervention group accompanied with a formula diet (INT): INT received a low-carbohydrate formula diet substituting 3 meals/day (~1,200 kcal/day) within the first week, 2 meals/day during week 2–4, and one meal/day during week 5–26 (1,300–1,500 kcal/day).	Lifestyle intervention group only.	32.2
Arterburn et al. [43]	2018	USA	Adults with overweight or obesity	45.7	19.2	67	63	16	Parallel	Pre-portioned MRs (the reduced-calorie Medifast® 4 & 2 & 1 self guided plan; MED): Consists of 4 Medifast classic MRs, 2 lean and green meals and 1 healthy snack. The 4 & 2 & 1 plan is intended to provide 1,100–1,300 kcal.	Self-directed, reduced-calorie control diet.	34.2
										Pre-portioned MRs (the low-calorie OPTAVIA® 5 & 1 Plan® with telephone coaching; OPT): This plan consists of 5 MRs and 1 lean and green meal and is intended to provide 800–1,000 kcal/day.
Lee et al. [44]	2015	Taiwan	Metabolic syndrome subjects	49.7	26.9	45	44	12	Parallel	CR MR: This group received the CR diet (500–800 kcal/day less than the participants’ regular daily dietary intake) and low-calorie Nutrition Drink Mix powder for partial MR.	CR only.	29.7
Tsai et al. [45]	2009	Taiwan	Obese individuals	42	20/8	60	60	12	Parallel	Green tea MR formula: 5 MR.	Normal diet.	33/1
Shikany et al. [46]	2013	USA	Obese individuals	40.2	11.7	57	56	52	Parallel	The Medifast 5 & 1 Plan (MD): The plan consisted of five portion-controlled, nutritionally-balanced, low-fat meals plus one “Lean & Green” meal each day. MD provided approximately 800–1,000 kcal/day.	Reduced-energy, food-based diet (FB): Participants randomly assigned to the FB group were provided with a 1,000-kcal/day meal plan based on regular foods selected, procured, and prepared by the participants.	40.4
Flechtner-Mors et al. [47]	2000	Germany	Obese Patients	45.2	21	50	50	12	Parallel	Isoenergetic diet, including 2 meal and snack replacements and one meal high in fruits and vegetables: Two of three daily meals were replaced by diet shakes (SlimFast).	Prescribed a 1,200 to 1,500 kcal/day control diet.	33.6
Clifton et al. [48]	2005	Australia	Overweight Australians with raised triglycerides	49.3	58/1	26	29	12	Parallel	MR: MR were advised to consume 2 MRs as Slimfastt (1,800 kJ), a low-fat evening meal per day and at least five serves of fruit and vegetables/day (3,500 kJ) as outlined in the Slimfastt literature.	Control group (C) with conventional low-fat diet (subjects randomized to C were advised to follow a structured low-fat high carbohydrate diet).	31.8
Khoo et al. [49]	2011	Australia	Obese diabetic men	59.7	100	19	12	52	Parallel	MR-based LCD ~1,000 kcal/day: Subjects in the LCD group consumed 2 sachets daily (one at breakfast and lunch or dinner) of a liquid MR.	Low-fat, high-protein, reduced-carbohydrate (HP) diet.	35.3
Flechtner-Mors et al. [50]	2010	Germany	Metabolic syndrome subjects	49.3	20	31	49	144	Parallel	Protein-enriched MRs (P group): In the first 3 months, subjects in the P group consumed 2 protein enriched MRs, one conventional meal, and two snacks as either a protein bar or a low-fat curd with fruit. After the first 3 months, participants in the P group consumed one protein-enriched MR, 2 meals, and 2 snacks, meeting an increased protein goal.	Conventional diet (C group): Subjects in the conventional diet group consumed three meals and two snacks with no replacements for the first 3 months. after 3 month, the C group consumed one standard MR, 2 meals, and 2 snacks per day, meeting the conventional protein goal.	36.2
Sun et al. [51]	2008	China	T2DM	51	71	100	50	24	Parallel	The Intervention Group received more intensive intervention, including diabetes education with frequent blood glucose monitoring, nutritional counseling, meal plans with diabetes-specific nutritional MR: Participants in the Intervention Group were also provided with a low glycemic,12 diabetes-specific nutritional MR that they used to replace breakfast food.	The Reference Group received diabetes education including diet and physical activity instruction only.	26.9
Zhong et al. [52]	2023	China	Obese individuals	33	69.6	33	33	13	Parallel	Low carbohydrate diet combined with partial MR: 38 g nutritional protein powder for breakfast and dinner to replace staple foods.	Low carbohydrate diet only.	30.5
Stenvers et al. [53]	2014	Netherlands	Diagnosed and untreated T2DM	60	50	20	20	12	Cross-over	Liquid MR with a low glycaemic response: breakfast replacement consisting of an isoenergetic amount of Glucerna SR.	Free-choice breakfast.	30
Gulati et al. [54]	2017	India	Overweight/obese Asian Indians	39.8	42/65	62	60	12	Parallel	HPMR: Participants assigned to the HPMR group were instructed to replace two daily meals (mainly breakfast and dinner, but flexible replacement allowed) with commercially available whey and soya protein isolates in the form of a protein shake.	Conventional diet: diet rich in vegetables and fruits; select whole-grain, high-fibre foods; Select fat-free or low-fat dairy products.	30.4
Kempf et al. [55]	2017	Germany	T2DM	59	54	93	74	52	Parallel	The Telemedical Lifestyle intervention Program (TeLiPro): TeLiPro is a newly developed 12-week multimodal approach that combines telemonitoring, telemedical coaching, a structured lifestyle intervention program including dietary intervention with a protein-rich MR therapy, self-monitoring of blood glucose, and evaluated mental motivational training.	The control subjects remained in routine care (quarterly visits with their attending physician for routine health care visits as defined by the Disease Management Programs for Type 2 Diabetes in Germany).	35.3
Gulsin et al. [56]	2020	USA	Working-age adults with T2DM	50.5	59	24	22	12	Parallel	Low-energy MR diet (MRP).	Routine care.	36.6
Shih et al. [57]	2019	Taiwan	Overweight white-collar workers	38.7	50	29	27	8	Parallel	White sweet potato MR: The WSP-MR group was advised to replace 2 daily meals, namely lunch and dinner, with 2 packs of shakes and one normal diet meal. The participants received a daily serving of two packets with 132 g of WSP-MR formula.	The normal diet in daily three meals comprised vegetables, fruits, whole grain cereals, lean meat, and low-fat dairy products.	24.99
Sawashita et al. [58]	2009	Japan	Middle-aged and older overweight	61.9	100	40	23	24	Parallel	MCR and HIW: The MCR + HIW group consumed MR formula (240 kcal): a mixture of low-carbohydrates and -fat and high-protein, for either lunch or dinner everyday.	High-intensity interval walking (HIW) only.	26.2
Ashley et al. [59]	2001	USA	Premenopausal women	41.4	0	26	23	96	Parallel	Traditional Dietitian Intervention Group incorporating MRs: This group received similar self-selected diets, except that 2 of the 3 main meals (breakfast, lunch, or dinner) were replaced with MR shakes or MR bars (Slim-Fast).	Traditional Dietitian Intervention Group: The diet consisted of all meals and snacks prepared from self-selected conventional foods.	30
Lean et al. [60]	2019	UK	T2DM	54.4	59.1	129	143	96	Parallel	Weight management programme (intervention): The intervention comprised withdrawal of anti-diabetes and antihypertensive drugs, total diet replacement (825–853 kcal/day formula diet) for 12–20 weeks, stepped food reintroduction (2–8 weeks), and then structured support for weight loss maintenance.	Best-practice care by guidelines.	34.6
Chee et al. [61]	2017	Malaysia	T2DM	55	37	57	115	24	Parallel	MRs: Replace 1 or 2 meals with a diabetes-specific formula MR. Behavioral support provided using conventional counselling.	Followed the clinical care pathway of the Malaysian clinical practice guidelines for T2DM and received advice to follow a conventional low-calorie diet.	29.4
										MRs: Replace 1 or 2 meals with a diabetes-specific formula MR. Behavioral support provided using motivational interview.

RCT, randomized controlled trial; BMI, body mass index; MRP, meal replacement plan; T2DM, type 2 diabetes mellitus; MR, meal replacement; USDA, United States Department of Agriculture; TMR, total meal replacement; TDR, total diet replacement; IBT, intensive behavioral therapy; LEI, lifestyle education intervention alone; CR, calorie-restriction; LCD, low-calorie diet; HPMR, high-protein meal replacement; MCR, mild calorie restriction; HIW, high-intensity interval walking.

Table 2 shows the results of the evaluation that was done to determine how good the studies were that met the criteria [12,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. Furthermore, a GRADE score of 9.2 was obtained, indicating that the present meta-analysis is of good quality, when evaluating its quality.

Table 2. Risk of bias assessment according to the Cochrane collaboration’s risk of bias assessment tool.

Studies	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Overall assessment of risk of bias
Kreider et al. [23]	Low	Low	Low	Low	Unclear	Low	Low
Lean et al. [24]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Armborst et al. [25]	Low	Low	Low	High	Unclear	Low	Unclear
Davis et al. [12]	Low	Low	Low	Low	Unclear	Low	Low
Rock et al. [26]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Metzner et al. [27]	Low	Low	Low	Low	Unclear	Low	Low
Guo et al. [28]	Low	High	Low	Low	Unclear	Low	Low
Shirai et al. [29]	Low	Low	High	Low	Unclear	Low	Unclear
Astbury et al. [30]	Low	Low	Unclear	Low	Unclear	Low	Low
Truby et al. [31]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Cheskin et al. [32]	Low	Low	Low	Low	Unclear	Low	Low
Halle et al. [33]	Low	Unclear	Unclear	Low	Unclear	Low	Low
Ard et al. [34]	Low	High	High	Low	High	Low	High
Brown et al. [35]	Low	Low	High	Unclear	Unclear	Low	Unclear
Xu et al. [36]	Low	Low	Unclear	Unclear	Unclear	Low	Unclear
Wadden et al. [37]	Low	Low	High	Low	Unclear	Low	Unclear
Taheri et al. [38]	Low	Low	Unclear	Low	Unclear	Low	Low
Chaiyasoot et al. [39]	Low	Low	Unclear	Unclear	Unclear	Low	Unclear
Astbury et al. [40]	Low	Low	High	Low	Unclear	Low	Unclear
Siener et al. [41]	Low	Low	Unclear	Low	Unclear	Low	Low
Röhling et al. [42]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Arterburn et al. [43]	Low	Low	Unclear	Unclear	Unclear	Low	Unclear
Lee et al. [44]	Low	Low	Low	Low	Unclear	Low	Low
Tsai et al. [45]	Low	High	Low	Low	Unclear	Low	Low
Shikany et al. [46]	Low	Low	Unclear	Low	Unclear	Low	Low
Flechtner-Mors et al. [47]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Clifton et al. [48]	Low	Low	Unclear	Unclear	Unclear	Low	Unclear
Khoo et al. [49]	Low	Low	Unclear	Low	Unclear	Low	Low
Flechtner-Mors et al. [50]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Sun et al. [51]	Low	Low	Low	Low	Unclear	Low	Low
Zhong et al. [52]	Low	High	Low	Low	Unclear	Low	Low
Stenvers et al. [53]	Low	Low	High	Low	Unclear	Low	Unclear
Gulati et al. [54]	Low	Low	Unclear	Low	Unclear	Low	Low
Kempf et al. [55]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Gulsin et al. [56]	Low	High	Low	Low	Unclear	Low	Low
Shih et al. [57]	Low	High	Low	Low	Unclear	Low	Low
Sawashita et al. [58]	Low	Low	Low	Low	Unclear	Low	Low
Ashley et al. [59]	Low	High	Low	Low	Unclear	Low	Low
Lean et al. [60]	Low	Low	High	Low	Unclear	Low	Unclear
Chee et al. [61]	Low	Low	Unclear	Low	Unclear	Low	Low

Meta-analysis results

The results from the random-effects model showed that compared to the control group, the intake of meal replacements significantly reduced SBP (weighted mean difference [WMD], −2.51 mmHg; 95% confidence interval (CI), −3.48 to −1.54; P < 0.001) and DBP (WMD, −1.43 mmHg; 95% CI, −2.02 to −0.85; P < 0.001). Also, as compared to the control group, those who replaced some or all of their meals with supplements had a much lower levels of CRP (WMD, −0.50 mg/L; 95% CI, −0.89 to −0.11; P = 0.012). In addition, there was a notable absence of consistency across the studies for SBP (Cochran Q test, P = 0.018, I² = 35.4%) and CRP (Cochran Q test, P < 0.001, I² = 81.5%). The Cochran Q test for DBP revealed modest heterogeneity (P = 0.076, I² = 26.2%) (Figs. 2, 3, 4).

Fig. 2. Forest plot of randomized controlled trials investigating the effects of total and partial meal replacements on SBP (mm/Hg).

SBP, systolic blood pressure; WMD, weighted mean difference; CI, confidence interval.

Fig. 3. Forest plot of randomized controlled trials investigating the effects of total and partial meal replacements on DBP (mm/Hg).

DBP, diastolic blood pressure; WMD, weighted mean difference; CI, confidence interval.

Fig. 4. Forest plot of randomized controlled trials investigating the effects of total and partial meal replacements on CRP (mg/L).

CRP, C-reactive protein; WMD, weighted mean difference; CI, confidence interval.

Subgroups analysis

The findings obtained from the subgroup analysis showed that MRs cause a greater reduction in SBP in people over 50 years of age, and the duration of the intervention ≤ 24 weeks. Furthermore, the subgroup analysis reveals that the effect on DBP and CRP is more pronounced in interventions utilizing TMR and in individuals aged ≤ 50 years, respectively. It seems that all 3 types of subgroup analysis, including type of intervention, mean age, and length of intervention, can be considered as sources of high heterogeneity for SBP (Supplementary Table 1).

Meta-regression

Meta-regression between MR and absolute mean differences in SBP, DBP, and CRP level based on baseline values of BMI were performed, but no significance was found (Coef. = −0. 0148176, P = 0.185 for SBP; Coef. = −0.0058156, P = 0.594 for DBP; Coef. = −0.0288512, P = 0.444 for CRP) (Fig. 5).

Fig. 5. Meta-regression analysis encompassing factor changes according to the baseline BMI (kg/m²). (A) SBP, (B) DBP, and (C) CRP.

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; CRP, C-reactive protein; SMD, standardized mean difference.

Sensitivity analysis

We methodically removed every trial from the analysis so that we could evaluate the impact of each article on the total effect size for SBP, DBP, and CRP levels. The results were shown to be robust in the leave-one-out sensitivity analysis (Supplementary Fig. 1).

Publication bias

Based on the Egger’s tests, no indication of publication bias was found for the following variables: SBP (P = 0.811), DBP (P = 0.814), and CRP (P = 0.916; Supplementary Fig. 2).

DISCUSSION

The current systematic review and meta-analysis provided valuable insights into the effects of MR on BP and CRP levels. The findings indicated significant reductions in SBP, DBP, and CRP levels following MR consumption compared to the control group. Indeed, the pooled data articles revealed a mean difference of −2.51 mmHg in SBP and −1.43 mmHg in DBP associated with the use of MRs. These reductions in BP are particularly noteworthy due to the fact that hypertension is a major risk factor for CVD [62]. Therefore, incorporating MRs into one’s diet may lead to improvements in BP levels, thereby potentially reducing the risk of developing cardiovascular complications. Besides, our meta-analysis revealed a significant decrease in CRP concentration after the consumption of MRs. CRP is a biomarker of inflammation [63], and elevated CRP levels are associated with various chronic diseases, including cardiovascular diseases [64]. The observed reduction in CRP suggests that MRs may have anti-inflammatory effects, which could contribute to improving overall health and reducing the risk of inflammatory-related conditions.

The results of subgroup analyses also provided interesting insights. Specifically, the impact of MRs on SBP was found to be more significant in individuals aged ≥ 50 years, as well as when the intervention duration was ≤ 24 weeks. On the other hand, the type of intervention and age less than or equal to 50 years seemed to have a greater effect on DBP and CRP reduction. Furthermore, while TMR had an effect on DBP rather than PMR, PMR significantly contributed to SBP. These findings underscore the influence of factors such as age, intervention duration, and the specific type of MR on the outcomes observed. Considering these factors is crucial when implementing meal replacement strategies. The effectiveness of the strategy can be optimized by tailoring interventions to the appropriate age group, considering the ideal intervention duration, and selecting the most suitable type of MR.

Based on a systematic review and meta-analysis conducted by Astbury et al. [14], it has been established that adopting a MR diet is an effective strategy for reducing both SBP and DBP in obese or overweight individuals. Their findings revealed that individuals following the MR diet experienced a significant additional reduction in SBP by 8.30 mmHg compared to those who only followed a diet-based approach. Similarly, individuals on the MR diet experienced an additional reduction in DBP by 2.81 mmHg. In line with these findings, a separate systematic review and meta-analysis by Noronha et al. [13] revealed that the inclusion of liquid MRs in weight loss diets resulted in moderate decreases in body weight, BMI, and SBP. Furthermore, marginal decreases in body fat, waist circumference, and DBP were observed, albeit with limited clinical implications. Another study by López-Gómez et al. [15] also compared the effects of one-versus-two meal replacement strategies on body composition and cardiovascular risk parameters in obese patients. Their findings indicated that both strategies were effective in facilitating weight loss, reducing fat mass, and lowering SBP. Notably, there were no notable disparities observed between the two groups, suggesting that substituting either one or 2 MRs yielded comparable outcomes in terms of improving body composition and cardiovascular risk parameters. In contrast, Heymsfield et al. [11] conducted a distinct meta-analysis and systematic review, which MR did not yield any additional benefits in terms of reducing SBP and DBP compared to a conventional reduced calorie diet. Nevertheless, the study emphasized that improvements in both SBP and DBP were strongly linked to weight reduction throughout the 3-month and 1-year treatment periods.

The effect of meal replacement on SBP is more pronounced when the intervention period is 24 weeks or shorter because dietary changes have a quicker impact on lowering BP in the short term. Rapid modifications in salt intake, saturated fats, and the increase of beneficial nutrients like potassium and fiber can immediately reduce SBP. Additionally, weight loss and improvements in risk factors such as blood sugar and cholesterol levels occur more quickly during shorter periods. Moreover, closer monitoring in short-term interventions helps to detect the effects on BP more promptly. In contrast, in longer interventions, the body may develop resistance to changes, diminishing their impact.

Multiple hypotheses can elucidate the reasons behind the beneficial impact of MRs on BP and CRP levels. One possible factor may contribute to weight loss, which has been shown to be associated with lower SBP and DBP [65,66]. Interestingly, there is a body of irrefutable evidence indicating that MRs can be a successful strategy for weight loss compared to control groups relying solely on conventional diet programs [11,14,67]. Regarding CRP, Selvin et al. [68] conducted a systematic review that revealed a significant association between weight loss and a decrease in CRP levels. Based on the pooled data from both lifestyle and surgical interventions, it has been shown that a 1 kg decrease in weight is linked to an average reduction of −0.13 mg/L in CRP levels (weighted Pearson correlation, r = 0.85). Another potential explanation pertains to the composition of MR. MRs are carefully formulated to provide a precise balance of macronutrients and essential micronutrients. This ensures adequate nutrient intake and promotes balanced nutrition, which ultimately leads to overall health improvement and a decreased risk of inflammation and high BP. Indeed, given that excessive sodium consumption is a well-known contributor to high BP [69] and MRs often have controlled sodium content [70], it can be hypothesized that the positive effects of MRs on BP, to some extent, are related to their sodium content. Likewise, MRs tend to have low saturated fat [71,72]. It has been indicated that there is a potential positive correlation between saturated fatty acids and CRP [73]. Hence, replacing meals that typically contain pro-inflammatory foods with healthier alternatives, such as MRs, can contribute to reduced inflammation and improved CRP levels.

To the best of our knowledge, this review and meta-analysis is the first to examine and suggest a potential positive impact of MR, including both TMR and PMR, on BP and CRP levels. However, it is important to acknowledge the limitations of the present study. First, the observed heterogeneity among the included studies for SBP and CRP highlights the presence of variations in study design, participant characteristics, and other factors that may contribute to the variability in outcomes. Nevertheless, through a subgroup analysis of the duration and type of intervention, as well as the mean age of participants, we provided a clear explanation for the sources of heterogeneity in our meta-analytic studies. Furthermore, CRP assays are not completely standardized which may have been a reason for the large heterogeneity. Second, the possible mechanisms by which MR strategies can reduce BP and CRP have not been well studied, particularly in terms of behavioral aspects and the specific contents of MRs. Further research is needed to delve into these details and gain a better understanding of the mechanisms involved. Also, the BP reduction with MR, which is around 2 mmHg, while statistically significant is not of great difference in clinical practice. Furthermore, due to the limited data reported in the articles included in this meta-analysis to examine weight or BMI changes, we were unable to perform meta-regression on weight or BMI changes with MR-related BP changes, which might have provided further insight into the mechanisms behind MR-related BP changes.

CONCLUSIONS

In summary, this comprehensive review and meta-analysis present persuasive findings that support the notion that integrating MRs into an individual’s dietary regimen leads to noteworthy decreases in BP and CRP levels. These findings underscore the potential benefits of MRs as a dietary strategy for improving cardiovascular health and alleviating inflammation. However, further studies are warranted to better understand the mechanisms through which MR strategies exert their effects on BP and CRP levels. Specifically, investigations focusing on behavioral aspects, the specific contents of MRs, and the observed heterogeneity among studies are necessary. Moreover, considering individual characteristics and tailoring intervention protocols when implementing MR interventions are crucial for optimizing outcomes. Continued research in this field will enhance our understanding of the potential of MRs and facilitate their effective implementation in clinical practice.

Abbreviations

BMI

body mass index

BP

blood pressure

CI

confidence interval

CR

calorie-restriction

CRP

C-reactive protein

CVD

cardiovascular disease

DBP

diastolic blood pressure

GRADE

Grading of Recommendations Assessment, Development, and Evaluation

HIW

high-intensity interval walking

HPMR

high-protein meal replacement

IBT

intensive behavioral therapy

LCD

low-calorie diet

LEI

lifestyle education intervention alone

MCR

mild calorie restriction

MR

meal replacement

MRP

meal replacement plan

PMR

partial meal replacement

RCT

randomized controlled trial

SBP

systolic blood pressure

SD

standard deviation

SEM

standard error of the mean

SMD

standardized mean difference

T2DM

type 2 diabetes mellitus

TDR

total diet replacement

TMR

total meal replacement

USDA

United States Department of Agriculture

WMD

weighted mean difference

SUPPLEMENTARY MATERIALS

Supplementary Table 1

The effect of TMR and PMR on several subgroups

Supplementary Fig. 1

Sensitivity analysis of the WMD with CI. (A) SBP, (B) DBP, and (C) CRP.

Supplementary Fig. 2

Funnel plots for evaluation of publication bias. (A) SBP, (B) DBP, and (C) CRP.