Proliferating rapidly over the past few decades, metabolic syndrome has become a major global epidemic and is a significant contributor to morbidity and mortality around the globe (1). Metabolic syndrome was formally defined by the World Health Organization (WHO) in 1999 as glucose intolerance, impaired glucose tolerance (IGT) or diabetes mellitus (DM), and/or insulin resistance, together with two or more of the components: raised arterial pressure, plasma triglyceride and or low HDL-C, central obesity, microalbuminuria (2).

Although the actual definition of this entity is heavily debated, the consequence of metabolic syndrome is undisputed. Metabolic syndrome leads to increased risk for obesity-related comorbidities such as cardiovascular disease (3), chronic renal disease (4), certain types of cancers (such as breast, colorectal, endometrial cancer) (5), and non-alcoholic fatty liver disease (NAFLD), which are leading causes of preventable death among adults. Among them, NAFLD is the most common cause of chronic liver disease worldwide, affecting ~25% of the global population (6). NAFLD is exacerbated by often interdependent metabolic syndrome parameters such as central obesity, insulin resistance, and elevated plasma triglyceride. These obesity-related comorbid parameters are thought to increase the accumulation of fat in the liver via the suppression of lipolysis and stimulation of de novo lipogenesis, which then promotes lipotoxicity and the activation of Kupffer cells, progressively leading to hepatic fibrogenesis, simple steatosis, steatohepatitis and eventually advanced cirrhosis (7).

Patients with metabolic syndrome are often prescribed standard medical therapy (SMT), which includes lifestyle modifications such as dietary alterations, physical exercise and pharmacological management. However, compliance and efficacy are often poor. Weight loss by the means of SMT alone is likely inadequate to effectively treat the rising incidences of these obesity-related comorbidities, particularly since less than 10 percent of patients are able to achieve at least 10 percent of weight loss (8) to ensure major improvement in the histological features of fatty-liver fibrosis (8, 9).

While bariatric surgery is well known to be one of the most effective treatment modalities for morbidly obese patients, it is invasive and associated with short term (bleeding, infection, and other perioperative risks), and long-term surgical risks. As a result, only one percent of the eligible patients choose to undergo bariatric surgery for obesity in the United States annually (10). This has prompted the development of newer, yet minimally invasive treatment armamentarium for weight loss – endoscopic bariatric and metabolic therapies (EBMTs).

EBMTs are devices that require flexible endoscopy for placement or removals and are used as an alternative treatment for patients who do not qualify for or do not wish to undergo bariatric surgery. EBMTs are prized for their reversibility (12), short procedure time, technical ease, and lower adverse event rates and complications such as liver abscess, anastomotic leakage and bleeding (13).

In this review, we focus on four main EBMTs - intragastric balloon (IGB), duodenal-jejunal bypass liner (DJBL), duodenal mucosal resurfacing (DMR) and endoscopic sleeve gastroplasty (ESG) (11).

IGB was one of the earliest endoscopic bariatric therapies developed. It works by the temporary endoscopy-assisted introduction of a balloon into the stomach, which can be inflated with either air or liquid solution to different volumes to achieve the feeling of satiety, which eventually leads to reduced caloric consumption. DMR and DJBL are performed with endoscopic and fluoroscopic guidance. DMR targets the post papillary duodenal mucosa using hydrothermal ablation which results in alterations in the mucosa and absorptive properties. Submucosal expansion is first performed, followed by progressive ablation of the duodenal mucosa distal to the Ampulla of vater. On the other hand, DJBL involves the endoscopic insertion of an impermeable, fluoropolymer sleeve into the duodenum and proximal jejunum for up to 12 months. This prevents further digestion and absorption of gastric contents as it passes directly from the pylorus into the mid jejunum. Finally, ESG uses a miniature suturing device introduced endoscopically to create folds in the mucosa which reduces total gastric volume and aims to achieve similar results as sleeve gastrectomy without undergoing laparoscopic surgery.

This systematic review and meta-analysis aims to summarize and analyze existing data available on these four main EBMT modalities (IGB, ESG, DJBL and DMR) and their impact on metabolic syndrome parameters (weight change and BMI) and all-cause obesity-related metabolic comorbidities such as glycemic control and NAFLD. Our main focus was on high quality studies, predominantly randomized controlled trials with appropriate control arms i.e., standard medical therapy (SMT).

We conducted a systematic review and meta-analysis of the four promising endoscopic bariatric metabolic therapies – intragastric balloon, endoscopic sleeve gastroplasty, duodenal jejunal bypass liner, and duodenal mucosal resurfacing. They fill an important gap between pharmacotherapy and bariatric surgery by offering subjects who have failed lifestyle and medical therapies but are not willing or fit enough to go for major surgery. Our review covers the most current available literature and focuses on high-quality studies that include an appropriate control study group, to evaluate the benefits and risks of each modality in NAFLD and in the control of the accompanying cardiovascular risk factors.

To date, IGB is one of the most widely studied EBMTs, as it was one of the first EBMTs conceptualized. IGB showed promising results on total body weight loss at 6 months, although there was an increase in participant's weight 6 months post-removal of IGB, suggesting limitations in the durability of weight loss. The concept of weight recidivism after IGB removal was also reviewed by Tate and Geliebter (45), suggesting that most patients would have difficulty maintaining weight loss following the standard 6 months treatment with IGB. However, there is still a significant effect on total body weight with IGB compared to the standard medical therapy group. The American Society for Gastrointestinal Endoscopy (ASGE) Bariatric Endoscopy Task Force (46) concluded that IGB therapy resulted in 25% of excess weight loss at 12 months, recommending IGB as a suitable EBMT of choice either as a primary EBMT modality, or bridging therapy to eventual bariatric surgery. However, most IGBs are designed to last for 6 months, and there is a paucity of data on the effect of repeated placement of IGB.

From our systematic review of the four modalities, IGB, ESG and DJBL show promising benefits on weight loss reduction compared to SMT, while DMR appears to have the least weight reduction benefit. However, the impact on glycemic control features more prominently in DMR as compared to the rest of the modalities. Van Baar et al. (47) conducted a multi-centered, open-label study of 46 patients and found significant improvements in HbA1c, FPG, and HOMA-IR 6 months post DMR with sustained effects at 12 months. Hepatic transaminase levels also decreased. However, it was noted that change in HbA1c did not correlate with weight loss. As DMR is a relatively new EBMT developed, more prospective controlled clinical trials are required for validation given the current paucity of high-quality studies.

Our meta-analysis focused on two main outcomes in the IGB and DJBL intervention group: weight loss (%TBWL and BMI) and glycemic control (FPG, HbA1c). Overall, our results suggest that participants treated with IGB showed superior results in both weight loss and glycemic control compared to SMT alone, while DJBL showed a positive impact on glycemic control but not on weight loss reduction. There were a large number of patients included in each analyses, with more than 400 patients analyzed for each outcome. This is despite excluding some studies that lacked available data for the calculation of standard deviation. In general, the large number of patients analyzed makes this a robust analysis.

There is inconclusive evidence on the overall impact of the four EBMTs on cardiometabolic risk factors (systolic blood pressure, total cholesterol, triglycerides). This is likely because BMI was featured as the main patient selection criteria (primary endpoint), with hypertension, diabetes, and dyslipidemia featured as the secondary endpoints. For example, the baseline prevalence of type II DM was 7% and 6% in the IGB and SMT groups respectively in the study conducted by Courcoulas et al. (21). Future studies focusing on cardiometabolic risk as a primary endpoint should be conducted to draw more conclusive evidence.

Additionally, there was a general lack of high-quality studies looking at the impact of each EBMT on liver biochemistries or NASH as many did not include an appropriate control arm. From our literature review of existing studies that did not include a control arm, both IGB and ESG show promising effects on NASH and liver biochemistries. We identified one unique pilot randomized, controlled trial of IGB vs. SMT in NAFLD subjects, with repeat liver biopsy, which showed a trend toward improvement in the median steatosis scores after 6 months. However, the sample size is too small to be conclusive. A prospective study conducted by Bazerbachi et al. (48) analyzed the impact of IGB on metabolic and histologic improvements in nonalcoholic steatohepatitis (NASH) and found that the nonalcoholic fatty liver disease activity score (NAS) improved in 90% of the patients, with a median decrease of three points. Similarly, prospective studies conducted by Jagtap et al. (49), Hajifathalian et al. (50), Rosenblatt et al. (51) showed that ESG had significant improvement in ALT, NAFLD fibrosis and FIB-4 score and hepatic steatosis index (HSI). There are only two studies in our systematic review that looked at the impact of DMR on liver biochemistry by Mingrone et al. (43) and Kaur et al. (44), and both concluded that DMR has no significant difference in the liver profile.

There is a paucity of data comparing EBMTs and their effects on weight loss and metabolic syndrome parameters. Available literature mainly featured IGB vs. ESG. Fayad et al. (52) conducted a retrospective review of prospectively collected data analyzing the outcomes of IGB and ESG, and found that IGB patients showed a significantly lower mean %TBWL than ESG patients at 1 month (6.6 vs. 9.9 %), 3 months (11.1 vs. 14.3 %), 6 months (15.0 vs. 19.5 %), and 12 months (13.9 vs. 21.3 %). The study also concluded that IGB had a significantly greater rate of adverse events compared with the ESG group (17 vs. 5.2%). However, no adverse events required surgical intervention in both groups and there was no reported mortality with either procedure.

Device-related adverse events featured more prominently in DJBL. In 2015, the US ENDO trial was terminated due to a higher than expected hepatic abscess rate (3.5%) compared with the global incidence (0.73%) (53). Caiazzo et al. (39) observed device-related severe adverse events in about 39% of the patients, which led to premature removal of the device in 22% of them. Given the lower safety profile compared to the rest of the EBMTs, the present versions of DJBL are less favored in the clinical setting.

Intrinsic limitations of this systematic review and meta-analysis are evaluated. Firstly, although our comprehensive search of the electronic databases allowed us to identify a large number of articles (a total of 648 records screened), our review eventually only included a total of twenty-one studies. Many studies are excluded due to the lack of a proper control arm, which should include lifestyle modifications for weight loss and physical exercises. Secondly, there may be an element of publication bias for positive outcomes over those with negative results. Thirdly, some studies could not be included because of language barriers, for example, non-English literature was excluded and some articles could not be accessed fully due to access limitations. Lastly, although a large number of patients were included in our meta-analysis, there was modest to substantial heterogeneity observed. This is likely because of the different BMI selection criteria of patients in each study and most studies only analyzing diabetes as a secondary outcome. As mentioned earlier, the baseline prevalence of type II diabetes mellitus was <10 percent in the study by Courcoulas et al. (21).

Finally, none of these EBMTs exist alone in silos. EBMTs could be recommended as a short-term booster weight-loss strategy, but standard medical therapy such as adequate physical exercise and dietary modifications must also be strictly reinforced to achieve and sustain the desired outcomes of weight loss, reduction in glycemic control and improvement in cardiometabolic parameters. Given human variability, compliance to the recommended dietary or exercise regimens will always be in question, and patient factors eventually play a large role in battling obesity and metabolic syndrome. However, when EBMTs are utilized in complementarity with physician supervision and lifestyle therapy, they offer exciting new opportunities and the much-needed obesity armamentarium for many patients who prefer minimally invasive options.

In this systematic review and meta-analysis, we summarized the evidence behind the four EBMT modalities (IGB, ESG, DJBL, and DMR) and concluded that they have a significant impact on weight loss and emerging evidence on obesity-related metabolic comorbidities. Both IGB and ESG are more widely used due to their relatively greater safety profile and significant impact on weight loss. The limitations of IGB lie in the durability of its weight loss effect post removal and eventual long-term benefit on cardiovascular outcomes. Both modalities also show emerging evidence in their benefits on NASH, although more studies with control groups can be conducted for higher-quality evidence. DJBL has more commonly reported severe adverse events, lacks sufficient controlled studies that demonstrate robust results, and is thus less commonly recommended in clinical practice. DMR is a new development and seems to demonstrate potential in the improvement of glycemic control, although more data is required before it can be recommended as a standard treatment modality. Newer and better EBMT modalities can be expected to emerge in the coming years to fill the unmet need for safe and effective minimally invasive therapies for NAFLD and metabolic syndrome.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

S-YL is responsible for data analysis and preparation of manuscript. HL and YC performed the literature search, data collection, and data analysis. MW carried out the data analysis for the meta-analysis, completed part of the methodology, and result sections of the manuscript. G-HL is the corresponding author responsible for the study design, data analysis, final manuscript preparation, and submission. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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