Bariatric embolization

An emerging minimally invasive therapy for patients with obesity

Since the late 1970s, the prevalence of obesity in the United States has been growing at an alarming rate. Based on the latest epidemiological data reported by the Centers for Disease Control and Prevention, an estimated 42.4% of adults and 18.5% of children in the U.S. are obese.1,2 Obesity is a multiorgan, systemic metabolic disease and patients face increased risk for over a dozen severe chronic co-morbidities, including type-2 diabetes mellitus (T2DM), cardiovascular disease, degenerative joint disease, stroke, fatty liver disease, renal microvascular diseases, obstructive sleep apnea, polycystic ovarian syndrome, psychiatric disturbances and some forms of cancers.3–12

Historically, therapeutic strategies for patients with obesity have consisted of behavioral, pharmacologic and surgical approaches to induce and sustain weight loss. With advancements in imaging technology during the past decade, endovascular and endoscopic techniques have emerged that demonstrate promising weight-loss efficacy in animals and early-phase human clinical trials.

What is bariatric embolization?

Bariatric embolization (BE) is an emerging, minimally invasive weight-loss procedure for patients with obesity. During BE, embolic microspheres are delivered under imaging guidance via a catheter directly into the arteries supplying the gastric fundus, an area where most ghrelin-producing X/A-like endocrine cells reside. The vascular supply to the gastric fundus from the left gastric artery (LGA) and left gastroepiploic artery (LGEA) are distinct and identifiable and are accessed using a percutaneous approach.

Embolization induces fundal oxyntic mucosal ischemia, suppresses orexigenic hormone (ghrelin) production and presumably reduces feeding behavior to induce weight loss. The upper gastrointestinal tract’s rich collateral supply allows for continued but lowered perfusion to the gastric fundus, preventing necrosis and perforation. Although the exact mechanism is unknown, decreased perfusion is believed to partially defunctionalize the stomach, possibly reducing ghrelin production. Similar to bariatric surgery, bariatric embolization has been reported to induce weight loss, decrease subcutaneous adiposity, suppress fundal ghrelin-producing cellular expression and increase levels of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and leptin (anorexigenic hormones) in both animal and human studies.13–23

The origin of BE and embolic development

The concept of using LGA embolization to achieve weight loss originated from observational studies of patients with gastrointestinal bleeding, who were treated with LGA embolization and had follow-up evaluations demonstrating varying degrees of weight loss.22–25

In the early 2000s, Arepally et al. conducted the first pre-clinical study of BE by injecting a liquid embolic agent into the gastric arteries of growing swine and reported suppression of serum ghrelin levels and a postprocedural reduction in animal weight gain not observed in control animals. Since precise targeting of the liquid embolic agent was clinically unachievable, subsequent pre-clinical studies focused on the use of particle embolics to minimize risks associated with nontarget embolization.

Bawudun et al.13 investigated BE-induced weight loss in obese canines by comparing mixed sclerosant (bleomycin/lipiodol) vs. a large-particle embolic (500–700 µm PVA). After BE with the particle embolic, dogs showed decreases in body weight and plasma ghrelin levels, with a reduction in subcutaneous adiposity as assessed by computed tomography (CT). To achieve distal penetration comparable to the original liquid sclerosant, Paxton et al.26 investigated a smaller particle embolic in swine, and reported efficacy in suppressing weight gain, plasma ghrelin levels and fundal ghrelin production by gastric X/A-like endocrine cells. However, the smaller-particle embolic also resulted in gastric ulceration in 40–50% of BE-treated animals, raising concerns about the potential for similar adverse events in humans. In addition, the prophylactic use of gastroprotectants (proton pump inhibitor and sucralfate) failed to prevent gastric ulceration, regardless of the number of fundal vessels embolized.26

Using two groups of larger particle embolics (100–300 µm and 300–500 µm diameter), Fu et al. demonstrated that BE using off-the-shelf 100–300 µm microspheres was able to reduce body weight and gastric ghrelin-producing cell density to a greater degree than the larger, 300–500 µm microspheres with a similar safety profile.27

The ideal embolic agent for bariatric embolization

Based on subsequent preclinical investigations, the ideal embolic particles for BE should be sized to target submucosal layer vessels (75–120 µm) in the gastric fundus and be image-visible to improve on-target delivery.28 These findings have led to the development of X-ray-visible embolic microspheres (XEMs), which are approximately 50 µm in size and specifically designed to optimize the safety and efficacy of BE.29,30 Extensive animal studies using XEMs demonstrated statistically significant weight loss in treated animals compared to controls. Plasma ghrelin levels were lower in BE-treated swine than control animals, while plasma levels of GLP-1 and PYY were consistently higher than in controls.29 A follow-up prospective, single-arm clinical trial examining BE using a novel, image-visible, 100–200 µm embolic microsphere specifically designed for BE is currently underway (clinicaltrials.gov: NCT04197336).

Human clinical trials of BE

With over 100 patients treated worldwide, more than half a dozen prospective human clinical trials have demonstrated significant weight loss after BE, without any major adverse sequelae. In a meta-analysis of six prospective, single-arm clinical trials of BE consisting of 47 patients with obesity (mean age: 38–48 years, baseline weight: 79–160 kg, baseline body mass index [BMI]: 28.9-45 kg/m2), Hafezi-Nejad et al. reported a pooled mean weight loss of 8.11% ± 1.46% from baseline at 12 months (range: 4.77–17.19%). Furthermore, the first randomized, sham-controlled clinical trial of bariatric embolization, using 300–500 µm embolic microspheres on 44 patients (treatment group N=22; control group N=22), was conducted in Eastern Europe. Of the 31 patients included in the per-protocol group, the participants exhibited a percent mean weight loss of 6.5% over the sham group (per-protocol 8.3% vs control 1.8% at 6 months). In the intent-to-treat (ITT) group, embolized participants demonstrated a percent mean weight loss of 3.6% over sham (intent-to-treat 6.4% vs control 2.8% at 6 months).31 Comparing these findings to behavioral obesity therapies, a meta-analysis of 22 studies on lifestyle modifications alone demonstrated a mean 4% weight loss from the participants’ baseline weight at 12 months.

Further research

Given the current limitations in obesity therapeutics, the Society of Interventional Radiology Foundation commissioned a Research Consensus Panel (RCP) to establish a research agenda on obesity therapeutics in IR. An eleven-member RCP was assembled from a list of leading scientists and clinicians with expertise in metabolic physiology, nutrition science, obesity medicine, gastroenterology, bariatric surgery, IR, and US Food and Drug Administration (FDA) medical device pre-market regulation. The meeting provided a platform for a dialogue about the current state of obesity medicine and therapeutics, to review current evidence for experimental obesity interventions and establish a research agenda for the evaluation of emerging weight loss procedures in IR. The final list of prioritized research topics for IR obesity therapeutics, as voted by the RCP panelists and participants, included the following:

Where should IR obesity therapies fit into the obesity treatment schema?

What are patient characteristics best suited for IR obesity therapies?

What type of research data is necessary for treatment reimbursement?

The expert panelists reached a consensus that a staged approach for treating obesity, initially with behavioral and pharmacologic therapies, followed by minimally invasive IR or endoscopic interventions, and finally bariatric surgery for severe cases of obesity, ideally should be implemented. After reviewing data on IR bariatric interventions, the panelists identified several patient populations that could benefit from these novel procedures, including patients with obesity who could not achieve significant weight loss despite behavioral and pharmacologic therapies, patients who were ineligible or elected not to have bariatric surgery, patients with weight regain after bariatric surgery, and patients with obesity and concomitant liver diseases who required endovascular interventions for their hepatic pathology.

With the current FDA regulatory guidelines in mind, the panelists agreed that achieving a ~10% weight loss at 12 months was a desirable therapeutic goal for IR bariatric interventions and might facilitate these procedures’ general adaptation by meeting reimbursement criteria. The final consensus on the ideal research design included a blinded randomized controlled trial (RCT) comparing IR obesity procedures versus sham control arms, with all patients receiving behavioral weight loss therapy. The panelists concluded that the RCT study design generated the highest level of evidence for evaluating device or procedural safety, efficacy, and justifications for reimbursement.

The results of this panel have been submitted to the Journal of Vascular and Interventional Radiology.

What’s next for BE?

Although data indicate that BE is safe for human use, several questions remain unanswered and deserve future investigation.

First, the long-term vascular outcomes, such as the degree of recanalization or collateralization and gastric perfusion changes, remain unknown. Future research should investigate the long-term effect of revascularization as it pertains to the procedure’s efficacy and durability to sustain weight loss.

Second, whether bariatric embolization predisposes patients to an increased risk of future bariatric surgery remains to be determined.

Third, future studies should explore the technical feasibility of performing bariatric embolization in patients after bariatric reconstructive surgeries (i.e., Rou-en-Y gastric bypass), as these patients represent a potentially untapped population that may benefit from a less invasive procedure.

Finally, in patients with local revascularization after bariatric embolization, the feasibility and safety of repeat LGA embolization and its long-term weight loss efficacy should be investigated. 

References

  1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Products - Data Briefs - Number 360 - February 2020. 2020; Available at: gov/nchs/products/databriefs/db360.htm.
  2. Childhood Obesity Facts | Overweight & Obesity | CDC. 2021; Available at: gov/obesity/data/childhood.html.
  3. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: A pooled analysis. PLoS One. 2013;8:e65174.
  4. Czernichow S, Kengne AP, Stamatakis E, Hamer M, Batty GD. Body mass index, waist circumference and waist–hip ratio: Which is the better discriminator of cardiovascular disease mortality risk? Evidence from an individual-participant meta-analysis of 82,864 participants from nine cohort studies. Obes Rev 2011;12:680–687.
  5. Anandacoomarasamy A, Caterson I, Sambrook P, Fransen M, March L. The impact of obesity on the musculoskeletal system. Int J Obes (Lond) 2008;32:211–222.
  6. Mitchell AB, Cole JW, McArdle PF, et al. Obesity increases risk of ischemic stroke in young adults. Stroke 2015;46:1690–1692.
  7. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010;51:679–689.
  8. Kovesdy CP, Furth SL, Zoccali C, World Kidney Day Steering Committee. Obesity and Kidney Disease: Hidden Consequences of the Epidemic. Can J Kidney Health Dis 2017;4:2054358117698669.
  9. Jehan S, Zizi F, Pandi-Perumal SR, et al. Obstructive sleep apnea and obesity: Implications for public health. Sleep Med Disord 2017;1.
  10. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord. 2002;26:883–896.
  11. Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev 2011;12:e426–37.
  12. Lauby-Secretan B, Scoccianti C, Loomis D, et al. Body Fatness and cancer—Viewpoint of the IARC Working Group. N Engl J Med. 2016;375:794–798.
  13. Bawudun D, Xing Y, Liu WY, et al. Ghrelin suppression and fat loss after left gastric artery embolization in canine model. Cardiovasc Intervent Radiol. 2012.
  14. Kipshidze N, Archvadze A, Bertog S, Leon MB, Sievert H. Endovascular bariatrics: First in humans study of gastric artery embolization for weight loss. JACC: Cardiovascular Interventions
  15. Bai ZB, Qin YL, Deng G, Zhao GF, Zhong BY, Teng GJ. Bariatric Embolization of the Left Gastric Arteries for the Treatment of Obesity: 9-Month Data in 5 Patients. Obes Surg. 2018;28(4):907-915. doi:10.1007/s11695-017-2979-9
  16. Zaitoun MMA, Basha MAA, Hassan F, et al. Left gastric artery embolization in obese, prediabetic patients: A pilot study. J Vasc Interv Radiol 2019;30:790-796.
  17. Syed MI, Morar K, Shaikh A, et al. Gastric artery embolization trial for the lessening of appetite nonsurgically (GET LEAN): Six-month preliminary data. J Vasc Interv Radiol. 2016 Oct;27:1502-1508.
  18. Arepally A, Barnett BP, Montgomery E, Patel T. Catheter-directed gastric artery chemical embolization for modulation of systemic ghrelin levels in a porcine model: Initial experience. Radiology
  19. Weiss CR, Akinwande O, Paudel K, et al. Clinical safety of bariatric arterial embolization: preliminary results of the BEAT Obesity Trial. Radiology 2017 May;283:598–608.
  20. Kordzadeh A, Lorenzi B, Hanif MA, Charalabopoulos A. Left Gastric Artery Embolisation for the Treatment of Obesity: a Systematic Review. Obes Surg. 2018;28(6):1797-1802.
  21. Weiss CR, Abiola GO, Fischman AM, et al. Bariatric embolization of arteries for the treatment of obesity (BEAT Obesity) trial: Results at 1 Year. Radiology 2019 Jun;291:792–800.
  22. Kim DJ, Raman HS, Salter A, et al. Analysis of weight changes after left gastric artery embolization in a cancer-naive population. Diagn Interv Radiol. 2018;24(2):94-97.
  23. Elens S, Roger T, Elens M, et al. Gastric embolization as treatment for overweight patients; efficacy and safety. Cardiovasc Intervent Radiol. 2019;42:513–519.
  24. Gunn AJ, Oklu R. A preliminary observation of weight loss following left gastric artery embolization in humans. J Obes. 2014;2014:185349.
  25. Takahashi EA, Takahashi N, Reisenauer CJ, Moynagh MR, Misra S. Body composition changes after left gastric artery embolization in overweight and obese individuals. Abdominal Radiology 2019;44:2627–2631.
  26. Paxton BE, Kim CY, Alley CL, et al. Bariatric embolization for suppression of the hunger hormone ghrelin in a porcine model. Radiology 2013;266:471–479.
  27. Fu Y, Weiss CR, Paudel K, et al. Bariatric Arterial Embolization: Effect of Microsphere Size on the Suppression of Fundal Ghrelin Expression and Weight Change in a Swine Model. Radiology. 2018;289(1):83–
  28. Vairavamurthy J, Anders R, Beh C, Mao HQ, Wang TH, Kraitchman D, Weiss C. Identifying the target vessel size for bariatric arterial embolization: A comparative histologic analysis of swine and human fundi.
  29. Weiss CR, Fu Y, Beh C, et al. Bariatric erterial embolization with calibrated radiopaque microspheres and an antireflux catheter suppresses weight gain and appetite-stimulating hormones in swine. J Vasc Interv Radiol. 2020 Sep;31:1483–1491.
  30. Beh CW, Fu Y, Weiss CR, et al. Microfluidic-prepared, monodisperse, X-ray-visible, embolic microspheres for non-oncological embolization applications. Lab Chip 2020;20:3591–3600.
  31. Reddy VY, Neuzil P, Musikantow D. Sramkova P, Rosen R, Kipshidze N, Kipshidze N, Fried M. Transcatheter bariatric embolotheraphy for weight reduction in obesity: A single-blind, sham-procedure, randomized controlled trial. Journ Am Cardiol. 2020;76(20):2305–2317.