Module II: Use of OMMs after MBS
Combined medical-surgical treatment of obesity
In the first presentation of the second module by Professor Lee M. Kaplan (Chief, Section of Obesity Medicine, Geisel School of Medicine at Dartmouth, NH), he began by noting that two major and distinct challenges for metabolic/bariatric surgery are suboptimal initial weight loss (SIWL) and recurrent weight gain (RWG). Weight loss varies widely among patients who undergo the same procedure, largely as a result of genetic background and other biological factors (Hatoum IJ et al., J Clin Endocrinol Metab 2011).
The percentage of patients who experience SIWL is somewhat subjective and depends on both the patient’s clinical needs (e.g., weight loss necessary for optimal improvement in relevant obesity complications) and desires. A commonly used criterion for a suboptimal response to MBS is <30% total body weight loss.
Regardless of the criterion used, SIWL is best considered as a reflection of a suboptimal effect of the surgery itself. Although the precise cellular and molecular mechanisms of MBS remain largely unknown, multiple lines of evidence demonstrate that the clinical response is driven by modification of the pathophysiology that led to obesity in the first place. Thus, surgery improves obesity in a manner that closely parallels the effects of medications, albeit more powerfully and durably. Indeed, the physiological effects of MBS should be expected to persist as long as the anatomic alteration induced by the surgery remains intact.
Thus, management of SIWL is best addressed by enhancement of the physiological effect of the surgery or addition of a complementary mechanism, either through modification of the initial MBS procedure or addition of a treatment that complements the effects of that procedure. For modification of the surgery to be effective, it appears that the second surgical alteration needs to be substantial enough to recruit additional therapeutic mechanisms. Although known mechanistic data are incomplete, clinical evidence demonstrates that addition of a diversionary element to sleeve gastrectomy, substantial elongation of the alimentary and/or nutrient-excluded limbs of diversionary initial MBS procedures, and replacement of gastric restrictive devices with more standard MBS procedures provides the additional mechanisms that can significantly augment the benefit of the initial operation.
These surgical interventions fall into the category of conversion surgery, i.e. converting from one procedure to another more powerful and potentially complementary one. Clinical evidence demonstrates that minor mechanical manipulations that aim to enhance the effectiveness of the initial operation without recruiting additional mechanisms (e.g., reduction of gastric pouch volume, anastomotic size or sleeve diameter) is very limited.
With the emergence of a new generation of safe and highly effective obesity management medications, including those that activate brain GLP-1 receptors, SIWL can often be effectively addressed by treating post-operative patients with one of these agents. The proven effectiveness of adding an OMM to MBS (Miras AD et al., Lancet Diab Endocrinol 2019; Mok J et al., JAMA Surg 2023) underscores the physiological nature of the response to MBS and the complementary (rather than duplicative) effect of GLP-1 receptor activation. Each of these studies demonstrated that the GLP-1 receptor agonist liraglutide induced substantial weight loss in patients who had previously undergone MBS. In both studies, the magnitude of the weight loss was at least as great as that seen in previous studies in similar patients who had not undergone MBS, suggesting that the effects of the GLP-1 receptor agonist were at least additive to – and possibly synergistic with – the surgery.
RWG after an adequate initial response to surgery presents different challenges. Mechanisms underlying RWG are less clear than those underlying SIWL, and it is likely that RWG can result from multiple mechanisms. Over time, progression of the underlying obesity and increased exposure to obesogenic influences (e.g., medications, toxins, foods and food additives, chronic stress, etc.) can counteract the beneficial effects of MBS. The contribution of genetic and other biological factors to RWG is less well defined that for SIWL. Nonetheless, clinical evidence suggests that optimal treatment of RWG is similar to that for SIWL: substantial surgical or endoscopic modification of the initial MBS to recruit additional physiological mechanisms and/or addition of a complementary endoscopic procedure or OMM. Clinical observations suggest that these additional therapies are somewhat less effective in treating RWG than they are for SIWL, but they remain the most effective approaches in current usage.
“For both SIWL and RWG, each treatment option has its own benefit, risk and cost characteristics,” explained Dr. Kaplan. “And each one can be used alone or in combination with others.”
Dr. Kaplan explained that there are two strategies for using medical-surgical combinations. The first is pre- and peri-operative medical therapy including:
Stepped care (medical followed by surgical care) – this approach is particularly appropriate for lifestyle-based treatment, and when it includes the preoperative use of an OMM, the medication is generally stopped at the time of surgery
Weight loss immediately before MBS – this approach is used primarily to induced mobilization of liver fat and may enhance the ease and safety of the surgical procedure; effective approaches include short-term calorie-reduced diets and/or OMM treatment
Simultaneous initiation of combination therapy – this approach has been increasing discussed among clinical experts; however, it is limited by the wide patient-to-patient variation in the clinical response to both the MBS and the OMM, and clinical experience has shown that the preoperative response to an OMM may not predict the response after MBS; the only way to determine whether the combination is necessary or effective is to stop the medication after the patient reaches their weight plateau, followed by testing of different medications if the first OMM is found to provide limited benefit; this is a cumbersome but necessary process to ensure that long-term OMM therapy is worthwhile
The second strategy is post-operative initiation of medical therapy that either enhances weight loss in patients with SIWL or limits or reverses RWG. This approach facilitates individualization of treatment to account for the wide patient-to-patient variability in response to the initial MBS and the absence of tools that can predict the optimal treatment for a particular patient. This approach allows targeted testing of each added OMM for its effect on that patient. It is important to recognize that failure of a particular medication or endoscopic procedure to treat SIWL or RWG effectively has little or no predictive value for the effectiveness of a different medication or endoscopic procedure with a different mechanism of action.
“The empiric use of combination medical-surgical therapy that allows pharmacological treatment after completion of surgical weight loss is the most promising strategy. Pharmacological treatment works particularly well for suboptimal initial weight loss. It also appears to be beneficial for recurrent weight gain, but this use is less well studied,” he noted. “Therefore, it seems that the optimal strategy is a step-wise approach, waiting for the clinical effects of surgery to stabilize (when the patient reaches a weight plateau) and serially test specific medications or endoscopic treatments after surgery as you would do in the absence of surgery, adding or substituting new OMMs only after a stable response to previous ones. It is now clear that drugs and MBS can be complementary and can enhance the benefit of either treatment alone, but the key to long-term clinical success is long-term effectiveness of both the initial MBS operation and the additional medical therapy. There is no short-term fix for a chronic disease like obesity.”
Treatment with OMM due to recurrent/persistent metabolic disease
In the next presentation, Dr Dror Dicker (Tel Aviv University, Israel) examined the impact of OMMs on recurrent/persistent metabolic disease. Firstly, he outlined that MBS has been proven to achieve diabetes remission, as demonstrated in a study by Mingrone G et al. (Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial. The Lancet 2021) that showed ten-year remission of 5.5% for medical therapy, 50% for BPD and 25% for RYGB. In addition, participants in the RYGB and BPD groups had greater weight loss and had fewer diabetes-related complications than those in the medical therapy group.
The GRAVITAS Study (Miras AD et al. Lancet Diabetes Endocrinol 2019; 549-559) was the first RCT to show the effectiveness of liraglutide post-MBS in T2DM patients vs. placebo in terms of greater weight loss and changes in HbA1c from baseline. Moreover, a multivariable linear regression analysis from the BARI-OPTIMISE RCT (Mok J et al, JAMA 2023), revealed liraglutide treatment was associated with a difference of -13.3mmol/mol (p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo.
Dicker cited a paper by Başaran et al (Post metabolic bariatric surgery weight regain: the importance of GLP-1 levels. International Journal of Obesity 2024) that hypothesised maintaining higher basal-bolus GLP-1-RA levels may be a promising treatment choice in people with obesity who failed to lose weight after bariatric surgery (Basal Bolus Hypothesis).
“GLP1RA treatment after MBS may improve metabolic outcomes in the case of persistent or recurrent type 2 diabetes compared to surgery alone and GLP1RA treatment after MBS may improve metabolic outcomes in the case of insufficient weight loss compared to surgery alone,” he concluded. “Metformin continuation after MBS did not prevent better relapse of diabetes compared MBS in short term follow-up and diabetes remission after MBS can be achieved with the use of adjunctive OMM.”
Continuous vs. intermittent use of OMMs after metabolic surgery
In the following presentation, Dr David Cummings (University of Washington) explored continuous vs. intermittent use of OMMs after MBS and began by highlighting the escalating costs of continuous use of OMMs – stating that the approximate costs of semaglutide or tirzepatide vary between ~$900 to $1,350/month – compared with the total cost of MBS of ~$17,000 to $26,000.
But if one discontinues OMMs, do they confer any lasting benefits? The STEP-1 RCT (Wilding, et al. NEJM 384:989 (2021)) showed 14-15% weight loss and the STEP 1 Trial Extension (Wilding JPH et al. Diab Obes Metab 24:1553 (2022)) 17.3% weight loss, however, two-thirds of weight loss was regained after semaglutide was discontinued. This weight regain was mirrored in all weight loss groups. It was not only weight regain that was shown to return, but also systolic blood pressure, diastolic blood pressure, C-Reactive Protein and HbA1c.
The SURMOUNT 4 RCT (Aronne LJ et al. JAMA 33:38 (2024)) showed 21% weight loss at 36 week and this increased to 26% at 88 weeks however, half of those who discontinued tirzepatide at 36 weeks regain half of their weight.
He concluded that weight regain after OMM cessation has been documented in trials of semaglutide, tirzepatide, orlistat and lorcacerin, but whether the results be similar with discontinuation of OMMs after MBS is unknown.
Endoscopic procedures and OMM
In the following presentation, Professor Silvana Perretta (University of Strasbourg, France) began by saying that is it important to understand what patients want from their treatment. They want it to be safe, effective on weightloss and comorbidities, no long-term consequences, organ sparring, good quality of life (QoL), personalised, scalable, modular, progressive and they want ownership.
Endoscopic bariatric therapies have both a weight loss and metabolic effect, and include gastric and small bowel interventions, endoscopic suturing and plication, intragastric balloons (IGB) and duodenal exclusion.
She said that in her opinion, and supported by the evidence, endoscopic suturing and plication is the most effective endoscopic bariatric therapy resulting TWL 17% at 12 months with low severe adverse event rates (1-1.2%). Furthermore, a procedure such as endoscopic sleeve gastrectomy (ESG) preserves the anatomy, is durable, repeatable, convertible, scalable, better QoL and has the same impact on metabolic disease than LSG, and no de novo GERD and Barrett Disease.
ESG have proven long-term outcomes, as demonstrated in a study by Sharaiha RZ et al (Five-Year Outcomes of Endoscopic Sleeve Gastroplasty for the Treatment of Obesity. Clin Gastroenterol Hepatol. 2021 May;19(5):1051-1057.e2. doi: 10.1016/j.cgh.2020.09.055. Epub 2020 Oct 1. PMID: 33011292) that resulted in mean TBWL was 15.9% (p<0.001) and 90 and 61% of patients maintained five and 10% TBWL, respectively. There was an overall rate of 1.3% moderate AEs, without any severe or fatal AEs.
ESG has also been found to be cost-effective, according to a study by Kelly J et al (UK cost-effectiveness analysis of endoscopic sleeve gastroplasty versus lifestyle modification alone for adults with class II obesity. Int J Obes (Lond). 2023 Nov;47(11):1161-1170. doi: 10.1038/s41366-023-01374-6. Epub 2023 Sep 6. PMID: 37674032; PMCID: PMC10599990), the procedure resulted in higher overall costs than lifestyle modification alone but led to an increase in quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for ESG vs LM alone was £2453/QALY gained. ESG was consistently cost effective across a wide range of sensitivity analyses, with no ICER estimate exceeding £10,000/QALY gained. In probabilistic sensitivity analysis, the mean ICER was £2502/QALY gained and ESG remained cost effective in 98.25% of iterations at a willingness-to-pay threshold of £20,000/QALY.
In study by Thompson C et al (Endoscopic Sleeve Gastroplasty with Anti-obesity Medications: Analysis of Combination Therapy, Optimal Timing and Agents), patients were categorised into 3 groups: monotherapy: ESG alone (n=77, 34%), combination therapy (n=69, 31%) AOM prescribed within six months prior to or after ESG sequential therapy (n=78, 35%). They reported that combination of ESG with GLP-1RA was superior to ESG alone, and that the optimal time to add an AOM is within 6 months of ESG. All patients (100%) in the ESG + GLP-1RA combination therapy group experienced ≥10% TWL at 12 months. However, being on an AOM for greater than 6 months prior to ESG appeared to be a predictor of poor response following the procedure.
In a study that assessed efficacy of ESG and liraglutide (ESG-L) compared with ESG alone (Badurdeen D, Hoff AC, Hedjoudje A, Adam A, Itani MI, Farha J, Abbarh S, Kalloo AN, Khashab MA, Singh VK, Oberbach A, Neto MG, Barrichello S, Kumbhari V. Endoscopic sleeve gastroplasty plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss. Gastrointest Endosc. 2021 Jun;93(6):1316-1324.e1. doi: 10.1016/j.gie.2020.10.016. Epub 2020 Oct 17. PMID: 33075366), ESG-L had a statistically greater reduction in percent body fat compared with ESG (7.85%±1.26% vs 10.54%±1.88%, respectively; p<0.001) at 12 months.
A RCT by Hoff et al (Endoscopic Sleeve Gastroplasty Plus Semaglutide Versus Endoscopic Sleeve Gastroplasty Alone for Weight Loss: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study. EC Gastroenterology and Digestive System 9.7 (2022): 54-65) assessed whether adults with overweight and obesity can achieve superior weight loss and metabolic improvement with ESG and semaglutide (ESG-S) compared to ESG alone. The results revealed that patients who received injectable semaglutide within one month of ESG had a superior mean% TBWL at 12 months vs. those who received placebo, 25.21% (SD 2.14%) versus 18.65% (SD 1.44%) (p<0.001).
A second study by Haseeb M et al (Semaglutide vs Endoscopic Sleeve Gastroplasty for Weight Loss. JAMA Netw Open. 2024 Apr 1;7(4):e246221. doi: 10.1001/jamanetworkopen.2024.6221. PMID: 38607627; PMCID: PMC11015347) assessed the cost-effectiveness of semaglutide vs. ESG over 5 years for individuals with class II obesity. They concluded ESG is cost saving compared with semaglutide in the treatment of class II obesity. On price threshold analyses, a 3-fold decrease in the price of semaglutide is needed to achieve non-dominance.
A study by Saumoy M et al (Cost-effectiveness of endoscopic, surgical and pharmacological obesity therapies: a microsimulation and threshold analyses. Gut. 2023 Nov 24;72(12):2250-2259. doi: 10.1136/gutjnl-2023-330437. PMID: 37524445) assessed the cost-effectiveness of sleeve gastrectomy (SG), lifestyle intervention (LI), endoscopic sleeve gastroplasty (ESG) and semaglutide. They revealed ESG was cost-effective in class I obesity (US$4105/QALY). SG was cost-effective in class II obesity (US$5883/QALY) and class III obesity (US$7821/QALY). In class I/II/III obesity, SG and ESG were cost-effective compared with LI. However, semaglutide was not cost-effective compared with LI for class I/II/III obesity (ICER US$508 414/QALY, US$420 483/QALY and US$350 637/QALY). For semaglutide to be cost-effective compared with LI, it would have to cost less than US$7462 (class III), US$5847 (class II) or US$5149 (class I) annually. For semaglutide to be cost-effective when compared with ESG, it would have to cost less than US$1879 (class III), US$1204 (class II) or US$297 (class I) annually.
Regarding weight recidivism, Hajifathalian K et al (Efficacy of endoscopic resuturing versus pharmacotherapy to treat weight recidivism after endoscopic sleeve gastroplasty. Gastrointest Endosc. 2023 Dec;98(6):944-949. doi: 10.1016/j.gie.2023.07.018. Epub 2023 Jul 18. PMID: 37473967) reported that 55 patients were started on AOM and 24 patients underwent revisional-ESG. They found that additional TBWL after R-ESG was significantly (both clinically and statistically) better than after initiation of AOM (9.5% ± 7.2% vs 2.1% ± 8.6%, respectively; p=0.001).
Regarding IGBs and OMMs, Badurdeen D et al (Efficacy of Liraglutide to Prevent Weight Regain After Retrieval of an Adjustable Intra-gastric Balloon-a Case-Matched Study. Obes Surg. 2021 Mar;31(3):1204-1213. doi: 10.1007/s11695-020-05117-8. Epub 2020 Nov 19. PMID: 33211267) evaluated the efficacy of liraglutide (IGB-L) to prevent weight regain following IGB retrieval. There was significantly less weight regain in IGB-L compared to IGB, - 1.15 ± 0.94 kg versus - 0.66 ± 0.99 kg (p=0.010) nine months after balloon retrieval. Additionally, %BF decline in IGB-L was superior to IGB - 10.83 ± 1.50 versus - 7.94 ± 2.02 (p<0.01).
A study by Mathur W et al (Effect of Swallow Balloon Therapy with the Combination of Semaglutide Oral Formulation: a Randomised Double-Blind Single-Centre Study. Obes Surg. 2024 Jan;34(1):198-205. doi: 10.1007/s11695-023-06975-8. Epub 2023 Dec 13. PMID: 38091192) assessed weight reduction efficacy in the novel swallow balloon procedure and semaglutide. The %TWL in those who had semaglutide plus balloon was was 7.9%, 12.5%, 15.2%, and 17.6% and in those who only had a balloon was 6.1%, 10.5%, 12.8%, and 13.7% at 1, 2, 3, and 4 months, respectively. The outcomes support the efficacy of swallow balloon therapy combined with semaglutide oral formulation in promoting weight loss and improving comorbid conditions.
“Endoscopic bariatric therapies have evolved as safe and effective, and ESG is the most effective procedure and is gaining traction worldwide. Endoscopic bariatric therapies and OMMs may be synergistic but evidence is weak,” she concluded. “More evidence is needed to identify which indications work best with which patient and which drug, what dosage is needed, what happens when treatment is stopped, what are the long term side effects and what are the (long-term) cost implications?”
Comparison of the WL efficacy of obesity management medications, with and without metabolic bariatric surgery
Dr Kwang-Wei Tham (National University Singapore, Singapore) said there are many challenges and limitations concerning OMMs, with at least seven approved OMM currently available globally there is varying availability and exposure of use with MBS which can impact results. There is also limited evidence with the majority of papers retrospective and of small sample sizes (6 RCTs available). Some included OMM which have been withdrawn and do not include the newer OMM (especially incretin-based).
There are also variable periods of follow-up but mostly short term (3-6 months); a handful up to 12 months and no long-term studies. In addition, indications for use of OMM can differ: insufficient WL vs weight regain vs metabolic control, GLP-1ra used for T2DM management are at lower doses and may result in different amount of WL or make it more challenging to compare the doses approved for obesity management. Used after various types of surgeries, primary and revisional, and combinations of OMM, the impact on WL & metabolic efficacy and side-effects is unknown, she added.
A retrospective analyses of mixed OMM reveals that phentermine results in 4.5 – 7.65%; 6.4kg weight loss, phentermine-topiramate 9.8%; 11kg weight loss and topiramate(-based) 3.8 - 9.2kg weight loss. A summary of weight loss from RCTs of OMM use (without MBS) showed phentermine resulted in 4-6kg weight loss, phentermine-topiramate 8.6-10.5% weight loss, naltrexone/bupropion 6.1-6.4%, liraglutide: 6.1-8% weight loss. Weight loss with OMM after MBS revealed phentermine resulted in 4.5 – 7.65% 6.4kg additional weight loss, phentermine-topiramate 9.8% 11kg additional weight loss and GLP-1 6.9-7.7% additional weight loss.
A paper by Suliman M et al (Routine clinical use of liraglutide 3 mg for the treatment of obesity: Outcomes in non-surgical and bariatric surgery patients. Diabetes Obes Metab. 2019 Jun;21(6):1498-1501. doi: 10.1111/dom.13672. Epub 2019 Mar 25. PMID: 30768836), found there was no difference in percentage weight loss between post-bariatric surgery (n=76) and non-surgical patients (n=711).
Weight loss with the use of semaglutide 1mg and liraglutide 3mg post-MBS, reported by N Murvelashvili et al (Obesity 2023 Mar 30) showed that treatment regimens including semaglutide 1.0 mg weekly lead to superior weight loss, compared with liraglutide 3.0mg daily for treating post-MBS weight recurrence, regardless of procedure type or the magnitude of weight recurrence.
Bonnet JB et al (Semaglutide 2.4 mg/wk for weight loss in patients with severe obesity and with or without a history of bariatric surgery. Obesity (Silver Spring). 2024 Jan;32(1):50-58. doi: 10.1002/oby.23922. Epub 2023 Nov 5. PMID: 37927153) assessed the effectiveness of semaglutide 2.4mg in patients with severe obesity (BMI ≥ 40 kg/m2) who had previously undergone MBS but failed to achieve satisfactory weight loss or experienced weight regain, compared with patients without a history of MBS with similar BMI. They reported semaglutide treatment resulted in significant 9.1% weight loss in the MBS+group, with no significant difference in weight loss between the MBS+group and MBS-groups.
“Within each class of OMM there appears to be no difference in (similar) weight loss efficacy when used in those post-MBS and those who did not undergo MBS. Earlier studies with non-GLP-1 based OMM suggested higher weight loss post-RYGB (& AGB), compared to LSG. However, studies of GLP-1 based OMM revealed no differences among/between types of surgeries,” Dr Tham concluded. “The incidence of reported side effects, at least with GLP-1 based OMM, is not higher in post-MBS patients compared to non-surgical patients. In fact, there is a suggestion that these are possibly higher in non-surgical patients.”
To access Module I, please click here
To access Module III, please click here
A review and outcomes of the Consensus Meeting in Vienna will be presented at the following session in Melbourne: Session 2.2.2 - Consensus meeting in Vienna: The use of Obesity Management Medications in the context of MBS, on Thursday 5 September from 1.30pm – 3pm.
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