Module III: The future
Obesity management medications & metabolic surgery perspectives on cost-effectiveness
In the first presentation in module III, Dr Ricardo Cohen (Hospital Oswaldo Cruz, Sao Paulo, Brazil) said it was essential to analyse studies on the cost-effectiveness of the association of modern obesity management medications and MBS to determine the optimal role of pre-and post-operative OMMs. He stressed that the broad implementation of adjunctive OMM will depend on the cost-benefit ratio compared to other therapeutic approaches to treat obesity and its complications.
Firstly, he outlined the effectiveness of MBS and that weight loss after MBS is sustained for at least 20 years and is superior to all other treatments (Sjöström L et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012 Jan 4;307(1):56-65. doi: 10.1001/jama.2011.1914. PMID: 22215166). In addition to weight loss, MBS is associated with a significantly lower risk of incident MACE, compared with nonsurgical management (Aminian A et al. Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity. JAMA. 2019 Oct 1;322(13):1271-1282. doi: 10.1001/jama.2019.14231. PMID: 31475297; PMCID: PMC6724187), for every 13 patients that have surgery, one life is saved.
MBS also results in a reduction of all-cause mortality (Syn NL et al. Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants. Lancet. 2021 May 15;397(10287):1830-1841. doi: 10.1016/S0140-6736(21)00591-2. Epub 2021 May 6. PMID: 33965067) is associated with reduced overall and cardiovascular mortality and increased life expectancy regardless of baseline diabetes status (Carlsson LMS et al. Life expectancy after bariatric surgery or usual care in patients with or without baseline type 2 diabetes in Swedish Obese Subjects. Int J Obes (Lond). 2023 Oct;47(10):931-938. doi: 10.1038/s41366-023-01332-2. Epub 2023 Jul 12. PMID: 37438611; PMCID: PMC10511310).
Semaglutide 2.4 mg reduced the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by ~20%, compared to placebo. So far, this is the only level 1 evidence showing that treating obesity leads to beneficial cardiovascular outcomes (Lincoff AM et al. SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-2232. doi: 10.1056/NEJMoa2307563. Epub 2023 Nov 11. PMID: 37952131). However, as reported by Wilding et al. (STEP 1 Study Group. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564. doi: 10.1111/dom.14725. Epub 2022 May 19. PMID: 35441470; PMCID: PMC9542252), one year after the withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. This is direct proof that obesity needs lifelong treatment.Hence, this raises the issue of the need of keeping OMMs long term, impacting the costs of treating obesity.
Cohen said that the economic impact of obesity and it is associated conditions (CVD, CKD, etc) are considerable, and it was important to examine the cost-effectiveness of all treatments for obesity. A study by Choi JG et al (First-Line Therapy for Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists: A Cost-Effectiveness Study. Ann Intern Med. 2022 Oct;175(10):1392-1400. doi: 10.7326/M21-2941. Epub 2022 Oct 4. PMID: 36191315; PMCID: PMC10155215) found that oral GLP1ra was not cost-effective (ICER, $823 000 per QALY). Indeed, to be cost-effective at under $150,000 per QALY, costs for SGLT2 inhibitors would need to be under $5 per day and under $6 per day for oral GLP-1ra.
In comparison, RYGB has been found to be cost-effective vs medical therapy (ICER of $46,877 per QALY gained), and the cost-effectiveness of RYGB improved over a longer time horizon (Lauren BN et al. Estimated Cost-effectiveness of Medical Therapy, Sleeve Gastrectomy, and Gastric Bypass in Patients With Severe Obesity and Type 2 Diabetes. JAMA Netw Open. 2022 Feb 1;5(2):e2148317. doi: 10.1001/jamanetworkopen.2021.48317. PMID: 35157054; PMCID: PMC8845022). However, surgery is not cost-effective in severe T2D, insulin use, diabetes medication use, and poor glycaemic control.
Furthermore, Cohen et al. (What is the impact on the healthcare system if access to bariatric surgery is delayed? Surg Obes Relat Dis. 2017 Sep;13(9):1619-1627. doi: 10.1016/j.soard.2017.03.025. Epub 2017 Mar 31. PMID: 28499887), reported that delaying bariatric operations is more expensive and less effective compared with prompt surgery, and very cost effective compared with no surgery. In addition, 15-year findings from the Swedish Obese Subjects study (Keating C et al. Healthcare costs over 15 years after bariatric surgery for patients with different baseline glucose status: results from the Swedish Obese Subjects study. Lancet Diabetes Endocrinol. 2015 Nov;3(11):855-65. doi: 10.1016/S2213-8587(15)00290-9. Epub 2015 Sep 17. Erratum in: Lancet Diabetes Endocrinol. 2015 Dec;3(12):e11. PMID: 26386667; PMCID: PMC4880549) reported that the long-term healthcare cost results support prioritising T2DM patients with obesity for bariatric surgery. Moreover, MBS also leads to significant medication discontinuation within one year for high-risk veterans with diabetes or hyperlipidaemia (Maciejewski ML et al. Discontinuation of diabetes and lipid-lowering medications after bariatric surgery at Veterans Affairs medical centers. Surg Obes Relat Dis. 2010 Nov-Dec;6(6):601-7. doi: 10.1016/j.soard.2010.07.005. Epub 2010 Jul 29. PMID: 20965791).
Cohen said more studies are needed to assess whether combined strategies pre-and/or postop would add health benefits or if they would increase costs. He also stated that indications for revisional surgery and OMMs require customized evaluation, including risk assessment and economic analysis.
What is in the pipeline?
Next, Dr Matthias Blüher (Leipzig University & Helmholtz Munich, Germany) looked at what the future may hold for OMMs and began by saying MBS has paved the way for more effective drugs, as malabsorption/restrictive procedures demonstrated the importance of hormonal changes in achieving weight loss. Despite the advances in OMMs, MBS still remains the gold standard treatment for maximising weight loss (Müller TD et al., Nat Rev Drug Discov. 2022; 21: 201-223).
He said that the future obesity pharmacotherapy will focus on the development of four medicines: oral incretin agonists, dual incretin agonists, triple incretin agonists and combination therapies and therapies to reduce muscle wasting upon weight loss.
Oral incretin agonists
Orforglipron (Eli Lilly and Company) is an oral nonpeptide GLP-1 receptor agonist and Wharton S et al (Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023 Sep 7;389(10):877-888. doi: 10.1056/NEJMoa2302392. Epub 2023 Jun 23. PMID: 37351564) report that in a phase 2, randomised, double-blind trial, at week 26 the mean change from baseline in body weight ranged from −8.6% to −12.6% across the orforglipron dose cohorts vs. −2.0% in the placebo group. At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron vs. −2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron vs. 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which led to discontinuation of orforglipron in 10 to 17% of participants. Importantly, the safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.
Combination therapies
CagriSema (cagrilintide+semaglutide, Novo Nordisk) – is a combination of GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide. Frias et al (The Lancet 2023. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial) reported that in people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA1c with CagriSema was greater versus cagrilintide, but not vs. semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated.
Dual incretin agonists
Survodutide (Zealand Pharma) is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist and Blüher M et al (Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial. Diabetologia. 2024 Mar;67(3):470-482. doi: 10.1007/s00125-023-06053-9. Epub 2023 Dec 14. Erratum in: Diabetologia. 2024 Apr;67(4):758. doi: 10.1007/s00125-024-06095-7. PMID: 38095657; PMCID: PMC10844353) reported that in a phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, survodutide produced greater bodyweight reductions than patients in the diet control or semaglutide groups, as well as reduced HbA1c levels and bodyweight after 16 weeks’ treatment in participants with type 2 diabetes.
AMG-133 (Amgen) is a novel bispecific glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist and GLP-1R agonist molecule. In December 2022, the company reported mean percent changes in body weight ranged from -7.2% at the lowest dose (140mg Q4W), to -14.5% at the highest dose (420mg Q4W) by day 85.
Therapies targeting loss of muscle mass
Bimagrumab (Eli Lilly and Company) is an antibody that blocks activin type II receptors and stimulates skeletal muscle growth. In a study by Heymsfield SB et al (Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021 Jan 4;4(1):e2033457. doi: 10.1001/jamanetworkopen.2020.33457. Erratum in: JAMA Netw Open. 2021 Feb 1;4(2):e211376. doi: 10.1001/jamanetworkopen.2021.1376. Erratum in: JAMA Netw Open. 2021 Mar 1;4(3):e212581. doi: 10.1001/jamanetworkopen.2021.2581. PMID: 33439265; PMCID: PMC7807292), ActRII blockade with bimagrumab led to significant loss of fat mass, gain in lean mass and metabolic improvements during 48 weeks in patients with overweight or obesity who had type 2 diabetes.
GLP1/GIP/glucagon triple agonists
Retatrutide (Eli Lilly and Company) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptor. Jastreboff AM et al (Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023 Aug 10;389(6):514-526. doi: 10.1056/NEJMoa2301972. Epub 2023 Jun 26. PMID: 37366315) revealed that retatrutide resulted in a mean weight reduction up to 24.2% at 48 weeks and achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight.
Dr Blüher concluded that despite their effectiveness, triple incretin agonists will not replace MBS as there will always be non-responders, lower effect size in T2D patients, and the plateau weight effect.
Revisional surgery and modern pharmacotherapy
In his presentation, Dr Phil Schauer (Pennington Biomedical Research Center, Baton Rouge, LA) looked at whether modern pharmacotherapy can be used pre- and post- revisional MBS. He began by stating that research has shown that revisional MBS has higher complication rates, and in some instances two or three times more, compared to primary MBS (McLennan et al. Characteristics and outcomes for patients undergoing revisional bariatric surgery due to persistent obesity: a retrospective cohort study of 10,589 patients. Surg Endosc. 2023 Jun;37(6):4613-4622. doi: 10.1007/s00464-023-09951-6. Epub 2023 Mar 1. PMID: 36859722).
Several studies have shown that anti-obesity medications for weight regain can be effective with weight loss varying from 5% to 15% (Schwartz et al. Obes Surg .2016;26(2):452-458; Stanford et al. Surg Obes Relat Dis. 2017;13(3):491-501; Rye et al. Obes Surg. 2018:28(11):3553-3558; Hanipah et al. Surg Obes Relat Dis. 2018;14(1):93-98; Wharton et al. Clin Obes. 2019;9(4):e12323; Edgerton et al. J Gastroint Surg. 2021;25(2):369-377). A study by Gazda CL et al (Pharmacotherapies for Post-Bariatric Weight Regain: Real-World Comparative Outcomes. Obesity (Silver Spring). 2021 May;29(5):829-836. doi: 10.1002/oby.23146. Epub 2021 Apr 4. Erratum in: Obesity (Silver Spring). 2021 Sep;29(9):1567. doi: 10.1002/oby.23241. PMID: 33818009) comparing outcomes of therapies (intensive lifestyle modification (ILM) group, a non-glucagon-like-1 receptor agonist (GLP-1-RA)-based weight-loss pharmacotherapy (WLP) group, and a GLP-1-RA-based WLP group (the latter two groups in conjunction with ILM)) for weight regain after bariatric surgery. The outcomes revealed GLP-1-RA -based WLP therapies were found to be more effective for treating post-MBS weight regain than non-GLP-1-RA-based WLP or ILM, regardless of surgery type.
Two additional studies (GRAVITAS, Miras et al. Lancet Diabetes Endocrinol. 2019;7(7):549-559; and BARI-OPTIMISE Mok J et al Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery: The BARI-OPTIMISE Randomized Clinical Trial. JAMA Surg. 2023 Oct 1;158(10):1003-1011. doi: 10.1001/jamasurg.2023.2930. PMID: 37494014; PMCID: PMC10372755) showed 46% of liraglutide group lost ≥5% weight vs 9% lost by placebo group (GRAVITAS) and body weight change for liraglutide, vs placebo was -8.03 (p< 0.001).
A paper by Horber FF et al (Reversal of Long-Term Weight Regain After Roux-en-Y Gastric Bypass Using Liraglutide or Surgical Revision. A Prospective Study. Obes Surg. 2021 Jan;31(1):93-100. doi: 10.1007/s11695-020-04856-y. Epub 2020 Jul 21. Erratum in: Obes Surg. 2021 Jul;31(7):3386. doi: 10.1007/s11695-021-05426-6. PMID: 32691401; PMCID: PMC7808975) examined whether pharmacotherapy with liraglutide was similarly effective in reversing weight regain more than 6 years after RYGB as revisional surgery aimed at restoring restriction. The authors reported that weight regain can be safely and effectively reversed with liraglutide. Compared with revisional surgery, pharmacotherapy with liraglutide was low risk and resulted in an important improvement in hypertension and dyslipidaemia. Therefore, daily subcutaneous injections of liraglutide are a valid option to treat weight regain after RYGB.
“For patients with recurrent weight gain after MBS, but who do not require revisional or conversion for a complication, treatment with an OMM should be considered before any MBS reoperation”, said Schauer. “If treatment with OMMs after MBS results in a suboptimal initial clinical response or recurrent weight gain, or if there is an inability to continue medications (e.g., due to cost or an adverse reaction), then patients should be considered for conversion or revisional surgery.
He added that any consideration for revisional MBS should be after a full MDT assessment and discussion, and should not be limited to laparoscopic surgery, but also include endoscopic bariatric therapies.
How to deal with the challenges of MBS and lifelong OMM use
In the next presentation, Professor Arya Sharma (University of Alberta, Edmonton, Canada) looked at the specific challenges and possible solutions to patient adherence and discontinuation when using OMM.
He highlighted the STEP 1 RCT (Wilding JPH et al. Diabetes Obes Metab. 2022;24:1553-1564) and STEP 4 RCT (Rubino D et al. JAMA. 2021;324(14):1414-1425) that showed weight regain in terms of mean percent change in body weight after the discontinuation of semaglutide.
Although sceptics of OMMs have claimed that there could be complications of patients taking OMMs for the rest of their lives, Sharma said that there are many common disorders that require life-long medications including hypertension, lipid disorders, diabetes mellitus, heart failure, arrhythmias, thyroid disease, chronic kidney failure, thrombotic disorders, AIDS, convulsive disorders, organ transplants, psychotic disorders, breast cancer and auto-immune diseases.
That said, he added there are several barriers to long-term treatment of all drugs, not just OMMs, including patient adherence, evidence of benefit, tolerability/adverse effects, HCP conviction/knowledge/ideology, cost/coverage, discrimination, misinformation and hope.
In a study by Ganguly R et al (Persistence of newer anti-obesity medications in a real-world setting. Diabetes Res Clin Pract. 2018 Sep;143:348-356) that evaluated real-world data on persistence with AOMs and explore associated patient factors, they reported patients on liraglutide 3.0 mg had significantly lower risk of discontinuation vs. those on lorcaserin (p<0.0001), naltrexone/bupropion (p<0.0001) and phentermine/topiramate (p<0.0001) over the course of follow-up (mean follow-up duration, 342-427 days). Older age, male gender, having hyperlipidaemia and no prior phentermine use were associated with higher persistence. Over 95% of study patients had commercial insurance.
A study Fischer MA et al (Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010 Apr;25(4):284-90. doi: 10.1007/s11606-010-1253-9. Epub 2010 Feb 4. PMID: 20131023; PMCID: PMC2842539) examined primary non-adherence in community-based practices and sought to identify predictors of non-adherence. They found that medication class was the strongest predictor of adherence, and non-adherence was common for newly prescribed medications treating chronic conditions such as hypertension (28.4%), hyperlipidaemia (28.2%) and diabetes (31.4%).
According to Kardas P et al (Determinants of patient adherence: a review of systematic reviews. Front Pharmacol. 2013 Jul 25;4:91. doi: 10.3389/fphar.2013.00091. PMID: 23898295; PMCID: PMC3722478), there are 771 individual factor items associated with non-adherence these include socio-economic-related factors, healthcare team- and system-related factors, condition-related factors, therapy-related factors and patient-related factors. However, Sharma said there are potential solutions to improve patient adherence including HCP/policy maker/payer/patient recognition of obesity as a chronic progressive disease, evidence of long-term health and QoL benefits, evidence of cost-benefit, prioritisation, personalisation/HCP-Patient relationship and competition/generics/price negotiations.
With regards to costs, a study by Barber MJ et al (Estimated Sustainable Cost-Based Prices for Diabetes Medicines. JAMA Netw Open. 2024 Mar 4;7(3):e243474. doi: 10.1001/jamanetworkopen.2024.3474. Erratum in: JAMA Netw Open. 2024 Apr 1;7(4):e2414263. doi: 10.1001/jamanetworkopen.2024.14263. PMID: 38536176; PMCID: PMC10973901) estimated the cost of manufacturing insulins, SGLT2Is and GLP1As, by deriving sustainable cost-based prices (CBPs) and compared these with current market prices. They found that higher prices limit access to newer diabetes medicines in many countries and are therefore a barrier to effective treatments. The findings of this study suggested that robust generic and biosimilar competition could reduce prices to more affordable levels and enable expansion of diabetes treatment globally. The prices of semaglutie and tirzepatide are currently being investigated by the US Senate.
In agreeing with the Consensus Statements, Sharma said: “People living with obesity need access to all evidence-based obesity treatments, including MBS and OMMs, as part of standard healthcare. Health systems need to support the long-term management of obesity as they do for other chronic diseases (e.g., diabetes or cardiovascular disease). All healthcare providers need a basic understanding of the complex etiology, pathophysiology and evidence-based management of obesity,” adding, “Chronic diseases required chronic treatments.”
Potential need for future studies
In the final presentation, Professor Francesco Rubino (King’s College London, London, UK) said that there needs to be a ‘reframing of obesity’, because currently there is an implication that obesity is a ‘risk factor’ for other diseases and a harbinger of other diseases, the implication being that obesity is not itself an illness.
The causes of adipose tissue expansion are genetic, environmental and psychological, and the mechanisms of adipose tissue expansion are the result of alterations of homeostatic regulation of fat mass, appetite and satiety.
Once established, excess adiposity can induce mechanical stress, lipotoxicity, insulin resistance, low-grade, inflammation, hormonal alterations, mitochondrial damage, ectopic fat and endotelial dysfunction.
These mechanisms can lead to obesity-related diseases such as T2DM, CVD, cancer and mental health disease. The above mechanisms, however, can also directly and negatively affect the functioning of various organs, independently of the onset of other diseases. This means that obesity can cause illness on its own; yet the conventional framing of obesity does not describe such illness but only portrays obesity as a risk factor for other diseases.
Professor Rubino said MBS had been proven to be the most effective treatment for severe obesity, and for improvement of obesity-related diseases and conditions, reducing all-cause mortality while also being cost-effective; yet only 0.82% of suitable candidates receive MBS. Despite overwhelming evidence of benefits, many patients are unaware of its effectiveness. In a recent research survey carried out in August 2023 (Qualtrics/Metabolic Health Institute) 1,017 US adults with self-reported obesity were asked “What is THE most effective treatment today for severe obesity?”: 53% said diet and exercise, 12% said drugs, 18% did not know and only 17% said MBS.
One issue is how obesity is measured, and he argues BMI leads to a misguided prioritisation of treatment. BMI is not an accurate measure of adiposity and can therefore misclassify obesity; most importantly, BMI does not discriminate between health and ongoing illness. The current framing of obesity as merely a risk factor for other diseases implies that all treatment for obesity are used with “prophylactic intent”, that is, they are conceived as an intervention for risk reduction rather than as a treatment of ongoing illness with the aim to improve clinical manifestations. The low uptake of BMS may therefore be explained with the widespread idea that such surgery is merely a prophilcactic approach to reduce obesity-related risk, rather than treating a disease as in the case of surgery for other indications.
According to Professor Rubino, primary prevention should focus on the causes of adipose tissue expansion (genetic, environmental, psychological); secondary prevention should focus on prophylactic treatment (interventions aimed at weight loss for risk reduction). In people with obesity-induced illness (the new concept of clinical obesity) interventions should should have therapeutic intent and aim at the improvement/remission of clinical manifestations of obesity to prevent complications and end-organ damage.
“Future research should have clinical obesity at the centre and focus on pathophysiology of the sub-forms of obesity, mechanisms of action of interventions, staging of clinical obesity, cost-effectiveness, improvement of clinical manifestations as endpoint of clinical trials and stage-specific treatment protocols (Adjuvant/Neo adjuvant treatments),” he concluded.
To access Module I, please click here
To access Module II, 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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