Article
`Impact of Treatment with GLP1 Receptor Agonists, Liraglutide
`3.0 mg and Semaglutide 1.0 mg, While on a Waiting List for
`Bariatric Surgery
`Miguel A. Rubio-Herrera 1,2,*,†
`
`, Sara Mera-Carreiro 1, Andrés Sánchez-Pernaute 3,4 and Ana M. Ramos-Levi 4,†
`
`1 Departament of Endocrinology and Nutrition, Hospital Clínico San Carlos, Instituto de Investigación
`Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
`2 Department of Medicine, Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain
`3 Department of Surgery, Hospital Clínico San Carlos (IdISSC), Faculty of Medicine, Department of Surgery,
`Universidad Complutense, 28040 Madrid, Spain; pernaute@yahoo.com
`4 Departament of Endocrinology and Nutrition, Hospital La Princesa, Instituto de Investigación Princesa,
`Universidad Autónoma de Madrid, 28049 Madrid, Spain; ana_ramoslevi@hotmail.com
`* Correspondence: marubioh@gmail.com
`†
`These authors contributed equally to this work.
`
`Abstract: Background: Weight loss before undergoing metabolic and bariatric surgery (MBS) has
`been suggested to reduce perioperative complications, although with controversial results. The
`objective of this study is to evaluate the impact of treatment with GLP1-R agonists (liraglutide 3.0 mg
`and semaglutide 1.0 mg) on preoperative weight loss and patients’ decisions regarding MBS while on
`a surgical waiting list. Materials and methods: One hundred and two patients on a waiting list for
`MBS started treatment with GLP1-RA for at least 6 months. Changes in weight at 26 and 52 weeks,
`the number of patients achieving >5% weight loss, and patients’ decisions regarding MBS were
`evaluated. Results: After 52 weeks, patients lost 16.9 ± 7.2% of weight with semaglutide 1.0 mg
`and 16.1 ± 5.8% of weight with liraglutide 3.0 mg. All patients lost ≥5% of initial weight, 84.7% lost
`≥10%, 54.6% lost ≥15%, and 27.5% reached ≥20%. A total of 68.6% of participants were satisfied
`with the achieved weight loss and withdrew from the waiting list for MBS. A threshold of >15.1%
`weight loss had the greatest sensitivity and specificity for the final decision regarding undergoing
`MBS. Conclusions: Losing >15% of initial weight after 52 weeks of treatment with liraglutide 3.0 mg
`or semaglutide 1.0 mg during the waiting list for MBS impacts patients’ decisions regarding the final
`acceptance or rejection of the procedure.
`
`Keywords: severe obesity; bariatric surgery; liraglutide; semaglutide; waiting list
`
`1. Introduction
`Metabolic and bariatric surgery (MBS) has been proven to be a safe and effective
`treatment for severe obesity (BMI > 35 kg/m2) and its associated comorbidities and all-
`cause mortality [1]. Moderate weight loss (5–10%) is enough to achieve a significant
`improvement in accompanying cardiovascular risk factors, but sustained weight loss is one
`of the greatest challenges in the management of obesity [2].
`Numerous healthcare insurance plans call for a minimum of 5–15% weight loss before
`undergoing MBS to provide financial coverage in their attempt to limit the indications and
`reduce access to bariatric procedures. However, there are no randomized clinical trials,
`prospective studies, or meta-analyses that support preoperative weight loss as an essential
`prerequisite. In fact, the 1991 NIH Consensus Statement on the Treatment of Obesity [3]
`did not suggest the need for weight loss prior to undergoing MBS. In addition, the authors
`of the Updated Position Statement on Insurance Mandated Preoperative Weight Loss
`Requirements of the American Society for Metabolic and Bariatric Surgery (ASMBS) [4]
`considered this preoperative requirement arbitrary, discriminatory, and without scientific
`
`Citation: Rubio-Herrera, M.A.;
`Mera-Carreiro, S.; Sánchez-Pernaute,
`A.; Ramos-Levi, A.M. Impact of
`Treatment with GLP1 Receptor
`Agonists, Liraglutide 3.0 mg and
`Semaglutide 1.0 mg, While on a
`Waiting List for Bariatric Surgery.
`Biomedicines 2023, 11, 2785. https://
`doi.org/10.3390/biomedicines11102785
`
`Academic Editors: Juan Gambini and
`Ángel Luis Orteg
`
`Received: 14 September 2023
`Revised: 8 October 2023
`Accepted: 10 October 2023
`Published: 13 October 2023
`
`Copyright: © 2023 by the authors.
`Licensee MDPI, Basel, Switzerland.
`This article is an open access article
`distributed under
`the terms and
`conditions of the Creative Commons
`Attribution (CC BY) license (https://
`creativecommons.org/licenses/by/
`4.0/).
`
`Biomedicines 2023, 11, 2785. https://doi.org/10.3390/biomedicines11102785
`
`https://www.mdpi.com/journal/biomedicines
`
`biomedicines
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`evidence, which only leads to delaying an effective surgical approach for the management
`of obesity and its life-threatening comorbid conditions. Indeed, the attrition rate may be
`high and entails more risks than benefits.
`However, there have been studies that have attempted to evaluate the potential impact
`of acute preoperative weight loss on perioperative and postsurgical outcomes, including the
`reduction in liver volume, intraoperative bleeding, anastomotic leakage, deep infections,
`mean hospital stay or postsurgical complications, or even trying to evaluate its utility
`as a predictor of surgical success. In this regard, data derived from systematic reviews
`and meta-analyses conclude that preoperative weight loss may have a modest impact
`on perioperative issues, but there is no clear evidence supporting the effectiveness of
`several different weight loss intervention programs on long-term postoperative weight
`loss [5,6]. Moreover, highly experienced surgical teams that use advanced technology, such
`as laparoscopic and robotic-assisted approaches, have such low complication rates that the
`beneficial effect of preoperative weight loss to reduce postoperative complications becomes
`almost insignificant [7].
`Pharmacological treatment for obesity has been mainly focused on the setting of in-
`sufficient or inadequate postsurgical weight loss, weight plateau, or post-surgical weight
`regain [8–10]. In this regard, GLP1 receptor agonists have been the In this regard, GLP1
`receptor agonists have been one of the most frequently evaluated drugs for weight treat-
`ment, but data are limited to small retrospective and observational studies with short-term
`follow-up (less than 6 months), reaching 3.4–9.7% weight loss, depending on the dose
`used [11–15]. In the few studies that followed up patients for up to 12 months, mean weight
`loss reached 14–17% [16–18]. The only randomized clinical trial comparing liraglutide
`3.0 mg versus a placebo, after weight regain, was carried out in 70 patients with poor weight
`response following gastric bypass or sleeve gastrectomy and a follow-up of 24 weeks. The
`results showed that liraglutide 3.0 mg was better than the placebo in achieving weight
`loss: −8.82 ± 4.94% vs. −0.54 ± 3.32%; p < 0.001 [19]. Overall, the results have proven
`to be similar to real-world studies in patients who have not undergone prior bariatric
`surgery [20–22].
`Data regarding the use of anti-obesity drugs for the preoperative management of
`patients are rather limited. There are studies with orlistat 60 mg three times per day,
`sibutramine, topiramate–fluoxetine combinations, and extended-release phentermine–
`topiramate, attempting to achieve 10% weight loss prior to bariatric surgery [23–25], but to
`our knowledge, and to date, GLP1 receptor agonists have not been specifically evaluated
`for this preoperative indication. The European Medicines Agency (EMA) has authorized
`the commercialization of the GLP1 receptor agonist liraglutide 3.0 mg for patients with
`obesity, and semaglutide 0.25, 0.5, and 1 mg and dulaglutide 0.75 and 1.5 mg for patients
`with obesity and type 2 diabetes. Semaglutide 2.4 mg has been also approved by the EMA
`for the treatment of obesity, but its commercialization is still to come.
`The objective of our study is to analyze the effect of liraglutide 3.0 mg and semaglutide
`1.0 mg on preoperative weight loss in MBS candidates awaiting the procedure, as well as
`to evaluate the impact of pre-surgical weight loss on patients’ final decisions regarding
`acceptance or rejection to undergoing surgery.
`
`2. Materials and Methods
`2.1. Study Design
`We performed a single-center retrospective observational study. The study was
`approved by the Ethics Committee of the Hospital Clínico San Carlos (code: 23/581-
`O_M_NoSP), and is in compliance with the Helsinki Declaration.
`
`2.2. Subjects
`During the years 2019–2022, 102 consecutive patients with severe obesity (BMI ≥
`40 kg/m2 or BMI ≥ 35 kg/m2 with associated comorbidities), aged 18–65 years, eligible
`for MBS, who were scheduled for the procedure with a waiting list of more than 12 months,
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`were offered the possibility of initiating pharmacological treatment during their waiting
`time in an attempt to improve potential obesity-related comorbidities until the surgical
`procedure was performed. Specifically, patients with type 2 diabetes were prescribed
`semaglutide 1.0 mg weekly, according to product label and public healthcare system
`funding. For individuals with obesity and no type 2 diabetes, liraglutide 3.0 mg daily was
`offered according to the product label, but because this treatment has no public healthcare
`grant, only patients who could afford a minimum 6-month treatment were included.
`Patients underwent the same treatment and follow-up as obese patients who were not
`eligible for MBS, thus resembling an approximation to a real-world study.
`
`2.3. Treatment and Follow-Up
`Participants with liraglutide 3.0 mg were instructed to dose escalate, starting with
`0.6 mg once daily and increasing by 0.6 mg weekly until 3.0 mg was reached at week 5 or
`6, depending on gastrointestinal tolerance. Similarly, individuals on semaglutide 1.0 mg
`were instructed to begin with a 0.25 mg weekly dose, and progressively titrate it after four
`weeks until 1.0 mg per week was reached at week 12. If after 3 months of treatment with
`the maximum tolerated dose a minimum 5% weight loss was not reached, treatment was
`withdrawn, according to the product label and indications. We did not include in our study
`patients who, once GLP1-RA was started, required adding another hypoglycemic agent
`potentially affecting weight (such as SGLT2-I, pioglitazone, or insulin) after inclusion in the
`study in order to avoid bias regarding the evaluation of GLP1-RAs’ efficacy. At each visit, a
`healthcare professional recorded any possible adverse effects and verified the titration of
`the drugs.
`In parallel, all participants received lifestyle counseling (from qualified health care
`professionals) every 4–6 weeks, in person or by telephone, to improve adherence. Partic-
`ipants were prescribed a reduced-calorie diet (−600 kcal/d deficit relative to estimated
`energy expenditure calculated at week 0) and increased physical activity (>150 min/wk,
`such as brisk walking and strength exercises). Both diet and activity were recorded daily in
`a diary and were reviewed during counseling visits.
`After 12 months of pharmacological treatment, when the waiting time for bariatric
`surgery came to an end, patients were offered to choose one of three options: (1) con-
`tinue pharmacological treatment and withdraw from the bariatric surgery waiting list;
`(2) continue pharmacological treatment and reconsider undergoing surgery later on; or
`(3) withdraw pharmacological treatment and undergo bariatric surgery.
`
`2.4. Main Outcomes and Measures
`Co-primary endpoints were a percentage change in body weight from baseline to
`week 52 and an achievement of weight loss of at least 5% of baseline weight at weeks 26
`and 52. Body weight was measured using a weighing scale (SECA 684), with participants
`wearing light clothes and no shoes, and rounding to the nearest 0.1 kg. The percentage
`of body weight loss was calculated as 100 × [(body weight at baseline − body weight at
`week 26 or 52)/body weight at baseline].
`Metabolic secondary outcomes included change from baseline in glycemic indices
`(fasting glucose, insulin, HOMA-IR, and hemoglobin A1c), lipids (total cholesterol, low-
`density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-HDL cholesterol,
`and triglycerides), and hepatic function (alanine aminotransferase (ALT), aspartate amino-
`transferase (AST) and gamma-glutamyl transferase (GGT)).
`
`2.5. Statistical Analysis
`Continuous variables were summarized as mean ± standard deviation. Categorical
`variables were expressed as absolute frequencies (percentages). The Shapiro–Wilk test was
`used to check the normality of the variable’s distribution. Comparison between continuous
`variables was performed using an independent-sample t-test. For variables with a skewed
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`distribution, the Mann–Whitney U-test was used for mean comparisons. The chi-squared
`test was used to analyze categorical data.
`Repeated-measures ANOVA was conducted for each outcome using time (moment
`of assessment) as a within-subjects factor and group (semaglutide vs. liraglutide) as a
`between-subjects factor. For the moment of assessment, only baseline, 6-month, and
`12-month evaluations were included due to the presence of missing values in the visits at 3
`and 9 months. Mauchly’s test was used to determine whether the assumption of sphericity
`was met, and Leven’s test was used to assess the homogeneity of variance. When a violation
`of sphericity was observed, Greenhouse–Geisser-corrected p-values were reported.
`The change in laboratory variables in the whole sample was compared using the
`Wilcoxon signed-rank test.
`Receiver operating characteristic (ROC) curves were calculated to evaluate the capac-
`ity of detecting patients who rejected bariatric surgery after pharmacological treatment.
`Youden’s index (YI) was estimated to evaluate the best cutoff points.
`A p-value < 0.05 was considered statistically significant. All statistical analyses were
`performed using IBM® SPSS 26.0, JASP Team (2023, version 0.17.1 computer software) and
`Jamovi (version 2.4.).
`
`3. Results
`3.1. Characteristics of the Sample
`One hundred and two patients were included. The mean age was 52.88 ± 10.38 years,
`and 71 (69.3%) patients were women. A total of 35 patients were treated with semaglutide
`1.0 mg, and 67 were treated with liraglutide 3.0 mg. As expected, the frequency of T2D was
`higher in the semaglutide group than in patients taking liraglutide (100% vs. 0%, X2 = 86.07,
`p < 0.001).
`The main clinical and demographic characteristics are depicted in Table 1 for the whole
`sample and each therapeutic group. There were no statistically significant differences in
`weight and BMI at baseline. However, the semaglutide group was older and showed a
`higher prevalence of arterial hypertension and dyslipidemia. Other comorbidities, such as
`obstructive sleep apnea and knee osteoarthritis, showed no significant differences.
`
`Table 1. Demographic characteristics, comorbidities, and laboratory tests at baseline and according
`to the type of pharmacological treatment received (semaglutide 1.0 mg or liraglutide 3.0 mg).
`
`Characteristics
`
`Age, years
`Sex, female (%)
`Body weight, kg
`BMI, kg/m2
`BMI 35–39.99 n (%)
`BMI 40–44.99 n (%)
`BMI ≥ 45 n (%)
`Comorbidities
`Arterial hypertension (%)
`Dyslipidemia (%)
`Obstructive sleep apnea (%)
`Knee osteoarthritis (%)
`
`Semaglutide 1.0 mg
`(n = 35)
`57.22 ± 5.79
`60.0
`117.77 ± 13.80
`43.05 ± 4.25
`10 (28.6)
`15 (42.9)
`10 (28.6)
`
`Liraglutide 3.0 mg
`(n = 67)
`50.61 ± 11.50
`74.62
`119.60 ± 29.47
`43.92 ± 8.14
`24 (35.8)
`24 (35.8)
`19 (28.4)
`
`77.1
`54.28
`28.57
`22.85
`
`38.80
`31.3
`17.91
`22.38
`
`Statistic
`(p-Value)
`3.19 (0.002) a
`2.32 (0.127) b
`−0.34 (0.729) a
`−0.58 (0.557) a
`
`0.661 (0.719) b
`
`13.53 (<0.001) b
`5.07 (0.024) b
`1.54 (0.214) b
`0.003 (0.957) b
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`Table 1. Cont.
`
`Characteristics
`
`Semaglutide 1.0 mg
`(n = 35)
`
`Liraglutide 3.0 mg
`(n = 67)
`
`Statistic
`(p-Value)
`
`Laboratory tests *
`100.70 ± 13.89
`133.96 ± 43.40
`1221 (<0.001) c
`Glycemia (mg/dL)
`5.61 ± 0.54
`6.82 ± 1.48
`1194 (<0.001) c
`HbA1c (%)
`20.27 ± 14.95
`26.07 ± 12.76
`578 (0.031) c
`Insulin (µUI/mL)
`5.22 ± 4.10
`8.26 ± 4.86
`613 (0.007) c
`HOMA-IR
`191.55 ± 43.05
`167.53 ± 47.36
`572 (0.074) c
`Total cholesterol, mg/dL
`141.46 ± 40.55
`119.68 ± 44.73
`587 (0.099)c
`Non-HDL cholesterol
`50.08 ± 12.67
`47.84 ± 8.99
`639 (0.261) c
`HDL-c, mg/dL
`114.17 ± 34.94
`92.12 ± 36.89
`499 (0.020) c
`LDL-c, mg/dL
`134.40 ± 59.83
`155.96 ± 99.69
`809 (0.573) c
`Triglycerides, mg/dL
`24.27 ± 13.10
`24.25 ± 9.63
`797 (0.653) c
`AST, U/L
`26.02 ± 19.76
`26.81 ± 15.22
`829 (0.441) c
`ALT, U/L
`34.74 ± 34.83
`37.87 ± 22.51
`943 (0.057) c
`GGT, U/L
`a: Student’s t; b: X2-squared; c: Mann–Whitney’s U. * Laboratory tests were available in a subgroup of 77 patients.
`
`3.2. Efficacy of Pharmacological Treatment
`Eighty-five (83.3%) participants completed 52 weeks of therapy. For the variable
`of weight, time-by-group interaction was not significant (F(1,83) = 0.437, p = 0.582). A
`significant main effect of time was observed (F(1,83) = 328.189, p < 0.001). The mean
`observed change in the percentage of weight loss is shown in Figure 1. The mean change in
`percentage weight loss at 52 weeks was 16.99 ± 7.17 for semaglutide 1.0 mg and 16.01 ± 5.77
`for liraglutide 3.0 mg (t = 0.644, p = 0.522).
`
`Figure 1. Changes in percentage of weight loss at 26 and 52 weeks for liraglutide and semaglutide.
`
`When categorizing the percentage of weight loss achieved at 52 weeks, 100% of
`patients lost ≥5%, 85.1% lost ≥10%, 54.1% lost ≥15%, and 27.5% lost ≥20%. There were no
`differences between treatments (X2 = 1.105, p = 0.576) (Figure 2).
`
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`Figure 2. Categories of percentage of weight loss at 52 weeks of pharmacological treatment for
`semaglutide and liraglutide.
`
`There were no significant differences in the percentage of weight loss at 52 weeks
`across BMI ranges (F(2,73) = 0.659, p = 0.520). The mean percentage of weight loss, consid-
`ering both drugs together, was 17.45% ± 4.93% in patients with a BMI of 35–39.99 kg/m2,
`16.06% ± 6.34% with a BMI of 40–44.99 kg/m2, and 15.35% ± 8.09% with BMI > 45 kg/m2
`(Figure 3).
`
`Figure 3. Changes in in percentage of weight loss at 26 and 52 weeks according to BMI range:
`35–39.99 kg/m2 (blue), 40–44.99 kg/m2 (green), and >45 kg/m2 (red).
`
`When analyzing the percentage of weight loss achieved, according to the ranges of
`BMI, there were no statistically significant differences between BMI groups. However,
`a trend for a lower response rate for more ambitious weight loss goals was observed in
`patients with higher BMI (X2 = 5.15, p = 0.076 for ≥10%; X2 = 4.85, p = 0.088 for ≥15%; and
`X2 = 0.463, p = 0.793 for ≥20%; (Figure 4).
`
` 
`
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`Figure 4. Categories of percentage of weight loss at 52 weeks post-pharmacological treatment
`according to BMI ranges.
`
`3.3. Adverse Events
`Nausea was present in 33 (32.35%) and vomiting in 8 (7.43%), with no differences
`between semaglutide and liraglutide (28.57% vs. 34.32% X2 = 0.348, p = 0.555 for nausea,
`and 8.57% vs. 7.46%, X2 = 0.039, p = 0.843 for vomiting). Constipation was present
`in 16 (23.88%) cases under treatment with liraglutide, and no cases were reported with
`semaglutide (X2 = 9.91, p = 0.002). Conversely, diarrhea was more frequent in patients with
`semaglutide (6 (17.14%) vs. 1 (1.49%), X2 = 8.810, p = 0.003). Most adverse events were
`mild, limited in time, and did not imply treatment withdrawal.
`
`3.4. Decision of Rejection of Bariatric Surgery
`At week 52, 70 patients (68.62%) reported their intention to abandon the waiting list
`for bariatric surgery, while 32 (31.4%) were willing to undergo bariatric surgery. Among
`patients withdrawing from the waiting list, there were two levels of certainty in the decision:
`52 (51%) expressed their intention to definitely abandon the plan for surgery, while 18
`(17.6%) did not exclude this possibility in the future. There were no statistically significant
`differences in the final decision to reject surgery plans between patients taking liraglutide
`(20, 29.9%) or semaglutide (12, 34.3%) (X2 = 0.210, p = 0.647). The baseline and follow-up
`characteristics of groups withdrawing or not from bariatric surgery plans are shown in
`Table 2. These results are also shown according to the drug used (semaglutide 1.0 mg or
`liraglutide 3.0 mg) in Supplementary Table S1. Patients remaining on a bariatric surgery
`waiting list showed a greater BMI at baseline and worst response to pharmacological
`treatment at 6 and 12 months.
`
`Table 2. Baseline and 12-month follow-up characteristics of patients according to the decision of
`rejection of bariatric surgery after 52 weeks of pharmacological therapy.
`
`Characteristics
`
`Age, years
`Sex, female (%)
`Baseline body weight, kg
`Baseline BMI, kg/m2
`52-week BMI, kg/m2
`
`Abandoning Bariatric Surgery
`Plans (n = 70)
`53.94 ± 10.18
`53 (75.7%)
`113.94 ± 17.78
`42.50 ± 5.22
`34.75 ± 4.88
`
`Bariatric Surgery (n = 32)
`50.56 ± 10.58
`18 (56.3%)
`129.98 ± 34.27
`46.07 ± 9.59
`39.95 ± 8.20
`
`Statistic (p-Value)
`
`1.536 (0.128) a
`3.933 (0.047) b
`−2.498 (0.017) a
`−1.970 (0.056) a
`−3.597 (0.001) a
`
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`Characteristics
`
`BMI 35–39.99 n (%)
`BMI 40–44.99 n (%)
`BMI ≥ 45 n (%)
`Comorbidities
`Type 2 DM (%)
`
`Hypertension (%)
`
`Dyslipidemia (%)
`
`Obstructive sleep apnea (%)
`
`Knee osteoarthritis (%)
`WL (%)
`26 weeks
`52 weeks
`≥5%
`≥10%
`≥15%
`≥20%
`Laboratory tests (at baseline)
`Glycemia (mg/dL)
`HbA1c (%)
`Insulin (µUI/mL)
`HOMA-IR
`Total cholesterol, mg/dL
`Non-HDL cholesterol
`HDL-c, mg/dL
`LDL-c, mg/dL
`Triglycerides, mg/dL
`AST, U/L
`ALT, U/L
`GGT, U/L
`Laboratory tests (at 12 months)
`Glycemia (mg/dL)
`HbA1c (%)
`Insulin (µUI/mL)
`HOMA-IR
`Total cholesterol, mg/dL
`Non-HDL cholesterol
`HDL-c, mg/dL
`LDL-c, mg/dL
`Triglycerides, mg/dL
`AST, U/L
`ALT, U/L
`GGT, U/L
`
`Table 2. Cont.
`
`Abandoning Bariatric Surgery
`Plans (n = 70)
`27 (38.6)
`27 (38.6)
`16 (22.9)
`
`37.1
`
`48.6
`
`38.7
`
`21.4
`
`21.4
`
`−13.51 ± 5.61
`−17.81 ± 6.32
`100
`92.7
`
`63.6
`
`34.5
`
`109.28 ± 21.16
`5.98 ± 1.08
`22.99 ± 15.03
`6.36 ± 4.59
`182.32 ± 44.74
`132.31 ± 42.22
`50.00 ± 12.50
`104.67 ± 34.76
`135.86 ± 61.04
`26.11 ± 13.49
`27.49 ± 21.18
`36.62 ± 34.80
`
`99.96 ± 14.25
`5.49 ± 0.41
`14.73 ± 9.40
`3.71 ± 2.58
`172.38 ± 36.93
`120.09 ± 34.31
`52.29 ± 11.85
`98.06 ± 31.03
`114.65 ± 61.44
`22.35 ± 8.96
`22.27 ± 10.24
`28.63 ± 24.23
`a: Student’s t; b: X2-squared; c: Mann–Whitney’s U.
`
`Bariatric Surgery (n = 32)
`
`Statistic (p-Value)
`
`7 (21.9)
`12 (37.5)
`13 (40.6)
`
`40.6
`
`59.4
`
`40.6
`
`21.9
`
`25.0
`
`−9.75 ± 3.65
`−12.31 ± 4.37
`100
`63.2
`
`26.3
`
`5.3
`
`124.15 ± 49.47
`6.40 ± 1.39
`23.47 ± 11.69
`7.67 ± 5.03
`180.80 ± 49.65
`133.30 ± 46.47
`47.50 ± 8.37
`106.96 ± 42.38
`157.96 ± 105.70
`20.50 ± 5.47
`24.00 ± 8.04
`34.76 ± 18.63
`
`107.52 ± 24.79
`5.76 ± 0.82
`13.70 ± 7.26
`5.95 ± 8.85
`178.17 ± 45.62
`125.43 ± 42.03
`49.39 ± 9.13
`105.28 ± 35.62
`124.65 ± 75.94
`21.24 ± 7.21
`22.16 ± 8.32
`28.42 ± 17.67
`
`4.282 (0.118) b
`
`0.113 (0.737) b
`1.027 (0.311) b
`0.039 (0.844) b
`0.003 (0.959) b
`0.160 (0.689) b
`
`626 (<0.001)
`242 (0.001)
`-
`9.757(0.002) b
`7.920 (0.005) b
`6.140 (0.013) b
`
`595 (0.334) c
`559 (0.385) c
`315 (0.627) c
`285 (0.318) c
`671 (0.855) c
`688 (0.992) c
`585 (0.280) c
`650 (0.898) c
`635 (0.577) c
`510 (0.061) c
`636 (0.580) c
`610 (0.413) c
`
`517 (0.149)
`530 (0.290)
`327 (0.876)
`296 (0.486)
`574 (0.576)
`553 (0.609)
`498 (0.250)
`495 (0.362)
`577 (0.809)
`623 (0.872)
`614 (0.799)
`591 (9.811)
`
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`3.5. ROC Curve Analysis
`The AUC for the detection of the rejection decision of bariatric surgery using the
`percentage of weight loss was 0.752 (p = 0.001) at 6 months and 0.768 at 12 months (Figure 5).
`
`Figure 5. ROC curve for the detection of the rejection decision of bariatric surgery using the percentage
`of weight loss at 6 months (in red) and at 12 months (in blue). Each line represents 0.2 of sensitivity
`or 1-specificity.
`
`According to DeLong’s test, there were no significant differences between both ROC
`curves (p > 0.05). The best cutoff in the first case was 12.13 (YI = 0.384; sensitivity, 57.14;
`specificity, 81.25%) and 15.12 in the second case (YI = 0.426; sensitivity, 63.64%; specificity,
`78.95%). All cutoff points are shown in Table 3.
`
`Table 3. Sensitivity and specificity at different cutoff points at 26 and 52 weeks.
`
`Percentage of Weight Loss at 26 Weeks
`Sensitivity (%)
`Cutoff Point
`10.17
`72.86%
`10.29
`71.43%
`10.3
`70%
`10.6
`68.57%
`11.84
`60%
`12.06
`58.57%
`12.08
`57.14%
`12.13
`57.14%
`12.2
`55.71%
`12.23
`54.29%
`12.42
`52.86%
`Percentage of weight loss at 52 weeks
`Cutoff Point
`Sensitivity (%)
`11.48
`85.45%
`11.53
`83.64%
`11.78
`81.82%
`14.39
`67.27%
`14.66
`65.45%
`15.12
`63.64%
`15.45
`61.82%
`15.88
`60%
`16.67
`54.55%
`17.46
`49.09%
`
`Specificity (%)
`62.5%
`65.62%
`65.62%
`65.62%
`75%
`75%
`78.12%
`81.25%
`81.25%
`81.25%
`81.25%
`
`Specificity (%)
`57.89%
`57.89%
`57.89%
`73.68%
`73.68%
`78.95%
`78.95%
`78.95%
`84.21%
`89.47%
`
`PPV (%)
`80.95%
`81.97%
`81.67%
`81.36%
`84%
`83.67%
`85.11%
`86.96%
`86.67%
`86.36%
`86.05%
`
`PPV (%)
`85.45%
`85.19%
`84.91%
`88.1%
`87.8%
`89.74%
`89.47%
`89.19%
`90.91%
`93.1%
`
`NPV (%)
`51.28%
`51.22%
`50%
`48.84%
`46.15%
`45.28%
`45.45%
`46.43%
`45.61%
`44.83%
`44.07%
`
`NPV (%)
`57.89%
`55%
`52.38%
`43.75%
`42.42%
`42.86%
`41.67%
`40.54%
`39.02%
`37.78%
`
`Youden’s Index
`0.354
`0.371
`0.356
`0.342
`0.350
`0.336
`0.353
`0.384
`0.370
`0.355
`0.341
`
`Youden’s Index
`0.433
`0.415
`0.397
`0.410
`0.391
`0.426
`0.408
`0.389
`0.388
`0.386
`
`AUC
`0.720
`0.720
`0.720
`0.720
`0.720
`0.720
`0.720
`0.720
`0.720
`0.720
`0.720
`
`AUC
`0.768
`0.768
`0.768
`0.768
`0.768
`0.768
`0.768
`0.768
`0.768
`0.768
`
`Metric Score
`0.354
`0.371
`0.356
`0.342
`0.350
`0.336
`0.353
`0.384
`0.370
`0.355
`0.341
`
`Metric Score
`0.433
`0.415
`0.397
`0.410
`0.391
`0.426
`0.408
`0.389
`0.388
`0.386
`
` 
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`3.6. Changes in Laboratory Parameters
`During the study, we found statistically significant changes in the metabolic param-
`eters associated with glycemic control, atherogenic dyslipidemia, insulin resistance, and
`ALT and GGT concentrations (Table 4). Supplementary Table S2 shows separate laboratory
`outcomes for semaglutide 1.0 mg and liraglutide 3.0 mg. Supplementary Table S2 shows
`laboratory outcomes for semaglutide 1.0 mg and liraglutide 3.0 mg. In the subgroup of
`36 patients with T2D and the available laboratory data, the percentage of patients reaching
`HbA1C < 6.5% changed from 59% at baseline to 82.1% at the end of the study. When
`considering the goal of HbA1c < 5.7%, the percentage at baseline was 12.8% and 53.8% after
`1 year of pharmacological treatment.
`
`Table 4. Baseline and follow-up laboratory parameters in the whole sample *.
`
`Laboratory Tests
`Glycemia (mg/dL)
`HbA1c (%)
`Insulin (µUI/mL)
`HOMA-IR
`Total cholesterol, mg/dL
`Non-HDL cholesterol
`HDL-c, mg/dL
`LDL-c, mg/dL
`Triglycerides, mg/dL
`AST, U/L
`ALT, U/L
`GGT, U/L
`* Data available for 77 patients.
`
`Baseline
`114.18 ± 33.65
`6.12 ± 1.19
`23.12 ± 14.10
`6.71 ± 4.71
`181.82 ± 46.10
`132.64 ± 43.37
`49.17 ± 11.32
`105.41 ± 37.11
`143.13 ± 78.57
`24.27 ± 11.75
`26.34 ± 17.96
`36.01 ± 30.32
`
`At 12 Months
`102.42 ± 18.52
`5.58 ± 0.58
`14.44 ± 8.81
`4.33 ± 5.14
`174.21 ± 39.66
`121.73 ± 36.64
`51.40 ± 11.11
`100.21 ± 32.38
`117.72 ± 65.86
`21.99 ± 8.39
`22.24 ± 9.59
`28.56 ± 22.22
`
`Z (p-Value)
`−4.13 (<0.001)
`−5.01 (<0.001)
`−5.09 <0.001)
`
`−2.52 (0.012)
`−3.39 (0.001)
`−1.48 (0.137)
`−1.36 (0.174)
`−3.59 (<0.001)
`−1.74 (0.081)
`−2.57 (0.010)
`−4.02 (<0.001)
`
`4. Discussion
`Our results show that 68.6% of patients with obesity awaiting MBS who were treated
`with GLP1-receptor agonists reconsidered their decision and rejected undergoing the initial
`plan for a surgical approach. A percentage weight loss >15% after 52 weeks of treatment
`resulted in 63.64% sensitivity and 78.95% specificity for the final decision reached. Among
`patients withdrawing from the waiting list, 17.6% were uncertain and did not express if they
`would definitely remain on the MBS waiting list or if they would eventually withdraw. For
`the time being, they expressed their willingness to continue pharmacological treatment, but
`long-term economic issues, the status of their associated comorbidities, and their perceived
`quality of life will surely influence their final decision.
`Metabolic and bariatric surgery is undoubtedly the most efficient long-term treatment
`for severe obesity, especially in terms of weight loss and the amelioration of associated
`comorbidities [1]. However, waiting lists may significantly hamper its accessibility in
`public healthcare systems. For instance, in Spain, in 2018, waiting time ranged between 397
`and 1661 days [26]. Unfortunately, delaying bariatric procedures contributes to increasing
`obesity-related morbidity and mortality if no other approach is established [26–29].
`The consensus statement of the American Society of Metabolic and Bariatric Surgery
`(ASMBS) and the International Federation for the Surgery of Obesity and Metabolic Dis-
`orders (IFSO) described the current indications for MBS [30]. Specifically, MBS is rec-
`ommended for individuals with a body mass index (BMI) > 35 kg/m2, regardless of the
`presence, absence, or severity of comorbidities, and should be considered for individuals
`with metabolic disease and a BMI of 30–34.9 kg/m2. However, there is increasing clinical
`evidence of the usefulness of attempting a pharmacological approach prior to undergoing
`MBS [31]. For this purpose, in Spain, as in the rest of the European Union, GLP1-receptor
`
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`agonists are the only commercialized drugs. We offered our patients liraglutide 3.0 mg
`for those with obesity but no diabetes and semaglutide 1.0 mg for those with both med-
`ical conditions. Additionally, in both cases, we encouraged the modification of lifestyle
`habits to try to maximize weight loss and ameliorate associated comorbidities and the
`overall quality of life. Unfortunately, semaglutide 2.4 mg is still under consideration for
`approval for commercialization by the EMA, and tirzepatide is not yet EMA-approved for
`obesity treatment.
`The pivotal clinical trial with liraglutide 3.0 mg in patients with obesity and prediabetes
`showed a mean percentage weight loss of 8.0 ± 6.7% after 56 weeks [32] and reached 10.8%
`in early responders, defined as a weight loss >4% at 16 weeks [33]. Similarly, in the clinical
`trial with semaglutide 1.0 mg in patients with type 2 diabetes, the mean percentage of
`weight loss reached 6.5% [34]. In our study, the percentage of weight loss achieved with
`liraglutide 3.0 mg and semaglutide 1.0 mg was relatively similar, at both 6- and 12-month
`follow-up, reaching around 16% at the end of treatment, and clearly superior to the clinical
`trials mentioned above. Reasons for this difference may be related to the close follow-up
`performed in our patients and carrying out the lifestyle change advice, which is reinforced
`via the effects of appetite reduction and satiety induced by the GLP1-receptor agonists, as
`well as the motivation of patients awaiting MBS or because obese patients must bear the
`cost of their medication. Nevertheless, in real-world studies, similar weight loss rates have
`been reported after 6 and 12 months of treatment [16–18,35,36].
`Current indications on the management of obesity suggest that at least 10% weight
`loss should be reached in order to significantly improve associated comorbidities. This
`therapeutic recommendation seems to include one of the two following definitions: (1) the
`ability to safely produce an average of >10% placebo-subtracted weight loss in randomized
`clinical trials in the majority of patients, or (2) the ability to safely produce a ≥15% weight
`loss in over half the patients as an adjunct to lifestyle [37]. In our study, more than 80%
`of participants reached a weight loss of more than 10%, more than half of the patients
`achieved a weight loss greater than 15%, and one out of four participants lost more than
`20% of the initial weight. Indeed, these data are similar to what has been reported in prior
`randomized clinical studies with more potent drugs, such as semaglutide 2.4 mg in obese
`patients [38] or tirzepatide in patients with obesity and type 2 diabetes [39].
`Interestingly, 68.6% of patients, who had lost around 15% of their initial body weight,
`decided to withdraw from the waiting list for MBS without any influence from the physician.
`In this regard, the threshold that best determined the highest sensitivity and specificity for
`the final decision to either continue with the surgical plan or drop out was a weight loss of
`15.12% (63.64% sensitivity and 78.95% specificity, AUC ROC of 0.768), although this was
`observed after 6 months when weight loss was above 12%. To our knowledge, this is the
`first time that a sustained weight loss over a period of at least 26 weeks has had such a
`remarkable influence on the deci