Adjunctive use of liraglutide at a dose of 3mg/day with conversional Roux-en-Y Gastric Bypass (cRYGB) results in significant weight loss, resolves diabetes mellitus and other associated medical problems with good tolerability, even after discontinuing the drugs, according to the outcomes from a randomised controlled trial (RCT) by researchers from the Medical Research Institute of Alexandria University, Alexandria, Egypt.
The investigators noted that despite the popularity of laparoscopic sleeve gastrectomy (LSG) revision rates range from 10 to 22% according to a systematic review by Guan et al (1), with weight regain (WR) and insufficient weight loss (IWL) accounting for about 70% of revisions after LSG. Roux-en-RYGB gastric bypass (RYGB) is the most popular revisional procedure for failed LSG with good outcomes in terms of weight loss and resolution of associated medical problems. However, revisional/conversional Roux-en-Y Gastric Bypass (cRYGB) has worse outcomes than primary RYGB.
“Previous studies have shown significant augmentation of weight loss with liraglutide (Saxenda) after different bariatric procedures. However, the effects of liraglutide after conversional surgery are unknown,” explained lead author of the study, Professor Mohamed Hany from Alexandria University and Consultant of Bariatric Surgery at Madina Women’s Hospital, Alexandria, Egypt. “Therefore, this study was designed as a double-blind, randomised, placebo-controlled trial aiming to assess the impact of liraglutide administration after conversional RYGB for failed LSG on weight loss, resolution of associated medical problems, and gut hormone changes, compared to the cRYGB with placebo use.”
Patients who had cRYGB between March 2022 and September 2022 were invited to participate in the study. Primary endpoint was weight loss measured by the %TWL and excess weight loss (%EWL) measured throughout the liraglutide/placebo treatment at one month, six weeks and six months. After discontinuing the drugs at six months and unblinding the patient, EWL and TWL were recorded at 12 months. Secondary endpoints were changes in metabolic biomarkers measured at the end of treatment, including fasting glucose levels, HbA1c, HOMA-IR, fasting insulin level, GLP-1 gastric inhibitory peptide (GIP), leptin, ghrelin and peptide-YY (PYY) secreted from ileum and colon.
Randomisation and treatment
In total, 80 patients were included in the RCT – 40 patients in the liraglutide group and 40 patients in the placebo group. Patients in the liraglutide group received daily subcutaneous injections of liraglutide at increasing doses starting on postoperative week six with 0.6mg daily injections, increasing by 0.6mg every week to reach the maximum dose of 3mg daily after five weeks, the liraglutide therapy continued for 24 weeks. The patients in the placebo group received pens filled with normal saline (NaCl 0.9%) in the same increasing dose regime. After six months,11 patients discontinued the liraglutide/placebo treatment, leaving 38 patients in the liraglutide group and 31 in the placebo group.
At baseline there were no significant differences between both groups. Gastroesophageal reflux disease (GERD) was diagnosed by preoperative routine endoscopy in 17 (44.7%) and 18 (53%) patients in the liraglutide and placebo groups, respectively (p=0.270). Grade ‘A’ and grade ‘B’ formed 64.7 and 35.3% in the liraglutide group and 72.2 and 27.7% in the placebo group (p=0.485).
The mean BMI values before LSG were 46.6±8.0, and 43.3±6.2 in the liraglutide and placebo groups (p=0.061), respectively. The mean nadir BMI values were 29.98±2.53 and 31.19±3.21 in the liraglutide and placebo groups (p=0.093), respectively.
The mean time between the LSG and the cRYGB was 7.00±3.15 years in the liraglutide group and 7.65±3.39 years in the placebo group (p=0.416). The mean BMI values before cRYGB were 35.85±0.93, and 36.18±0.87 in the liraglutide and placebo groups, respectively (p=0.135). There were no significant differences between both groups regarding preoperative routine lab tests and metabolic biomarkers assay.
Outcomes
After one month of the liraglutide/placebo treatment, the mean BMI was 32.21±0.93 in the liraglutide group and 32.80±0.76 in the placebo group, after six weeks, 31.36±0.99 vs. 32.10±0.83 and after six months, 29.38±1.20 vs. 30.56±0.84 (p<0.001). After discontinuing the drugs at six months, the results at 12 months were 27.22±0.90 vs. 27.95±0.75, what was not significant between the groups (p=0.912).
For mean %EWL in the cRYGB with liraglutide group group, after six months 60.59±7.05 vs. 50.61±5.45 and at 12 months 79.77±7.49 vs. 73±65±6.04. Measured from primary LSG this was at six months 76.90±10.15 vs. 66.45±13.38 and after discontinuing the drugs at six months, the results showed at 12 months 88.31±6.23 vs. 82.04±8.31 (all p<0.001).
“After analysing the data for patients who were lost to follow-up, results at all time points revealed also a significant difference between the two groups,” he added. “The liraglutide group consistently demonstrated a higher %EWL and %TWL up to six months of treatment with the drugs in both cRYGB and from primary LSG analysis. Furthermore, after discontinuing the drugs at six months, both %TWL and %EWL were significantly higher at 12 months in favour of the liraglutide group.”
Metabolic biomarkers after six months showed comparable changes from baseline in both cohorts regarding lipid profile, fasting blood sugar, HbA1c, fasting insulin levels, leptin, ghrelin, and PYY levels. The level of GLP-1 decreased significantly in the liraglutide cohort (p≤0.001), as the GLP-1 level decreased in the liraglutide cohort and increased in the placebo cohort. Moreover, the levels of GIP increased in both cohorts, with a significantly more increase in the liraglutide cohort (p=0.014).
Severe and intolerable side effects were the cause of discontinuation of treatment in two (5.26%) patients in the liraglutide group after three and four weeks of treatment. Thirty-eight patients continued the 24 weeks of treatment, 31 could reach and tolerate the 3mg/day dose, while seven patients continued lower doses, including two patients on 2.4mg/day, four on 1.8mg/day, and one on 1.2mg/day.
The recorded adverse events in the liraglutide group included: nausea and vomiting in six (15.8%) patients, chronic fatigue in one (2.6%) patient, bloating in two (5.26%) patients, severe abdominal pain and vomiting in one (2.6%) patient and severe injection site reactions in one (2.6%) patient. There were no recorded adverse events in the placebo group (p<0.001).
A significantly higher incidence of resolution/improvement of associated medical problems in the liraglutide cohort was recorded for diabetes mellitus (p<0.001), hypertension (p<0.001), dyslipidaemia (p=0.041), obstructive sleep apnoea (p<0.001), and arthritis (p=0.008). GERD resolution was observed in 76.5% of cases in the liraglutide group and 83.3% in the placebo group, with no significant difference between the two (p=0.611).
In the liraglutide group, 90.0% of cases, and in the placebo group, 95.0% of cases, experienced an uneventful postoperative course within 30 days (p=0.871). A Clavien–Dindo class I complication occurred in 5.0% of cases (p=1.000) within 90 days in both liraglutide and placebo groups. For Class II complications, the rates were 5.0% in the liraglutide and 2.5% in the placebo group (p=0.876). In the liraglutide cohort, side effects were observed in 27.5% of patients, predominantly manifesting as mild gastrointestinal symptoms, including nausea, vomiting, and bloating. A maximum dosage of 3mg/day was well-tolerated by 81.5% of the patients, while the remaining 18.5% persisted on a reduced dose.
“The cost of the drug is a significant barrier that affects patients’ compliance. Therefore, the studies that provided the drug to the patients, as well as this study, had lower discontinuation rates, commonly less than 10%, related to side effects of the drug”, Professor Hany explained. “On the other hand, when patients bore the cost of the drug, there were higher discontinuation rates, varying between 26 and 60%. Previous studies have revealed the primary reasons for discontinuation were the drug’s high cost or outcomes that fell short of the patient’s expectations. In this study, the less-than-anticipated results were the cause of discontinuation in 22.5% of patients in the placebo cohort, while not reported by the liraglutide cohort.”
After six months on liraglutide/placebo, all three patients (100%) with type 2 diabetes mellitus in the liraglutide group achieved normoglycemia without the need for additional medications. In contrast, only one patient (50%) in the placebo group failed to achieve normoglycemia and required ongoing oral medications (p<0.001).
“This outcome suggests an added benefit to the adjunctive use of liraglutide, which is already approved for diabetes treatment at doses ranging from 1.2 to 1.8 mg/day,” Professor Hany reported. “However, it is crucial to note that the resolution of diabetes cannot be conclusively determined while patients remain on liraglutide treatment.”
The findings were reported in the paper, ‘Boosting weight loss after conversional Roux-en-Y Gastric Bypass with liraglutide and placebo use. A double-blind-randomized controlled trial’, published in the International Journal of Surgery. To access this paper, please click here
References
Guan B, Chong TH, Peng J, et al. Mid-long-term revisional surgery after sleeve gastrectomy: a systematic review and meta-analysis. Obes Surg 2019;29:1965–1975.
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