Discussion
cholecystitis, abdominal pain, gastrointestinal AEs, Weight loss, pain, weight gain, Diabetes, weight loss, T2DM, diabetes
CHOLECYSTITIS, ADVERSE EVENTS, SECONDARY, REMISSION, DIABETES, DIABETES
The GLIDE trial aimed to assess the metabolic impact of the addition of a GLP-1 receptor agonist in the form of liraglutide 1.8 mg once daily following a LAGB in patients with T2DM. We hypothesised that the addition of a GLP-1 receptor agonist would increase the efficacy of LAGB compared to LAGB alone. To our knowledge, this is the first randomised, double-blind, placebo-controlled trial investigating the impact of GLP-1 receptor agonist treatment following LAGB insertion.Our findings did not reveal significant differences in either HbA1c or weight at 6 months between the LAGB and liraglutide arm compared to LAGB and placebo. However, after cessation of IMP at 6 months, those in the liraglutide arm experienced both a statistically significant rise in HbA1c and weight that was not seen in the placebo arm. These results may be reflective of a suppressant effect of liraglutide on weight and HbA1c in the treatment arm. However, the trial’s target sample size was 58 in total and was therefore underpowered to detect a significant difference in the primary and secondary endpoints at all time points.Remission of T2DM in both the liraglutide and placebo arms was similar, with three patients in both groups achieving full remission of T2DM at 12 months as defined by HbA1c < 48 mmol/mol and stopping all diabetes medication. Weight loss of around 10–15% leads to remission of T2DM in patients with early T2DM [Importantly, whilst there was no significant difference between groups in diabetes duration at screening, graphs showed that seven participants in liraglutide arm had duration ≥5 years, but only four participants in placebo had duration ≥5 years. In addition, two participants in the liraglutide and seven in the placebo arm had diabetes duration ≤2 years duration. Diabetes duration affects chance of diabetes remission following weight loss [There were no other significant metabolic differences between the two arms at 6 and 12 months, except for an improvement in diastolic blood pressure in the placebo arm. This is likely to have been driven by the additional weight loss in the placebo arm compared to the relative weight gain after cessation of GLP-1 therapy in the liraglutide arm. No significant differences were observed between the two groups in terms of quality-of-life scores, indicating that additional liraglutide therapy is safe and not detrimental to quality of life.This randomised controlled trial had a target sample size of 58 (29 per group), however only 27 participants were randomised to the trial. This trial was therefore significantly underpowered to detect a difference between groups in the primary and secondary endpoints. This principally relates to the change in practice over time whereby the LAGB is now less popular, with RYGB and LSG being the preferred procedures. However, this data does provide important pilot data regarding adjuvant GLP-1 receptor agonist therapy following bariatric surgery.Our study showed no differences in HbA1c or weight at 6 months between the two arms. However given the treatment duration of only 6 months, small sample size and the use of relatively less powerful adjunctive therapy further evaluation may be warranted post-metabolic surgery. A Study in rodents, although without diabetes, revealed that the administration of a GLP-1 agonist enhanced the effect of gastric banding [Additional observational and clinical studies have evaluated liraglutide post-bariatric surgery [The number of glucose-lowering therapies varied between trial groups during follow-up. In the liraglutide arm six patients commenced new medications, whereas only three patients in the placebo arm did. This may be due to liraglutide being stopped at 6 months following randomisation, and consequently glycaemic control worsened. In addition, as per the trial protocol, we stopped metformin if HbA1c < 48 mmol/mol. In the intervention arm the HbA1c at 6 months was on average 42.5 mmol/mol, whereas in placebo was 52.0 mmol/mol. Finally, liraglutide was stopped in five instances due to AE, this could have contributed towards sub-optimal glycaemic response.The study intervention was safe, with no statistical differences reported in total adverse events between the placebo and liraglutide arms. There was a numerically higher number of gastrointestinal AEs with liraglutide, in line with previous experience with GLP-1 therapy.. There was a numerically higher number of gastric-band-related AEs in the liraglutide arm vs placebo, although unlikely to be related to GLP-1 therapy. The number of band adjustments was similar in both groups, with an average of 3 band adjustments over 12 months. This number is generally lower than seen in routine clinical practice over 12 months and is likely to be related to a reduction in face-face appointments and limited band adjustments during the Covid-19 pandemic. This may also explain the suboptimal response to gastric band intervention in both groups in terms of body weight and glycaemic response. Importantly, in terms of serious adverse events there was one in the placebo arm (cholecystitis) and two in liraglutide arm (left upper quadrant pain and abdominal pain). The cholecystitis required cholecystectomy and hospital admission. The left upper quadrant abdominal pain required analgesia and anti-emetics, and the abdominal pain required cessation of IMP. Overall, this shows the safety of liraglutide in combination with LAGB.