Improving Glycaemic Control in Prader-Willi Syndrome with the GLP-1 analogue Liraglutide
Ali SN and Goldstone AP
Imperial Centre for Endocrinology and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
Introduction: Prader-Willi Syndrome (PWS) is a complex multisystem genetic disorder, associated with learning difficulties, short stature, GH deficiency, hypogonadism, and childhood-onset hyperphagia leading to morbid obesity. Although insulin resistance appears lower than expected for obesity in PWS adults related to reduced visceral adiposity, type 2 diabetes mellitus (T2DM) has been described in ~25% of PWS adults.
Treatment of the hyperphagia and obesity in PWS is problematic. Management involves rigorous control of the food environment, caloric restriction and exercise. Best practice for drug treatment of T2DM in PWS is unclear, with use of Metformin, thiazolidinediones and insulin. The role for GLP-1 agonists, such as Exenatide and Liraglutide, is unknown, but given their potential benefits in producing weight loss they may be beneficial in PWS, supported by 2 recent case reports. The safety of GLP-1 agonists in patients with PWS is however of potential concern in view of theoretical adverse effects on gastric motility.
Case report: A 21 year old woman of Bangladeshi ethnicity with PWS developed T2DM aged 11. As a child she was originally controlled with Metformin and a thiazolidinedione with no diabetic complications (HbA1c <7.0%, 53 mmol/mol). Subsequent glycaemic control at age 20 was suboptimal (HbA1c 7.5%, 58mmol/mol) despite good dietary compliance and exercise regime. Hence, long-acting insulin therapy with Detemir was commenced prior to planned GH therapy. However over the next 20 months, glycaemic control steadily worsened (HbA1c 9.5%, 80 mmol/mol) despite increases in insulin dose (24 units daily), with weight increasing from 72.8kg to 79.6kg (BMI 36.1 to 39.5 kg/m2). A Tc-99 semisolid meal scintiscan demonstrated normal gastric emptying with t1/2 48 min (normal <60). The GLP-1 analogue, Liraglutide, was commenced initially at 0.6mg sc od with improvement in post-prandial glycaemic control despite a reduction in insulin dose, with no reported side effects. The dose of Liraglutide is being titrated up further, with plans to repeat gastric emptying studies once she is established on the maximum dose of 1.8mg.
Discussion: Gastric emptying may be delayed in patients with PWS. There have been several reports of idiopathic and binge-eating related gastric necrosis, dilatation and fatal rupture in patients with PWS. This may be related to their reduced vomiting, increased pain threshold and delayed gastric emptying. GLP-1 agonists may delay gastric emptying (which contributes to their beneficial effects on satiety and glycaemic control, in addition to their insulinotropic action). Indeed, diabetic gastroparesis is a contraindication for their use. Since (further) delays in gastric emptying may be particularly dangerous in PWS, appropriate assessment and monitoring of gastric emptying should be considered in patients with PWS both before and after commencement of GLP-1 agonists.