Long-acting octreotide (Sandostatin LAR®) causes marked and sustained decrease in total and acyl ghrelin concentrations in adolescents with Prader-Willi Syndrome

Ghrelin is secreted primarily by the stomach. It circulates as acyl-(AG) and desacyl-(DG) forms. AG (but not DG) stimulates appetite. Ghrelin is elevated in Prader Willi syndrome (PWS), suggesting it may cause the characteristic hyperphagia and overweight. Short-acting somatostatin analogue octreotide suppresses ghrelin in PWS. We hypothesized that long-acting octreotide (Sandostatin LAR®, L-Oct) would decrease AG and total (TG=AG+DG) ghrelin and compulsive behaviour towards food intake in adolescents with PWS. In this randomised, double blind, cross-over trial (24 wks washout period), we included 9 PWS subjects (age 5.6 [2.8] yrs, weight Z-score +2.0 [1.0], mean [SD]). They received either L-Oct (30 mg) or saline (Placebo [Plac]) IM every 4 wks for 16 wks. AG and TG (Linco®), glucose and insulin (during an OGTT), food-related behaviour as well as HbA1c and gallbladder ultrasound were evaluated at the beginning and end of each phase. Stat: ANOVA, repeated measures. Order of treatment (Plac vs L-Oct) did not affect the results. L-Oct caused a marked decrease in both AG and TG concentrations throughout the OGTT (Fig). BMI Z-scores remained similar before (+2.0 [ .0]) and after (+2. [ .0], P=0.5) L-Oct therapy. Appetite (Visual Analogue Scale), food seeking and obsessive/compulsive behaviours were not affected by L-Oct. HbA1c and 2-hour glucose were not significantly affected by L-Oct despite the expected decrease (-39%, P=0.02) in insulin area under the curve caused by L-Oct. L-Oct caused asymptomatic gallstones development in 4 subjects that improved/resolved after L-Oct discontinuation. Thus: 1.Prolonged L-Oct treatment caused a marked decrease in AG (-60%) and TG (-50%) that was sustained for 4 months. The absence of clinically relevant changes in BMI/behaviour towards food despite these major L-Oct-induced changes may suggest that ghrelin is not a primary cause of overweight in PWS or that effects of L-Oct on other appetite-regulating hormones mitigate those on ghrelin concentrations; 2. L-Oct is associated with a high incidence of gallstones in PWS.