INCIDENCE OF GALLSTONES AND ASSOCIATED COMPLICATIONS WITH USE OF THE SOMATOSTATIN ANALOGUE LANREOTIDE FOR POLYCYSTIC KIDNEY AND LIVER DISEASE.

Abstract Background and Aims Recently, we performed a large randomized-controlled trial to assess the effects of the somatostatin analogue lanreotide on kidney function and kidney and liver volume in autosomal dominant polycystic kidney disease (ADPKD), the DIPAK-1 trial. Lanreotide had no effect on rate of kidney function decline, but slowed kidney and especially liver growth and is used for this indication in clinical practice1,2. A higher incidence of gallstones has been suggested with lanreotide use, but the exact size and implications of this problem are unknown. Therefore, we systematically studied the incidence of gallstones with lanreotide in ADPKD patients. Method In the DIPAK-1 trial, 305 ADPKD patients (age 18-60 years and eGFR 30-60 ml/1.73m2/min) were randomized to lanreotide or standard of care. MRIs were performed at baseline and end of study (120 weeks). For this post-hoc study, patients with a medical history of cholecystectomy (n=7) or absence of a MRI at the end of study (n=28) were excluded. For the remaining study population (n=270), all MRIs were assessed for presence of gallstones by two trained investigators blinded for study treatment and study period and in case of disagreeing results, an abdominal radiologist was consulted for a final assessment. For patients with gallstones additional follow up after the end of the trial was obtained. Results In 2 baseline and 8 end-of -study MRIs, it was not possible to identify the gallbladder, due to multiple adjacent liver cysts. Of the remaining 260 patients (age 48.5 years, female 49.6%, eGFR 50.0 ml/min/1.73m2), 14 patients (5,4%) had gallstones at baseline, of whom 5 were randomized to lanreotide and 9 to standard care. At the end of study, 32 patients (12,3%) had gallstones, of whom 21 patients had received lanreotide and 11 standard care. During the 120 week lasting study, new gallstones occurred in 17 out of 128 patients receiving lanreotide (13.3%) and 3 out of 132 patients receiving standard care (2.3%), rendering an adjusted Odds Ratio for gallstone formation with lanreotide use of 6.9 (95% Confidence Interval 1.9-24.7) p<0.005). The only other significant risk factor for gallstone formation was female gender (OR 3.5, CI 1.2-10.6, p<0.05). Age, body-mass-index and importantly liver volume were not associated with gallstone formation. Of the 32 patients with gallstones at the end of study, seven experienced gallstone-associated complications. Three experienced a biliary pancreatitis (1 during and 2 after the study). Another one had signs of a chronic pancreatitis as accidental finding on imaging during the study, without having had symptoms. Furthermore, another 3 patients underwent a cholecystectomy for symptomatic gallstones after the study. Importantly, all patients with gallstone-associated complications were part of the subgroup of patients that developed de novo gallstones during lanreotide use in the study. Conclusion Lanreotide increases the risk of gallstone formation in ADPKD sevenfold. Gallstones were associated with severe complications, most occurring after the end of the trial. The benefit of somatostatin analogues to reduce kidney and liver size in ADPKD should therefore be weighed against the higher incidence of these adverse events, and patients and doctors should be aware of the risk of (symptomatic) gallstones with use of these drugs.