Incident Gallstones During Somatostatin Analog Treatment are Associated with Acute Biliary Complications Especially After Discontinuation

Abstract

Introduction: Gallstones are a known adverse effect of somatostatin analogs, but the exact incidence and clinical implications are unknown.

Objectives: The aim of this study was to investigate the incidence of gallstones on imaging and related complications in unbiased trial data.

Methods: Data from the DIPAK 1 trial, in which 305 polycystic kidney disease patients were randomized to standard of care (SoC) or lanreotide for 120 weeks, were used. Magnetic resonance imaging (MRI) was performed at baseline and end of treatment and was assessed for the presence, number, and size of gallstones. For all patients who had gallstones at the end of the trial, we obtained follow-up after the trial.

Results: Of 249 patients with data available, 11 patients randomized to lanreotide and four randomized to SoC had gallstones at baseline. During the study, new gallstones were formed in 19/124 patients using lanreotide (15%) and 1/125 patients receiving SoC (1%). The odds ratio for gallstone formation with lanreotide use was 25.9 (95% confidence interval 3.37-198.8; p < 0.001). Gallstones during lanreotide treatment were multiple (> 20 stones in 69% of patients) and small (≤ 3 mm in 63% of patients). Of the 19 patients with incident gallstones during lanreotide treatment, 9 experienced gallstone-associated complications, 8 of whom experienced gallstone-associated complications after discontinuation of treatment (median time after discontinuation 2.5 years). In patients with gallstones at baseline and in patients receiving SoC, no complications occurred.

Conclusions: Treatment with a somatostatin analog leads to the formation of multiple, small gallstones that are associated with severe complications, especially after discontinuation of therapy.

Clinical trial registry website and trial number: ClinicalTrials.gov ( https://ichgcp.net/clinical-trials-registry/NCT01616927" title="See in ClinicalTrials.gov">NCT01616927.

Conflict of interest statement

Ron T. Gansevoort received grant support and fees from Galapagos, IPSEN, Otsuka Pharmaceuticals, and Sanofi-Genzyme for serving on advisory boards and steering committees. He also holds the Orphan Medicinal Product Designation status at the European Medicines Agency for lanreotide as treatment for ADPKD (EMA/OD/027/15). Joost P.H. Drenth has received grant support and fees from IPSEN and Novartis for serving on advisory boards and consultancy. Esther Meijer has received consultancy fees from Otuska. All money is paid to their respective institutions. Sophie E. Aapkes, Robbert J. de Haas, Lucas H.P. Bernts, Charles J. Blijdorp, Sosha E.I. Dekker, Maatje D.A. van Gastel, and Abigail Veldman have no other potential conflicts of interest relevant to this article to report.

Figures

Fig. 1

Selection of patients from the DIPAK1 trial, used for this analysis. DIPAK Developing Interventions for Polycystic Autosomal Kidney disease, MRI magnetic resonance imaging, FU follow-up

Fig. 2

Representative magnetic resonance images at the end of the trial. The gallbladder is marked with a yellow line in all panels, except panel a. a An example of a patient with severe polycystic kidney and liver disease in whom the gallbladder could not be identified due to the large number of cysts. b A patient with many small gallstones, treated with lanreotide, in whom the presence of gallstones is easily missed on coronal slices since the intensity of the gallstones is similar to the intensity of the liver parenchyma (b1). However, on axial slices, one can recognize the gallstones more easily because they are located at the dorsal side of the gallbladder due to gravity (b2). c Typical example of gallstones present at baseline (a limited number of larger stones). These stones mostly remained unchanged during the study period. d Typical example of gallstones formed during lanreotide use (multiple small stones)

Fig. 3

Differences in the number and size of incident gallstones in patients receiving lanreotide compared with other gallstones. Size of the gallstones and the number of gallstones differed significantly between patients with incident gallstones receiving lanreotide, and gallstones that were present at baseline and persisted during the trial (p = 0.001 and p = 0.004, respectively)