Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies

Abstract

PurposeOctreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety.MethodsTwo studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries.ResultsMedian duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61–2.03]; OCT30, RR = 1.09 [95% CI, 0.70–1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28–3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69–3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia.ConclusionsThe results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.

Insulin translates unfavourable lifestyle into obesity

“…Both compounds used to decrease insulin secretion have other pharmacological effects that may contribute to the weight loss observed. Diazoxide causes smooth muscle relaxation and fluid retention, while octreotide has a low risk of cardiac, hepatic and renal toxicity [48, 49]. However, the two drugs represent quite different pharmacological approaches, which share an insulin lowering effect but not adverse effects.…”

Somatostatin and Its Receptors in Myocardial Ischemia/Reperfusion Injury and Cardioprotection

“…Moreover, octreotide protects against high intraocular pressureinduced retina ischemia/reperfusion damage in a mouse model (Wang et al, 2015), reduces ischemia/reperfusion injury in rat pancreas and in rabbit liver (Hoffmann et al, 1996;Yang et al, 2013) and reduces infarct size in a coronary occlusion model in rats (Wang et al, 2005). It is worth mentioning that, according to the results of a recent clinical trial, long-acting octreotide treatment shows low risk for cardiac adverse events in patients with diabetic retinopathy (Pivonello et al, 2018). Another synthetic analog of SST, pasireotide, also protects against chemically induced ischemia/reperfusion injury ex vivo in a rat retina (Kokona et al, 2012).…”

Somatostatin and diabetic retinopathy: an evolving story

“…This study revealed that long-acting octreotide given intramuscularly every 4 weeks in moderate-to-severe NPDR to low-risk PDR patients was unable to arrest DR progression significantly. The cohorts included in this clinical trial were recently used by Pivonello et al [9] to evaluate the long-term safety of long-acting octreotide by means of a targeted post-hoc analysis. The authors confirmed the established cardiac, hepatic, and renal safety profile of longacting octreotide in diabetic patients with DR with a median duration of treatment of over 3.5 years.…”