CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

Abstract

Background & Aims Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. Methods This randomized, double‐blind, placebo‐controlled, phase 2 study began with a 5‐week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16‐week double‐blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy‐confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. Results At Week 4, all OCA groups had an increase from baseline in mean low‐density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. Conclusions The CONTROL study showed that OCA‐induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).

Review article: the impact of liver‐directed therapies on the atherogenic risk profile in non‐alcoholic steatohepatitis

“…136 Results revealed that OCA increased mean LDL-C, mostly attributable to an increase in large LDL. 136 More importantly, the study showed that the lowest available dose of atorvastatin was able to reverse the OCA-mediated increase in LDL-C to below baseline levels. However, atorvastatin did not reverse the OCA-mediated decrease in HDL-C. showed that initiation of a statin in NGM282-treated patients resulted in a rapid decline in plasma lipid levels (Figure 3), showing that the increase in LDL-C is related to the LDL receptor and that statins can reduce the increased LDL-C observed with NGM-282 treatment.…”

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

“…POISE study data showed that three-year OCA treatment reduced or stabilized hepatic collagen deposition and ductular injury in PBC patients with cirrhosis (69). The Combination OCA and Statins for Monitoring of Lipids (CONTROL) clinical trial study found increased LDL in NASH patients treated with OCA (5, 10, or 25 mg) indicating altered lipid metabolism (73). The observed increase in LDL cholesterol was reduced in NASH patients concurrently treated with OCA and atorvastatin, a statin utilized to reduce endogenous cholesterol production (73).…”

“…The Combination OCA and Statins for Monitoring of Lipids (CONTROL) clinical trial study found increased LDL in NASH patients treated with OCA (5, 10, or 25 mg) indicating altered lipid metabolism (73). The observed increase in LDL cholesterol was reduced in NASH patients concurrently treated with OCA and atorvastatin, a statin utilized to reduce endogenous cholesterol production (73). The authors noted that these two drugs were well-tolerated when utilized together, addressing the observed increase in LDL cholesterol following OCA treatment in NASH patients, but remained inconclusive with respect to the combinatorial effect on hepatic injury (70,73).…”

Phase 3 drug pipelines in the treatment of non‐alcoholic steatohepatitis

“…OCA-induced increases in LDL-C levels in NASH patients were mitigated with atorvastatin. 17 A phase 3 trial of OCA in NASH patients with cirrhosis is now ongoing (REVERSE trial). The REVERSE trial will be carried out at sites in North America, Europe, Australia, and New Zealand.…”

“…This phase 2, multicenter, RDBPCT evaluated the effect of OCA and the subsequent addition of statin therapy, on lipoprotein metabolism in patients with NASH with fibrosis stage 1–4, but no evidence of hepatic decompensation. OCA‐induced increases in LDL‐C levels in NASH patients were mitigated with atorvastatin . A phase 3 trial of OCA in NASH patients with cirrhosis is now ongoing (REVERSE trial).…”