Ursodeoxycholic acid (UDCA), the standard treatment of primary biliary cholangitis (PBC), has changed the prognosis of this chronic cholestatic disease. Those patients with adequate response to UDCA (around 60%) present similar survival to the standard population. However, there is still a high rate of suboptimal responders to therapy and these patients require further therapies (1–5).
Over the past few years, new therapies in UDCA nonresponders have been proposed, including obeticholic acid (OCA) (6–8) and fibrates (bezafibrate (9–13) or fenofibrate (14)). OCA is a selective farnesoid X receptor agonist with a net effect of decreased synthesis of bile acid and improved choleresis (15,16). OCA in addition to UDCA (6,8) or in monotherapy (7,8) results in biochemical improvement in liver parameters such as alkaline phosphatase (ALP) and bilirubin, which are associated with the prognosis of the disease, and has demonstrated efficacy in phase II (6,7) and III placebo-controlled (8) trials. Moreover, OCA results in favorable effects in long-term therapy, although there are still a significant number of patients with suboptimal biochemical response (17). Furthermore, long-term OCA treatment in patients with PBC is associated with improvements or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry features (18).
Fibrates (bezafibrate and fenofibrate), which are agonists of peroxisome proliferator–activated receptors (9), have the potential both to improve biochemical measures (9–14) and to reduce the symptoms of PBC; these have been used for more than 2 decades in combination with UDCA as a therapy for PBC. Long-term treatment with UDCA and bezafibrate, in a cohort of 48 patients, was effective in decreasing cholestasis, without significant changes in liver elastography (11). Bezafibrate has been evaluated more recently in a 2-year placebo-controlled trial in a cohort of 100 PBC patients with suboptimal response to UDCA. The primary outcome was total bilirubin, ALP, aminotransferases, and albumin, as well as a prothrombin index normalization; this occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (12). A retrospective cohort from Japan, Showed that addition of bezafibrate to UDCA monotherapy improves not only the validated scores to predict transplantation-free survival in PBC patients treated with UDCA scores GLOBE (19) and UK (20) but also the long-term prognosis of PBC patients, especially those with early-stage PBC (13).
Despite these promising results and because both the placebo-controlled trials with bezafibrate or OCA have been published very recently, there is a lack of data about the effects of these agents outside of a clinical trial setting. Therefore, our aim has been to evaluate the effectiveness of OCA or fibrates in a cohort of PBC patients, with the specific impact on liver chemistries as well as adverse events and treatment discontinuation.
The study assesses patients with PBC from 34 hospitals of Spain, included in the ColHai registry (Spanish registry of cholestatic and autoimmune liver diseases), treated with fibrates (bezafibrate or fenofibrate), OCA, or both. Four hundred eighty-one treatments were analyzed in 426 patients diagnosed with PBC according to established criteria between June 1987 and February 2019. Fibrates or OCA was given from November 2009 to January 2020 as a supplementary treatment to UDCA or alone in rare cases of UDCA intolerance. Prescription was done by the attending physician because of lack of UDCA response according to Paris II criteria (67.5%), increased ALP and disease progression (25.4%), or UDCA intolerance (1.4%). The reason for adding OCA or fibrates was not recorded in 5.7% of patients.
Initial treatment dosage and dose changes during therapy with OCA were recorded. The cohort was divided into 3 groups according to the drug given as second-line therapy: (i) fibrates (bezafibrate or fenofibrate), (ii) OCA, and (iii) fibrates plus OCA at the same time.
Patients were included if they had abnormal ALP values despite therapy with UDCA or were intolerant to UDCA. Eighty-four patients were excluded because of missing or normal baseline ALP, 12 were excluded because of lack of at least 3 months washout periods between OCA and fibrates, and 24 were excluded because of no follow-up visits. Thirty-four patients were treated for a period lower than 3 months, and they were only evaluated for adverse events and reasons for therapy discontinuation. Finally, 351 treatments were evaluated for laboratory changes and 361 for adverse events and therapy discontinuation.
Data were recorded through the online registry (ColHai) supported by Spanish Association for Liver Diseases (Asociación Española para el Estudio del Hígado) and the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Patients who accepted to participate in the registry signed an informed consent that was approved by the Ethical Committee of each center, and data were anonymously recorded by physicians or specialized personnel in each hospital.
Clinical features and laboratory measurements were recorded at diagnosis of PBC, after 1 year of UDCA therapy, at the beginning of the second-line treatment, and every 3 months thereafter until a follow-up of 12 months. ALP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) values are expressed as times the upper limit of normal established by each laboratory.
Baseline and changes during treatment of features of advanced disease, portal hypertension, cirrhosis or events of liver decompensation, and development of hepatocellular carcinoma were also recorded in addition to liver biochemistries. The variant form of PBC with autoimmune hepatitis was documented as well including immunosuppression treatment. Cirrhosis was defined by elastography over 16.9 kPa, liver biopsy, or features of portal hypertension in abdominal ultrasonography.
Effects of the second-line therapy were evaluated as changes in the liver biochemistries between the time of treatment initiations and 1 year of follow-up or the last biochemical measurement in patients treated within a period lower than 1 year. Response to UDCA after 1 year: Barcelona (1), Paris I (3) and Paris II (4) criteria, and the GLOBE-PBC (19) and UK-PBC (20) prognostic scores were calculated in the cases with available data.
Early discontinuation and reasons for discontinuation were recorded. Adverse events, their severity, and if they were related to the second-line therapy were recorded as well.
Standard statistics were used to describe patients' characteristics. Results are expressed as mean ± SEM. The χ2 test was used to examine the differences in categorical variables between 2 independent groups. Student t test was used for differences in continuous variables between 2 independent groups. Comparisons of baseline vs last treatment data were performed with paired Student t test, as well as comparisons between baseline and every 3-month period. All statistical tests were based on 2-sided probability, and significance levels were ≤ 0.05. Statistical analyses were performed with the SPSS, version 23, software (Chicago, IL).
The demographic, clinical, and biochemical characteristics of the 3 groups of patients are summarized in Table 1. Overall, most patients (91.4%) were women, and the age at diagnosis was 48 ± 0.6 years. They were treated with UDCA for 7.2 ± 0.3 years before starting second-line treatment.
Eighty-six patients were treated with OCA (83 patients 5 mg/d; 1 patient 10 mg/d; 2 patients 5 mg/wk). Two hundred three patients received bezafibrate (195 patients 400 mg/d; 6 patients 200 mg/d; 1 patient 900 mg/d) and 47 fenofibrate (20 patients 200 mg/d; 10 patients 145 mg/d; 10 patients 160 mg/d; 1 patient 900 mg/d). Fifteen received OCA plus bezafibrate or fenofibrate. Data of patients under bezafibrate and fenofibrate were merged in the same group (fibrates) because demographic, clinical, and analytical data were comparable before starting second-line therapy. The OCA and fibrates treatment groups were similar regarding the demographics and severity of PBC (fibrosis or cirrhosis), but patients treated with OCA had higher baseline ALP (P = 0.01), lower platelet count (P = 0.003), and higher GLOBE score (P = 0.01) than patients treated with fibrates (Table 1).
Changes in hepatic biochemistry during treatment are summarized in Table 2 and Figure 1. Second-line therapy was associated with a significant decrease in ALP (P < 0.001), GGT (P < 0.001), AST and ALT levels, as well as an improvement in the GLOBE score in both groups. Albumin and platelet count increased in patients treated with fibrates with no significant changes in patients under OCA. Immunoglobulin type M (IgM) was evaluated only in some patients and although a decrease in both groups was observed, it only reached significance in the fibrates group. Bilirubin and UK-PBC score were not modified significantly in patients treated with fibrates or OCA.
Patients treated with fibrates experienced a statistically significant improvement in ALP, GGT, ALT, IgM, and platelets particularly in the first 3 months, except for AST, which significantly decreased after 6 months.
OCA treatment resulted in a significant decrease in ALT, AST, and IgM after 3 months of treatment, whereas ALP and GGT decreased significantly not only at 3 months but also at 6 months. The Percentage decrease in the laboratory values was similar in the 2 groups, except for the ALP decrease, which was more evident in the fibrates (41%) than in the OCA group (19%) (P < 0.001), whereas the ALT decrease was higher in patients under OCA, effects that were particularly evident at 12 months of therapy (Figure 2). ALP normalized in 34.2% of patients (44.8% in the fibrates group and 3.5% in the OCA group, P < 0.001) after 1 year and ALT normalized in 66.9% of patients with initially elevated values (79.4% in the OCA and 61.5% in the fibrates group, P = 0.06). After 1 year, ALP was within normal levels in 34.2% of patients (44.8% in the fibrates group and 3.5% in the OCA group, P < 0.001) and ALT was under normal levels in 66.9% of patients with initially elevated values (79.4% in the OCA and 61.5% in the fibrates group, P = 0.06).
Overlap with autoimmune hepatitis (AIH) was recorded in 44 patients (22.7% with OCA, 65.9% with fibrates, and 11.4% with OCA plus fibrates). Sixteen were under prednisone (10 patients), azathioprine (5 patients), and budesonide (1 patient) while starting OCA or fibrates. The patients with overlap were younger (52.6 ± 1.7 vs 56.9 ± 0.6 years, P = 0.017) and had higher transaminases (ALT 1.8 ± 0.2 vs 1.4 ± 0.6 upper limit normal; P = 0.03) and lower platelets (217 ± 16 vs 249 ± 5; P = 0.02) without differences in other liver biochemistries and the rate of cirrhosis before initiation of second-line therapy. A significant decrease in ALP, GGT, ALT, and IgM with no changes in other variables were observed after second-line therapy.
Although only validated as biochemical criteria of UDCA response, Paris II and Barcelona criteria were applied to assess changes after second-line therapy. Response to Paris II and Barcelona criteria was higher in patients under fibrates (59.8% and 55.6%, respectively) than in patients treated with OCA (18.8% and 30.8%, respectively). The criteria of response to OCA in the POISE trial (ALP of less than 1.67 upper limit normal, with a reduction of at least 15% from baseline, and a total bilirubin level at or below the upper limit of the normal range) were available in 173 patients (54 OCA, 119 fibrates). These criteria of response were achieved in 29.6% and 61.2% of patients under OCA and fibrates, respectively (P < 0.001).
During the period of assessment, OCA dosage was increased in 34 patients (18 at 6 months, 10 at 9 months, 3 at 3 months, and other 3 at 12 months). In 22 of them, the effect could be analyzed, and in 12 (54%), a further reduction in ALP was observed.
OCA plus fibrates
Fifteen patients were concurrently treated with OCA and fibrates (12 bezafibrate and 3 fenofibrate) for 11.6 ± 1.9 months. Eleven patients had been previously treated with fibrates, 2 with OCA, and 2 started OCA and fibrates at the same time. The baseline characteristics of this group are summarized in Table 1. The variant AIH form and the worse liver biochemistries were observed in the patients with OCA plus fibrates, along with higher AST, ALT, and GGT levels than the patients with only OCA or fibrates, but with no differences in the prevalence of fibrosis or cirrhosis features as compared with the other groups. Therapy with OCA plus fibrates was associated with significant improvement of ALP (P = 0.007), GGT (P = 0.02), ALT (P = 0.04), and GLOBE score (P = 0.04) with a trend to IgM decrease (P = 0.05) (Table 3).
Adverse events and treatment discontinuation
During the year of assessment, at least one adverse event was reported in 14.7% of patients (21.3% OCA, 17.6% fenofibrate, 10.7% bezafibrate, and 16% OCA plus fibrates). These adverse events were considered to be associated with treatment in 11.4% of patients (20.2% with OCA, 13.7% with fenofibrate, 6.3% with bezafibrate, and 18.8% with OCA plus fibrates; P = 0.004).
The main adverse event reported by patients with OCA (alone or in combination) was pruritus and dyspepsia or gastroesophageal reflux disease in both groups (Table 4). The other adverse effects occurred in 1% or a less of the patients. The percentage of severe adverse events or those resulting in treatment discontinuation was similar among the different regimens but higher in patients under fenofibrate (3.4% OCA, 11.8% fenofibrate, 3.4% bezafibrate, and 6.2% OCA plus fibrates) (Table 4). Treatment was discontinued in 60 patients, being higher in patients under fenofibrate (16.6%; P < 0.001) than under bezafibrate (14.1%) or OCA (12.4%). The incidence of adverse events and treatment discontinuation was not related with advanced disease or cirrhosis.
The results of the current study clearly indicate that both treatments result in a biochemical improvement, with substantial decreases in the markers of cholestasis (ALP and GGT) with improvement in transaminases and IgM levels. Furthermore, both treatments increase the rates of biochemical response to UDCA (Barcelona and Paris II criteria) and the improvement of the GLOBE-PBC score, supporting that second-line treatments are useful in PBC patients. These effects were observed very early within the first 3 months of therapy and remained stable for the year of follow-up. There were some differences in the effectiveness of both therapies in terms that apparently fibrates have better consequences on cholestasis, whereas OCA has more effect on decreasing transaminases, as the markers of inflammation. Regarding this, the percent of ALP decrease at 3 months was higher in the fibrate group and the rate of ALP normalization at 1 year was reached more frequently in patients under fibrates than under OCA. These results are important because ALP is a recognized surrogate marker of outcome.
Moreover, the percentage of POISE criteria fulfilment at 1 year was higher in the fibrates than in the OCA group. The effects on markers of cholestasis observed in the fibrate group may be, however, influenced by the higher baseline ALP levels at treatment initiation and the initial dose of OCA treatment, which was subsequently increased in more than one-third of the patients. The effectiveness of OCA in clinical practice regarding achieving the POISE criteria is approximately 30%, and the reduction in ALP was around 20%, a rate very similar to that reported recently in a series from Canada (21), and a bit lower than that reported in the placebo-controlled trial with OCA (8).
In our study, platelet count increased in patients treated with fibrates, suggesting an additional positive effect on this surrogate marker of portal hypertension, as reported by the Japanese study as well (13). Moreover, the GLOBE score was significantly improved both in patients treated with OCA and those with fibrates, thus further supporting the effectiveness of the second-line therapy in PBC patients with incomplete response to UDCA (13,21).
The low number of patients with advanced PBC is one of the limitations for assessing the effectiveness of the second-line therapy in this subgroup of patients. On the other hand, there is a lack of information on the effects of both OCA and fibrates in PBC patients with features of AIH because these patients were not included in the placebo-controlled trials (7,12) and few were included in a real-world report (21). In the current study, response to second-line treatment with OCA or fibrates was assessed in 44 patients with features of AIH, resulting in a significant improvement of cholestasis (ALP and GGT) and inflammation (ALT and IgM). Therefore, these results suggest its potential usefulness in patients with the PBC-AIH overlap syndrome.
Although this is a retrospective study, a very relevant fact is the number of patients who discontinued because of an adverse effect or intolerance, particularly in patients taking fenofibrate. Pruritus was the most common side effect reported in the OCA group and absent in the fibrate group. A pulmonary thromboembolism occurred in the bezafibrate group and creatinine increase, neutropenia, and increased transaminases were observed in 3 patients with fenofibrate. All these data on adverse events should be taken with caution because they are those included in the clinical reports within the 1 year of assessment. Either way, these results would indicate that bezafibrate and OCA are safe with a low rate of severe side effects, whereas there are worries about fenofibrate. Pruritus should be taken into account in patients treated with OCA as reported in phase 2 and 3 trials and with OCA monotherapy (6–8).
Despite the high number of patients assessed in this report, there are some limitations mainly with the fact that it is a retrospective evaluation. Moreover, the differences among second-line treatments in some baseline data, indications for therapy and observation periods, and the fact that some patients were included in more than one group, although with at least a 3-month washout period, may result in some biases. Therefore, differences between OCA and fibrates treatments should be taken with caution and only validated in prospective assessments. However, the study raises relevant data on the effectiveness and safety of the second-line therapy in PBC. In conclusion, the study confirms that second-line treatments with OCA and bezafibrate are effective improving the prognostic markers of PBC. Both agents improve cholestasis and OCA may have a further effect on inflammation. Pruritus is the main adverse event associated with OCA.
CONFLICTS OF INTEREST
Guarantor of the article: Anna Reig, MD, and Albert Parés, MD, PhD.
Specific author contributions: Article concept: A.R. and A.P. Article design: A.R. and A.P. Information collection: A.R., C.Á.-N., M.V., A.G.-M., I.M.P.-M., M.H.-G., M.B., P.E., A. Arencibia., D.H., A. Albillos, M.C., G.d.l.C., E. F.-B., E.M., L.H., M.D., J.M.G.-S., J.G.-C., M.R.-G., F.S., V.V., C.F.-A., R.J.A., N.C., and A.P. Writing of the article: A.R. and A.P. Revising the article: A.R., C.Á.-N., M.V., A.G.-M., I.M.P.-M., M.H.-G., M.B., P.E., A. Arencibia, D.H., A. Albillos, M.C., G.d.l.C., E.F.-B., E.M., L.H., M.D., J.M.G.-S., J.G.-C., M.R.-G., F.S., V.V., C.F.-A., R.J.A., N.C., and A.P.
Financial support: ColHai registry was funded by AEEH (Asociación Española para el Estudio del Hígado) and CIBEREHD which were sponsored by Intercept Pharmaceuticals, a company which was not involved in the study design, collection, analysis, interpretation, and writing, nor in the decision to submit this article for publication. No other financial support was provided.
Potential competing interests: C.Á.-N. reports personal fees from Intercept, AbbVie, and Gilead outside the submitted work. M.V. reports personal fees from AbbVie, Gilead, and MSD outside the submitted work. A.G.-M. reports personal fees from Intercept outside the submitted work. M.H. reports personal fees from Intercept outside the submitted work. M.R.-G. reports grants from Intercept and Gilead-Sciences and personal fees from Shionogui, Alfa-Wasserman, Prociento, Kaleido, Novonordisk, MSD, BMS, Allergan, and Boehringuer-Ingelheim outside the submitted work. M.B. reports personal fees from Intercept, AbbVie, Alexion, Gmp-orphan, Novartis, and Astellas and grants from Gilead outside the submitted work. R.M.M. reports personal fees from Intercept, Gilead, and AbbVie outside the submitted work. A. Albillos reports personal fees from AbbVie, Gilead Sciences, Gore, Griffols, Intercept, Merck & Co, and Pfizer and grants from Gilead outside the submitted work. E.M. reports personal fees from Intercept, Abbvie, and Gilead outside the submitted work. C.M.F.-R. reports personal fees from Intercept outside the submitted work. V.V. reports personal fees from Intercept and Promethera Biosciences outside the submitted work. M.S. reports personal fees from Bayer and Eisai outside the submitted work. R.J.A. reports personal fees from AbbVie, Gilead, Intercept, Mylan, Daiichi Sankyo Inc, Obseva, and Novo Nordisk and grants from Wilmar Schwabe GmbH & Co and Gedeon Richter/Perglem S.A outside the submitted work. E.G.-D. reports personal fees from Intercept outside the submitted work. J.G.-C. reports personal fees from Intercept outside the submitted work. A.Parés reports personal fees from Intercept Pharmaceuticals and Novartis outside the submitted work. A.R. reports the ColHai registry was funded by AEEH (Asociación Española para el Estudio del Hígado) and CIBEREHD. No other conflicts of interest. D.H., M.C., G.d.l.C., E.F., A. Arencibia, P.E., M.C., E.F.-B., C.F.-A., F.S., J.M.G.-S., M.D., I.M.P.-M., L.H., and N.C. have nothing to disclose.
WHAT IS KNOWN
- ✓ Based on trials, obeticholic acid (OCA) and fibrates are new treatments for nonresponders' primary biliary cholangitis.
- ✓ Evidence about their effectiveness and rate of adverse events is limited.
WHAT IS NEW HERE
- ✓ OCA and fibrates improve markers of cholestasis, inflammation, and the Globe score.
- ✓ OCA plus fibrates ameliorates liver biochemistries and prognostic scores in difficult-to-treat patients.
- ✓ Bezafibrate and OCA presented a low adverse events rate, which was higher with fenofibrate.
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