Obeticholic acid for the treatment of primary biliary cholangitis

Introduction: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease.

Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.

Areas covered: This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.

Expert opinion: If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.     

Investigational drugs in phase II clinical trials for primary biliary cholangitis

Introduction: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that may lead to biliary fibrosis, and eventually cirrhosis. The primary treatment for PBC is ursodeoxycholic acid (UDCA), which has favorably altered its natural history. However, up to 40% of patients have an inadequate response to UDCA, and are therefore at high risk of liver-related complications. Obeticholic acid has recently been approved for use in patients with PBC with inadequate response or who are intolerant to UDCA, but improvement in long-term outcomes has not yet been demonstrated. Alternative therapeutic options for PBC are needed.

Areas covered: Recent advances in research including epidemiological, genetic and pre-clinical studies in animal models of PBC have yielded numerous agents currently at different stages of development for treatment of patients with PBC; in this review, we cover novel therapies that were recently or are recently being investigated in phase II clinical trials.

Expert opinion: Despite the evolving landscape in PBC, the main challenges facing development of novel therapies remain the rarity of the disease and the limitations to design and conduct of controlled clinical trials in PBC, which are needed to determine the long-term effects of novel therapies on the clinical outcomes of PBC.     

Primary biliary cirrhosis: safety and benefits of established and emerging therapies

Introduction: Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease characterized histologically by lymphocytic cholangitis and intralobular bile duct destruction. It is a progressive disorder associated with increased mortality and decreased quality of life related to hepatic fibrosis, troublesome symptoms such as fatigue and pruritus, and ultimately endstage cirrhosis. PBC affects adults around the world, and therefore effective treatment of PBC and its associated symptoms constitute significant issues for patients and providers as well as on a public health level. The only approved pharmacotherapy for PBC to date is ursodeoxycholic acid (UDCA), a choleretic, hydrophilic bile acid which has been in clinical use for decades. UDCA is effective in a majority of patients with PBC, but nearly a third of patients are UDCA non-responders. Non-response to UDCA is associated with an increased risk of death or need for liver transplantation (LT). Whereas LT is an effective treatment, it engenders substantial cost and a risk of PBC recurrence, among other complications. Patients who are non-responders to UDCA or have highly symptomatic disease (e.g., intractable pruritus) are thus in critical need of novel therapeutic approaches, which are both safe and effective.

Areas covered: In this review, we provide a synopsis regarding the safety and benefits of established and emerging pharmacotherapies for PBC and present viewpoints on how they may evolve over the next several years.

Expert opinion: It is our belief that the pharmacoscope of PBC, as with other cholestatic liver diseases, is likely to see important advancements in the near future.     

Obeticholic acid and budesonide for the treatment of primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of adults. Treatments are needed when patients have incomplete response to ursodeoxycholic acid (UDCA).

Areas covered: Discoveries of the key role played by bile acids (BAs) and nuclear receptors (NRs) in regulating liver and metabolic homeostasis have led to promising therapeutic approaches in liver diseases. A PubMed search for the recent literature on NRs in liver disease was conducted. In particular, obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist that has an important role in the enterohepatic circulation of BAs. Preliminary studies of OCA in patients with PBC have demonstrated marked biochemical improvement when administered in combination with UDCA and alone. Pruritus is the most common side effect, limiting treatment at higher doses. Budesonide is a glucocorticoid receptor/pregnane X receptor (PXR) agonist also involved in BA synthesis, metabolism and transport. Studies with budesonide have shown positive effects of short-term combination therapy in selected patients with early stage disease and overlapping features of autoimmune hepatitis.

Expert opinion: Though larger studies are needed, preliminary results of agents targeting FXR and PXR have been encouraging, particularly in subsets of patients with PBC and may mark a new therapeutic era.     

Advances in pharmacotherapy for primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.

Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.

Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.     

Current pharmacotherapy for cholestatic liver disease

Importance of the field: The cholestatic liver diseases comprise a heterogeneous group of disorders which, left untreated, usually progresses to cirrhosis and liver failure. Most are recognized before the onset of advanced fibrosis, thereby affording an opportunity for disease modifying therapy.

Areas covered: This review will cover the current pharmacologic management of the most common causes of cholestatic liver disease in adults, including primary biliary cirrhosis, primary biliary cirrhosis-autoimmune hepatitis overlap syndrome, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, intestinal failure-associated liver disease, and immunoglobulin G4-associated cholangitis. Pharmacologic management of complications of cholestasis will also be reviewed.

Expert opinion: Effective therapy for most cholestatic liver disease is lacking. Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis but the majority of patients do not have a full response. Even in those with a complete response, UDCA does not cure the disease. There is currently no effective medical therapy for primary sclerosing cholangitis. Symptoms and serum liver biochemistry values in intrahepatic cholestasis of pregnancy are improved with UDCA, but it is not certain if this alters the course of disease. Immunoglobulin G4-associated cholangitis is responsive to steroids but may relapse. The farnesoid X receptor agonists are a promising new class of drugs currently being tested in cholestatic liver disease.     

Current and promising therapy for primary biliary cholangitis

Introduction: Primary biliary cholangitis is a chronic, cholestatic liver disease that may progress to cirrhosis with complications of end-stage liver disease. Approved treatment options include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) but novel therapies are being investigated.

Areas covered: In this review, the authors describe the current pharmacotherapy for the treatment of primary biliary cholangitis (PBC) and for management of side effects such as pruritus and fatigue based on the currently available literature.

Expert opinion: Patients diagnosed with PBC should be offered treatment with UDCA at 13–15 mg/kg per day if liver enzymes are elevated. If they do not meet the defined criteria of response, adjunctive therapy should be considered. This may include OCA at 5 mg per day for patients without cirrhosis or investigational therapy. Management of the most common side effects, pruritus, and fatigue, is nuanced and includes lifestyle modifications as well as pharmacological approaches. Several tools such as the Mayo Risk Score and GLOBE are available for prognostic modeling. Ultimately, patients with PBC may end up requiring liver transplantation and referral to a transplant center may also be needed.     

A randomized trial in primary biliary cirrhosis comparing ursodeoxycholic acid in daily doses of either 10 mg/kg or 20 mg/kg

Background:

Ursodeoxycholic acid (UDCA) prolongs transplantation-free survival in primary biliary cirrhosis (PBC). However, the optimal therapeutic dose has not been established.

Aim:

To compare the effects of UDCA administered in daily doses of 10 vs. 20 mg/kg on symptoms, liver biochemistry and biliary UDCA enrichment.

Methods:

A 6-month multicentre randomized open controlled trial was conducted to assess the effects of an increase in the dose of UDCA to 20 mg/kg/day vs. continuation of 10 mg/kg/day for patients who had not achieved biochemical normalization during treatment for at least 6 months with the 10 mg/kg dose. Clinical and laboratory evaluations were performed at entry and at 3-month intervals. The percentage UDCA in duodenal bile was assessed at entry and at 6 months.

Results:

Sixty-one patients were enrolled. No side-effects of UDCA were observed. Within the 20 mg/kg/day group significant decreases were found for alkaline phosphatase (? 8%; P = 0.003), aspartate aminotransferase (? 11%; P = 0.01), alanine aminotransferase (? 17%; P < 0.001), γ-glutamyl transferase?(? 34%; P < 0.001), immunoglobulin M (? 11%; P = 0.002) and cholesterol (? 8.1%; P < 0.001). In the 10 mg/kg group none of these parameters differed significantly from baseline. No significant differences between dose groups for symptom scores or serum bilirubin were found. Biliary enrichment with UDCA increased from 37% to 46% in the 20 mg/kg group (P = 0.02) while remaining stable in the 10 mg/kg group.

Conclusions:

Liver biochemistry improved in PBC patients receiving UDCA 20 mg/kg/day compared to a dose of 10 mg/kg/day. Both doses were equally well tolerated. These results indicate that UDCA 10 mg/kg/day is a suboptimal dose for treating PBC.

     

Ten-year combination treatment with colchicine and ursodeoxycholic acid for primary biliary cirrhosis: a double-blind, placebo-controlled trial on symptomatic patients

BACKGROUND: Combined medical treatment may provide further benefit to primary biliary cirrhosis (PBC) patients administered ursodeoxycholic acid (UDCA). AIM: To evaluate the long-term effects of colchicine and UDCA in symptomatic PBC patients. PATIENTS/METHODS: We extended up to 10 years the double-blind treatment of 44 symptomatic PBC patients originally included in a 3-year multicentre study comparing UDCA and colchicine (U + C) versus UDCA and placebo (U + P). Outcome measures were death or liver transplantation; incidence of clinically relevant events; clinical and quantitative variables retaining prognostic information. RESULTS: Mean follow-up was 7 +/- 3 years. One patient was lost, three withdrew because of jaundice (U + P); two patients stopped colchicine but remained on UDCA. Eleven patients (two for liver-unrelated reasons, U + P) and six patients (U + C) died, three and two patients, respectively, were transplanted (incidence rate difference, five cases per 100 patient-years; 95% CI, -1 to 11). Hepatocellular carcinoma developed in one (U + P) and four (U + C) patients (difference, -2; CI, -5 to 1), portal hypertension complications in nine patients from each group (difference, 1; CI, -5 to 6). Trends of serum bilirubin, Mayo score, antipyrine clearance were similar among treatment groups. CONCLUSIONS: In cirrhotic PBC patients, colchicine does not offer additional benefits to UDCA. In this population, UDCA does not obviate disease progression.     

Long-term results of treatment of malignant carcinoid syndrome with prolonged release Lanreotide (Somatuline Autogel)

Aliment Pharmacol Ther 2011; 33: 235–242

Summary

Background Newer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation. Aim To evaluate the efficacy and safety of fenofibrate in patients with primary biliary cirrhosis and incomplete response to UDCA. Methods We undertook a pilot study involving 20 patients with primary biliary cirrhosis and serum alkaline phosphatase (ALP) ≥ 2× ULN. Nonparametric statistical tests and Spearman correlation test were used as appropriate. Results Twenty patients received fenofibrate (160 mg/day) in addition to UDCA for 48 weeks. Median serum ALP decreased significantly at 48 weeks compared with baseline values [351 (214–779) U/L at baseline vs. 177 (60–384) U/L at 48 weeks, P < 0.05]. A rebound in ALP occurred upon drug discontinuation. Serum aspartate aminotransferase and Immunoglobulin M also decreased significantly, while bilirubin and albumin remained unchanged. Median IL‐1 decreased from 28.9 (2.7–10 000) to 11.3 (2.5–277.7) pg/mL (P = 0.049), and median IL‐6 from 4.6 (3.2–5205) to 3.5 (3.2–73.4) pg/mL (P = 0.027). Heartburn was the most frequent adverse event, leading to discontinuation of two study subjects. Conclusions Combination therapy of fenofibrate and UDCA induced significant biochemical improvement in patients with primary biliary cirrhosis and incomplete response to UDCA. Further studies are warranted.     

Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets

Introduction: The common predominant clinical features of cholangiopathies such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and biliary atresia (BA) are biliary damage/senescence and liver fibrosis. Curative therapies are lacking, and liver transplantation is the only option. An understanding of the mechanisms and pathogenesis is needed to develop novel therapies. Previous studies have developed various disease-based research models and have identified candidate therapeutic targets.

Areas covered: This review summarizes recent studies performed in preclinical models of cholangiopathies and the current understanding of the pathophysiology representing potential targets for novel therapies. A literature search was conducted in PubMed using the combination of the searched term ‘cholangiopathies’ with one or two keywords including ‘model’, ‘cholangiocyte’, ‘animal’, or ‘fibrosis’. Papers published within five years were obtained.

Expert opinion: Access to appropriate research models is a key challenge in cholangiopathy research; establishing more appropriate models for PBC is an important goal. Several preclinical studies have demonstrated promising results and have led to novel therapeutic approaches, especially for PSC. Further studies on the pathophysiology of PBC and BA are necessary to identify candidate targets. Innovative therapeutic approaches such as stem cell transplantation have been introduced, and those therapies could be applied to PSC, PBC, and BA.     

Meta-analysis of the incidence and risk of arterial and venous thromboembolic events associated with anti-EGFR agents in non-small-cell lung cancer patients

Background: To determine the risk of arterial and venous thromboembolic events (ATEs and VETs) associated with anti-epidermal growth factor receptor (EGFR) agents in non-small-cell lung cancer (NSCLC) patients.

Methods: Prospective randomized trials evaluating therapy with or without anti-EGFR agents in NSCLC patients. Data on VTEs and ATEs were extracted.

Results: A total of 8,410 patients from 12 trials were included for analysis. Anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs (Peto OR 1.50, 95%CI 1.16–1.95, P = 0.002; Peto OR 1.73, 95%CI: 1.32–2.26, p < 0.001, respectively), but not for all-grade and high-grade ATEs.

Conclusion: The use of anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs but not for ATEs in NSCLC patients.     

The effect of molecular weights of microencapsulating polymers on viability of mouse-cloned pancreatic β-cells: biomaterials,osmotic forces and potential applications in diabetes treatment

Introduction: Ideal cell-containing microcapsules should be capable of maintaining cell viability and exhibit significant structural stability to support cellular functionality. To date, such microcapsules remain unavailable; thus, this study used our well-established microencapsulating methods to examine a total of 32 different microencapsulating formulations and correlate polymers’ molecular weights (M_wt) and UDCA addition, with cell viability and microcapsules’ stability, postmicroencapsulation.

Methods: MIN6 mouse-cloned pancreatic β-cells were microencapsulated using control (n?=?16; without UDCA) and test (n?=?16; with UDCA) different polymers. Confocal microscopic imaging, cell viability, and microcapsules’ stability were assessed.

Results: Best cell viability (>50%) was obtained at average M_wt of 50,000?g/mol (poly-l-ornithine), followed by 110,000?g/mol (poly-l-lysine). There was no linear correlation between M_wt and viability. Confocal imagining showed similar microcapsules’ shape and cell distribution among all different polymers’ molecular weights, which suggests that the microencapsulating method was efficient and maintained microcapsules’ uniformity. UDCA addition resulted in enhanced osmotic stability of the microcapsules and improved cell viability, when the formulation contained 1% polylornithine, 1% polyethylene glycol, 20% Eudragit^® NM30D, 1% polytetrafluoroethylene, or 5% pentamethylcyclopentasiloxane.

Conclusions: UDCA addition improved microenvironmental conditions within the microcapsules but this effect was largely dependent on the polymer systems used.     

Clinical aspects and perspectives of erlotinib in the treatment of patients with biliary tract cancer

Introduction: Patients with non-resectable biliary tract cancer have a poor prognosis even if treated with systemic chemotherapy. One hope for improving treatment is through molecular biology and the characterization of specific cancer driving alterations followed by the design of targeted drugs. The epidermal growth factor receptor system is upregulated in many cancers and can be targeted by the protein kinase inhibitor erlotinib. Erlotinib has demonstrated a clinically applicable effect in pancreatic and lung cancer

Areas covered: In this review, the author presents the published clinical data about erlotinib in biliary tract cancer. The data is interpreted with respect to its clinical value and in regards to its future development.

Expert opinion: Erlotinib has low activity as a monotherapy, but has shown synergistic effects when combined with bevacizumab. The only phase III trial with erlotinib was negative, but suggested improved progression free survival in cholangiocarcinoma patients when added to gemcitabine and oxaliplatin. There is no clinical, radiological or molecular marker to guide therapy, but genomic profiling and basket or umbrella trials may be useful in identifying the subset of patients benefitting from erlotinib. Until this subgroup has been defined, erlotinib has no value to biliary tract cancer patients in the daily clinic.     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview

Introduction: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events.

Areas covered: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs.

Expert opinion: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium.     

An update on male hypogonadism therapy

Introduction: Men who have symptoms associated with persistently low serum total testosterone level should be assessed for testosterone replacement therapy.

Areas covered: Acute and chronic illnesses are associated with low serum testosterone and these should be recognized and treated. Once the diagnosis of male hypogonadism is made, the benefits of testosterone treatment usually outweigh the risks. Without contraindications, the patient should be offered testosterone replacement therapy. The options of testosterone delivery systems (injections, transdermal patches/gels, buccal tablets, capsules and implants) have increased in the last decade. Testosterone improves symptoms and signs of hypogonadism such as sexual function and energy, increases bone density and lean mass and decreases visceral adiposity. In men who desire fertility and who have secondary hypogonadism, testosterone can be withdrawn and the patients can be placed on gonadotropins. New modified designer androgens and selective androgen receptor modulators have been in preclinical and clinical trials for some time. None of these have been assessed for the treatment of male hypogonadism.

Expert opinion: Despite the lack of prospective long-term data from randomized, controlled clinical trials of testosterone treatment on prostate health and cardiovascular disease risk, the available evidence suggests that testosterone therapy should be offered to symptomatic hypogonadal men.     

Direct anticoagulant drugs to overcome limitations of vitamin K antagonists. A critical appraisal of data in atrial fibrillation patients

Introduction: The usefulness of anticoagulation in patients with atrial fibrillation (AF) is well known. However, the inherent limitations of vitamin K antagonists (VKAs) have made the development of new oral anticoagulants necessary. Drugs directed against thrombin or the factor Xa are currently available.

Areas covered: These molecules, being administered at fixed doses and not requiring laboratory monitoring, overcome one crucial problem associated with the use of VKAs. However, data about the bleeding risk related to the use of these molecules should be further analyzed.

Expert opinion: The efficacy of direct anticoagulants (DACs) in AF-related stroke prevention has been considered the primary outcome in all Phase III published trials. On the other hand, the reduction of the bleeding risk is an important goal achieved by the DACs as compared with VKAs. Besides data deriving from randomized trials, when talking about new drugs, the need of evidences from the ‘everyday clinical practice' are often requested. The aim of this literature revision is to report and analyze data from specific subgroups about which little is known. In particular, information about the use of DACs in oncologic patients, in patients receiving concomitant antiplatelet drugs and in the perioperative period is currently lacking. The parallel evaluation of all these data may lead to the identification of clinical and demographical criteria to choose when to switch to DACs.     

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Areas covered in this review: To date, clinical trials conducted in type 2 diabetes patients have used combinations of sitagliptin (100 mg/day) and pioglitazone (30 – 45 mg/day) as separate tablets. These trials have shown that the combinations offer additive efficacy in reducing blood glucose when given as initial antidiabetic therapy and as add-on therapy when pioglitazone alone fails to maintain glycemic control.

What the reader will gain: Initial therapy with a combination of sitagliptin (100 mg/day) and pioglitazone (30 mg/day) reduced HbA1c by > 2% starting from a baseline > 9%. Adding sitagliptin (50 – 100 mg/day) to patients inadequately controlled on pioglitazone reduced HbA1c by 0.7 – 1.4% from a baseline of 8 – 8.5%. The combination did not increase the risk of hypoglycemia and produced similar or slightly more weight gain than pioglitazone alone when introduced as initial antidiabetic therapy.

Take home message: The combination of sitagliptin and pioglitazone was well tolerated in these trials, and would appear to be suited to a fixed-dose single-tablet combination for once-daily administration.     

Imagine how many lives you save: angiotensin-converting enzyme inhibition for atherosclerotic vascular disease in the present era of risk reduction

Introduction: Angiotensin-converting enzyme (ACE) inhibition is clearly beneficial in patients with hypertension, heart failure, and post-myocardial infarction left ventricular (LV) dysfunction. However, whereas initial trials had reported a benefit of ACE inhibition in high-risk vascular patients, current trials of ACE inhibition have failed to demonstrate a clear benefit in vascular patients who are receiving risk-reduction interventions. The purpose of this review is to analyze the reasons behind the failure of the most recent trials of ACE inhibitors in vascular patients without overt LV dysfunction. The reader will gain an understanding of the time-dependent trend towards a reduction in the absolute benefit conferred by ACE inhibition in patients with vascular atherosclerosis as risk reduction interventions are increasingly implemented.

Areas covered: Major trials with a follow-up period of at least 1 year assessing the use of ACE inhibitors in patients with a history of cardiac or vascular events were identified via a PubMed literature search. All-cause and cardiovascular mortality outcomes were reported for each trial, as well as the use of aspirin, lipid-lowering drugs and β-blockers, and the mean LV ejection fraction.

Expert opinion: The findings of recent trials do not support the use of ACE inhibitors in vascular patients who, adherent with risk reduction therapy, do not have hypertension, diabetes, or LV dysfunction.     

Farnesoid X receptor modulators (2011 – 2014): a patent review

Introduction: Farnesoid-X-receptor (FXR) is the receptor for primary bile acids expressed in enterohepatic tissues where it regulates bile acid uptake, metabolism and disposal. For its role as a bile acid sensor, FXR has been thought to be an important target in the treatment of cholestatic disorders, a family of diseases in which endogenous bile acids accumulate in the body. Cholestasis might occur as a consequence of inborn metabolic errors and three major disorders, intra-hepatic cholestasis in pregnancy, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis account for the vast majority of clinical cholestasis occurring in adulthood. In addition, FXR agonists are gaining attention as potential regulators of lipid and glucose metabolism and therefore as new therapeutical approaches to the treatment of fatty liver disease, type 2 diabetes and obesity.

Areas covered: New chemical entities as FXR modulators and their in vitro and in vivo efficacy are reviewed with particular focus on patents and peer-reviewed publications in the period 2011 – 2014.

Expert opinion: FXR agonists have shown robust therapeutic potential and results from clinical trials have supported their use in the treatment of liver disorders including PBC and fatty liver disease despite side effects.