2 Minute Medicine Rewind December 9, 2019
1. Obeticholic acid, a farnesoid X receptor agonist, prompts fibrosis improvement in patients with non-alcoholic steatohepatitis (NASH)
Evidence Rating Level: 1 (Excellent)
Non-alcoholic steatohepatitis (NASH) is an increasingly common cause of chronic liver disease and cirrhosis. Currently, there are no approved treatments for NASH. The farnesoid X receptor, a nuclear receptor, regulates bile acids and metabolism, and recent data indicates that its activation can reduce hepatic fibrosis and inflammation. Obeticholic acid is a potent farnesoid X receptor agonist that is approved for the treatment of primary biliary cholangitis, but has not yet been studied in the treatment of NASH. In this randomized controlled trial, 1,968 patients with NASH (stage F1-F3 fibrosis) were assigned to receive obeticholic acid 25 mg daily, obeticholic acid 10 mg daily, or placebo to assess fibrosis improvement (≥1 stage) with no worsening of NASH, and NASH resolution with no worsening of fibrosis, at 18 months. The intention-to-treat population included 931 patients with stage F2-F3 fibrosis. Researchers found that more patients in the obeticholic acid groups achieved fibrosis improvement when compared to patients in the placebo group (25 mg: 23%, p=0.0002 vs. placebo; 10 mg: 18%, p=0.045 vs. placebo; placebo: 12%). Although more patients in the obeticholic acid group achieved NASH resolution than in the placebo group, this did not meet statistical significance (25 mg: 12%, p=0.13; 10 mg: 11%, p=0.18). Decreases in key liver enzymes were also observed in patients treated with obeticholic acid (decrease in ALT: 33% for obeticholic acid 25 mg, 26% for obeticholic acid 10 mg, 6% for placebo; decrease in AST: 24%, 19%, and 4%, respectively). The rate of adverse events was similar across groups as was the rate of serious adverse events. Pruritus was the most common adverse event, and occurred more frequently in the obeticholic acid groups (25 mg: 51%; 10 mg: 28%; placebo: 19%), which led to more frequent treatment discontinuation in the 25 mg obeticholic acid group). This study was limited by the lack of clinical outcomes data at the time of analysis. In summary, this study indicates that obeticholic acid 25 mg daily may improve liver fibrosis and NASH disease activity, though may cause intolerable pruritus in some patients. Further studies are necessary in assessing clinical outcomes.
1. Ixekizumab, an IL-17 inhibitor, elicits disease response in patients with non-radiographic active axial spondyloarthritis who have failed treatment with NSAIDs.
Evidence Rating Level: 1 (Excellent)
Axial spondyloarthritis is a chronic inflammatory disease of the axial skeleton that is typically treated with non-steroidal anti-inflammatory drugs (NSAIDs). Biologic disease-modifying anti-rheumatic drugs (bDMARDs) have also been recommended for patients with active disease, however, only a small number of TNF inhibitors are approved for patients with non-radiographic disease at this current time. Therefore, alternative bDMARD options are needed. In this randomized controlled trial, 303 patients with active axial spondyloarthritis with objective signs of inflammation were assigned to either subcutaneous 80 mg ixekizumab every 4 weeks (q4w) or every 2 weeks (q2w), or placebo, to assess the proportion of patients achieving an Assessment of SpondyloArthritis international Society-40 (ASAS40) response. The ASAS40 response is defined as an improvement of 40% or more and an absolute improvement from baseline of 2 or more units (range 0-10) in at least 3 of 4 domains: patient global score, spinal pain score, function score, and inflammation score. Patients were eligible if they had an inadequate response or intolerance to NSAIDs, were bDMARD-naïve, and did not have definite radiographic sacroiliitis. Researchers found that a higher proportion of patients in both ixekizumab groups achieved the primary outcome compared to the placebo group at 16 weeks (q4w: 35%, p=0.0094; q2w: 40%, p=0.0016) and 52 weeks (q4w: 30%, p=0.0045; q2w: 31%, p=0.0037). Patients in each ixekizumab treatment group also had greater reductions in disease activity and had greater improvements in Medical Outcome Short Form-36 Physical Component Summary (SF-36 PCS) scores than patients in the placebo group. The rate of at least one treatment-related adverse event was 57% in the placebo group, 66% in the ixekizumab q4w group, and 77% in the ixekizumab q2w group, similar to previous ixekizumab studies. The most common treatment-related adverse events were nasopharyngitis and injection site reactions. The rate of serious adverse events was similar across the three groups. Overall, results from this study support the use of ixekizumab in patients with non-radiographic axial spondyloarthritis after treatment failure with first-line therapies.
1. Children of mothers with diabetes are more likely to develop cardiovascular disease.
Evidence Rating Level: 2 (Good)
The prevalence of cardiovascular disease (CVD) in children and young adults is increasing. Growing evidence suggests that maternal health during or before pregnancy may impact the development of CVD among offspring. Maternal diabetes is known to be associated with increased risks of metabolic syndrome and congenital heart disease among offspring. The effects on early onset CVD, however, are unknown. In this retrospective cohort study, 2,432,000 live-born children (born between 1977 and 2016) without congenital heart disease were studied to assess the impact of maternal pre-gestational or gestational diabetes on early onset CVD in children. Overall, 2.3% of children were exposed to maternal pre-gestational diabetes and 1.1% were exposed to gestational diabetes. At baseline, mothers with diabetes were more likely to be older, to be more highly educated, to have higher parity, to live alone, and to smoke less during pregnancy than those without diabetes. Furthermore, children exposed to maternal diabetes were more likely to have a parental history of CVD, and to have a higher rate of developing diabetes, obesity, hypertension, hypercholesterolemia, and chronic kidney disease. During the 40 years of follow-up, researchers found that children exposed to maternal diabetes had a higher rate of overall CVD than unexposed children (HR 1.29, 95% CI 1.21 to 1.37). Both pre-gestational diabetes (HR 1.34, 95% CI 1.25 to 1.43) and gestational diabetes (HR 1.19, 95% CI 1.07 to 1.32) were associated with an increased rate of CVD in offspring. These rates were more pronounced in children of mothers with diabetic complications (HR 1.60, 95% CI 1.25 to 2.05). The most common types of CVD were pulmonary embolism (HR 1.91, 95% CI 1.31 to 2.80), deep vein thrombosis (HR 1.82, 95% CI 1.38 to 2.41), and hypertension (HR 1.78, 95% CI 1.50 to 2.11). A sibling comparison analysis of exposed vs. unexposed siblings yielded similar results. Overall, this study indicates that children of mothers with diabetes may be at an increased risk of developing CVD, underlining the importance of diabetes prevention, screening, and treatment in women of child-bearing age.
1. A decrease in circulating progenitor cells during exercise stress-testing in patients with stable coronary artery disease is associated with worse outcomes than the presence of myocardial ischemia.
Evidence Rating Level: 2 (Good)
Risk stratification for stable coronary artery disease (CAD) typically involves the measurement of stress-induced myocardial ischemia, often using single-photon emission computed tomography (SPECT) myocardial perfusion imaging. However, given the cost and radiation exposure associated with this technique, efforts are being focused towards the identification of surrogate biomarkers. Recent evidence suggests that levels of circulating progenitor cells (CPCs) and resident stem cells may be decreased in patients with myocardial ischemia, however, the impact on adverse cardiovascular events is unknown. In this prospective cohort study, 454 patients with stable CAD were studied to investigate the association between the change in CPC counts during stress testing and the risk of adverse cardiovascular events, specifically, cardiovascular death and myocardial infarction (MI). CPCs were enumerated with flow cytometry as CD34+ mononuclear cells, with additional evaluation of subsets co-expressing the chemokine receptor 4 (CXCR4+), at rest and 45 minutes after stress testing. Stress-induced myocardial ischemia was measured with SPECT myocardial perfusion imaging at rest and 30 to 60 minutes after stress testing. At baseline, 76% of patients were men, and 31.3% had stress-induced ischemia by SPECT. Researchers found that those with stress-induced ischemia had a decrease in circulating CD34+/CXCR4+ cells (median decrease 20.2%, IQR -45.3 to 5.5, p<0.001), whereas those without stress-induced ischemia experienced a cell count increase (median increase 3.2%, IQR -20.6 to 35.1, p<0.001). After adjusting for demographic variables and comorbidities, every unit increase in the ischemic defect was found to be associated with a 13% decrease in CD34+ cell counts after exercise stress. During a median follow-up of 3 years, 5.2% of patients experienced adverse events (12 cardiovascular deaths, 12 MIs). Stress-induced ischemia was significantly associated with adverse events after adjustment for covariates (HR 2.79, 95% CI 1.55 to 5.03). Furthermore, each 50% decrease in the CD34+/CXCR4+ count after stress testing, was found to be significantly associated with adverse outcomes, even after adjusting for presence of ischemia (HR 1.84, 95% CI 1.34 to 3; HR 2.59, 95% CI 1.15 to 5.32, respectively). In summary, this study suggests that a decreased CPC count during and after exercise is an even stronger predictor of adverse outcomes in patients with stable CAD than stress-induced myocardial ischemia. Thus, further research on the prognostic implications of increasing CPC mobilization are warranted.
1. Chemotherapy and/or radiotherapy may provoke significant declines in CD4 counts in HIV patients as compared to other treatments, which in turn are associated with increased mortality.
Evidence Rating Level: 2 (Good)
Treating cancer in patients with human immunodeficiency virus (HIV) infection can be problematic due to the immunosuppressive effects of certain cancer treatments. Pronounced periods of immunosuppression after various chemotherapy and radiotherapy regimens have been observed in HIV patients, but the impact of these periods on mortality remains unclear. In this prospective cohort study, data was collected on 196 patients with HIV who had an incident first cancer to compare the impact of cancer treatment with chemotherapy and/or radiotherapy versus surgery or other treatment on HIV RNA levels and CD4 counts. The researchers hypothesized that chemotherapy and/or radiotherapy would be associated with an increase in HIV RNA levels, a larger initial decline in CD4 count, a slower CD4 recovery, and higher mortality compared with surgery or other cancer treatments. At baseline, 68.9% of patients were male with a median age of 50 years at cancer treatment initiation (IQR 43 to 55 years), and 36.7% had no viral suppression. Most patients (60.2%) received chemotherapy and/or radiotherapy, and 11.7% were antiretroviral therapy (ART)-naïve at baseline. Researchers found that in patients with a baseline CD4 count of greater than 500 cells/ml, the initial decline in CD4 count associated with chemotherapy and/or radiotherapy (versus surgery or other treatment) was 203 cells/ml (95% CI 92 to 306), and in those with a baseline CD4 count of no greater than 350 cells/ml, the decline in CD4 count was attenuated by 158 cells/ml, resulting in a mean decline of 45 cells/ml (95% CI 31 to 276 cells/ml). Chemotherapy and/or radiotherapy was not found to be associated with increased HIV RNA levels; in fact, among those who were virally unsuppressed before cancer treatment, HIV RNA levels declined more in the chemotherapy and/or radiotherapy group than in the surgery or other treatment group (interaction estimate -0.53, 95% CI -1.09 to -0.02). Limitations of this study included the lack of data on cancer response. Overall, results from this study suggest that chemotherapy and/or radiotherapy may induce more substantial declines in CD4 counts than other therapies, which in turn may lead to increased mortality.
Image: PD
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