• Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients with Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL

      Majithia, Arjun; Bhatt, Deepak L; Friedman, Allon N; Miller, Michael; Steg, Ph Gabriel; Brinton, Eliot A; Jacobson, Terry A; Ketchum, Steven B; Juliano, Rebecca A; Jiao, Lixia; et al. (American Heart Association, 2021-10-28)
      Background: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. Methods: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) was a multicenter, double-blind, placebo-controlled trial that randomized statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and one additional risk factor to treatment with icosapent ethyl (4 grams daily) or placebo. Patients from REDUCE-IT were categorized by prespecified eGFR categories to analyze the effect of icosapent ethyl on the primary endpoint (composite of cardiovascular [CV] death, nonfatal myocardial infarction nonfatal stroke, coronary revascularization, or unstable angina) and key secondary endpoint (a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke). Results: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL/min/1.73m2 (range: 17 to 123 mL/min/1.73m2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and secondary composite endpoints across baseline eGFR categories. Patients with eGFR<60 mL/min/1.73m2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite endpoint (icosapent ethyl versus placebo, 21.8% versus 28.9%, hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.59-0.85, P=0.0002) and key secondary composite endpoints (16.8% versus 22.5%, HR 0.71, 95% CI 0.57-0.88, p=0.001). The numerical reduction in CV death was greatest in the eGFR <60 mL/min/1.73m2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR 0.70, 95% CI 0.51-0.95, P=0.02). While patients with eGFR <60 mL/min/1.73m2 treated with icosapent ethyl had the highest numerical rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42, 95% CI 0.86-2.32, P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR 1.40, 95% CI 0.90-2.18, P=0.13), hazard ratios for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter = 0.92; P-interaction for serious bleeding = 0.76). Conclusions: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01492361.
    • HIV treatment is associated with a twofold higher probability of raised triglycerides: Pooled analyses in 21 023 individuals in sub-Saharan Africa

      Ekoru, K.; Young, E.H.; Dillon, D.G. (Cambridge University Press, 2018)
      Background Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TGs) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations.Methods Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (>2.3 mmol/L) was analysed using regression models.Findings Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51-2.77, I2 = 45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies.Interpretation Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SSA. Copyright The Author(s) 2018.
    • Liver Function in Pediatric Recipients: A Comparison of Intralipid and Smoflipid

      Daniel, Shawnée; Svoboda, Leanne; Chen, Justin (Pediatric Pharmacy Advocacy Group, Inc., 2021-03-31)
      OBJECTIVES An adverse consequence of primarily soybean oil–based parenteral nutrition is the development of intestinal failure–associated liver disease (IFALD), defined as bilirubin ≥ 2 mg/dL. Fish oil– containing lipid emulsion products, such as soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion (SMOF-ILE), have been shown to be beneficial in patients at risk of developing IFALD. This study aimed to review the safety profile of SMOF-ILE and soybean oil–based lipid injectable emulsion (SO-ILE) in regard to liver function and cholestasis in the pediatric and neonatal population. METHODS A retrospective review was performed for patients who received SO-ILE or SMOF-ILE over a 3-year period. Patients < 18 years of age who received at least 2 weeks of either product were included. The primary endpoints were 2 consecutive bilirubin readings ≥ 2 mg/dL that were separated by at least 1 week and time to first bilirubin ≥ 2 mg/dL. Secondary endpoints included assessment of select laboratory values (i.e., aspartate aminotransferase, alanine aminotransferase, triglycerides, serum creatinine, serum sodium, coagulation laboratory test, albumin) up to 6 months while on intravenous lipid products. Ursodiol use and mortality were also noted. RESULTS There was a higher prevalence of IFALD in pediatric patients receiving SO-ILE than those who received SMOF-ILE (32% vs 12%, p = 0.03). There was no detectable difference in the time it took for IFALD to develop (19 days vs 15 days, p = 0.08). CONCLUSION In our cohort of pediatric and neonatal patients, the incidence of IFALD was higher with SOILE than with SMOF-ILE. ABBREVIATIONS ALT, alanine aminotransferase, AST, aspartate aminotransferase, EFAD, essential fatty acid deficiency, FDA, US Food and Drug Administration, GI, gastrointestinal, IFALD, intestinal failure–associated liver disease, ILEs, lipid injectable emulsions, INR, international normalized ratio, NICU, neonatal intensive care unit, PN, parenteral nutrition, SMOF-ILE, soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion, SO-ILE, soybean oil–based lipid injectable emulsion. © Pediatric Pharmacy Association. All rights reserved.
    • Microglia orchestrate neuroinflammation.

      Feldman, Ricardo A (eLife, 2022-08-22)
      Experiments in genetically altered mice reveal that microglia play an important role in the neurological damage associated with neuro-nopathic Gaucher disease.
    • REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States

      Bhatt, D.L.; Miller, M.; Brinton, E.A. (American Heart Association, 2020)
      Background: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. Methods: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points. Results: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59–0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57–0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49–0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56–0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43–0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55–0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort. Conclusions: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01492361.