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Inclisiran is a novel RNA agent that prevents production of PCSK9 protein, thus lowering concentrations of PSCK9 and LDL-C. It is administered subcutaneously twice yearly, potentially reducing burden of administration in comparison to PCSK9 monoclonal antibodies (mAbs). Despite this advantage, earlier studies have found that prior authorization requirements complicate inclisiran approval in outpatient settings. Understanding patient characteristics associated with the timely initiation of inclisiran is crucial to care coordination and successful therapy nitiateon. This study aimed to identify clinical and demographic characteristics associated with successful initiation of inclisiran in outpatient infusion clinics. This was a retrospective, longitudinal cohort study of patients referred for treatment with inclisiran between February and July 2022 at 23 infusion centers in eleven states. Patients were followed until they received their first dose of inclisiran or until the time of noted non-initiation. Individuals still awaiting approval as of November 2022 were censored at that time. The Kaplan Meier method was used to estimate median time to initiation. Overall, 234 patients were referred for inclisiran initiation. The majority (55.1%) were female, 56.9% were Medicare beneficiaries, and the median age was 69 (IQR: 64-74) years. In total, 73% were referred with a primary diagnosis of atherosclerotic cardiovascular disease (ASCVD) and 5.6% with heterozygous familial hypercholesterolemia (HeFH). Through July 2022, 112 (47.9%) have successfully initiated treatment and 20 (8.6%) are pending for approval. Median time to initiation was 30 (IQR: 17-88.5) days and median time to non-initiation was 70 (IQR: 36-105). Payer denial and inability to pay contributed to 47.1% of all non-initiations. Of those who initiated treatment, 51.8% were previously treated with PCSK-9 mAbs, 65.2% had documented statin intolerance, 31.3% were prescribed concurrent statin therapy, and 31.3% were prescribed concurrent ezetimibe. Median Elixhauser comorbidity score was 6.0 (IQR: 0-14.5) with 72.3% and 34.8% having hypertension or diabetes, respectively. Median baseline LDL-C was 135 (IQR: 96-175) mg/dL. Compared to non-initiators, initiators were notably older (70.5±0.83 vs. 66.7±0.85, a higher proportion were male (61.2% vs 43.8%) and Medicare beneficiaries (52.9% vs 27.8%). Inclisiran is an accessible treatment option for patients with ASCVD and elevated LDL-C. Medicare beneficiaries were more likely to be successfully initiated due to favorable prior authorization policies. Future work will focus on measuring adherence to inclisiran and real-world effectiveness among those who successfully initiate therapy. Yes Novartis Pharmaceuticals Corporation [ABSTRACT FROM AUTHOR]

Objective: To assess, among overweight non-hispanic black adolescents the relationship of changes in plasma retinol binding protein 4 (RBP4) over 3 years to changes in insulin resistance (IR) and 4 associated cardiometabolic risks. Study design: Nested, retrospective study of 51 overweight, post-pubertal non-Hispanic black participants in the Princeton School District Study. Participants were in the top (worsening IR) or bottom (improved IR) quartile for 3-year change in IR. RBP4 was measured by quantitative Western blot with frozen plasma. Regression analyses adjusted for age, sex, and adiposity (baseline and change). Three measures of adiposity were assessed (waist circumference, body mass index, and weight) in separate regression models. Results: RBP4 increased in one third (n = 17). In logistic regression analyses, increased RBP4 was associated with significantly higher odds of worsening as opposed to improved IR independent of age, sex, or adiposity. Odds ratios were 5.6 (weight, P = .024), 6.0 (BMI, P = .025) and 7.4 (waist circumference, P = .015). Initial RBP4 (β = 0.81, P = .005) and change in RBP4 (β = 0.56, P = .046) also predicted change in triglycerides, but not change in high-density lipoprotein–cholesterol, low-density lipoprotein–cholesterol, or fibrinogen. Conclusion: This retrospective cohort study provides evidence that RBP4 may be a mechanism through which obesity influences insulin resistance and hypertriglyceridemia in overweight postpubertal black youth and suggests utility of RBP4 as a biomarker of risk. [Copyright &y& Elsevier]

Summary: Intra-abdominal fat is associated with insulin resistance and cardiovascular risk. Levels of serum retinol-binding protein (RBP4), secreted by fat and liver cells, are increased in obesity and type 2 diabetes (T2D). Here we report that, in 196 subjects, RBP4 is preferentially expressed in visceral (Vis) versus subcutaneous (SC) fat. Vis fat RBP4 mRNA was increased ∼60-fold and 12-fold in Vis and SC obese subjects respectively versus lean subjects, and ∼2-fold with impaired glucose tolerance/T2D subjects versus normoglycemic subjects. In obese subjects, serum RBP4 was increased 2- to 3-fold, and serum transthyretin, which stabilizes RBP4 in the circulation, was increased 35%. Serum RBP4 correlated positively with adipose RBP4 mRNA and intra-abdominal fat mass and inversely with insulin sensitivity, independently of age, gender, and body mass index. RBP4 mRNA correlated inversely with GLUT4 mRNA in Vis fat and positively with adipocyte size in both depots. RBP4 levels are therefore linked to Vis adiposity, and Vis fat may be a major source of RBP4 in insulin-resistant states. [Copyright &y& Elsevier]

Summary Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide-induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues. Graphical Abstract Highlights • Post-developmental deletion of autophagy in adipocytes causes insulin resistance • Mitochondrial dysfunction develops in autophagy-deficient adipocytes • Enhanced Nrf2 and Keap1 signaling in autophagy-deficient adipocytes • Crosstalk between fat and liver mediated by lipid peroxide-induced Nrf2 signaling Cai et al. describe how lack of autophagy in mature adipocytes causes insulin resistance with no change in body weight. Adipocytes lacking Atg3 or Atg16L1 accumulate dysfunctional mitochondria and have increased lipid peroxidation and Nrf2 and keap1 activation. This study reveals a role for lipid peroxides and Nrf2 signaling in an adipose-liver crosstalk. [ABSTRACT FROM AUTHOR]

Vitamin A (retinol) is absorbed in the small intestine, stored in liver, and secreted into circulation bound to serum retinolbinding protein (RBP4). Circulating retinol may be taken up by extrahepatic tissues or recycled back to liver multiple times before it is finally metabolized or degraded. Liver exhibits high affinity binding sites for RBP4, but specific receptors have not been identified. The only known high affinity receptor for RBP4, Stra6, is not expressed in the liver. Here we report discovery of RBP4 receptor-2 (RBPR2), a novel retinol transporter expressed primarily in liver and intestine and induced in adipose tissue of obese mice. RBPR2 is structurally related to Stra6 and highly conserved in vertebrates, including humans. Expression of RBPR2 in cultured cells confers high affinity RBP4 binding and retinol transport, and RBPR2 knockdown reduces RBP4 binding/ retinol transport. RBPR2 expression is suppressed by retinol and retinoic acid and correlates inversely with liver retinol stores in vivo. We conclude that RBPR2 is a novel retinol transporter that potentially regulates retinol homeostasis in liver and other tissues. In addition, expression of RBPR2 in liver and fat suggests a possible role in mediating established metabolic actions of RBP4 in those tissues. [ABSTRACT FROM AUTHOR]