Lipidology

Dyslipidemia associated with obesity is characterized by alterations in lipid metabolism, insulin resistance, and chronic inflammation, which contributes to progression of atherosclerotic cardiovascular disease. Evidence suggests that obesity promotes elevations in triglycerides, apolipoprotein B, LDL, non-HDL cholesterol, as well as reductions in HDL cholesterol through adiponectin deficiency, cholesteryl ester transfer protein (CETP) activity, insulin resistance, and inflammation. In this review, the authors examine the evidence for the underlying mechanism behind this phenomenon as well as the effects of weight loss and therapeutic modalities that may change the trajectory of atherogenesis in the obese population using meta-analyses, randomized clinical trials, and basic science research studies. A reduction in as little as 5-15% of total body weight has been shown to improve triglyceride levels, promote insulin sensitivity, and optimize lipoprotein concentrations. Glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonists improve metabolic parameters, while semaglutide demonstrates cardiovascular event reduction. Emerging therapies targeting apolipoprotein C-III, cholesteryl ester transfer protein, ANGPTL3, and PCSK9 demonstrate promising lipid-lowering effects, although long-term cardiovascular outcomes remain uncertain. Obesity-associated dyslipidemia is a modifiable risk factor for pathologic changes to the atherogenic profile while weight reduction can reverse the process to some degree. Further investigation is necessary to establish long-term efficacy, safety, and to prove cardiovascular outcome benefit among those suggesting from obesity.

Bone homeostasis is a dynamic process governed by the balanced activity of osteoblasts and osteoclasts, tightly regulated through complex signaling networks. Emerging evidence highlights sphingolipid metabolism as a critical modulator of skeletal integrity, influencing bone remodeling in both health and disease. Each individual step, however, appears to have a unique role in these processes, with some overlap in function that is not well understood yet. This review explores the interplay between sphingolipid metabolism and bone homeostasis. It provides a comprehensive overview of the diverse roles of the various sphingolipid metabolic enzymes in bone remodeling and the maintenance of bone health. Special focus is given to the key enzymes from the de novo and turnover pathways that have been shown to play a pivotal role in modulating osteoblast and osteoclast differentiation, survival, and function, thereby impacting bone formation and resorption. Emerging data also suggest that alterations in sphingolipid metabolism may serve as biomarkers or therapeutic targets in metabolic bone diseases. Understanding these sphingolipid-mediated mechanisms opens new avenues for targeted interventions in bone disorders. It also highlights the need for further research into the therapeutic potential of modulating the sphingolipid metabolic pathway.

Chronic kidney disease (CKD) confers a high burden of atherosclerotic cardiovascular disease (ASCVD) and a characteristic, evolving dyslipidaemia that is incompletely addressed by conventional care. Statin-based therapy remains first-line in most non-dialysis CKD populations, yet many patients fail to reach lipid goals or remain at substantial residual risk. This structured narrative review evaluates injectable lipid-lowering agents across the CKD spectrum, focusing on the pharmacology and clinical utility of therapies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). The monoclonal antibodies evolocumab and alirocumab are subcutaneous biologics that bind circulating PCSK9, prevent PCSK9-mediated degradation of the low-density lipoprotein (LDL) receptor, and enhance hepatic LDL-cholesterol (LDL-C) clearance. Their catabolic elimination and negligible cytochrome-P450 interaction burden are advantageous in polypharmacy-heavy CKD care. Inclisiran is a hepatocyte-directed, GalNAc-conjugated small interfering RNA that silences PCSK9 messenger RNA, enabling durable LDL-C lowering with twice-yearly maintenance dosing after initiation. Across major programmes, injectable PCSK9 inhibition produces a ~50–60% LDL-C reduction, with consistent efficacy and safety across renal function strata, although outcome data in advanced CKD and dialysis remain limited. Importantly, cardiovascular outcome benefit is established for the monoclonal antibodies evolocumab and alirocumab, whereas inclisiran currently has robust LDL-C-lowering evidence but no completed cardiovascular outcome trial; these agents should not be regarded as having equivalent outcome evidence. Historical dialysis statin trials showed attenuated or neutral cardiovascular benefit, underscoring the biological and trial-design complexity of late-stage kidney disease and the need for dedicated injectable-era trials. We propose a stage-specific framework for integrating injectable therapies into CKD pathways—covering patient selection, sequencing, monitoring and implementation—and outline priorities for CKD-enriched outcome trials, kidney-relevant endpoints, and the integration of emerging lipoprotein(a)-targeted injectables into cardio-renal risk reduction.