The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m², absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.

Statins are the cornerstone of lipid-lowering therapies effective for cardiovascular risk reduction. Although they are generally well tolerated, statin intolerance (SI) is frequent in clinical practice, and it is usually related to the onset of muscle symptoms, which are defined under the acronym SAMS (Statin-Associated Muscle Side Effects). These side effects are responsible for statin treatment discontinuation that results in increased cardiovascular risk. The National Lipid Association (NLA) has recently provided an updated definition of statin intolerance, and a distinction between complete and partial statin intolerance has been reported. The evaluation of symptom severity and the presence of muscle damage biomarker alterations make it essential to adopt a patient-centered approach aimed at obtaining a personalized therapeutic strategy. Firstly, it could be useful to administer a different statin, reduce the dosage or adopt an alternate dosage regimen. However, some patients are unable to tolerate any statin at every dosage, or despite taking statins at the maximum tolerated dose, they fail to achieve the recommended LDL-C target, and thus it is necessary to introduce a non-statin hypolipidemic treatment. Ezetimibe, proprotein-convertase subtilisin/kexin type 9 (PCSK9) inhibitors such as monoclonal antibodies (alirocumab and evolocumab) or RNA messenger silencing (inclisiran), bempedoic acid or nutraceuticals are non-statin lipid-lowering therapies that could be used as an alternative or in addition to statins to achieve an early and sustained LDL-C reduction in clinical practice. In this review, we evaluated SI management focusing on non-statin lipid lowering therapies and their implications in lipid lowering approaches in clinical practice.

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management.

Familial hypercholesterolemia (FH) is a genetic condition characterized by high low-density lipoprotein cholesterol (LDL-C). The presence of risk modifiers could promote the atherosclerotic injury beyond LDL-C. Our aim was to evaluate metabolic and innate immunity profiles in FH subjects with or without subclinical atherosclerosis. In this cross-sectional observational study, we evaluated 211 genetically confirmed FH subjects on LDL-C target and without cardiovascular diseases. Biochemical analyses, LDL-C burden (LCB) calculation and vascular profile evaluation were obtained from all subjects. Study population was divided into two groups according to subclinical atherosclerosis: the subclinical atherosclerosis (SA) group and non-subclinical atherosclerosis (NSA) group. SA group had higher LDL-C at diagnosis (288.35 ± 24.52 vs 267.92 ± 23.86, p < 0.05) and LCB (13,465.84 ± 3617.46 vs 10,872.63 ± 3594.7, p < 0.001) than NSA group. SA group had higher white blood cell count (WBCC, 6.9 ± 1.66 vs 6.1 ± 1.16), neutrophil count (NC, 4.2 ± 1.3 vs 3.6 ± 1.11), monocyte count (MC, 0.8 ± 0.2 vs 0.4 ± 0.1), triglyceride to high-density lipoprotein ratio (TG/HDL, 1.73 ± 0.72 vs 1.45 ± 0.69), triglyceride-glucose index (TyG, 8.29 ± 0.35 vs 8.01 ± 0.33) than NSA group (p value for all < 0.01). Multivariate logistic regression analysis showed that LCB (p < 0.01), WBCC (p < 0.01), NC (p < 0.05), MC (p < 0.05) were associated with subclinical atherosclerosis. Simple linear regression analyses showed that LCB was associated with WBCC, NC, MC (p value for all < 0.01). An increased LCB and an impaired innate immunity profile were found in FH subjects with subclinical atherosclerosis and they were independently associated with atherosclerotic injury. LCB could modulate the innate immunity profile.

Background: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein-cholesterol (LDL-C) and increased cardiovascular risk. While the role of LDL-C in atherogenesis is well established, the contribution of inflammatory activation in FH, particularly in relation to genotype, remains poorly defined. We aimed to evaluate the impact of genotype on neutrophil-to-lymphocyte ratio (NLR) and on subclinical atherosclerosis in a cohort of FH subjects. Methods: We conducted a cross-sectional study on 423 FH subjects not on lipid-lowering therapy and free from atherosclerotic cardiovascular disease. Biochemical, genetic, and vascular assessments were performed in all participants. The population was divided into 2 groups based on genotype: low-density lipoprotein receptor (LDLR; n = 273) and non-LDLR (NLDLR, n = 150). Vascular profile was assessed by coronary artery calcium score and carotid/femoral plaque presence. NLR was calculated from peripheral blood counts. Results: The LDLR group exhibited an higher NLR (2.27 ± 0.86 vs 2.05 ± 0.68, P < .05) than the NLDLR group. LDL-C levels and LDLR genotype were significantly associated with NLR (both P < .05). Multiterritorial plaque involvement was more frequent in the LDLR group than the NLDLR group (P for trend <.05). Age (P < .001), LDL-C (P < .001), smoking status (P < .05), and NLR (P < .05) were independently associated with subclinical atherosclerosis. Conclusion: FH subjects with LDLR mutations had a higher NLR and a more severe atherosclerosis distribution. Our findings support the role of NLR as a noninvasive biomarker of early immune activation and highlights the importance of lipoinflammatory status evaluation in FH subjects.