Clinical significance of small dense low-density lipoprotein cholesterol measurement in type 2 diabetes.

Low-density lipoprotein cholesterol (LDL-C) is known to be a causal substance of atherosclerosis, but its usefulness as a predictive biomarker for atherosclerotic cardiovascular disease (ASCVD) is limited. In patients with type 2 diabetes (T2D), LDL-C concentrations do not markedly increase, while triglycerides (TG) concentrations are usually elevated. Although TG is associated with ASCVD risk, they do not play a direct role in the formation of atheromatous plaques.

Excess Triglycerides in Very Low-Density Lipoprotein (VLDL) Estimated from VLDL-Cholesterol could be a Useful Biomarker of Metabolic Dysfunction Associated Steatotic Liver Disease in Patients with Type 2 Diabetes.

Aims: We report that small dense low-density lipoprotein cholesterol (sdLDL-C) levels are sensitive biomarkers of metabolic dysfunction-associated steatotic liver disease (MASLD). Since triglyceride (TG)-rich very low-density lipoprotein (VLDL) is a precursor of sdLDL and is overproduced by MASLD, the composition of VLDL may be more directly associated with MAFLD than sdLDL-C or plasma TG. To identify TG-rich VLDL, this author proposed "Excess TG" and examined its association with MASLD.

Impact of Direct Measurement of Small Dense Low-Density Lipoprotein Cholesterol for Long-Term Secondary Prevention in Patients with Stable Coronary Artery Disease.

Background: This study investigated whether directly measured small dense low-density lipoprotein cholesterol (D-sdLDL-C) can predict long-term coronary artery disease (CAD) events compared with low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), and estimated small dense low-density lipoprotein cholesterol (E-sdLDL-C) determined by the Sampson equation in patients with stable CAD.

Methods: D-sdLDL-C measured at Showa University between 2010 and 2022, and E-sdLDL-C were evaluated in 790 male and 244 female patients with stable CAD. CAD events, defined as sudden cardiac death, onset of acute coronary syndrome, and/or need for coronary revascularization, were monitored for 12 years.

Managing hypertriglyceridemia for cardiovascular disease prevention: Lessons from the PROMINENT trial.

Background: Numerous epidemiological studies have shown that hypertriglyceridemia is a significant risk factor for cardiovascular diseases (CVD). However, large clinical studies on triglyceride-lowering therapy have yielded inconsistent results. In the current review, we reassess the importance of triglyceride-lowering therapy in preventing CVD based on previous literature and the recently published findings of the PROMINENT trial.

Prospective randomized comparative study of the effect of pemafibrate add-on or double statin dose on small dense low-density lipoprotein-cholesterol in patients with type 2 diabetes and hypertriglyceridemia on statin therapy.

Aims/introduction: Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C levels, pemafibrate and statins can reduce sdLDL-C levels. However, it remains unclear whether adding pemafibrate or increasing statin doses would more effectively reduce sdLDL-C levels in patients receiving statin therapy.

Specific Increase in Small Dense Low-Density Lipoprotein-Cholesterol Levels beyond Triglycerides in Patients with Diabetes: Implications for Cardiovascular Risk of MAFLD.

Aims: Small dense (sd) low-density lipoprotein (LDL)-cholesterol (C) is the most powerful predictor of cardiovascular (CV) disease among lipid biomarkers and is generated by hypertriglyceridemia and insulin resistance. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed liver disease with a high CV risk. We investigated the specific association of sdLDL-C with MAFLD beyond triglycerides (TG) and obesityMethods: Participants were 839 non-alcoholic drinkers with type 2 diabetes enrolled in a regional diabetes cohort.

Hypertriglyceridemia contributes significantly to high prevalence of small dense LDL-cholesterol in patients with type 2 diabetes, even when LDL-C targets are achieved.

Background: Small-dense (sd)LDL-cholesterol (C) is a potent risk factor for atherosclerotic cardiovascular disease (ASCVD) beyond LDL-C, and 35 mg/dL has been proposed as a cut-off value for high-sdLDL-C. sdLDL-C levels are strongly regulated by triglycerides (TG) and LDL-C levels. LDL-C has detailed targets for the prevention of ASCVD, while TG is only defined as abnormal at  ≥ 150 mg/dL.

Clinical significance of skin autofluorescence for diabetic macroangiopathy and comparison with conventional markers of atherosclerosis: a cross-sectional and prospective study.

Background: Skin autofluorescence (SAF) is a marker for the accumulation of advanced glycation end products (AGEs), and is associated with diabetic macroangiopathy. However, whether SAF is superior to conventional markers of atherosclerosis such as carotid intima-media thickness (IMT) and pulse wave velocity (PWV) in detecting macroangiopathy remains unclear.

Methods: We recruited 845 patients with type 2 diabetes enrolled in a community diabetes cohort (ViNA cohort) who had SAF, IMT, and PWV measured at baseline.

The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial failed to show the preventive effects of pemafibrate, a triglyceride (TG)-lowering drug, on atherosclerotic cardiovascular disease in patients with type 2 diabetes and dyslipidemia. We recently reported that TG-lowering with pemafibrate did not decrease the calculated small dense (sd) low-density lipoprotein cholesterol (LDL-C), and speculated that the effect of TG on sdLDL-C is attenuated in low LDL-C levels. This report examined this possibility in 1,508 patients with type 2 diabetes and 670 healthy controls.

Accuracy of Small Dense Low-density Lipoprotein-cholesterol Concentration Estimated via Sampson's Equation in Healthy Subjects and Patients with Diabetes.

Aim: Sampson et al. proposed a method to calculate small dense low-density lipoprotein-cholesterol (sdLDL-C) concentrations using common lipid measurements, but its accuracy remains unresolved. We examined the difference between Sampson's equation and direct measurement in patients with diabetes.

Circadian Rhythm of Subspecies of Low-Density Lipoprotein-Cholesterol and High-Density Lipoprotein-Cholesterol in Healthy Subjects and Patients with Type 2 Diabetes.

Aims: We established automated assay kits for quantifying small dense low-density lipoprotein (sdLDL)-cholesterol (C), LDL-triglyceride (TG), and high-density lipoprotein (HDL)3-C, and apolipoprotein (apo)E-rich HDL-C, and these have been recognized as sensitive biomarkers for predicting coronary artery disease. We investigated the circadian rhythms of these novel lipids to determine if fasting is required to determine basal levels.

Methods: Forty-eight inpatients with type 2 diabetes and 19 healthy volunteers were studied.

Dyslipidemia in diabetic kidney disease classified by proteinuria and renal dysfunction: A cross-sectional study from a regional diabetes cohort.

Aims/introduction: Diabetic kidney disease (DKD) exacerbates dyslipidemia and increases the incidence of atherosclerotic cardiovascular disease. DKD is a concept that includes typical diabetic nephropathy and an atypical phenotype without proteinuria. We investigated dyslipidemia in different DKD phenotypes that have not been fully studied.

Effects of omarigliptin on glucose variability and oxidative stress in type 2 diabetes patients: A prospective study.

Aims: To date, no clinical studies have compared once-weekly dipeptidyl peptidase 4 (DPP-4) inhibitors with once-daily DPP-4 inhibitors in terms of glucose variability (GV) and oxidative stress (OS).

Methods: Thirty-six patients with type 2 diabetes mellitus (T2DM) treated with once-daily DPP-4 inhibitors for at least 12 weeks were randomized to either continue once-daily DPP-4 inhibitors or receive omarigliptin, a once-weekly DPP-4 inhibitor, for 24 weeks. The primary end points were changes in the diacron-reactive oxygen metabolite (d-ROMs) test, a marker of OS, and GV using flash glucose monitoring.

Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway.

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and expression in, macrophages extracted from GIP receptor-deficient () and mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala]GIP(1-42).

GIP_HUMAN[22-51] is a new proatherogenic peptide identified by native plasma peptidomics.

We recently established a new plasma peptidomic technique and comprehensively identified a large number of low-molecular weight and low-abundance native peptides using a single drop of human plasma. To discover a novel polypeptide that potently modulates the cardiovascular system, we performed a bioinformatics analysis of the large-scale identification results, sequentially synthesized the selected peptide sequences, tested their biological activities, and identified a 30-amino-acid proatherogenic peptide, GIP_HUMAN[22-51], as a potent proatherosclerotic peptide hormone. GIP_HUMAN[22-51] has a common precursor with the glucose-dependent insulinotropic polypeptide (GIP) and is located immediately N-terminal to GIP.

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m ), moderately impaired (M) (≥30 to <60 ml/min/1.

Metabolic Properties of Lowdensity Lipoprotein (LDL) Triglycerides in Patients with Type 2 Diabetes, Comparison with Small Dense LDL-Cholesterol.

Aims: Abnormal compositional changes in low-density lipoprotein (LDL) particles, such as triglyceride (TG) enrichment and size reduction, are common in patients with diabetes. Several cohort studies have demonstrated that LDL-TG and sdLDL-cholesterol (C) are sensitive biomarkers for predicting atherosclerotic cardiovascular diseases beyond LDL-C. Although sdLDL has been extensively studied, little is known about the properties of LDL-TG.

Glucose Variability is Independently Correlated with Serum Level of Pigment Epithelium-Derived Factor in Type 2 Diabetes.

Introduction: Pigment epithelium-derived factor (PEDF) may play a role in cardiometabolic disorders. The aim of this study was to investigate which biochemical and clinical parameters are independently associated with serum PEDF levels in patients with type 2 diabetes mellitus (T2DM).

Methods: We performed a cross-sectional analysis of 124 patients with T2DM who underwent continuous glucose monitoring (CGM) and blood chemistry analysis, including the diacron-reactive oxygen metabolites (d-ROMs) test and serum PEDF measurement (study 1).

Anti-inflammatory and atheroprotective properties of glucagon.

Although glucagon has been shown to exert pleiotropic actions in various types of cells and organs through the interaction with its receptor, its pathophysiological role in atherosclerotic cardiovascular disease remains unclear. Here, we examined whether and how glucagon could attenuate the progression of atherosclerotic plaques in apolipoprotein E-deficient mice (ApoE), an animal model of atherosclerosis. Glucagon (138 or 413 nmol/kg/day) or vehicle was infused to mice at 16 weeks of age.

Dapagliflozin Influences Ventricular Hemodynamics and Exercise-Induced Pulmonary Hypertension in Type 2 Diabetes Patients - A Randomized Controlled Trial.

Background: This prospective randomized multicenter open-label trial evaluated whether sodium-glucose cotransporter-2 inhibitor (SGLT2-i) improves left ventricular (LV) pump function and suppresses elevation of LV filling pressure (LVFP) and right ventricular systolic pressure (RVSP) during exercise in type 2 diabetes mellitus (T2DM) patients.

Methods and results: Based on HbA1c and LV ejection fraction, 78 patients with poorly controlled T2DM were randomly assigned to D-group (dapagliflozin 5 mg/day add-on) or C-group (conventional therapy add-on). Physical examination, home and office blood pressure examination, blood tests, and echocardiography at rest and during ergometer exercise were performed at baseline and at 1.

A Dipeptidyl Peptidase-4 Inhibitor Inhibits Foam Cell Formation of Macrophages in Type 1 Diabetes via Suppression of CD36 and ACAT-1 Expression.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to play a protective role against atherosclerosis in both animal models and patients with type 2 diabetes (T2D). However, since T2D is associated with dyslipidemia, hypertension and insulin resistance, part of which are ameliorated by DPP-4 inhibitors, it remains unclear whether DPP-4 inhibitors could have anti-atherosclerotic properties directly by attenuating the harmful effects of hyperglycemia. Therefore, we examined whether a DPP-4 inhibitor, teneligliptin, could suppress oxidized low-density lipoprotein (ox-LDL) uptake, foam cell formation, and acyl-coenzyme A: cholesterol acyltransferase-1 () gene expression of macrophages isolated from streptozotocin-induced type 1 diabetes (T1D) mice and T1D patients as well as advanced glycation end product (AGE)-exposed mouse peritoneal macrophages and THP-1 cells.