Type 2 diabetes mellitus and insulin resistance feature substantial modifications of the lipoprotein profile, including a higher proportion of smaller and denser low-density lipoprotein (LDL) particles. In addition, qualitative changes occur in the composition and structure of LDL, including changes in electrophoretic mobility, enrichment of LDL with triglycerides and ceramides, prolonged retention of modified LDL in plasma, increased uptake by macrophages, and the formation of foam cells. These modifications affect LDL functions and favor an increased risk of cardiovascular disease in diabetic individuals. In this review, we discuss the main findings regarding the structural and functional changes in LDL particles in diabetes pathophysiology and therapeutic strategies targeting LDL in patients with diabetes.

Despite decades of therapeutic advances, myocardial infarction remains a leading cause of death worldwide. Recent studies have identified HDLs (high-density lipoproteins) as a potential candidate for mitigating coronary ischemia/reperfusion injury via a broad spectrum of signaling pathways. HDL ligands, such as S1P (sphingosine-1-phosphate), Apo (apolipoprotein) A-I, clusterin, and miRNA, may influence the opening of the mitochondrial channel, insulin sensitivity, and production of vascular autacoids, such as NO, prostacyclin, and endothelin-1. In parallel, antioxidant activity and sequestration of oxidized molecules provided by HDL can attenuate the oxidative stress that triggers ischemia/reperfusion. Nevertheless, during myocardial infarction, oxidation and the capture of oxidized and proinflammatory molecules generate large phenotypic and functional changes in HDL, potentially limiting its beneficial properties. In this review, new findings from cellular and animal models, as well as from clinical studies, will be discussed to describe the cardioprotective benefits of HDL on myocardial infarction. Furthermore, mechanisms by which HDL modulates cardiac function and potential strategies to mitigate postmyocardial infarction risk damage by HDL will be detailed throughout the review.

High density lipoproteins (HDLs) are commonly known for their anti-atherogenic properties that include functions such as the promotion of cholesterol efflux and reverse cholesterol transport, as well as antioxidant and anti-inflammatory activities. However, because of some chronic inflammatory diseases, such as type 2 diabetes mellitus (T2DM), significant changes occur in HDLs in terms of both structure and composition. These alterations lead to the loss of HDLs’ physiological functions, to transformation into dysfunctional lipoproteins, and to increased risk of cardiovascular disease (CVD). In this review, we describe the main HDL structural/functional alterations observed in T2DM and the molecular mechanisms involved in these T2DM-derived modifications. Finally, the main available therapeutic interventions targeting HDL in diabetes are discussed.

In individuals with very low high-density lipoprotein (HDL-C) cholesterol, such as Tangier disease, LCAT deficiency, and familial hypoalphalipoproteinemia, there is an increased risk of premature atherosclerosis. However, analyzes based on comparisons of populations with small variations in HDL-C mediated by polygenic alterations do not confirm these findings, suggesting that there is an indirect association or heterogeneity in the pathophysiological mechanisms related to the reduction of HDL-C. Trials that evaluated some of the HDL functions demonstrate a more robust degree [...] ABSTRACT In individuals with very low high-density lipoprotein (HDL-C) cholesterol, such as Tangier disease, LCAT deficiency, and familial hypoalphalipoproteinemia, there is an increased risk of premature atherosclerosis. However, analyzes based on comparisons of populations with small variations in HDL-C mediated by polygenic alterations do not confirm these findings, suggesting that there is an indirect association or heterogeneity in the pathophysiological mechanisms related to the reduction of HDL-C. Trials that evaluated some of the HDL functions demonstrate a more robust degree

Endothelial dysfunction (ED) is a hallmark in type 2 diabetes mellitus (T2DM) that favor both atherogenesis and ischemia and reperfusion injury (IRI). Sodium-glucose-2 co-transporter inhibitors (SGLT2i) may hypothetically improve microvascular and macrovascular functions via a broad spectrum of mechanisms, being superior to traditional antidiabetic therapy such as sulfonylurea, even in subjects under equivalent glycemic control. Hence, the present clinical trial was designed to compare the effect of these two treatments on markers of arterial wall function and inflammation in T2DM patients as well as on the potential mediating parameters. ADDENDA-BHS2 is a prospective, single-center, active‐controlled, open, randomized trial. Ninety-eight participants (40–70 years old) with HbA1c 7–9% were randomized (1:1, stratified by gender, BMI and HbA1c levels) to either dapagliflozin 10 mg/day or glibenclamide 5 mg/day on top of metformin. The primary endpoint was the change of flow-mediated dilation (FMD) after a 12-week period of treatment evaluated at rest and after IRI between dapagliflozin and glibenclamide arms. Secondary outcomes were defined as the difference between treatments regarding: plasma nitric oxide (NO) change after FMD, plasma isoprostane, plasma levels of vascular inflammatory markers and systemic inflammatory markers, plasma levels of adipokines, anthropometric measures, glucose control parameters, office and ambulatory BP control. Safety endpoints were defined as systolic and diastolic function assessed by echocardiography and retinopathy change. Serious adverse events were recorded. The study protocol was approved by the Independent Scientific Advisory Committee. The ADDENDA-BHS2 trial is an investigator-initiated clinical trial comparing the effect of dapagliflozin versus glibenclamide on several aspects of vascular function in high cardiovascular risk T2DM patients. Besides, a large clinical and biochemical phenotype assessment will be obtained for exploring potential mediations and associations. Trial registration Clinical trial registration: NCT 02919345 (September, 2016)

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.