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.

Summary Despite being approved for clinical use, evidence of cardiovascular safety (CV) is lacking for treatment with bupropion, naltrexone, or their combination (B‐N). The purpose of the study is to determine the relationship between these treatments and the risk of major cardiovascular adverse events (MACE). Phase 3 randomized clinical trials (RCT) evaluating bupropion, naltrexone, or B‐N versus control with reported incidence of MACE. The meta‐analysis included 12 RCTs, 69% for weight loss and 29% for smoking cessation, with 19,176 patients and 7354 patient‐years who were randomized to an active treatment (bupropion [n = 2965] or B‐N [n = 6980] or naltrexone [n = 249]) versus control (placebo [n = 6968] or nicotine patch [n = 2014]). The mean age was 54 ± 8 years (55% female), and the baseline BMI was 32 ± 5 kg/m2. The additive network meta‐analysis model for random effects showed no association between bupropion, B‐N, or naltrexone and MACE (odds ratio [OR] = 0.90 [95%CI 0.65–1.25], p = 0.52; OR = 0.97 [95%CI 0.75–1.24], p = 0.79; OR = 1.08 [95%CI 0.71–1.63], p = 0.73, respectively; I2 = 0%, p = 0.86). Meta‐regression analyses showed no significant association between MACE and potential confounders from RCT demographic disparities (p = 0.58). The statistical power (post hoc two‐tailed) for non‐inferiority was 91%, giving a strong probability of validity. Naltrexone, bupropion, or B‐N is not associated with the incidence of MACE as compared with placebo.

Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known. Objectives To assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i. Methods Individuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane. Results A total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [−1.7 (5.9) vs. −1.1 (5.3); p < 0.001). Conclusions In individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

BACKGROUND Sodium glucose co-transporter 2 inhibitors (SGLT2i) prevent hospitalization due to heart failure (HHF). However, patients with type 2 diabetes mellitus (T2DM) use multiple anti-hyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations the risk of HHF is unpredictable, so is the parallel effect of glucose-lowering. PURPOSE To examine the impact of anti-hyperglycemic drugs and their association on HHF. DATA SOURCES Forty randomized controlled trials (RCT) reporting HHF. STUDY SELECTION Published RCTs were the data source. DATA EXTRACTION Incidence rates of HHF. DATA SYNTHESIS Random additive-effects network meta-analysis showed that metformin (p=0.55), sulfonylureas (p=0.51), glucagon-like peptide-1 receptor-agonist (GLP-1RA; p=0.16) and dipeptidyl peptidase 4 inhibitors (DPP4i; p=0.54) were neutral on the risk of HHF. SGLT2i and SGLT2i+DPP4i reduced the risk of HHF with Hazard Ratio (HR) of 0.68 (95% Confidence Interval (CI) 0.60-0.76, p&lt;0.0001) and 0.70 (95% CI 0.60-0.81, p&lt;0.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZD) as monotherapy or in combination with DPP4i (HR: 1.45; 95% CI 1.18-1.78, p=0.0004) and 1.49 (95% CI 1.18-1.88, p=0.0008), respectively. Regardless the therapy, 1% reduction in HbA1c reduced the risk of HHF by 31.3% [95% CI 9-48%, p=0.009]. LIMITATIONS There is no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. CONCLUSIONS The risk of HHF is reduced by SGLT2i as monotherapy or in combination with DPP4i and increased by TZD as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.

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 of association between the HDL system and atherosclerotic risk, but as they were not designed to modify lipoprotein functionality, there is insufficient data to establish a causal relationship. We currently have randomized clinical trials of therapies that increase HDL-C concentration by various mechanisms, and this HDL-C elevation has not independently demonstrated a reduction in the risk of cardiovascular events. Therefore, this evidence shows that (a) measuring HDL-C as a way of estimating HDL-related atheroprotective system function is insufficient and (b) we still do not know how to increase cardiovascular protection with therapies aimed at modifying HDL metabolism. This leads us to a greater effort to understand the mechanisms of molecular action and cellular interaction of HDL, completely abandoning the traditional view focused on the plasma concentration of HDL-C. In this review, we will detail this new understanding and the new horizon for using the HDL system to mitigate residual atherosclerotic risk.