Insulin resistance (IR) and cardiovascular disease (CVD) represent two universal public health hazards, especially in today’s Western societies. A causal-effect relationship has been established that links IR with CVD. The mediating mechanisms are perplexing, under ongoing, rigorous investigation and remain to be fully elucidated. IR is a condition encompassing hyperglycemia and compensatory hyperinsulinemia. It occurs when insulin is not capable of exerting its maximum effects on target tissues, including skeletal muscles, liver and adipose tissue. This alteration of insulin signaling pathways results in the development of cardiometabolic disorders, including obesity, dyslipidemia, low-grade inflammation, endothelial dysfunction and hypertension, all of which are predisposing factors for atherosclerosis and CVD. The management of IR can be achieved through dietary modifications, the inclusion of regular exercise routines in everyday life, pharmacological agents and other interventions tailored to each individual patient’s needs. It is important to underline though that, although various antidiabetic drugs that may improve IR are available, no medications are as yet specifically approved for the treatment of IR. This narrative review will focus on the current scientific and clinical evidence pertaining to IR, the mechanisms connecting IR with CVD, as well as plausible strategies for a holistic, personalized approach for IR management.

Atherosclerosis is an immunoinflammatory pathological procedure in which lipid plaques are formed in the vessel walls, partially or completely occluding the lumen, and is accountable for atherosclerotic cardiovascular disease (ASCVD). ACSVD consists of three components: coronary artery disease (CAD), peripheral vascular disease (PAD) and cerebrovascular disease (CCVD). A disturbed lipid metabolism and the subsequent dyslipidemia significantly contribute to the formation of plaques, with low-density lipoprotein cholesterol (LDL-C) being the main responsible factor. Nonetheless, even when LDL-C is well regulated, mainly with statin therapy, a residual risk for CVD still occurs, and it is attributable to the disturbances of other lipid components, namely triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Increased plasma TG and decreased HDL-C levels have been associated with metabolic syndrome (MetS) and CVD, and their ratio, TG/HDL-C, has been proposed as a novel biomarker for predicting the risk of both clinical entities. Under these terms, this review will present and discuss the current scientific and clinical data linking the TG/HDL-C ratio with the presence of MetS and CVD, including CAD, PAD and CCVD, in an effort to prove the value of the TG/HDL-C ratio as a valuable predictor for each aspect of CVD.

Several prospective epidemiological studies have shown that there is a clear inverse relationship between serum high-density lipoprotein-cholesterol (HDL-C) concentrations and risk for coronary heart disease (CHD), even at low-density lipoprotein-cholesterol (LDL-C) levels below 70 mg/dL. However, more recent evidence from genetic studies and clinical research has come to challenge the long-standing notion that higher HDL-C levels are always beneficial, while lower HDL-C levels are always detrimental. Thus, it becomes apparent that HDL functionality plays a much more important role in atheroprotection than circulating HDL-C levels. HDL cholesterol efflux capacity (CEC) from macrophages is a key metric of HDL functionality and exhibits a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease (CAD), independent of the HDL-C level. Thus, extensive research is being conducted to identify new agents with a favorable side effect profile, which would be able to enhance CEC, improve HDL functionality and potentially decrease cardiovascular risk. This review aims to present and discuss the current clinical and scientific evidence pertaining to the significance of HDL functionality over the actual HDL-C concentration in mediating the favorable effects on the cardiovascular system. Thus, we conducted a PubMed search until December 2017 through the English literature using the search terms 'HDL function/functionality', 'HDL properties', 'cardiovascular risk' and 'cholesterol efflux capacity'. We also included references from the articles identified and publications available in the authors' libraries.

The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, thus preventing translation. Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. This review aims to present and discuss the current clinical and scientific evidence pertaining to inclisiran, which is a new promising agent in the management of hypercholesterolemia.

The atheroprotective role of high-density lipoprotein cholesterol (HDL-C) in cardiovascular disease has been unequivocally established, and epidemiological data have clearly demonstrated a strong inverse relationship between HDL-C levels and the risk of cardiovascular events, which is independent of the low-density lipoprotein cholesterol (LDL-C) levels. Thus, it would be logical to hypothesize that raising HDL-C might potentially lead to a reduction of cardiovascular risk. Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to very low-density lipoprotein and LDL. Therefore, CETP inhibition raises HDL-C levels and decreases LDL-C levels. The first trials with CETP inhibitors failed to show a reduction in cardiovascular events. However, newer CETP inhibitors with more favorable effects on lipids are presently being tested in clinical trials with the hope that their use may lead to a reduction in cardiovascular risk. This review aims to provide the current evidence regarding CETP inhibition, as well as the clinical and scientific data pertaining to the new CETP inhibitors in development.

There is extensive evidence showing that insulin resistance (IR) is associated with chronic low-grade inflammation. Furthermore, IR has been shown to increase the risk for cardiovascular disease (CVD), even in nondiabetic patients, and is currently considered as a “nontraditional” risk factor contributing to CVD by promoting hypertension, oxidative stress, endothelial dysfunction, dyslipidemia, and type 2 diabetes mellitus. However, chronic kidney disease (CKD) is also considered a state of low-grade inflammation. In addition, CKD is considered an IR state and has been described as an independent risk factor for the development of CVD, as even early-stage CKD is associated with an estimated 40% to 100% increase in CVD risk. There is also strong evidence indicating that inflammation per se plays a crucial role in both the initiation and progression of CVD. Given the above, the combined effect of IR and CKD may significantly increase the risk of inflammation and CVD. This review aims to focus on the complex interplay between IR, CKD, inflammation, and CVD and will present and discuss the current clinical and scientific data pertaining to the impact of IR and CKD on inflammation and CVD.