Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis.

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality. Lipid lowering therapy (LLT) constitutes the cornerstone of ASCVD prevention and treatment. However, several patients fail to achieve therapeutic goals due to low treatment adherence or limitations of standard-of-care (SoC) LLTs. Inclisiran represents a pivotal low-density lipoprotein cholesterol (LDL-C) lowering agent aiming to address current unmet needs in LLT. It is the first available small interfering RNA (siRNA) LLT, specifically targeting PCSK9 mRNA and leading to post-transcriptional gene silencing (PTGS) of the PCSK9 gene. AREAS COVERED: Promising phase III trials revealed an ~ 50% reduction in LDL-C levels with subcutaneous inclisiran administration on days 1 and 90, followed by semiannual booster shots. Coupled with inclisiran's favorable safety profile, these findings led to its approval by both the EMA and FDA. Herein, the authors highlight the preclinical discovery and development of this agent and provide the reader with their expert perspectives. EXPERT OPINION: The evolution of gene-silencing treatments offers new perspectives in therapeutics. Inclisiran appears to have the potential to revolutionize ASCVD prevention and treatment, benefiting millions of patients. Ensuring widespread availability of Inclisiran, as well as managing additional healthcare costs that may arise, should be of paramount importance.

Is inverse association between lipoprotein(a) and diabetes mellitus another paradox in cardiometabolic medicine?

INTRODUCTION: The impact of Type II Diabetes mellitus (T2DM) on cardiovascular disease (CVD) is well-established, while lipoprotein(a) [Lp(a)] has recently emerged as a recognized CVD risk factor. The rising prevalence of T2DM resulting from modern lifestyles and the development of specific Lp(a)-lowering agents brought the association between T2DM and Lp(a) in the forefront. AREAS COVERED: Despite advancements in T2DM treatment, diabetic patients remain at very-high risk of CVD. Lp(a) may, to some extent, contribute to the persistent CVD risk seen in diabetic patients, and the coexistence of T2DM and elevated Lp(a) levels appears to synergistically amplify overall CVD risk. The relationship between T2DM and Lp(a) is paradoxical. On one hand, high Lp(a) plasma concentrations elevate the risk of diabetic microvascular and macrovascular complications. On the other hand, low Lp(a) plasma concentrations have been linked to an increased risk of developing T2DM. EXPERT OPINION: Comprehending the association between T2DM and Lp(a) is critical due to the pivotal roles both entities play in overall CVD risk, as well as the unique aspects of their relationship. The mechanisms underlying the inverse association between T2DM and Lp(a) remain incompletely understood, necessitating further meticulous research.

Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a).

Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.

Insulin resistance and cardiovascular disease.

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.

The Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio as a Risk Marker for Metabolic Syndrome and Cardiovascular Disease.

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.

Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia.

Cardiovascular disease (CVD) is the most common cause of death in a global scale and significantly depends on the elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and the subsequent formation of atherosclerotic plaques. While physicians have several LDL-C-lowering agents with diverse mechanisms of action, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and inclisiran, angiopoietin-like protein 3 (ANGPTL3) inhibitors have recently emerged as a powerful addition in the armamentarium of lipid-lowering strategies, especially for patients with refractory hypercholesterolemia, as in the case of patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 protein is a glycoprotein secreted by liver cells that is implicated in the metabolism of lipids along with other ANGPTL proteins. These proteins inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Loss-of-function mutations affecting the gene encoding ANGPTL3 are linked with lower total cholesterol, LDL-C, and triglyceride (TG) levels. Evinacumab is a monoclonal antibody that targets, binds to, and pharmacologically inhibits ANGPTL3, which was recently approved by the United States Food and Drug Administration (FDA) as a complementary agent to other LDL-C lowering regimens for patients aged 12 or older with HoFH, based on clinical trial evidence that confirmed its safety and efficacy in those patients. Antisense oligonucleotides (ASOs) also represent an interesting class of agents that target and inhibit the mRNA derived from the transcription of ANGPTL3 gene. This review aims to present and discuss the current clinical and scientific data pertaining to the role of ANGPTL3 inhibitors, a novel lipid-modifying class of agents capable of reducing LDL-C levels via a mechanism independent of LDL receptors.

Environmental Factors Modifying HDL Functionality.

BACKGROUND: Currently, it has been recognized that High-Density Lipoprotein (HDL) functionality plays a much more essential role in protection from atherosclerosis than circulating HDLcholesterol (HDL-C) levels per se. Cholesterol efflux capacity (CEC) from macrophages to HDL has been shown to be a key metric of HDL functionality. Thus, quantitative assessment of CEC may be an important tool for the evaluation of HDL functionality, as improvement of HDL function may lead to a reduction of the risk for Cardiovascular disease (CVD). INTRODUCTION: Although the cardioprotective action of HDLs is exerted mainly through their involvement in the reverse cholesterol transport (RCT) pathway, HDLs have also important anti-inflammatory, antioxidant, antiaggregatory and anticoagulant properties that contribute to their favorable cardiovascular effects. Certain genetic, pathophysiologic, disease states and environmental conditions may influence the cardioprotective effects of HDL either by inducing modifications in lipidome and/or protein composition, or in the enzymes responsible for HDL metabolism. On the other hand, certain healthy habits or pharmacologic interventions may actually favorably affect HDL functionality. METHODS: The present review discusses the effects of environmental factors, including obesity, smoking, alcohol consumption, dietary habits, various pharmacologic interventions, as well as aerobic exercise, on HDL functionality. RESULTS: Experimental and clinical studies or pharmacological interventions support the impact of these environmental factors in the modification of HDL functionality, although the involved mechanisms are not fully understood. CONCLUSION: Further research should be conducted to identify the underlying mechanisms of these environmental factors and to identify new pharmacologic interventions capable of enhancing CEC, improving HDL functionality and potentially improving cardiovascular risk.

Empagliflozin Induces White Adipocyte Browning and Modulates Mitochondrial Dynamics in KK Cg-Ay/J Mice and Mouse Adipocytes.

Background: White adipose tissue (WAT) browning is a promising target for obesity prevention and treatment. Empagliflozin has emerged as an agent with weight-loss potential in clinical and in vivo studies, but the mechanisms underlying its effect are not fully understood. Here, we investigated whether empagliflozin could induce WAT browning and mitochondrial alterations in KK Cg-Ay/J (KKAy) mice, and explored the mechanisms of its effects. Methods: Eight-week-old male KKAy mice were administered empagliflozin or saline for 8 weeks and compared with control C57BL/6J mice. Mature 3T3-L1 adipocytes were treated in the presence or absence of empagliflozin. Mitochondrial biosynthesis, dynamics, and function were evaluated by gene expression analyses, fluorescence microscopy, and enzymatic assays. The roles of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1-alpha (PGC-1α) were determined through AICAR (5-Aminoimidazole-4-carboxamide1-ß-D-ribofuranoside)/Compound C and RNA interference, respectively. Results: Empagliflozin substantially reduced the bodyweight of KKAy mice. Mice treated with empagliflozin exhibited elevated cold-induced thermogenesis and higher expression levels of uncoupling protein 1 (UCP1) and other brown adipose tissue signature proteins in epididymal and perirenal WAT, which was an indication of browning in these WAT depots. At the same time, empagliflozin enhanced fusion protein mitofusin 2 (MFN2) expression, while decreasing the levels of the fission marker phosphorylated dynamin-related protein 1 (Ser616) [p-DRP1 (Ser616)] in epididymal and perirenal WAT. Empagliflozin also increased mitochondrial biogenesis and fusion, improved mitochondrial integrity and function, and promoted browning of 3T3-L1 adipocytes. Further, we found that AMPK signaling activity played an indispensable role in empagliflozin-induced browning and mitochondrial biogenesis, and that PGC-1α was required for empagliflozin-induced fusion. Whether empagliflozin activates AMPK by inhibition of SGLT2 or by independent mechanisms remains to be tested. Conclusion: Our results suggest that empagliflozin is a promising anti-obesity treatment, which can immediately induce WAT browning mitochondrial biogenesis, and regulate mitochondrial dynamics.

New and emerging lipid-modifying drugs to lower LDL cholesterol.

Cardiovascular disease (CVD) represents the leading cause of death worldwide. The role of low-density lipoprotein-cholesterol (LDL-C) in the pathophysiology of atherosclerosis and CVD has been well recognized. Statins are the standard of care for the management of hypercholesterolaemia, and their effectiveness in lowering LDL-C and reducing CVD risk in both primary and secondary prevention has been well established. However, several patients fail to attain optimal LDL-C goals or are intolerant to statins, especially at high doses. PCSK9 inhibitors, bempedoic acid, inclisiran, ANGPTL3 inhibitors, PPARß/δ agonists and LXR agonists are novel or upcoming LDL-C-lowering agents that have shown promising beneficial results. This review aims to present and discuss the current clinical and scientific data pertaining to the new and emerging lipid-modifying LDL-C-lowering drugs.

Safety and Tolerability of PCSK9 Inhibitors: Current Insights.

The current era of preventive cardiology continues to emphasize on low-density lipoprotein cholesterol (LDL-C) reduction to alleviate the burden of atherosclerotic cardiovascular disease (ASCVD). In this regard, the pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme via monoclonal antibodies has emerged as a novel lipid-lowering therapy, leading to a marked reduction in circulating LDL-C levels and subsequent improvement of cardiovascular outcomes. As these agents are increasingly used in current clinical practice, mounting scientific and clinical evidence supports that PCSK9 inhibitors offer an excellent safety and tolerability profile with a low incidence of adverse events. Notably, the most frequently reported side effects are injection-site reactions. In contrast to statins, PCSK9 inhibitors do not appear to exert a detrimental effect on glycemic control or to increase the incidence of new-onset diabetes mellitus. Accumulating evidence also indicates that PCSK9 inhibitors are a safe, well-tolerated and effective therapeutic strategy for patients with statin intolerance. On the other hand, as PCSK9 inhibitors reduce LDL-C to unprecedented low levels, a large body of current research has examined the effects of their long-term administration on neurocognition and on levels of vitamin E and other fat-soluble vitamins, providing encouraging results. This review aims to present and discuss the current clinical and scientific evidence pertaining to the safety and tolerability of PCSK9 inhibitors.

Inclisiran for the Treatment of Cardiovascular Disease: A Short Review on the Emerging Data and Therapeutic Potential.

Proprotein convertase subtilisin kexin 9 (PCSK-9)-targeting therapy has arisen as a new line for the treatment of hyperlipidemia. Inclisiran is a double-stranded small RNA molecule that works by blocking the transcription of PCSK-9, leading to a reduction of PCSK9 levels in the hepatocytes, resulting in an increased expression of low-density lipoprotein (LDL) receptors in the hepatocyte membrane and, as a consequence, it reduces the circulating levels of LDL cholesterol (LDL-C). Compared to the other LDL-C-lowering medications, such as statins, ezetimibe and PCSK-9 inhibitors, inclisiran proposes an infrequent dosing of twice a year, while simultaneously providing a significant reduction of LDL-C. Its prolonged effect offers an advantage against medication non-compliance, which is one of the main causes for not achieving LDL-C goals with standard therapy. Inclisiran has also proven to have a relatively safe profile with adverse effects occurring in similar frequency as with placebo. This review aims to present and discuss the current clinical and scientific data pertaining to the role of inclisiran in the management of hypercholesterolemia and treatment of cardiovascular disease (CVD).

Galactin-3 and soluble ST2 as complementary tools to cardiac MRI for sudden cardiac death risk stratification in heart failure: A review.

Heart failure (HF) is recognized as one of the leading causes of morbidity and mortality worldwide. Every year about 500,000 new cases of HF are diagnosed in the United States. The predominant etiology of death in HF patients include sudden cardiac death (SCD) and pump failure. Prediction of mode of death may help in devising management decisions. In patients with HF, the presence of myocardial fibrosis has been a known risk factor for SCD and thus it could be used as a criterion in risk stratification for SCD. However, the underlying pathophysiology of SCD is uncertain and controversial, which makes it necessary to develop newer tools to enhance SCD risk stratification. The newer tools should be innovative enough either to complement or to replace the currently available tools. In this scoping review, we highlighted the utilization of novel biomarkers galectin-3 (gal-3) and soluble ST2 (sST2) and discussed that how they might complement currently available tools such as, cardiac MRI (CMR) for SCD risk stratification in HF patients.

Novel lipid-modifying therapies addressing unmet needs in cardiovascular disease.

Cardiovascular disease (CVD) remains a major cause of morbidity and mortality worldwide. Currently, it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD. Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality. In addition, recent advances in lipid-modifying therapies, such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors, have further improved cardiovascular outcomes in patients with hypercholesterolemia. However, despite significant progress in the treatment of dyslipidemia, there is still considerable residual risk of recurring cardiovascular events. Furthermore, in some cases, an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date. Thus, a number of novel pharmacological interventions are under early human trials, targeting different molecular pathways of lipid formation, regulation and metabolism. This editorial aims to discuss the current clinical and scientific data on new promising lipid-modifying therapies addressing unmet needs in CVD, which may prove beneficial in the near future.

Therapeutic management of hyperlipoproteinemia (a).

Cardiovascular disease (CVD) has consistently been the leading cause of death worldwide. Several clinical and epidemiological studies have demonstrated that an elevated plasma concentration of lipoprotein (a) [Lp(a)] is a causative and independent major risk factor for the development of CVD, as well as calcific aortic valve stenosis. Thus, the therapeutic management of hyperlipoproteinemia (a) has received much attention, as significant reductions in Lp(a) levels may, potentially, favorably affect cardiovascular risk. Aspirin, niacin, estrogens, and statins, which act on different molecular pathways, may be prescribed to patients with mild or modest elevations of Lp(a) levels. Other therapeutic interventions, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, Lp(a) apheresis, and the novel antisense oligonucleotides APO(a)-Rx and APO(a)-LRx, which are being evaluated in ongoing clinical trials, have provided some promising results and can potentially be used in severe cases of hyperlipoproteinemia (a). This review aims to present and discuss the current clinical and scientific data pertaining to the therapeutic options for the management of hyperlipoproteinemia (a).

Pharmacologic therapy of obesity: mechanisms of action and cardiometabolic effects.

Obesity is a chronic, relapsing, multifactorial disease, which has become a serious threat to public health globally, as the worldwide prevalence of obesity increases exponentially over time. It has been well established that obesity is associated with multiple adverse cardiometabolic effects. Although lifestyle changes are the first line of therapy for obesity, these are often insufficient in attaining weight loss goals. Orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide are agents that have been approved for the treatment of obesity but their effects on cardiometabolic risk factors and outcomes have not been clearly elucidated. Given the detrimental repercussions of obesity on cardiometabolic health, there is a pressing clinical need to fully understand the effects of these agents beyond weight loss alone. Certain previous weight loss drugs have been withdrawn due to safety concerns and this underlines the need for more careful assessment of the effects of the various pharmacologic agents currently used for the treatment of obesity. This review aims to provide an overview of the mechanisms, efficacy, safety and cardiometabolic effects of the currently available pharmacologic agents for weight loss.

Anti-inflammatory therapy for cardiovascular disease.

Chronic subclinical inflammation is a central process in the pathogenesis of cardiovascular disease (CVD) and it has been linked with both the initiation and progression of atherosclerosis. Several pro-inflammatory cytokines, such as the C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) have been described as independent risk factors for coronary heart disease and promoters of atherogenesis. Thus, extensive research is being conducted to assess the role of anti-inflammatory therapy in the primary and secondary prevention of CVD. Our review aims to provide the clinical and scientific data pertaining to the effects of different anti-inflammatory agents administered in patients with CVD.

Inheritance of high and low HDL: mechanisms and management.

PURPOSE OF REVIEW: The inverse association between plasma high-density lipoprotein cholesterol (HDL-C) concentration and the incidence of cardiovascular disease (CVD) has been unequivocally proven by many epidemiological studies. There are several genetic disorders affecting HDL-C plasma levels, either providing atheroprotection or predisposing to premature atherosclerosis. However, up to date, there has not been any pharmacological intervention modulating HDL-C levels, which has been clearly shown to prevent the progression of CVD. Thus, clarifying the exact underlying mechanisms of inheritance of these genetic disorders that affect HDL is a current goal of the research, as key roles of molecular components of HDL metabolism and function can be revealed and become targets for the discovery of novel medications for the prevention and treatment of CVD. RECENT FINDINGS: Primary genetic disorders of HDL can be either associated with longevity or, in contrast, may lead to premature CVD, causing high morbidity and mortality to their carriers. A large body of recent research has closely examined the genetic disorders of HDL and new promising therapeutic strategies have been developed, which may be proven beneficial in patients predisposed to CVD in the near future. SUMMARY: We have reviewed recent findings on the inheritance of genetic disorders associated with high and low HDL-C plasma levels and we have discussed their clinical features, as well as information about new promising HDL-C-targeted therapies that are under clinical trials.

An update on the CardioMEMS pulmonary artery pressure sensor.

Heart failure (HF) is one of the most important healthcare issues due to its prevalence, high morbidity and mortality, as well as its economic burden. A shift in the healthcare model towards reducing inpatient hospitalizations might have a significant impact on HF-related costs and quality of life. Recently, wireless monitoring has begun to be an essential part of the management in the patient with HF. The CardioMEMS HF system is one of the best examples pertaining to the success in this field. This article will discuss the CardioMEMS HF system and the rationale behind its development.

Impact of lipid-lowering therapy on glycemic control and the risk for new-onset diabetes mellitus.

Lipid-lowering therapy is used very commonly nowadays not only for the optimization of the lipid profile but also to reduce cardiovascular risk. However, some studies have linked the use of certain lipid-lowering agents with an increased risk for impaired glycemic control and new-onset diabetes mellitus, a condition well established as an important risk factor for cardiovascular disease. On the other hand, some other lipid-lowering agents have been shown to have a beneficial effect on glucose metabolism. Profound knowledge of these differences would enable the clinician to choose the right lipid-lowering medication for each individual patient, so that the benefits would outweigh the risk of side effects. This review aims to present and discuss the clinical and scientific data pertaining to the impact of lipid-lowering therapy on glycemic control and the risk for new-onset diabetes mellitus.