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Mechanisms linking HDL-C and diabetes. Dyslipidaemia (low HDL) causes lipid accumulation and inflammation propagating insulin
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Background:
Despite the increasing prevalence of type 2 diabetes, limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPi) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available...
Citations
... A recent randomised Phase II trial in dyslipidaemic participants using a new CETP inhibitor (obicetrapib) in combination with background high-intensity statin treatment found that, after 8 weeks, there was a significant decrease in median TG (−11% only with obicetrapib 5 mg), non-HDL-C (by up to −44%), LDL-C (by up to −51%) and apoB (by up to −30%) levels and an increase in median HDL-C levels (by up to 165%) [63]. Two meta-analyses found a significant reduction in the risk of new-onset diabetes of 12% [64] and 16% [65] in the CETP inhibitors group compared with the placebo group; glycaemic measures were also significantly improved in those with and without diabetes across most trials [65]. The results of the CVOT PREVAIL (NCT05202509) are eagerly awaited. ...
... A recent randomised Phase II trial in dyslipidaemic participants using a new CETP inhibitor (obicetrapib) in combination with background high-intensity statin treatment found that, after 8 weeks, there was a significant decrease in median TG (−11% only with obicetrapib 5 mg), non-HDL-C (by up to −44%), LDL-C (by up to −51%) and apoB (by up to −30%) levels and an increase in median HDL-C levels (by up to 165%) [63]. Two meta-analyses found a significant reduction in the risk of new-onset diabetes of 12% [64] and 16% [65] in the CETP inhibitors group compared with the placebo group; glycaemic measures were also significantly improved in those with and without diabetes across most trials [65]. The results of the CVOT PREVAIL (NCT05202509) are eagerly awaited. ...
Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle metabolism (LDL, VLDL, chylomicrons, HDL) have recently been approved by the European and US medical agencies, including anti- proprotein convertase subtilisin/kexin 9 (PCSK9) antibodies; an siRNA targeting PCSK9; bempedoic acid, which targets ATP citrate lyase; an antisense oligonucleotide targeting apolipoprotein C-III; an anti-angiopoietin-like 3 antibody; and a purified omega-3 fatty acid, icosapent ethyl. Other therapies are in different phases of development. There are several important considerations concerning the link between these new lipid-lowering therapies and diabetes. First, since concerns were first raised in 2008 about an increased risk of new-onset diabetes mellitus (NODM) with intensive statin treatment, each new lipid-lowering therapy is being evaluated for its associated risk of NODM, particularly in individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Second, people with diabetes represent a large proportion of those at high or very high cardiovascular risk in whom these lipid-lowering drugs are currently, or will be, prescribed. Thus, the efficacy of these drugs in subgroups with diabetes should also be closely considered, as well as any potential effects on glycaemic control. In this review, we describe the efficacy of next-generation therapies targeting lipoprotein metabolism in subgroups of people with diabetes and their effects on glycaemic control in individuals with diabetes and prediabetes and in normoglycaemic individuals.
Graphical Abstract
... Additionally, the use of CETP inhibitors, including obicetrapib, reduces the risk of new onset diabetes (RR = 0.84; 95% CI: 0.78-0.91), which means that it can be considered in patients with metabolic disturbances and the risk of diabetes or existing diabetes [65,66]. Ongoing phase-2 and phase-3 trials -OCEAN (NCT04770389; phase-2 study on the combination of obicetrapib and ezetimibe), BROOKLYN (NCT05425745; phase 3, HeFH), BROADWAY (NCT05142722; phase 3, HeFH and/or ASCVD), TANDEM (NCT06005597; phase 3, HeFH and/or ASCVD or multiple ASCVD risk factors), and the cardiovascular outcome trial PREVAIL (NCT05202509) -will address how best to configure obicetrapib in lipid lowering management (Figures 2, 3). ...
In 2023 there are still even 75% of patients over the target of low-density lipoprotein cholesterol (LDL-C), and hypercholesterolemia is the most common and the worst monitored cardiovascular risk factor. How it is possible, considering the knowledge we have on the role of cholesterol in the process of atherosclerosis, atherosclerotic cardiovascular disease (ASCVD) and its complications, on the methods of lipid disorders diagnosis, prevention, and treatment. Nowadays, almost 4 million deaths per year are attributed to LDL-C, and even 2/3 of all CVD deaths to ASCVD, therefore hypothetically we should easily prevent few to several million of deaths with early diagnosis, and early and intensive non-pharmacological and pharmacological therapies. Moreover, lipidology is now, besides oncology, the area with the highest number of new and ongoing trials with new effective and safe medications that have already appeared and will soon be available. Therefore, we have no doubt that year 2023 should be called the year of new and prospective lipid lowering therapies (LLTs).
In this State-of-the-Art paper we summarized the most important trials, studies, and recommendations on the new and prospective LLTs, with suitable graphical summaries that might be helpful for the physicians in their practice with a look to the nearest future with prospective therapies being still under investigation. Let’s hope all those medications helps to render dyslipidemia a rare disease in next few years.
Key words: atherosclerotic cardiovascular disease, combination therapy, innovative therapies, lipids, lipid lowering therapies, polypills.
... This protective ability can reduce the risk of new-onset diabetes mellitus by up to 16%. According to that, these medicaments also play an important role in the prevention of diabetic dyslipidemia occurrence [112]. The positive impact on glucose metabolism may be at least partially linked with an increase in the level of HDL-C [113]. ...
Dyslipidemias have emerged as prevalent disorders among patients, posing significant risks for the development and progression of cardiovascular diseases. These conditions are characterized by elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C). This review delves into the current treatment approach, focusing on equalizing these parameters while enhancing the overall quality of life for patients. Through an extensive analysis of clinical trials, we identify disorders that necessitate alternative treatment strategies, notably familial hypercholesterolemia. The primary objective of this review is to consolidate existing information concerning drugs with the potential to revolutionize dyslipidemia management significantly. Among these promising pharmaceuticals, we highlight alirocumab, bempedoic acid, antisense oligonucleotides, angiopoietin-like protein inhibitors, apolipoprotein C-III (APOC3) inhibitors, lomitapide, and cholesterol ester transfer protein (CETP) inhibitors. Our review demonstrates the pivotal roles played by each of these drugs in targeting specific parameters of lipid metabolism. We outline the future landscape of dyslipidemia treatment, envisaging a more tailored and effective therapeutic approach to address this widespread medical concern.
... Anacetrapib was the first CETP inhibitor shown to be effective in reducing the risk of atherosclerotic cardiovascular disease [44]. In addition, CETP inhibitors have been shown to reduce the risk of new-onset diabetes, and improve glucose tolerance and insulin sensitivity [45]. The latest generation of CETP inhibitor obicetrapib, specifically designed to reduce LDL-C and apoB, has achieved significant LDL-C reductions of up to 45% and may be the first CETP inhibitor to serve as adjunctive therapy for patients who do not achieve target LDL-C levels [46]. ...
Citation: Piko, P.; Jenei, T.; Kosa, Z.; Sandor, J.; Kovacs, N.; Seres, I.; Paragh, G.; Adany, R. Association of CETP Gene Polymorphisms and Haplotypes with Cardiovascular Risk. Int. J. Mol. Sci. 2023, 24, 10281. https://doi.org/10.3390/ Abstract: Cholesteryl ester transfer protein (CETP) is known to influence HDL-C levels, potentially altering the profile of HDL subfractions and consequently cardiovascular risk (CVR). This study aimed to investigate the effect of five single-nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene on 10-year CVR estimated by the Systematic Coronary Risk Evaluation (SCORE), the Framingham Risk Score for Coronary Heart Disease (FRS CHD) and Cardiovascular Disease (FRS CVD) algorithms. Adjusted linear and logistic regression analyses were used to investigate the association of SNPs and 10 haplotypes (H1-H10) on 368 samples from the Hungarian general and Roma populations. The T allele of rs7499892 showed a significant association with increased CVR estimated by FRS. H5, H7, and H8 showed a significant association with increased CVR based on at least one of the algorithms. The impact of H5 was due to its effect on TG and HDL-C levels, while H7 showed a significant association with FRS CHD and H8 with FRS CVD mediated by a mechanism affecting neither TG nor HDL-C levels. Our results suggest that polymorphisms in the CETP gene may have a significant effect on CVR and that this is not mediated exclusively by their effect on TG and HDL-C levels but also by presently unknown mechanisms.
... Beim Menschen bewirkt die Infusion von künstlichem rHDL eine akute Senkung des Glukosespiegels. Post-hoc-Analysen der CETP-Inhibitor-Studien fanden eine verbesserte Glykämiekontrolle bei den mit CETP-Inhibitoren behandelten Patienten sowie eine geringere Inzidenz von Diabetes im Vergleich zu den mit Placebo behandelten Kontrollen [25]. Mendelsche Randomisierungsstudien lieferten allerdings widersprüchliche Ergebnisse zur genetischen Kausalität von HDL-C bei Diabetes [1]. ...
Many epidemiological studies found low plasma levels of high-density lipoprotein (HDL) cholesterol (HDL-C) associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles show many anti-atherogenic actions. However, until now, clinical trials did not find any prevention of ASCVD events by drugs elevating HDL-C levels, at least not beyond statins. Also, genetic studies show no associations of HDL-C levels altering variants with cardiovascular risk. Therefore, the causal role and clinical benefit of HDL-C elevation in ASCVD are questioned. However, the interpretation of previous data has important limitations: First, the inverse relationship of HDL-C with the risk of ASCVD is limited to concentrations < 60 mg/dl (< 1.5 mmol/l). Higher concentrations do not reduce the risk of ASCVD events and are even associated with increased mortality. Therefore, neither the higher-the-better strategies of earlier drug developments nor the assumption of linear cause-and-effect relationships in Mendelian randomization trials are justified. Second, most of the drugs tested so far do not act specifically on HDL metabolism. Therefore, the futile endpoint studies question the clinical benefit of the investigated drugs, but not the importance of HDL in ASCVD. Third, the vascular functions of HDL are not exerted by its cholesterol content (i.e. HDL-C), but by a variety of other molecules. Comprehensive knowledge of the structure-function-disease relationships of HDL particles and their molecules is a prerequisite for testing their physiological and pathogenic relevance and possibly for optimizing the diagnosis and treatment of persons with HDL-associated risk of ASCVD, but also for other diseases, such as diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases.
... A new generation CETP inhibitor, such as TA-8899 [129], CKD-508 [135], and MK-8262 [136], which are still under evaluation, may change the picture. Although, CETP inhibitors were developed mainly as an ASCVD therapy, other studies have shown that they reduce diabetes and improve glycemic control [137]. ...
Purpose of review:
Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition.
Recent findings:
Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.
... 129 In randomized trials, CETP inhibition, leading to a 28-132% increase in HDL-C levels, improved glycaemic control and/or reduced the risk of new-onset diabetes. 130,131 The beneficial glycaemic effects could, however, be due to pleiotropic effects of CETP inhibition beyond HDL-C increases. However, infusion of artificial HDL acutely improved glycaemia in patients with diabetes. ...
... 123 In post hoc analyses of large trials, CETP inhibitors were also found to improve glycaemic control and delay the onset of diabetes. 130,131 Although pharmacologically increasing HDL-C levels has so far not shown any clinical benefit, several efforts have been launched to develop rHDL that are expected to improve specifically the HDL-mediated RCT rather than increasing its level. These were based on the observation that HDL infusion, as well as the overexpression of apoA-I in experimental animal models, were associated with the prevention or regression of atherosclerosis. ...
Previous interest in high-density lipoproteins (HDLs) focused on their possible protective role in atherosclerotic cardiovascular disease (ASCVD). Evidence from genetic studies and randomized trials, however, questioned that the inverse association of HDL-cholesterol (HDL-C) is causal. This review aims to provide an update on the role of HDL in health and disease, also beyond ASCVD. Through evolution from invertebrates, HDLs are the principal lipoproteins, while apolipoprotein B-containing lipoproteins first developed in vertebrates. HDLs transport cholesterol and other lipids between different cells like a reusable ferry, but serve many other functions including communication with cells and the inactivation of biohazards like bacterial lipopolysaccharides. These functions are exerted by entire HDL particles or distinct proteins or lipids carried by HDL rather than by its cholesterol cargo measured as HDL-C. Neither does HDL-C measurement reflect the efficiency of reverse cholesterol transport. Recent studies indicate that functional measures of HDL, notably cholesterol efflux capacity, numbers of HDL particles, or distinct HDL proteins are better predictors of ASCVD events than HDL-C. Low HDL-C levels are related observationally, but also genetically, to increased risks of infectious diseases, death during sepsis, diabetes mellitus, and chronic kidney disease. Additional, but only observational, data indicate associations of low HDL-C with various autoimmune diseases, and cancers, as well as all-cause mortality. Conversely, extremely high HDL-C levels are associated with an increased risk of age-related macular degeneration (also genetically), infectious disease, and all-cause mortality. HDL encompasses dynamic multimolecular and multifunctional lipoproteins that likely emerged during evolution to serve several physiological roles and prevent or heal pathologies beyond ASCVD. For any clinical exploitation of HDL, the indirect marker HDL-C must be replaced by direct biomarkers reflecting the causal role of HDL in the respective disease.
... In the same vein, the ABC-A1 polymorphism rs9282541 that results in a substitution of arginine 230 for cysteine is associated with the increased incidence of type 2 diabetes mediated by HDL cholesterol plasma levels [129]. Finally, a recent meta-analysis demonstrated that CETP inhibitors decrease the risk of new-onset of diabetes by 16%, concomitantly with significant increases in HDL-C [130]. ...
The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.
