Abbreviated lipid guidelines for clinical practice : Based on ESC lipid guidelines 2019 and ESC cardiovascular disease prevention in clinical practice guidelines 2021.

BACKGROUND: Lipid disorders are now considered causal for atherosclerotic cardiovascular disease (ASCVD) which remains one of the most important contributors to morbidity and mortality in the developed world. Identification and early treatment of lipid disarrays remains the cornerstone of good clinical practice to prevent, halt and even reverse ASCVD. Guidelines for lipid management are imperative to help promote good clinical practice. Given the detail involved in comprehensive guidelines and the multiple areas of knowledge required by clinical practitioners, abbreviated, easy to understand, practical versions of guidelines are required to ensure dissemination of the most important information. The recent ESC lipid guidelines 2019 and the ESC guidelines on CVD prevention in clinical practice 2021 (1,2), provide an excellent detailed summary of all the latest evidence supporting lipid interventions that reduce ASCVD. METHOD: We therefore developed a single-page document with hyperlinks to help practitioners gain easy access to practical information on lipid management. It has been developed for future electronic use in clinical practice. CONCLUSION: It is presented here in a tabular format together with printable versions of the associated hyperlinks that provide the additional information required in decision making. It is hoped to audit the impact of this approach to help guide future ways of disseminating the latest clinical guideline updates.

Investigational therapies for hypercholesterolemia.

INTRODUCTION: Cardiovascular morbidity and mortality are of increasing concern, not only to patients but also to the health care profession and service providers. The preventative benefit of treatment of dyslipidaemia is unquestioned but there is a large, so far unmet need to improve clinical outcome. There are exciting new discoveries of targets that may translate into improved clinical outcome. Areas covered: This review highlights some new pathways in cholesterol and triglyceride metabolism and examines new targets, new drugs and new molecules. The review includes the results of recent trials of relatively new drugs that have shown benefit in cardiovascular endpoint outcomes, drugs that have been licenced without endpoint trials yet available and new drugs that have not yet been licenced but have produced exciting results in animal studies and some in early phase 2 human studies. Expert opinion: The new areas that have been discovered as the cause of dyslipidaemia have opened up a host of new targets for new drugs including antisense RNA's, microRNA's and human monoclonal antibodies. The plethora of new targets and new drugs has made it an extraordinarily exciting time in the development of therapeutics to combat atherosclerosis.

Obesity diabetes and the role of bile acids in metabolism.

Bile acids have many activities over and above their primary function in aiding absorption of fat and fat soluble vitamins. Bile acids are synthesized from cholesterol, and thus are involved in cholesterol homeostasis. Bile acids stimulate glucagon-like peptide 1 (GLP1) production in the distal small bowel and colon, stimulating insulin secretion, and therefore, are involved in carbohydrate and fat metabolism. Bile acids through their insulin sensitising effect play a part in insulin resistance and type 2 diabetes. Bile acid metabolism is altered in obesity and diabetes. Both dietary restriction and weight loss due to bariatric surgery, alter the lipid carbohydrate and bile acid metabolism. Recent research suggests that the forkhead transcription factor FOXO is a central regulator of bile, lipid, and carbohydrate metabolism, but conflicting studies mean that our understanding of the complexity is not yet complete.

Dyslipidaemia of diabetes and the intestine.

Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care. In particular the economic burden is growing at an alarming rate in parallel with the increasing world-wide prevalence of diabetes. The major disturbance of lipid metabolism in diabetes relates to the effect of insulin on fat metabolism. Raised triglycerides being the hallmark of uncontrolled diabetes, i.e., in the presence of hyperglycaemia. The explosion of type 2 diabetes has generated increasing interest on the aetiology of atherosclerosis in diabetic patients. The importance of the atherogenic properties of triglyceride rich lipoproteins has only recently been recognised by the majority of diabetologists and cardiologists even though experimental evidence has been strong for many years. In the post-prandial phase 50% of triglyceride rich lipoproteins come from chylomicrons produced in the intestine. Recent evidence has secured the chylomicron as a major player in the atherogenic process. In diabetes chylomicron production is increased through disturbance in cholesterol absorption, in particular Neimann Pick C1-like1 activity is increased as is intestinal synthesis of cholesterol through 3-hydroxy-3-methyl glutaryl co enzyme A reductase. ATP binding cassette proteins G5 and G8 which regulate cholesterol in the intestine is reduced leading to chylomicronaemia. The chylomicron particle itself is atherogenic but the increase in the triglyceride-rich lipoproteins lead to an atherogenic low density lipoprotein and low high density lipoprotein. The various steps in the absorption process and the disturbance in chylomicron synthesis are discussed.

Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors.

In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes. Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality. Drugs which inhibit glucose re-absorption in the kidney, sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.

Investigational therapies for the treatment of atherosclerosis.

INTRODUCTION: There is great need for new drugs to reduce cholesterol in those patients who have not achieved target levels on statins as well as those who are statin intolerant. AREAS COVERED: In this review, the authors discuss the new antisense oligotide inhibitor of apo B synthesis, mipomersen; pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and cholesterol ester transport protein (CETP) inhibitors. Furthermore, the authors discuss cholesterol absorption and chylomicron synthesis with an emphasis on microsomal triglyceride transfer protein (MTP) inhibitors, which inhibit very-low-density lipoprotein production in the liver and chylomicron inhibition in the intestine. Finally, the authors also discuss Apo A1- and adenosine triphosphate-binding cassette transporter A1 (ABCA1)-promoting drugs. A literature review was performed through PubMed using the terms atherosclerosis, hypercholesterolemia, Apo B inhibition, PSCK9, CETP inhibitors, MTP inhibitors, apo A1 mimetics and ABCA1. EXPERT OPINION: So far, research suggests that PCSK9 inhibitors will be successful with mipomersen being used for those patients who do not respond well or who are still not at target. However, it is difficult to see where CETP inhibitors will fit in except with patients who have very low high-density lipoprotein. The MTP inhibitor lomitapide is currently only licensed for familial homozygous hypercholesterolemia but the intestinal inhibitors may have a future, particularly in familial combined hyperlipidemia. The future will be most exciting.

The detection of heterozygous familial hypercholesterolemia in Ireland.

Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant condition with a population prevalence of 1 in 500, and is associated with significant cardiovascular morbidity and mortality. It may be caused by mutations in the low-density lipoprotein (LDL) receptor, apolipoprotein B100 (Apo B100), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes, with over 1,000 causative mutations described. Statin therapy in HeFH is considered effective and safe. Audit data suggest that approximately 80% of the putative HeFH population remains unidentified and, therefore, there is a need to develop a strategy for the identification of affected individuals so that early lipid-lowering treatment may be offered. There is good evidence showing the effectiveness and acceptability of HeFH screening programs in Europe. The authors describe a protocol for an all island approach to HeFH detection in the Republic of Ireland/Northern Ireland. Index cases will be identified by opportunistic screening using the Simon Broome, or Make Early Diagnosis to Prevent Early Death (MedPed) and World Health Organization (WHO) criteria. Patients identified as "definite," "probable," or "possible" HeFH criteria will be offered genetic testing. The authors expect causative mutations to be identified in approximately 80% of patients with "definite" HeFH but in only approximately 20% of patients with "possible" HeFH. Cascade screening will be undertaken in first-degree relatives of the index case using genetic testing (where a causative mutation has been identified), or otherwise using LDL cholesterol concentration. The establishment of a HeFH screening program on an all-island basis will require: expansion of the existing molecular genetics diagnostic services, the establishment of a cohort of nurses/genetic counselors, a HeFH database to support cascade testing, the development of a network of lipid clinics (in a primary or secondary care setting), and an educational initiative to raise awareness of HeFH among healthcare professionals and the general population.

Linoleic acid increases monocyte chemotaxis and adhesion to human aortic endothelial cells through protein kinase C- and cyclooxygenase-2-dependent mechanisms.

The effects of polyunsaturated n-6 linoleic acid on monocyte-endothelial interactions were investigated with particular emphasis on the expression of platelet/endothelial cell adhesion molecule (PECAM)-1 and the role of protein kinase C (PKC) and cyclooxygenase-2 (COX-2). As a diet rich in polyunsaturated fatty acids may favour atherosclerosis in hyperglycaemia, this study was performed in both normal and high-glucose media using human aortic endothelial cells (HAEC). The HAEC were preincubated with normal (5 mM) or high (25 mM) D-glucose for 3 days before addition of fatty acids (0.2 mM) for 3 days. Linoleic acid enhanced PECAM-1 expression independently of tumor necrosis factor (TNF)-α and significantly increased TNF-α-induced monocyte adhesion to HAEC in comparison to the monounsaturated n-9 oleic acid. Chronic glucose treatment (25 mM, 6 days) did not modify the TNF-α-induced or fatty acid-induced changes in monocyte binding. The increase in monocyte binding was accompanied by a significant increase in E-selectin and vascular cell adhesion molecule (VCAM)-1 expression and could be abrogated by an interleukin (IL)-8 neutralising antibody and by the PKC and COX inhibitors. Inhibition of PKC-δ reduced VCAM-1 expression regardless of experimental condition and was accompanied by a significant decrease in monocyte binding. Conditioned medium from linoleic acid-treated HAEC grown in normal glucose conditions significantly increased THP-1 chemotaxis. These results suggest that linoleic acid-induced changes in monocyte chemotaxis and subsequent binding are not solely mediated by changes in adhesion molecule expression but may be due to secreted factors such as IL-8, monocyte chemoattractant protein-1 or prostaglandins (PGs) such as PGE(2), as IL-8 neutralisation and COX-2 inhibition reduced monocyte binding without changes in adhesion molecule expression.

The chylomicron: relationship to atherosclerosis.

The B-containing lipoproteins are the transporters of cholesterol, and the evidence suggests that the apo B48-containing postprandial chylomicron particles and the triglyceride-rich very low density lipoprotein (VLDL) particles play an important part in the development of the plaque both directly and indirectly by their impact on LDL composition. The ratio of dietary to synthesised cholesterol is variable but tightly regulated: hence intervention with diet at best reduces serum cholesterol by <20% andusually <10%. Statins are the mainstay of cholesterol reduction therapy, but they increase cholesterol absorption, an example of the relationship between synthesis and absorption. Inhibition of cholesterol absorption with Ezetimibe, an inhibitor of Niemann Pick C1-like 1 (NPC1-L1), the major regulator of cholesterol absorption, increases cholesterol synthesis and hence the value of adding an inhibitor of cholesterol absorption to an inhibitor of cholesterol synthesis. Apo B48, the structural protein of the chylomicron particle, is synthesised in abundance so that the release of these particles is dependent on the amount of cholesterol and triglyceride available in the intestine. This paper will discuss cholesterol absorption and synthesis, chylomicron formation, and the effect of postprandial lipoproteins on factors involved in atherosclerosis.

"European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses.

Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density liproproteins (LDL) subclasses. We sub-divided our statement in 2 sections. section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drug and lifestyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

Atherosclerosis, diabetes and lipoproteins.

The enormous burden of vascular disease is likely to expand rapidly as sedentary obesity and diabetes increase. Although cholesterol plays a major role in atherosclerosis and LDL is the major carrier of cholesterol in the blood, the importance of the postprandial triglyceride-rich lipoproteins in the development of atherosclerosis is gaining recognition. The role of HDL-cholesterol is also receiving more attention. These changes have been forced upon us by the realization that statins, which primarily lower LDL-cholesterol, only reduce the risk of atherosclerosis by 30%, suggesting that 70% of the risk still has to be explained and treated. In diabetes, abnormality in the metabolism of the triglyceride-rich lipoproteins and the inter-relationship with HDL-cholesterol appears to be of primary importance in atherosclerotic risk. Postprandial studies are difficult to carry out, which is one reason why large studies have not so far been performed. The important new findings in chylomicron metabolism suggest new treatments for the future.

Dyslipidaemia--hepatic and intestinal cross-talk.

Cholesterol metabolism is tightly regulated with the majority of de novo cholesterol synthesis occurring in the liver and intestine. 3 Hydroxy-3-methylglutaryl coenzyme A reductase, a major enzyme involved in cholesterol synthesis, is raised in both liver and intestine in diabetic animals. Niemann PickC1-like1 protein regulates cholesterol absorption in the intestine and facilitates cholesterol transport through the liver. There is evidence to suggest that the effect of inhibition of Niemann PickC1-like1 lowers cholesterol through its effect not only in the intestine but also in the liver. ATP binding cassette proteins G5/G8 regulate cholesterol re-excretion in the intestine and in the liver, cholesterol excretion into the bile. Diabetes is associated with reduced ATP binding cassette protein G5/G8 expression in both the liver and intestine in animal models. Microsomal triglyceride transfer protein is central to the formation of the chylomicron in the intestine and VLDL in the liver. Microsomal triglyceride transfer protein mRNA is increased in diabetes in both the intestine and liver. Cross-talk between the intestine and liver is poorly documented in humans due to the difficulty in obtaining liver biopsies but animal studies are fairly consistent in showing relationships that explain in part mechanisms involved in cholesterol homeostasis.

Albiglutide, an albumin-based fusion of glucagon-like peptide 1 for the potential treatment of type 2 diabetes.

Albiglutide, under development by GlaxoSmithKline plc for the treatment of type 2 diabetes mellitus (T2DM), is an albumin-fusion peptide. The compound is a mimetic of glucagon-like peptide 1 (GLP-1), a hormone that decreases glucose levels, but has a short half-life because of degradation by dipeptidyl peptidase (DPP)-4. Albiglutide has a longer half-life as a result of its fusion with albumin and its resistance to degradation by DPP-4, caused by an amino acid substitution (Ala to Glu) at the DPP-4-sensitive hydrolysis site. Data from phase II clinical trials in patients with T2DM revealed that albiglutide was well tolerated and that the drug significantly reduced HbA1c levels compared with placebo. At the time of publication, phase III trials assessing albiglutide alone and in combination with other antidiabetic drugs were recruiting patients with T2DM. Albiglutide represents a promising new drug for the treatment of patients with T2DM; the results of long-term trials are awaited with interest.

Ezetimibe - new anti-atherogenic properties?

Ezetimibe, a Niemann Pick C1-like1 inhibitor, inhibits cholesterol absorption. The drug has been shown to affect lipid raft function in monocytes and therefore may inhibit lipid accumulation in the atheromatous plaque with a mechanism that is unrelated to its effect in reducing cholesterol absorption. In this issue of the British journal of pharmacology, Gómez-Garre et al. demonstrate that ezetimibe and simvastatin both have a beneficial effect on the atheromatous plaque, which may be due to their effect on both monocyte/macrophage function and reduction in nuclear factor-kappaB activity. Whether these results in a rabbit model of atherosclerosis can be translated into human atherosclerosis awaits further studies.

The effect of antidiabetic drugs on genes regulating lipid metabolism.

PURPOSE OF REVIEW: Hyperglycaemia and dyslipidaemia are closely linked, yet, there has been difficulty in demonstrating that lowering blood sugar reduces cardiovascular events. The pathways linking abnormalities in fatty acid metabolism, insulin resistance and diabetes with abnormalities in cholesterol metabolism are being rapidly unravelled with new understandings of the effect of antidiabetic drugs on lipoprotein metabolism. The purpose of this review is to explore the recent literature. RECENT FINDINGS: Postprandial lipoproteins are now firmly established as a postprandial risk factor. Both insulin resistance and diabetes are associated with abnormalities in chylomicron production, and clearance and regulatory genes have been identified. Metformin, the most commonly used drug in type 2 diabetes, has multiple actions affecting numerous genes. The peroxisome proliferator-activated receptor-gamma regulation of insulin sensitivity and the important effects on lipoproteins are described. The entero-insulin axis and glucagon-like peptide-1 agonists, together with inhibitors of dipeptidyl peptidase 4 may have lipoprotein implications, but the evidence at present is sparse even though glucagon-like peptide-1 is found in high concentrations in the lymph. SUMMARY: Although antidiabetic drugs affect lipid metabolism, there is little evidence to suggest that these drugs can prevent atherosclerosis in diabetes and some may promote atherosclerosis through their adverse effect on lipoproteins.

The intestine as a regulator of cholesterol homeostasis in diabetes.

The chylomicron influences very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) composition but itself is atherogenic. Thus abnormalities of chylomicron production are of interest particularly in conditions such as diabetes which confer major cardiovascular risk. Intestinal function is abnormal in diabetes and is a major cause of the dyslipidaemia found in this condition. Studies have suggested that cholesterol absorption is decreased in diabetes and cholesterol synthesis increased. Molecular mechanisms involved in insulin resistance in the intestine and its effect on cholesterol homeostasis in diabetes are described. Abnormalities in triglyceride synthesis and alterations genes regulating cholesterol absorption and intestinal synthesis are discussed. In particular, increase in apolipoprotein B48 synthesis has been demonstrated in animal models of diabetes and insulin resistance. Intestinal mRNA expression of Niemann Pick C1-like 1, protein is increased in both experimental and human diabetes suggesting that an increase in cholesterol transportation does occur. mRNA expression of the ATP binding cassette proteins (ABC) G5 and G8, two proteins working in tandem to excrete cholesterol have been shown to be decreased suggesting increased delivery of cholesterol for absorption. Expression of microsomal triglyceride transfer protein, which assembles the chylomicron particle, is increased in diabetes leading to increase in both number and cholesterol content. In conclusion, diabetes is associated with considerable dysfunction of the intestine leading to abnormal chylomicron composition which may play a major part in the premature development of atherosclerosis.

Targets for intervention in dyslipidemia in diabetes.

Treatment for dyslipidemia in diabetes reduces cardiovascular events. Diabetes is associated with major abnormalities in fatty acid metabolism. The resulting disturbance results in an abnormal lipoprotein cascade from the large chylomicron through to the small HDL particle. This suggests that drugs that alter formation of the chylomicron particle might have a very important role in diabetic dyslipidemia. Achieving normal glycemia will reverse the abnormalities in fatty acid metabolism, but this is difficult, particularly as the disease progresses. Genes that regulate cholesterol absorption and excretion have been described (Niemann Pick C1-like 1 [NPC1-L1] and ATP binding cassette proteins [ABC] G5 and G8). An effective NPC1-L1 inhibitor (ezetimibe) improves the reduction in cholesterol caused by statins. Agonists of ABCG5 and G8 may become important in the treatment of dyslipidemia. Microsomal triglyceride transfer protein (MTP) is responsible for the assembly of the chylomicron and VLDL particles. New MTP inhibitors, acting only on the intestine, are exciting possible treatments. The advisability of sitosterol-enriched foods to lower cholesterol may have to be reassessed for patients with diabetes, since these products may lead to an increase in chylomicron sitosterol in diabetic patients. More successful treatment of diabetic dyslipidemia is essential if we are to reduce the burden of cardiovascular disease so commonly found in diabetes.

Genes that affect cholesterol synthesis, cholesterol absorption, and chylomicron assembly: the relationship between the liver and intestine in control and streptozotosin diabetic rats.

Chylomicrons and very low-density lipoproteins (VLDLs) are abnormal in diabetes. The aim of this study was to compare the expression of Niemann-Pick C1-like1 (NPC1L1), adenosine triphosphate-binding cassette (ABC) proteins G5 and G8, microsomal triglyceride transfer protein (MTP), and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase in the fasting and fed states in nondiabetic Sprague-Dawley rats fed a high-fat/cholesterol diet and to examine the messenger RNA (mRNA) expression of these proteins in the liver and intestine of diabetic and control animals using streptozotosin diabetic cholesterol-fed rats. Chylomicron and VLDL concentrations were significantly lower after a 12-hour fast in fasted compared with fed rats (P < .02). There was no change with fasting in mRNA expression of any of the genes in the intestine, but MTP level was significantly lower in the liver after the 12-hour fast (P < .01). There was a positive correlation between intestinal NPC1L1 mRNA and chylomicron cholesterol (P < .01) and between hepatic NPC1L1 mRNA and VLDL cholesterol (P < .01). The diabetic rats had significantly higher chylomicron and VLDL cholesterol, triglyceride, and apolipoprotein B-48 and B-100 levels compared with control rats (P < .0001). They had significantly increased NPC1L1 and MTP mRNA in both liver and intestine (P < .05 and P < .0005, respectively), and ABCG5 and ABCG8 mRNA were significantly reduced (P < .05). HMGCoA reductase mRNA was increased in diabetic animals (P < .01). In conclusion, fasting intestinal gene expression reflects the fed state. In diabetes, intestinal and hepatic gene expression correlates with abnormalities in chylomicron and VLDL cholesterol.

Intestinal microsomal triglyceride transfer protein in type 2 diabetic and non-diabetic subjects: the relationship to triglyceride-rich postprandial lipoprotein composition.

BACKGROUND: Microsomal triglyceride transfer protein (MTP) is responsible for the assembly of the triglyceride-rich lipoproteins (TRLs) and is increased in diabetic animal models. Human intestinal MTP expression has not been previously reported. This study examined the relationship between intestinal MTP gene expression and postprandial TRL composition in diabetic and non-diabetic subjects. Since the MTP promoter region has a sterol response element the effect of statins on intestinal MTP mRNA was analysed. METHODS: Twenty-seven diabetic and 24 non-diabetic subjects were examined. Duodenal biopsies were taken during gastroscopy and MTP mRNA was measured by RNase protection assay. Postprandial lipoprotein composition was determined. RESULTS: Diabetic subjects had significantly higher MTP mRNA than non-diabetic subjects. Statin therapy was associated with lower MTP mRNA in both groups. In the untreated diabetic patients compared to the untreated non-diabetic patients MTP mRNA was 25.0 +/- 25.1 amol/microg versus 13.1 +/- 5.6 amol/microg total RNA (p < 0.05). In the statin-treated diabetic group compared to statin-treated non-diabetic group MTP mRNA was 17.7 +/- 8.6 amol/microg versus 5.8 +/- 4.1 amol/microg total RNA (p < 0.05). In the whole group there was a positive correlation between the MTP mRNA and postprandial chylomicron cholesterol/B48 (r = 0.36, p < 0.01). CONCLUSIONS: This is the first study to demonstrate increased MTP expression in diabetic subjects. MTP mRNA expression was lower in statin-treated patients confirming the suggestion that the insulin and sterol response elements of the MTP gene are important regulators of MTP transcription in diabetes. Our results show that MTP plays a central role in regulating the cholesterol content of the chylomicron particle.