bms201038 and Dyslipidemias

Dyslipidaemias play a key role in determining cardiovascular risk; the discovery of statins has contributed a very effective approach. However, many patients do not achieve, at the maximal tolerated dose, the recommended goals for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol, and apolipoprotein B (apoB). Available agents combined with statins can provide additional LDL-C reduction, and agents in development will increase therapeutic options impacting also other atherogenic lipoprotein classes. In fact, genetic insights into mechanisms underlying regulation of LDL-C levels has expanded potential targets of drug therapy and led to the development of novel agents. Among them are modulators of apoB containing lipoproteins production and proprotein convertase subtilisin/kexin type-9 inhibitors. Alternative targets such as lipoprotein(a) also require attention; however, until we have a better understanding of these issues, further LDL-C lowering in high and very high-risk patients will represent the most sound clinical approach.

Topics: Azetidines; Benzimidazoles; Benzodiazepines; Carrier Proteins; Cholesterol, LDL; Dicarboxylic Acids; Dyslipidemias; Ezetimibe; Fatty Acids; Humans; Hypolipidemic Agents; Lipoprotein(a); Oligonucleotides; Oxazolidinones; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases

Apolipoprotein B (apoB) has a key role in the assembly and secretion of very low-density lipoprotein (VLDL) from the liver. Plasma apoB concentration affects the number of circulating atherogenic particles, and serves as an independent predictor of the risk of atherosclerotic cardiovascular disease. While statins are the most potent apoB-lowering agents currently prescribed, their efficacy in achieving therapeutic targets for low-density lipoprotein cholesterol (LDL-C) in high-risk patients, such as those with familial hypercholesterolaemia (FH), is limited. Resistance and intolerance to statins also occurs in a significant number of patients, necessitating new types of lipid-lowering therapies. Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9; AMG 145 and REGN727), a sequence-specific antisense oligonucleotide against apoB mRNA (mipomersen) and a synthetic inhibitor of microsomal triglyceride transfer protein (MTTP; lomitapide) have been tested in phase III clinical trials, particularly in patients with FH. The trials demonstrated the efficacy of these agents in lowering apoB, LDL-C, non-high-density lipoprotein cholesterol and lipoprotein(a) by 32-55 %, 37-66 %, 38-61 % and 22-50 % (AMG 145), 21-68 %, 29-72 %, 16-60 % and 8-36 % (REGN727), 16-71 %, 15-71 %, 12-66 % and 23-49 % (mipomersen) and 24-55 %, 25-51 %, 27-50 % and 15-19 % (lomitapide), respectively. Monoclonal antibodies against PCSK9 have an excellent safety profile and may be indicated not only in heterozygous FH, but also in statin-intolerant patients and those with other inherited dyslipidemias, such as familial combined hyperlipidaemia and familial elevation in Lp(a). Mipomersen and lomitapide increase hepatic fat content and are at present indicated for treating adult patients with homozygous FH alone.

Topics: Animals; Anticholesteremic Agents; Apolipoproteins B; Benzimidazoles; Cholesterol, LDL; Dyslipidemias; Humans; Lipid Metabolism, Inborn Errors; Lipoprotein(a); Oligonucleotides; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.

Topics: Antibodies, Monoclonal; Anticholesteremic Agents; Apolipoprotein A-I; Benzimidazoles; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Fibric Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Niacin; Oligonucleotides; Proprotein Convertase 9; Proprotein Convertases; Risk Factors; Serine Endopeptidases; Triglycerides

Current lipid-lowering drugs are often unable to achieve low density lipoprotein cholesterol (LDL-C) goals. Moreover, despite LDL-C lowering mostly by statins, a considerable residual vascular risk remains. This is partly associated with atherogenic dyslipidemia where apolipoprotein (apo) B-containing lipoproteins predominate. Mitochondrial Triglyceride (TG) transfer protein (MTP) is a key enzyme for apoB-containing lipoprotein assembly and secretion. This is mostly attributed to its capacity to transfer lipid components (TGs, cholesterol esters and phospholipids) to the endoplasmic reticulum lumen, where these lipoproteins are assembled. Several agents were developed to inhibit MTP wherever it is expressed, namely the liver and/or the intestine. Liver-specific MTP inhibitors reduce secretion of very low density lipoproteins (VLDL) mostly containing apoB100, while the intestine-specific ones reduce secretion of chylomicrons containing apoB48. These drugs can significantly reduce total cholesterol, LDL-C, TGs, VLDL cholesterol, as well as apoB levels in vivo. They may also exert anti-atherosclerotic and insulin-sensitizing effects. Limited clinical data suggest that these compounds can also improve the serum lipid profile in patients with homozygous familial hypercholesterolemia (HoFH). The accumulation of unsecreted fat in the liver and intestinal lumen is associated with elevation of aminotransferases and steatorrhea. Liver steatosis can be avoided by the use of intestine-specific MTP inhibitors, while steatorrhea by low-fat diet. Future indications for these developing drugs may include dyslipidemia associated with insulin resistant states, familial combined hyperlipidemia and HoFH. Future clinical trials are warranted to assess the efficacy and safety of MTP inhibitors in various clinical states.

Topics: Animals; Apolipoproteins B; Benzamides; Benzimidazoles; Carrier Proteins; Dyslipidemias; Flavanones; Humans; Hypolipidemic Agents; Malonates; Methaqualone

Several new or emerging drugs for dyslipidemia owe their existence, in part, to human genetic evidence, such as observations in families with rare genetic disorders or in Mendelian randomization studies. Much effort has been directed to agents that reduce LDL (low-density lipoprotein) cholesterol, triglyceride, and Lp[a] (lipoprotein[a]), with some sustained programs on agents to raise HDL (high-density lipoprotein) cholesterol. Lomitapide, mipomersen, AAV8.TBG.hLDLR, inclisiran, bempedoic acid, and gemcabene primarily target LDL cholesterol. Alipogene tiparvovec, pradigastat, and volanesorsen primarily target elevated triglycerides, whereas evinacumab and IONIS-ANGPTL3-L

Topics: Antibodies, Monoclonal; Anticholesteremic Agents; Benzimidazoles; Caproates; Cholesterol, HDL; Cholesterol, LDL; Diacylglycerol O-Acyltransferase; Dicarboxylic Acids; Dyslipidemias; Ezetimibe; Fatty Acids; Genetic Therapy; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Lipoprotein(a); Oligonucleotides; RNA, Small Interfering

Topics: Benzimidazoles; Cardiovascular Diseases; Dyslipidemias; Humans; Lipoproteins, HDL; Niacin; Propionates; Triazoles