The current situation and prospect of the research of new lipomodulation drugs

lipid abnormality is one of the main risk factors for atherosclerosisA large number of epidemiological data and large-scale clinical trial results have fully shown that correcting lipid abnormalities is conducive to the prevention and treatment of ischemic cardiovasculardiseaseTreatment targets for lipolate drugs that have been used include: (1) lowering total cholesterol and/or LDL-C levels: inhibiting intracellular cholesterol synthesis - HMG-CoA reductase inhibitors (statins); (2) Reduce triglyceride (TG) levels: inhibition of very low density lipoprotein cholesterol (VLDL-C) synthesis - niacin, berts; (3) Increased HDL-C levels of HDL-C: Bette, NiacinIn addition, scientists are exploring new lipid-regulating drugs that offer more options forto combat atherosclerosisdiseases in a comprehensive way's new drug to lower cholesterol
epidemiological data show that elevated levels of total cholesterol and LDL-C are the main risk factors for atherosclerosisThere is substantial evidence-based medical evidence that statins can significantly reduce LDL-C levels, and that it has become a widely used anti-atherosclerosis drugCholesterol absorption inhibitors are already available abroad, and their combination with statins significantly inhibits the synthesis of liver cholesterol and the absorption of intestinal cholesterol, further significantly reducing LDL-C levels and increasing the rate of LDL-C compliance in patientsAcetyl Coenzyme A Cholesterol-Cytyl Transferase (ACAT) is mainly present in the small intestine, liver, arterial vascular wall in humans and mammalsACAT catalyzes cholesterol into cholesterol esters, participates in lipoprotein assembly in the liver, and maintains intracellular cholesterol metabolismInhibition of ACAT inhibits the absorption of cholesterol in food and the synthesis of lipoproteins in the liver, increases cholesterol breakdown and bile excretion, thereby reducing total cholesterol and LDL-C levelsACAT inhibitor pacitimibe has been expected to adjust blood lipids to play an anti-atherosclerosis roleIn 2006, the New England Journal of Medicine published a randomized, double-blind, placebo-controlled multicenter clinical study using intravascular ultrasound (IVUS) to observe the effects of pacitimibe on coronary lesions In 408 coronary patients confirmed by coronary imaging, patients with coronary disease were treated with pacitimibe 100 mg/d and placebo for 18 months on the basis of regular secondary preventive treatment (including statins) respectively, and the effects of pacitimibe on coronary lesions were observed with IVUS The results showed that pacitimibe therapy failed to delay the progression of coronary atherosclerosis lesions, and even had adverse effects There was no significant difference in cardiovascular event rates in the Pacitimibe treatment group compared to the placebo group (P-0.53) As a result, pacitimibe was not allowed to go public Gemcabene is a new lipid-regulating drug that lowers TG and LDL-C and slightly increases HDL-C Clinical observation of patients with hypertriglycerides showed that small doses of gemcabene (150 mg/d) increased HDL-C by 16.7%, increased dose, and reduced the effect of HDL-C to 5%, but significantly reduced LDL-C Further studies have shown that gemcabene's combination with small doses of statins improves the reduction of LDL-C, but with high doses of statins, there is no further effect on the improvement of LDL-C levels and cannot be compared with the cholesterol absorption inhibitors now in use The drug was not approved for further clinical studies Policosanol is a lipid-modulating drug derived from sugar cane and has a role in lowering total cholesterol and LDL-C in the Cuban population But there is a lack of observational studies on its efficacy and safety in different races An international multicenter, randomized, double-blind, placebo-controlled clinical study was reported on Berthosanol's lipid-inuinol effect in different races 143 patients with hypercholesterolemia or mixed hyperlipidemia were treated with 10, 20, 40, 60 mg/policosanol or placebo for 12 weeks, compared to the placebo group, there was no significant change in total cholesterol, TG, LDL-C, HDL-C or LP (a) in the stile group, so the drug was not approved for clinical promotion The discovery of new drugs affecting HDL-C the level of HDL-C in plasma was independently negatively related to the risk of atherosclerosis cardiovascular disease, and low HDL-C levels were the predictors of coronary heart disease Reducing the risk of atherosclerotic cardiovascular disease and raising HDL-C levels are another potential target for future new drug development The impact of HDL-C mainly involves three aspects: improving HDL-C levels, improving HDL function and promoting the reverse transport of cholesterol First, to raise plasma HDL-C levels
cholesterol ester transporter protein (CETP) is one of the key enzymes in the reverse transport of cholesterol Under CETP, cholesterol esters in HDL are exchanged with LDL and VLDL TG, regulating plasma HDL levels, composition and particle size, and increasing plasma HDL-C levels The development of CETP inhibitors offers new hope in view of the fact that CETP defects can raise HDL-C levels Torcetrapib, a representative drug for CETP inhibitors that increases HDL-C levels, and studies have found that people with higher HDL-C levels have a lower risk of coronary heart disease in people with higher LEVELs of CETP Clinical trials in small samples also showed that torcetrapib-up HDL-C and ldL-C were 50% to 60% and 15% to 20% stronger than Atorvastatin, respectively But can torcetrapib clinically inhibit the onset and development of atherosclerosis? In this context, a multi-center randomized controlled clinical trial was conducted in the international community, using coronary vascular ultrasound or high-resolution ultrasound torcetrapib monolith or co-use with atorvastatin on the effects of coronary artery or cervical atherosclerosis plaque, including ILLUMINATRADIE, ANCE I and ILLUSTRATE studies 1 ILLUMINATE Study (2007): 15,000 patients at high risk of coronary heart disease were randomly divided into attovastatin groups and atorvastatin s torcetrapib groups, and the interim analysis showed that the number of deaths in the torcetrapib group was higher than in the Atorvastatin group, and the study ended prematurely 2 RADIANCEI Study (2007): With 850 cases of familial hematomy hypercholesterolemia and 758 mixed hyperlipidemia patients, randomly given totorcetrapib and atorvastatin or atorvastatin monotherapy, with high-resolution ultrasound to detect changes in the midliose thickness of the cerrial artery (CIMT) The results showed that after 24 months, the average HDL-C level of the Atorvastatin group increased by 0.6 mg/dl, and the attovastatin-torcetrapib group increased by 28.6 mg/dl But after 24 months of treatment, attovastatin-torcetrapib did not show a role in delaying the progression of atherosclerosis plaques in the neck, and even some indicators showed that it accelerated the process of atherosclerosis 3 ILLUSTRATE study (2007): 1188 patients with coronary stenosis of 20% to 50% were treated with atorvastatin 10 to 80 mg/d for 4 to 10 weeks, LDL-C (LDL-C) After 100 x 15) mg/dl, the patient was randomly divided into torcetrapib 60 mg/d-a-atavastatin group or atovastatin monodrug group, and the change in the volume of coronary plaques was measured by IVUS The results showed that after 24 months of follow-up, the HDL-C level of the combination therapy group increased by 61% and the LDL-C level decreased by 20%, but there was no significant difference in the volume of the coronary plaques (.12% vs .19%, P.72) The trial ended early in December 2006 because the mortality rate in the combination group was significantly higher than that of the attovastatin monodrug group (P.007), and the risk of myocardial infarction, angina, vascular reconstruction, and heart failure was higher than that of the attovastatin monodrug group In short, torcetrapib treatment did not achieve the desired anti-atherosclerosis effect Clinical trials have found that torcetrapib increases systolic blood pressure by 4.6 mmHg, a change that may affect the anti-atherosclerosis effect of torcetrapib In addition, it is not clear whether the problems caused by torcetrapib are related to the suppression of CETP or simply due to the serious side effects of the drug itself If it is related to its molecular structure and not to its mechanism, then whether other CETP inhibitors can avoid such serious side effects needs to be studied in depth Therefore, the complexity of cholesterol reverse transport can also be seen from the clinical trial results of CETP inhibitors, hdL's role in the process of reverse transshipment of cholesterol and atherosclerosis involves many pathways and mechanisms, it is difficult to explain and reflect its complex role by some mechanism Moreover, HDL-C only reflects the cholesterol content in HDL and does not reflect HDL function Therefore, it is necessary to study not only the changes in HDL-C levels caused by changes in relevant factors in HDL metabolism, but also the clinical results of this change Daniel Rader, a researcher at Torcetrapib, writes that when developing treatments that target HDL, more attention should be paid to THE function of HDL than to HDL-C levels alone Second, to improve HDL function Apo AI Milano is a gene mutation of ApoAI, although the plasma HDL-C level is low, but can extend life, inhibit the occurrence of atherosclerosis In a small sample clinical trial, the weekly cast of a group of ApoAI Milano phospholipid complexes for a total of 5 weeks, ivUS confirmed that the volume of coronary atherosclerosis hardened plaques was significantly smaller than baseline It is important to note that this infusion did not raise HDL-C levels in the body, suggesting that the mechanism may have increased the amount of HDL-C by promoting the reverse transport of cholesterol or enhancing HDL function An oral Apo AI simulated peptide (D-4F) is under clinical development It has been reported that oral D-4F in mice showed strong anti-atherosclerosis, but no elevated HDL-C effect Some data also show that the main function of D-4F may be to improve the anti-inflammatory function of HDL It has also been reported that D-4F can also promote the reverse transport of macrophages in mice Third, to promote the reverse transport of cholesterol this is the future impact of HDL metabolism of new drugs research and development direction, including: (1) regulation of the liver SR-BI receptors: is still in the research stage (2) Double PPAR agonis: macrophages also express PPAR, PPAR pyridotics used for the treatment of type 2 diabetes, such as pyrethroid, to promote macrophage cholesterol outflow by increasing the expression of LXR, ABCA1, and ABCG1 It was found that PPAR alpha and PPAR anagocine worked together to promote macrophage cholesterol outflow, and the research and development of "double" PPAR agonists with PPAR alpha and PPAR gamma activity would help improve insulin resistance and improve HDL-C levels But the safety of such drugs is currently a major concern (3) LXR agonisant: synthetic LXR agonisant increases macrophage ABCA1 and ABCG1 expression, and increases the inflow of elile cholesterol into fat-poor ApoAI and mature HDL Recent studies have shown that LXR agonists can reduce atherosclerosis in mice It has been speculated that LXR agonisant as a new drug for cholesterol-raising reverse transport and anti-atherosclerosis is of great concern (4) Inner sebum inhibitors: inhibition of HDL hydrolysis; (5) ABCA1 activators promote reverse transfer of cholesterol, and recent studies have found that PPAR agonisant (GW501516) enhances ABCA1 expression and increases HDL-C levels In summary, most of the newly developed drugs to affect LDL-C mainly with statins or ethyl wheat cloth than no more advantages, the development of new lipid-modulation drugs mainly focused on raising HDL-C levels and improving HDL function (Ye Ping Wang Fan)