ROLE OF CETP IN CARDIOVASCULAR DISEASES:
HDL has an atheroprotective nature. It is due to various mechanisms like antioxidative, anti-inflammatory, antithrombotic and antiapoptotic effects. CETP mediates the transfer of triglycerides (TG) an cholesteryl ester (CE) between lipoproteins like HDL, LDL, VLDL etc. CETP generally works by various pathways which include heterotypic pathway, homotypic pathway, shuttle pathway and tunnel pathway. Apart from all these pathways, CETP mainly works by Reverse Cholesterol Transport (RCT) pathway. In the first phase of RCT pathway, cholesterol flows out from peripheral tissue and goes towards HDL. It is occurred by various paths like through ATP binding cassette transporter A1 (ABCA1) to apolipoprotein A1(apoA-1), through the scavenger receptor B1 (SR-B1) to disc shaped and larger round HDL particles, through ABC transporters, G1 and G4 to the large round HDL particles. In the second phase of RCT pathway, cholesterol is carried to the liver. It is occurred by any one of the following ways- a) HDL directly interacts with hepatic SR-B1 receptors (maximumly as free cholesterol) or b) transferring of CE to very low density lipoprotein (VLDL) and low density lipoprotein (LDL), which contains apoB and successive uptake of LDL receptors which are in liver. When cholesterol is completely carried to the liver, cholesterol is excreted as a part of bile from body. Now previously it is mentioned that CETP is formed in liver and released into plasma. In plasma it is initially bound to small and disc shaped HDL particles. CETP develops the transfer of CE from HDL to VLDL and LDL and again boosts the transfer of TGs from VLDL to LDL and HDL. These two transportations are occurred by the exchange for TGs and CE respectively. By these transportation direct RCT pathway via the HDL/hepatic SR-B1 path is decreased. Now this CETP activity has proatherogenic effects, for which total HDL level is decreased. That is why cellular cholesterol flowing from the arterial wall is decreased, so atherogenic LDL level is increased. Finally cardiovascular diseases are developed.
CETP INHIBITORS & THEIR PRESENT STATUS:
Though many routes are there to prevent the CVDs, scientistis have found a new pathway to prevent the CVDs. Their aim was to increase the level of HDL, so that the level of LDL will be decreased and the CVDs will be reduced. This idea came from the concept that persons having genetic CETP deficiency, have increased level of HDL and have decreased level of LDL than the persons having CETP. Due to decreased level of LDL cholesterol the former persons are having lower rate of CVDs. This is a very novel therapeutic way, they have worked to prevent this. In clinical trials CETP inhibitors have shown their tremendous effect on elevating the level of HDL and reducing the LDL cholesterols in some cases.
Atorvastatin Merck & Co June, 2011 January, 2017 30,449 patients with Peripheral arterial disease, having history of myocardial infarction, diabetes mellitus, Cerebrovascular atherosclerotic disease like ischemic stroke and other symptomatic coronary heart diseases like angina pectoris, acute coronary syndrome etc. HDL level was elevated by 104%, LDL level was decreased by 17% and non HDL cholesterol level was decreased by 18%.
Anacetrapib monotherapy elevated the HDL level by 129% and decreased the LDL level by 38% in patients and ambulatory BP was affected in this case. Risk of heart attack, death from heat diseases and coronary revascularization was decreased by 9%.Chances of developing diabetes mellitus was decreased partly. Chances of myocardial infarction was decreased. Ischemic stroke was unaffected. Modest benefits were found in anacetrapib+ statin therapy. Trial was successfully completed.
In spite of showing effective action against CVD risk, Merck concluded that it was not as effective as other cholesterol reducing agents.
Atorvastatin Pfizer July, 2004 June, 2007 15,067 Men and Postmenopausal women, any HDL cholesterol level, congenital heart disease or any equivalent risk (like type 2 diabetes mellitus) HDL level elevated by 72.1% and LDL level reduced by 24.9% and 9% loss in TG. CV death and non CV death are increased only for torcetrapib than atorvastatin, death by changing level of Na+, K+ and HCO3- ions in serum, systolic BP was increased. Trial was stopped, when it was in phase III for excessive death.
ACCELERATE Evacetrapib Eli Lilly and Company October 2012 July 2016 12,092 patients having screening TG less than or equal to 400 mg/dL, HDL less than or equal to 80 mg/dL, LDL less than 100 mg/dL or less than 70 mg/dL, having acute coronary syndrome, diabetes mellitus, peripheral arterial diseases, cerebrovascular atherosclerotic diseases, coronary artery diseases. HDL level was elevated by 133.2% and LDL level was decreased by 31.1%.
Evacetrapib monotherapy elevated the HDL level by 54%-129% and decreased the level of LDL by 14%-36%. Major adverse CV events (MACE) were not decreased CV death, unstable angina pectoris, systemic BP, stroke, myocardial infarction were elevated. Trial was stopped prematurely for the inability of showing the clinically effective therapeutic effect.
Dal-OUTCOMES Dalcetrapib (RO4607381)/JTT-705 Hoffmann-La Roche April, 2008 September, 2012 Actual enrollment of patients was 15,865,but target sample was 15,600 individuals (men and women), who were >=45 years age, recently admitted in hospital for acute coronary syndrome, clinically stable, taking medicines for dyslipidemia routinely and not having uncontrolled diabetes or severe anaemia or uncontrolled hypertension. Highest dose elevated the HDL level by 34% and reduced the LDL level by 7.4%. CHD death, cardiac arrest with resuscitation, ischemic stroke, patients having unstable angina and acute myocardial ischemia were hospitalized, non fatal myocardial infarction, coronary revascularization, caused mortality, mean systolic blood pressure was elevated by 0.6 mm Hg. Trial was stopped due to it was unable to show the clinically meaningful efficacy.
TULIP Obicetrapib (TA-8995)/ AMG 899
Rosuvastatin Amgen/ Dezima August 2013 July 2014 364 patients having HDL level less than 1.8 mmol/L and greater than 0.8 mmol/L, LDL level greater than 2.5 mmol/L, level of TG less than 4.5 mmol/L and not having hyperaldosteronism history, type 1 or type 2 diabetes, atherosclerotic vascular disease Depended on dose TA-8995 monotherapy reduced LDL level by 27.4%-45.3%. In case of TA-8995(10 mg)+ atrovastatin and TA-8995(10 mg)+ rosuvastatin, it was 68.2% and 63.3% respectively. Depended on dose dose TA-8995 monotherapy elevated HDL level by 75.8%-179.0%. In case of TA-8995(10 mg)+ 20 mg atrovastatin and TA-8995(10 mg)+ 10 mg rosuvastatin it was 152.1% and 157.5% respectively. Not any evidence for any serious adverse effects and any toxicity in liver or muscle. CV risks were significantly reduced. No any significant change observed in BP, serum electrolytes and aldosterone. Phase II trial completed and the result reported.It was abolished in 2017.
SIDE EFFECTS: In spite of these advantages CETP inhibitors show various types of side effects. The CETP inhibitors have shown excellent clinical efficiency in increasing HDL cholesterol level and decreasing LDL cholesterol or VLDL cholesterol level; they block the transfer the CE from HDL to VLDL or LDL. Thus the level of HDL is increased and the levels of LDL and non HDL cholesterol are decreased. They can do it both by monotherapy and addition with statins like atrovastatin or rosuvastatin and by depending on respective doses. Anacetrapib is comparatively successful drug among the other CETP inhibitors, but has some serious side effects. It was observed that anacetrapib caused cognitive changes, depression, infectious diseases, hemorrhagic stroke, small reduction in kidney function etc. Apart from these it slightly elevated the systolic and diastolic blood pressure of 0.7 mmHg and 0.3 mmHg respectively. Merck explained that there were no dangerous side effects like cancer, cardio-metabolic diseases. Merck also claimed that there were no such serious adverse effects, which attributed to hypertension. Torcetrapib stimulated the transcription rates and enzyme activities of the two cytochrome p450 enzymes (CYP11B1 and CYP11B2) and hence cortisol and aldosterone were formed by an intracellular calcium-mediated mechanism. Thus it increased the blood pressure and also caused hyperaldosteronism, which was the severe side effect of it. Apart from these, it also elevated the level of endothelin-1 in the wall of the artery. It also changed the level of sodium, potassium or bicarbonate ion levels in serum, that is why many more patients were died in ILLUMINATE trial. Unlike torcetrapib, evacetrapib did not show any serious side effects. Recently, it was observed in phase III trial (ACCELERATE) that evacetrapib successfully elevated the HDL level and decreased the LDL and non HDL cholesterol level, but it could not decrease the serious CVDs and mortality in effective level. After the torcetrapib, dalcetrapib was the next invention as CETP inhibitor. Hoffmann-La Roche arranged the dal-HEART programme, which included the following phases: dal-OUTCOMES, dal-ACUTE, dal-OUTCOMES 2, dal-PLAQUE (completed), dal-PLAQUE 2, and dal-VESSEL (completed). Unfortunately, it’s trial was also terminated because of increasing mortality and apart from this it could not show the expected clinical effects against CHD diseases. It was also observed in the trial that dalcetrapib elevated the systolic BP by 0.6 mmHg as compared to placebo in the patients having acute coronary syndrome. TA-8995 (obicetrapib or AMG 899) is the recent CETP inhibitor; but in the trials no any serious adverse effects were observed both in monotherapy or addition with statins, claimed by the developer. It has no any side effects like the above mentioned such as increasing BP and endothelin-1, changing the concentrations of electrolytes in serum, hyperaldosteronism etc.
LIMITATIONS OF CETP INHIBITORS: A biggest limitation of CETP inhibitor that these drugs can only be used in those patients, having AA genotype and in ADCY9 gene, on the chromosome number 16. These types of patients having AA genotype are only 20% in the population. This was observed in dal-OUTCOMES and dal-PLAQUE-2 trial. But there are many controversies regarding this limitation. Many researchers performed experiment on it but found very much unconvincing evidence for the relationship between CETP inhibitors and ADCY9 gene. Further research is already going on in this matter. Previously it is mentioned that HDL particles are having a very complex structure. Now this complex structure contains various subtypes; the characteristics of which are not same. Here comes the another limitation of the CETP inhibitors that we do not know that by increasing of which type of HDL particles, CVD will be reduced. It is now proved that by increasing the HDL particles, LDL and non HDL cholesterols and TG level are decreased, thus the CVD risk is lowered. Now for keeping the heart healthy the level of HDL should be increased and for these we can take some challenges like sacrificing the fast foods and foods having fats, effective aerobic exercises in everyday, maintaining the balanced diet i.e. taking magnesium supplements in food, sacrificing the simple carbohydrate intaking, omega-3-fatty acids consumption like fish oil, etc. Apart from these smoking should be sacrificed and body weight should be reduced because obesity is the big curse and gateway of the CVDs. Alcohol can be taken in mild and controlled dose, but it actually sometimes elevates the TG level, because it is very much habit-forming, that is why it is not generally added in the suitable lifestyle, which is set for the healthy heart. It was claimed that niacin can be used to decrease and prevent the CVDs but when the Atherothrombosis was untimely stopped, there come a big question regarding the effectivity of niacin in elevating the HDL level.
FUTURE SCOPE OF CETP TREATMENT: Many more drugs in this field are found either with severe side effects or very poor clinical efficacy. Torcetrapib was the first invention in this class, but as previously mentioned that it caused CV death and non CV death in greater in number than that of atrovastatin. Apart from these it has shown various side effects like elevation of systemic BP, change in level of concentrations of electrolyte in the serum etc. Many more patients were died in this trial, for which this trial was halted. In case of dalcetrapib and evacetrapib, they shown comparatively less side effects in the respective clinical trials, but both the drugs were unable to show their clinically effective efficacy against the CVDs. They could not increase the HDL level and decrease the LDL and non HDL cholesterol in a suitable manner. Though the questions in this treatment raise for these drugs, there are the drugs like anacetrapib and obicetrapib (TA-8995 or AMG 899) which show fabulous clinical efficacy against CVDs. They increase the HDL level and decrease the LDL and non HDL cholesterol in unpredictably good manner, as mentioned earlier. Though their trial were halted for many causes as previously mentioned, they have proved that there is an another way to reduce CVDs and which is very much novel path. This treatment will be more useful when the limitations will be resolved, like as mentioned previously that we do not know by increasing of which HDL particle the CVDs will be reduced i.e. which HDL particle is responsible for reduction of CVDs. It is occurred for the complex structure of HDL particles. If in the future by further research this problem will be solved then this treatment will be more useful and easier. For all these things this topic is very much favourable and hopeful for further research and development.
CONCLUSION: Actually we all know that there are many more drugs and they have various mechanisms to reduce CVDs, but all pathways have to some extend adverse effects, which are very much harmful for human body; but by this treatment (obicetrapib, dalcetrapib, evacetrapib) it is proved that this pathway can be of without or less adverse effects and by the treatment with anacetrapib and obicetrapib it is proved that this pathway can be used for the reduction of CVDs and the duration of action and onset of action can also be decreased, if some further research will take place regarding this pathway. From all these reports and informations it is concluded that It is a very promising and innovative pathway to get relief from CVDs among the other pathways and this may furnish a strong inspiration to carry out the research for this novel path so that in the future days, extremely successful and efficacious drugs will be discovered to decrease CVDs by this pathway, of which will have no any serious or severe adverse effects.
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