Friday, March 30, 2007
statins
Dr. J. Wouter Jukema, MD, PhD
Head Section Invasive Cardiology, Leiden University Medical Center
Dr. Wouter JukemaAbstract
Statins have provided the breakthrough needed in regulating plasma lipid levels to prevent CHD. Their main mechanism of action is known but the fact that they influence a central pathway important for cell growth and division opens up the possibility of further beneficial effects. Which of the host of pleiotropic actions of these drugs, if any, contributes to clinical benefit in patients with CHD is yet to be established. Given their exemplary safety and efficiency record, it is hard to envisage any new agents supplanting these drugs in their central role in coronary disease prevention. However, the size of the market means that pharmaceutical companies will continue to develop more powerful statins and adjunctive treatment. The need to demonstrate superior additional clinical effectiveness is a significant hurdle for any new compound. It will require substantial investment in large-scale clinical trials. The caveat here is that ever lower LDL levels (i.e. < 3.0 mmol/l) may not generate dramatic, or even worthwhile, decreases in CHD incidence. However, the actions of 'superstatins' on VLDL and HDL metabolism and on inflammation and endothelial dysfunction may yet open the way to widespread use of novel compounds. On the other hand, many health authorities look forward to the day when the original statins go off patent and become considerably cheaper to prescribe.
The latest beautiful news in "statin land" comes from the Heart Protection Study The MRC/BHF Heart Protection Study (HPS) involved 20,000 volunteers aged 40-80 years for whom there was substantial uncertainty about the balance of benefits and safety of cholesterol-lowering therapy. It specifically targeted groups of patients in which there was relatively little direct evidence of benefit including women, the over 70s, people with diabetes, those with non-coronary vascular disease, and those with average or below-average cholesterol levels. Volunteers were allocated either 40mg daily simvastatin as cholesterol-lowering therapy, or matching placebo. Study treatment and follow-up continued for an average of five and a half years in 69 UK hospitals. The funding of £21 million (euro 34 million) was provided by the UK¹s Medical Research Council (MRC), the British Heart Foundation (BHF), and the pharmaceutical companies Merck & Co. Inc. and Roche Vitamins Ltd. The study was, however, designed, conducted and analysed entirely independently of all funding sources by the Clinical Trial Service Unit of Oxford University. It started in 1994 and ended only October 2001. The major findings in HPS were:
* Cholesterol lowering with 40 mg of simvastatin treatment reduced the risk of heart attacks and of strokes by at least one-third, as well as reducing the need for arterial surgery, angioplasty and amputations.
* Reductions of at least one-third in these 'major vascular' events were found in a very wide range of high-risk patients for whom there had previously been uncertainty about using cholesterol-lowering therapy:
o women as well as men;
o people aged over 70 as well as younger people;
o people with blood levels of total cholesterol below approx. 5 mmol/l or LDL cholesterol below approx. 3 mmol/l, as well as those considered having 'high' levels.
* The benefits increased throughout the study treatment period (so more prolonged therapy might be expected to produce even bigger benefits), and are additional to those of other treatments used to prevent heart attacks and strokes.
Thus, a very large statin trial provides reliable evidence about the safety of simvastatin 40 mg daily regimen, with no support for previous concerns about possible adverse effects of lowering cholesterol on particular non-vascular causes of death, on cancers or on strokes due to bleeding. Also no severe rhabdomyolysis problems were encountered. Statins definitely earned their place
It is arguable that of all the 'new' manipulations of lipoprotein metabolism likely to give rise to substantial clinical benefit additional to that achieved with statins, promotion of reverse cholesterol transport shows the most promise. If it is accepted that statins can adequately control levels of apo-B-containing atherogenic lipoproteins (chylomicron and VLDL remnants, IDL, LDL), then the next challenge is to increase the flow of cholesterol from the artery wall through the HDL system back to the liver (a.o. CETP inhibitors).
Fibrates already have properties that suggest they do this to some extent; however, the clinical efficiency of these drugs seems limited to patients with initially high plasma triglyceride and low HDL cholesterol. New drugs in the fibrate class that affect peroxisome proliferator-activated receptors (PPARs) are currently being studied.
In general, agents with a wider spectrum of activity and benefit are needed. New developments have emerged or are underway such as drugs acting in the intestine (a/o. enterocyte ACAT inhibitors, stanol- and sterolesters, selective cholesterol absorption inhibitors (ezitimibe), and drugs acting in the liver (a/o. hepatic ACAT inhibitors, MTP inhibitors). As stated, the need to demonstrate superior additional clinical effectiveness is a significant hurdle for any new compound.
Head Section Invasive Cardiology, Leiden University Medical Center
Dr. Wouter JukemaAbstract
Statins have provided the breakthrough needed in regulating plasma lipid levels to prevent CHD. Their main mechanism of action is known but the fact that they influence a central pathway important for cell growth and division opens up the possibility of further beneficial effects. Which of the host of pleiotropic actions of these drugs, if any, contributes to clinical benefit in patients with CHD is yet to be established. Given their exemplary safety and efficiency record, it is hard to envisage any new agents supplanting these drugs in their central role in coronary disease prevention. However, the size of the market means that pharmaceutical companies will continue to develop more powerful statins and adjunctive treatment. The need to demonstrate superior additional clinical effectiveness is a significant hurdle for any new compound. It will require substantial investment in large-scale clinical trials. The caveat here is that ever lower LDL levels (i.e. < 3.0 mmol/l) may not generate dramatic, or even worthwhile, decreases in CHD incidence. However, the actions of 'superstatins' on VLDL and HDL metabolism and on inflammation and endothelial dysfunction may yet open the way to widespread use of novel compounds. On the other hand, many health authorities look forward to the day when the original statins go off patent and become considerably cheaper to prescribe.
The latest beautiful news in "statin land" comes from the Heart Protection Study The MRC/BHF Heart Protection Study (HPS) involved 20,000 volunteers aged 40-80 years for whom there was substantial uncertainty about the balance of benefits and safety of cholesterol-lowering therapy. It specifically targeted groups of patients in which there was relatively little direct evidence of benefit including women, the over 70s, people with diabetes, those with non-coronary vascular disease, and those with average or below-average cholesterol levels. Volunteers were allocated either 40mg daily simvastatin as cholesterol-lowering therapy, or matching placebo. Study treatment and follow-up continued for an average of five and a half years in 69 UK hospitals. The funding of £21 million (euro 34 million) was provided by the UK¹s Medical Research Council (MRC), the British Heart Foundation (BHF), and the pharmaceutical companies Merck & Co. Inc. and Roche Vitamins Ltd. The study was, however, designed, conducted and analysed entirely independently of all funding sources by the Clinical Trial Service Unit of Oxford University. It started in 1994 and ended only October 2001. The major findings in HPS were:
* Cholesterol lowering with 40 mg of simvastatin treatment reduced the risk of heart attacks and of strokes by at least one-third, as well as reducing the need for arterial surgery, angioplasty and amputations.
* Reductions of at least one-third in these 'major vascular' events were found in a very wide range of high-risk patients for whom there had previously been uncertainty about using cholesterol-lowering therapy:
o women as well as men;
o people aged over 70 as well as younger people;
o people with blood levels of total cholesterol below approx. 5 mmol/l or LDL cholesterol below approx. 3 mmol/l, as well as those considered having 'high' levels.
* The benefits increased throughout the study treatment period (so more prolonged therapy might be expected to produce even bigger benefits), and are additional to those of other treatments used to prevent heart attacks and strokes.
Thus, a very large statin trial provides reliable evidence about the safety of simvastatin 40 mg daily regimen, with no support for previous concerns about possible adverse effects of lowering cholesterol on particular non-vascular causes of death, on cancers or on strokes due to bleeding. Also no severe rhabdomyolysis problems were encountered. Statins definitely earned their place
It is arguable that of all the 'new' manipulations of lipoprotein metabolism likely to give rise to substantial clinical benefit additional to that achieved with statins, promotion of reverse cholesterol transport shows the most promise. If it is accepted that statins can adequately control levels of apo-B-containing atherogenic lipoproteins (chylomicron and VLDL remnants, IDL, LDL), then the next challenge is to increase the flow of cholesterol from the artery wall through the HDL system back to the liver (a.o. CETP inhibitors).
Fibrates already have properties that suggest they do this to some extent; however, the clinical efficiency of these drugs seems limited to patients with initially high plasma triglyceride and low HDL cholesterol. New drugs in the fibrate class that affect peroxisome proliferator-activated receptors (PPARs) are currently being studied.
In general, agents with a wider spectrum of activity and benefit are needed. New developments have emerged or are underway such as drugs acting in the intestine (a/o. enterocyte ACAT inhibitors, stanol- and sterolesters, selective cholesterol absorption inhibitors (ezitimibe), and drugs acting in the liver (a/o. hepatic ACAT inhibitors, MTP inhibitors). As stated, the need to demonstrate superior additional clinical effectiveness is a significant hurdle for any new compound.
# posted by roodbont @ 12:58 PM 
