Current and Novel Therapies: Intensifying Treatment...Improving Outcomes
Peter H. Jones, MD, FACP



Combination Lipid Drug Treatment

Slide 1. I'll discuss what we have available in our armamentarium to achieve intensive goals, not only for low-density lipoprotein (LDL) cholesterol, but also for non-high-density lipoprotein (HDL) cholesterol and apolipoprotein B.

My discussion is going to focus on what we have available to us today. This is in conjunction with lifestyle changes. I'm not going to discuss the available lifestyle opportunities, but I do believe that our treatments, along with lifestyle changes, involve statins, which are our cornerstone of treatment. I think that's obvious from the clinical trial data that's been presented. There have been well over 65,000 to 70,000 patients in the 5-year statin trials.


Slide 2. We now have 6 statins available to us, and this will be our core treatment. That doesn't mean that there are not other medications that have good data. Niacin has been a very good drug for many years and had good data in the Coronary Drug Project. We have information about the bile acid sequestrants as well as the fibric acid derivatives. As single drugs, they are reasonable options, but I do believe that statins remain our core treatment.

You can certainly use niacin and fibric acid derivatives to take care of patients with high triglycerides and low HDL, as well as those patients who present with very severe triglycerides who are a risk for pancreatitis -- in those cases, those kinds of medications become our initial treatments and statins may not be our core therapies.


Slide 3. Combining drugs provides an option for achieving the sort of intensive goals that have been presented. The US Food and Drug Administration (FDA) agreed that at least 1 combination, a statin and niacin together, is a very viable option to achieve not only LDL goals, but also non-HDL and HDL goals.

We have a new entry into the LDL-lowering arena, a cholesterol-absorption inhibitor called ezetimibe, which probably fits in more in the combination arena than in single-drug treatment.

Looking for more intensive management, there are advantages to looking at combinations of lipid-lowering drugs, certainly for the additive effects in reducing LDL cholesterol so that we can achieve more intensive lowering, to goals well below 100 mg/dL. An old standby has been statins plus bile acid sequestrants or bile acid resins, and we have the new statin and cholesterol-absorption inhibitor, ezetimibe, as a combination possibility. And niacin -- an intestinally active drug -- has always been used in combination with a statin to get even more intensive control in patients who have familial hypercholesterolemia.

You can combine some of these drugs for patients who are at high risk for pancreatitis as well as vascular disease, who have very high triglyceride values, using fibrates and niacin together, as well as using fish oil, either alone or in 3-drug treatments. Fibrates, niacin, and omega-3 fatty acids can be used for these patients.

In patients with mixed dyslipidemia, the very common forms we see in diabetics, metabolic syndrome, and familial combined hyperlipidemia, using a drug that lowers LDL cholesterol, combining it with either niacin or fibrate, is a very viable option. It could be statins plus niacin or a fibrate, or an intestinally active drug plus a fibrate or niacin.

For reduction of lipoprotein(a) [Lp(a)], consider niacin as part of your drug regimen. For most patients we're going to be using niacin if we need to lower Lp(a), and that will usually be added onto our regimen. I believe that using lower doses of 2 or more medications achieves not only better outcomes on lipid parameters than using maximum doses of 1, but I think our patients also may have better tolerance.


Slide 4. Let me give you an example of a combination of statin plus ezetimibe. Dr. Ballantyne was responsible for this 2003 publication of atorvastatin vs ezetimibe. In red, atorvastatin 80 mg lowered LDL 54%. Using 10 mg of atorvastatin and 10 mg of ezetimibe, you got 53% LDL lowering. It's about the only time you'll ever see the equation 10 + 10 = 80, but that's what you see on LDL lowering. There's a slight benefit on HDL by using the combination of ezetimibe and atorvastatin, and similar effects on triglycerides.

I believe in the future you'll probably see a combination of single pills of ezetimibe and a statin available.


Slide 5. The therapy that the FDA's approved is a statin plus niacin, which is lovastatin and extended-release niacin. This information, published about a year and a half ago, shows the complementary effects on not only lowering LDL cholesterol by at least 45% with this combination, but also lowering triglycerides over 40%, raising HDL 30% to 40%, as well as lowering Lp(a) about 25%. There are clear obvious lipid outcome benefits to using this kind of combination.


Slide 6. In small numbers of patients, the tantalizing information from the HDL Atherosclerosis Treatment Study (HATS) is that using a statin/niacin combination vs placebo had benefits on event rates in patients who had low HDL and slightly high triglycerides, many of whom also had insulin resistance on their clinical events.


Slide 7. While combination lipid treatment may be quite familiar to many of you, not many of our colleagues -- particularly in primary care -- are comfortable with it. There are certainly questions about combination therapy from our patients. They all ask, "Are these drugs going to destroy my liver?" They also talk about muscle-related symptoms, whether it be myalgias, which are the least benign and best tolerated of these, or myositis, definite muscle weakness, and the most severe form of rhabdomyolysis.

From a patient's standpoint, niacin, while an excellent drug, does have some patient tolerability issues. Then there is the cost. When you have to use more than 1 copay in order for patients to get medications, it can limit their access to combination lipid treatment.


Adverse Events of Lipid Therapy

Slide 8. I'm going to focus a little more on the adverse events because, particularly with niacin, the cost of drugs is one thing; but the actual side effects are what concern us and our patients, not only from their standpoint, but from a legal standpoint as well. I think the myopathy issue of statins is not known. The cause of it has been speculated to be related to reduced farnesyl pyrophosphate or geranylgeranyl pyrophosphate prenylation of the small guanosine triphosphate (GTP) protein Rho, which may increase apoptosis of myocytes.

There has also been a suggestion that the mevalonate product ubiquinone (coenzyme Q10 [CoQ10]) may be reduced through inhibition of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase, which might reduce mitochondrial oxidation. Although the plasma level of CoQ10 decreases, it's not so clear that that is what is happening in the mitochondria. There are suggestions that perhaps decreased cell membrane stability may occur as a result of the cell's inability to use cholesterol that it synthesizes to maintain cell-wall integrity.

None of these have been proven to be the actual cause. It could be any combination of them. So it's hard to determine the exact mechanism of statins, as well as of other lipid-lowering drugs such as fibrates.


Slide 9. One of the things that did raise concern about rhabdomyolysis with statins was the removal of cerivastatin from the worldwide market more than a couple of years ago. A lot of that had to do with a particular fibrate -- gemfibrozil -- and statin interaction. At the time we knew that there were some cases of gemfibrozil plus statin-induced rhabdomyolysis, but we didn't realize what the potential mechanism was since gemfibrozil didn't seem to interfere with the cytochrome P450 metabolism of statins. But we do know that it does interfere with the glucuronidation of statins, which was and is an unknown important metabolic pathway for many of the statins. When given concomitantly in pharmacokinetic interactions, gemfibrozil significantly increases the concentration maximum, whereas fenofibrate does not have the effect of inhibiting statin glucuronidation. So there's something unique about gemfibrozil's interaction. It may increase the potential for myositis with statins.


Safety Issues With Statin Therapy

Slide 10. Over a year ago in the Journal of the American College of Cardiology, an American Heart Association (AHA)/American College of Cardiology (ACC)/National Heart, Lung, and Blood Institute (NHLBI) clinical advisory reported on the use of statins and the safety of them. It provides an excellent overview of what we know. In terms of the safety issues, the hepatic transaminase elevations are very, very low incidence. This is 3 times the upper limit of normal on 2 successive occasions. It's dose dependent, and it is totally reversible. The risk of true myositis with statins is very low, and severe myositis, which has a creatine kinase (CK) greater than 10 times the upper limit of normal, is less than .1% with all the statins.

The risk of myositis is there with fibrates, but it's also very low. Combined statin/fibrate use in controlled clinical trials has shown a very low incidence of severe myositis or even rhabdomyolysis. I emphasize "controlled" because in adverse event reporting, there are situations where significant statin/fibrate rhabdomyolysis had occurred. The vast majority of those are for concomitant use of gemfibrozil with other statins, and there was an undue proportion of those with cerivastatin. The mechanism of this myositis with statins is not known.


Slide 11. For clinical management in dealing with these safety issues, and for discussion with your patients, it's best that you measure alanine transaminase (ALT) and aspartate transaminase (AST) at baseline. You should also probably measure CK prior to the use of statins, and certainly prior to the use of combining a statin and fibrate or using certain other concomitant medications that are known to affect the cytochrome P450 metabolism of some of the statins through the 3A4 system.

Most ALT/AST elevations that are less than 3 times the upper limit of normal are not a contraindication to initiating or continuing statin treatment as long as they're carefully monitored. If muscle symptoms appear, consider withholding statin therapy and measuring the CK. You have a baseline. You can use the measured one to compare with it. If there's no elevation or it's less than 3 times the upper limit of normal and the patient clearly needs a statin, you can consider using it with careful monitoring of symptoms. You could also consider reducing the dose if you were tending toward maximum-dose statins.

If the CK is more than 10 times the upper limit of normal, which was the baseline, you should seriously consider discontinuing that statin. For asymptomatic patients who have a CK elevation at baseline, for instance, statins should be considered; not only initiating, but also continuing it. Their symptoms and possibly the CK could be monitored periodically. I believe this kind of statement is still viable in our clinical management of patients today.


Slide 12. I believe that if you're going to consider using statin/fibrate combinations, that most of the clinically important episodes have occurred under certain circumstances, and mostly with gemfibrozil. The certain circumstances are those using higher doses of statins with fibrates.

These are things that you need to do to reduce myositis risk. Use lower doses of statins. Since fibrates are renally excreted, make sure you avoid using this combination in patients with significant renal insufficiency. Avoid therapy with concomitant medications, some of which interfere with cytochrome P450 3A4 metabolism, such as the medications listed here. Cyclosporin does not interfere with 3A4. It seems to increase the plasma levels of all the statins, and that's not a cytochrome P450 mechanism. But in the statins that are 3A4 metabolized, these are concomitant medications that need to be considered. There should be very cautious use in patients over the age of 70, particularly women. And last but not least, I think the recommendation is just don't use gemfibrozil. If I'm going to use a fibrate, I would tend toward using fenofibrate.


Slide 13. Of standard lipid-lowering combinations, what's been used for familial hypercholesterolemia for many years has been a statin plus niacin, maybe with an intestinally acting bile acid sequestrant if the patient could tolerate it. Those are usually the more standard treatments.

But I believe that now that we have ezetimibe as a better tolerated, intestinally active agent than resin, we're probably not just going to use statins and niacin for very severe LDL elevations. We'll probably be using a statin plus ezetimibe plus niacin as the combination for patients with familial hypercholesterolemia.

While statins are the core single-drug treatment for elevated LDL, combinations may be necessary for those patients with severe genetic LDL elevations.

For combined hyperlipidemia, not so high triglycerides -- certainly not in the pancreatitis range -- and a high non-HDL cholesterol, single-drug treatment is an option and statins are still very good. Statins are quite good at lowering non-HDL cholesterol and triglycerides. But the possible combinations of statin plus niacin or statin and a fibrate are your considerations there.

When triglycerides are well above 500 mg/dL, statins are not your first-line treatment because of the pancreatitis risk. In addition, many of these patients may have poorly controlled diabetes. There's a multitude of potential mechanisms to control their triglyceride levels, but I do believe niacin, fibrates, and fish oils as your first-line treatment are your best options.


Assessing Rosuvastatin Therapy With the MERCURY Study: Objectives and Study Design

Slide 14. I'm going to present some information about rosuvastatin, which is the newest statin on the market. The Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY) study was a European trial comparing rosuvastatin with atorvastatin, simvastatin, and pravastatin on achieving European and Adult Treatment Panel III (ATP III) LDL goals.


Slide 15. It was an interesting study, in which they had parallel arms of rosuvastatin vs 2 doses of atorvastatin, 1 dose of simvastatin, and 1 dose of pravastatin for 8 weeks of treatment. At the end of 8 weeks, each of the comparator statins was then re-randomized to either continue on that dose or to 10 mg of rosuvastatin; the exception was in the atorvastatin 20-mg arm, where there was a rosuvastatin 10-mg and a rosuvastatin 20-mg arm for an additional 8 weeks. In a way, the researchers were looking at the effect of switching patients on treatment.


MERCURY Study: Results

Slide 16. This shows the achievement of the European LDL goal, which is less than 3 mmol/L or 116 mg/dL: 10 mg of atorvastatin vs the next most efficacious statin, atorvastatin, at 10 and 20 mg. There was a significant difference at 10 mg between atorvastatin and rosuvastatin, but not statistically significant between 10 and 20 mg of atorvastatin.


Slide 17. When they looked at ATP III LDL goals in these patients, success depended on their risk status -- some were less than 100 mg/dL; some were less than 130 mg/dL. The 10 mg of rosuvastatin was better than 10 and 20 mg of atorvastatin in achieving those LDL cholesterol ATP III goals.


Slide 18. When you look at the actual LDL numerical reduction at 8 weeks, rosuvastatin 10 mg was 47% compared with a 37% rate of reduction with atorvastatin 10 mg; and 10 mg of rosuvastatin was statistically better than 20 mg of atorvastatin.


Slide 19. On HDL cholesterol, rosuvastatin 10 mg vs the next most potent statin, atorvastatin at 10 and 20 mg, there was a 9.2% HDL increase with rosuvastatin, which was statistically different from the 10- and 20-mg effects on HDL.


MERCURY Study: Switching Treatment Data and Safety

Slide 20. Regarding the treatment-switching data, by switching from 10 mg of atorvastatin to 10 mg of rosuvastatin, a greater number of patients achieved the European LDL treatment goal of less than 3 mmol/L. Switching from 20 mg of atorvastatin to 10 mg did not produce a significant difference, but by switching from atorvastatin 20 mg to rosuvastatin 20 mg, a greater number of patients achieved their European goal.


Slide 21. The same sort of thing is seen with the ATP III goals. Switching from 10 mg of atorvastatin to 10 mg of rosuvastatin, and from 20 mg of atorvastatin to 20 mg of rosuvastatin, a significantly greater number of patients achieved their ATP III LDL goals.


Slide 22. As far as safety was concerned, myalgia in this patient population was very infrequent, and none of the cases were associated with clinically important elevations of CK greater than 10 times the upper limit of normal.

Asymptomatic CK increases of greater than 10 times the upper limit of normal were very rare in this population of patients, and they usually resolved. No patients had clinically significant elevations of ALT or AST greater than 3 times the upper limit of normal on 2 successive occasions.


The STELLAR Trial: Effects on Low-Density Lipoprotein Cholesterol

Slide 23. The study I know the most about, which my colleagues and I published in the summer of 2003 in the American Journal of Cardiology, was the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial.


Slide 24. This was also a comparative study of rosuvastatin across its dose range of 10, 20, and 40 mg vs the dose ranges of atorvastatin, simvastatin in yellow, and pravastatin in white. There is a difference in LDL reductions across the dose ranges of these statins.


Slide 25. In a pair-wise comparison statistical analysis, 10 mg of rosuvastatin lowered LDL 46%. This was greater than 10 mg of atorvastatin, and statistically different from 10, 20, and 40 mg of simvastatin and pravastatin.


Slide 26. In the 20- and 40-mg pair-wise comparison analysis, there was a 52% reduction at 20 mg and a 55% reduction at 40 mg. The 20 mg rosuvastatin was statistically different from the 20 and 40 mg of atorvastatin, and statistically different from the 20, 40, and 80 mg of simvastatin and 20 and 40 mg of pravastatin. The 40 mg of rosuvastatin was statistically different from the 40 mg of atorvastatin, the 40 and 80 mg of simvastatin, and the 40 mg of pravastatin.


Slide 27. Put another way, at the top is rosuvastatin 10 mg going through 46%. At 52% is rosuvastatin 20 mg, and you can see them in comparison with LDL lowering of the other statins. This is another way of presenting the STELLAR information.


The STELLAR Trial: Effects on High-Density Lipoprotein Cholesterol and Triglycerides

Slide 28. Here's information from the STELLAR trial. Across the dose range, the effect of rosuvastatin is a 7.5% to 9.5% HDL increase compared with a 5.5% to 2% effect on HDL across the dose range of atorvastatin.


Slide 29. The other statins in comparison (the yellow is simvastatin across its dose range, and the white is pravastatin) averaged about 5% to 6% across their dose range, and there was statistical significance across the doses of rosuvastatin compared with the other statins on HDL-raising effects.


Slide 30. On triglycerides in the STELLAR trial, there were differences between pravastatin, simvastatin, atorvastatin, and rosuvastatin. Rosuvastatin and atorvastatin had almost superimposable triglyceride lowering across their 10-, 20-, and 40-mg dose range.


Slide 31. So it's not surprising, when you take a look at the triglyceride lowering, the HDL effects, and the LDL effects, that when you look at non-HDL cholesterol (this information was presented at the European Society of Cardiology meeting) you get almost exactly the same sort of lines in a dose-dependent fashion (from 10, 20, and 40 mg between pravastatin, simvastatin, atorvastatin, and rosuvastatin) on non-HDL cholesterol lowering.


Slide 32. Twenty milligrams of rosuvastatin, which had an 89% achievement of LDL cholesterol goals by ATP III guidelines, was greater than 80 mg of atorvastatin, 80 mg of simvastatin, and 40 mg of pravastatin. The ability to achieve targets does track with the LDL-lowering efficacy of these statins; its not surprising information.


The STELLAR Trial: Safety and Tolerability

Slide 33. What about the adverse events that we saw in the STELLAR trial across the dose range of rosuvastatin compared with the dose ranges of atorvastatin, simvastatin, and pravastatin? Adverse events leading to withdrawal were pretty similar and not statistically different. Adverse events leading to death (there were a couple of deaths) were not statistically different. And myopathy, which was clinically important, severe myositis, was 0 in this 6-week trial across the dose ranges of all these statins in 2400 patients.


Slide 34. Regarding tolerability, again, there were no myopathies. Five patients had clinically important ALT elevations, which were successive ALT elevations 3 times the upper limit of normal on 2 or more occasions. You can see the doses of the statins that they occurred in. None of them were in the rosuvastatin arm.


Conclusions

Slide 35. I believe that the intensity of our lipid treatments should match the global risk of the patient. The higher the patient's risk, the more intensive we should be with our lipid management. That may include not only monotherapy with statins, which are the cornerstone of preventive treatment, but also combination treatments. And while I think that statins should be the drug we use in most of our high-risk individuals, make sure that adequate LDL reduction is achieved. At least 40 mg/dL or probably more than 30% LDL lowering is necessary for most patients to achieve clinical outcomes. Make sure you choose the statin to get the greatest LDL-lowering efficacy and safety that you can.


Slide 36. Don't forget that combination drug treatment may have advantages for certain patients at high risk for heart disease, including those with very severe LDL elevations, such as familial hypercholesterolemia, mixed dyslipidemia (which occur in diabetics, the metabolic syndrome) and familial combined hyperlipidemia, as well as in those that present with severe triglyceride elevations.

I've told you what the effective combinations are, of which statins are going to be an important part, and I think statins and niacin, statins and ezetimibe, and statins and fibrates are options. For some patients you may need to consider all 3 of those important classes of drugs in order to achieve effective lipid goals.


Slide 37. I think the concern for adverse events with combination therapy depends on several factors. First is the dose of the statin used, and I tend to not maximize statin dose if using combination drug treatments. I believe it also depends on the dose and type of niacin used. I do not use a lot of extended-release niacin or more than 2 g/day. I do not believe you should use gemfibrozil with statins, so I would try to avoid that if at all possible. And I believe you need to make sure of other concomitant medications; if you minimize those or use lower doses of drugs in combination, you may avoid the risk of myositis.

Last but not least, we can talk all day long about how to treat patients, but if they do not stick with the treatment and we do not find things that they will tolerate, then we will never get the patients to achieve the clinical event rate reductions that they deserve or that they can get.


 
 
 
 










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