Abstract
Professor Hans Rudolf Brunner
Born in 1937, Professor Brunner is a Swiss citizen. He is a Professor Emeritus of Medicine at the University of Lausanne, Switzerland. He has been at the forefront of research on the role of renin and the renin–angiotensin system in blood pressure regulation. He has been involved in the development of drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. He was among the first medical practitioners to introduce the use of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Professor Brunner has been a medical advisor to Speedel since 1999.
How has hypertension management changed over the past decade?
The newcomers of the last 10 years have been the angiotensin receptor blockers (ARBs), which were a wonderful continuation of our experiences with the angiotensin-converting enzyme (ACE) inhibitors. The advantage of the ARBs is that they cause no side effects, which is unique in the field of pharmacology in general, not just within cardiovascular medicine. This is particularly important with a disease such as hypertension, which has very few symptoms itself. A problem in the early days of treatment was that you would start by diagnosing a patient with hypertension who was feeling fine, and then begin treatment and they would feel a lot worse. ACE inhibitors were a big step forward, but they produced various side effects, such as cough and irritation of the throat. We now have treatments that can be prescribed with the knowledge that the patients will not immediately feel worse, and in the long-run they will feel better as their hypertension is controlled. Then of course, the most recent advance is the introduction of the renin inhibitors, namely aliskiren, which came onto the market in early 2007.
Another change over the past 10 years is the growing awareness among researchers that despite everything we have done, the job is not yet complete. It is appalling to see how badly blood pressure is controlled throughout the world. Even though we have experienced success in the major trials, better results would be feasible in patients and a great deal of tragedy would be avoided if doctors and patients were more committed to the treatment of hypertension. However, hopefully this awareness will be an encouragement to do better in the future.
Have we seen real benefits on a population scale?
Yes and no; of course we have seen improvements such as decreases in myocardial infarction and stroke. However, many people still experience strokes and heart attacks, along with renal failure, which could have been prevented. Hypertension is a very important producer of dialysis patients, more so when it is combined with diabetes. A lot of patients have a high BMI and uncontrolled blood pressure, which of course leads to patient requiring dialysis, many of which could be avoided.
What are the main challenges in treating hypertension?
By far the main challenge is achieving a better result. Statistics range from 10% to around 40% of patients achieving adequate blood pressure control (meaning levels below 140/90 mmHg), which is appalling. In high-risk patients the aim is to achieve levels below 130 or 120 mmHg; however, it could be argued that everybody should have a blood pressure target at this level. The evidence is only available for diabetic patients because they have a higher risk, and therefore experience more cardiovascular events in the usual trial observation period of 5 years, but it is likely that everybody would benefit from even lower blood pressure targets.
Aliskiren was approved for use by the US FDA early in 2007. What advantages did this new renin inhibitor offer over existing treatments?
We need to distinguish between the scientific and the clinical/practical aspects of this issue. As scientists, we have always looked forward to the ‘real thing’; in other words, when you have a system such as the renin–angiotensin–aldosterone system (RAAS) it is conceptually best to block renin. However, compounds came along that by coincidence blocked the system elsewhere. For example, no-one would have purposefully developed the ACE inhibitors knowing the RAAS. But it so happened that researchers at the Squibb Institute were able to isolate and synthesize peptides from snake venom, and then synthesized an orally active compound – captopril, which was the first ACE inhibitor. This was a fantastic step forward, but no-one would have ideally taken this as their primary target in the RAAS. We also have the ARBs, which were more selective, and therefore have the advantage over ACE inhibitors, which are not specific to the system. These were all major steps forward, but everyone wanted to see the renin inhibitors and a lot of research has been carried out in this area. For many years every company in the cardiovascular field had a renin inhibitor program, and finally the breakthrough came.
However, clinically speaking it is a different matter, as it remains to be proven that blocking renin at the source produces a result that is different from that already achievable with the ARBs. At present this evidence is limited, and for the moment the best evidence we have is to use aliskiren as an add-on treatment with ARBs, which can apparently produce a greater blockade of the RAAS than we have achieved previously. Evidence for this has been found in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, the Aliskiren Observation of Heart Failure Treatment (ALOFT) study, and also the paper written by Suzanne Oparil published in the Lancet
BNP and congestive heart failure. This is an achievement, but whether a renin inhibitor alone will produce any more than an ARB is unknown at present. But of course the only way we can find this out is to have an agent available to study, which will now be possible.
At present patient groups that are in more urgent need of a very effective treatment (such as those with diabetic nephropathy, congestive heart failure, etc.), are the ones who will most obviously benefit. These groups have the highest absolute risks and therefore they should also experience the most obvious benefits. In the long run, however, treatment should not be limited to these high-risk groups. There is evidence from the Oparil study that additional benefits can also be achieved in hypertensive patients in terms of blood pressure reduction, and therefore in the future we will have no excuse for not normalizing blood pressure. It should not be forgotten that this is not being suggested as an alternative to existing options; renin inhibition will not replace diuretics or calcium antagonists, this is a method of enhancing one component of treatment, namely RAAS blockade, and all the other components will still be available for treatment. So, there is less and less excuse for the appalling results currently being obtained for blood pressure normalization.
The main limitation is that aliskiren has not been available for long enough for us to know everything about it. However, the one other limitation, which is again a little theoretical, is that aliskiren has a bioavailability of only 3%. Speedel is working on that, along with others, and as with other drug classes there is room for improvement on pharmacological grounds. Having said that, aliskiren is a very good renin inhibitor.
It appears that the problem with bioavailability can be overcome. For example, at Hypertension 2008 data for one of Speedel’s new renin inhibitors have been presented and this compound demonstrated bioavailability of up to 30%. Whether any other changes will be made remains to be seen. But the most important thing now is that we gain experience with any good renin inhibitor available and learn more about what can and cannot be achieved in hypertension patients. We certainly hope that the development of these new compounds will contribute to a better result in controlling blood pressure in the hypertensive population.
I expect the situation will be the same as with the other hypertension treatments. There are seven ARBs on the market at present and the seventh one does very well; it is not the most sold agent, but still does very well because it is a good compound. So it should not be a question of superseding; if good compounds are available I am sure they will go very far. In fact, catopril was not really the ideal ACE inhibitor; it had much too short a half-life, etc. But captopril was a very good drug and that is why for many years and even today it is still thought of as a very good drug, the only drawback being the need to take it several times a day.
The rule has always been to show that a new agent is better than placebo and at least as good as other available treatments. There are also people who say a new compound should only be approved if it also shows it can improve outcome and is actually better than existing treatments. However, if that were the case, we may as well stop all drug development. I do not know where the pharmaceutical industry would have gone, and it would be very sad if the pharmaceutical industry became discouraged, because then we would not get al. the wonderful new drugs that have emerged over the last 30 years.
& what will the shape of hypertension therapy be 10 years from now?
It is very difficult to say, but in 10 years I believe that we will still be struggling as we are today. I would hope that there would be at least a 10 or 15% improvement in blood pressure control, but I do not want to be over-optimistic. But I hope that at least we will be more concerned about the results of what we are doing and not just about our ideas and that we can also convince patients to do better. But it will still be an up-hill struggle even in 10 years from now. However, thanks to this new compound things are moving. When I look back to when I was a young physician, despite all the disappointment that we are not doing better today, we are certainly doing better than we did 30 years ago.