Is Prehypertension a Useful Clinical Category? Part 2

Internal Medicine World ReportJanuary 2007
Volume 0
Issue 0

Interview with Joel M. Neutel, MD, Associate Professor of Medicine, University of California-Irvine, Medical Director, Clinical Pharmacology, Orange County Research Center, Tustin, and Staff Physician, Long Beach Memorial Medical Center and the Veterans Affairs Medical Center, Calif

In September 2006, Dr Myerson discussed this topic, quoting 2 hypertension experts who suggested that prehypertension was not a useful clinical category. In the present article, Dr Neutel suggests a direct link between prehypertension and hypertension, pointing to the dire implications of this association.

Do you agree that prehypertension is not a useful category?

I think it is definitely a useful clinical category. There is no question in my mind that high blood pressure (BP) is a late manifestation of a much more complicated syndrome (or abnormality) that occurs in people who are likely genetically linked. In the past, we had done much work in the young normotensive adult children of hypertensive parents who have what would be considered by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) as “prehypertension.” In comparing these children to young normotensive adult children of normotensive parents, we found that even in their prehypertensive stage they already exhibit these abnormalities:

• Left ventricular hypertrophy

• Decreased arterial compliance and elevated insulin levels or insulin resistance

• Some protein in their urine.

So already at this early stage, those with prehypertension have some of the cardiovascular (CV) target-organ damage that we frequently see in hypertensive patients. Thus, in prehypertension we see an early warning sign of those who are at increased risk for CV disease, and certainly people who are at increased risk for overt hypertension. I therefore believe that prehypertension is a very important and useful clinical category. Moreover, prehypertension presents an opportunity for clinicians to start instituting treatment earlier, with the hope that we may delay or prevent overt hypertension, and thereby delay or prevent other CV events.

The difficulty is what can we do about it, and how do we approach this treatment?

The current JNC 7 recommendations say that if there are no other CV risk factors, you should just be more aware that these patients have a marker for pending hypertension and CV disease. You also need to be instituting lifestyle changes in their diet and implement exercise regimens. We begin with a nonpharmacologic approach to improve elevated BP in these patients. If, however, they have other CV risk factors, then my threshold for treating BP drops significantly, and I would be more inclined to take a pharmacologic approach to the management.

So you consider prehypertension clinically important?

I am particularly interested in prehypertension, because I think it does give us an opportunity to intervene earlier in the process, which is clinically very important. Before JNC 7 had described prehypertension, we considered patients whose BP was between 120 and 139 mm Hg as normal, but we are now finding CV risk factors present in these patients, and treating this increased risk of CV disease may prevent or slow this process.

I think part of the problem is that many physicians think that if you are not going to advocate treatment, what is the point of concerning the patient? You get people concerned by telling them they have an abnormality, and yet you haven’t got much to offer them. Diet and exercise are all very well and good, but they don’t work all that well because people don’t follow them all the time. If, however, we can offer them treatment and can ultimately show some benefit, then it becomes much more important to diagnose and to treat.


There is still some confusion among physicians and patients about the implications of prehypertension. Many people just see it as another form of normal and are resistant to take drugs. The recently published Trial of Preventing Hypertension (TROPHY)1 provides further evidence to the benefit of treating prehypertensive patients. In comparing an angiotensin receptor blocker (ARB) and placebo, those taking the ARB showed slower progression to or reduced onset of overt hypertension when compared with the placebo group after a period of 2 years. This was clear evidence that you can impact the course of this disease and prevent progression to hypertension, although experts are still arguing about this trial (see , September 2006). For me, however, there is no question that we treat this disease too late.

What about diet and exercise?

You can try and get patients to follow a certain diet and exercise regimen, but most prehypertensive patients feel they are normal, and in most cases it just doesn’t work. It does not work because they don’t follow a diet or exercise regimen consistently. So as a clinician I need something else.

But are there treatments for prehypertension?

Increasingly I have become interested in some of the natural products, or nutraceutical products, that are available now and have been shown in clinical studies to reduce BP. My clinical experience shows that patients would be more willing to take natural products. Vitamins are fine, but to my knowledge there are not any that have been shown in clinical studies to reduce BP. I am currently involved in a product called AmealPeptide, which comes out of the fermentation process of milk. A natural product that can reduce BP slightly and may offer the normalization of BP and slowing the progression to overt hypertension becomes much more interesting, because it is easier to get patients to take something that they believe is a natural product than it would be to get them to take a “chemical” compound.

The tripeptide that comes out of the fermentation process is very similar to the tripeptide, or part of the tripeptide, that you see in angiotensin-converting-enzyme (ACE) inhibitors. It was shown that much like an ACE inhibitor, these tripeptides result in the blockade of the renin-angiotensin system and as a consequence reduce BP.

A series of double-blind, placebo-controlled studies conducted in Japan and in the United States2-4 have shown that this particular tripeptide lowers BP. So for me that is very interesting, because it provides something that is considered to be natural and has been shown in clinical trials to reduce BP, and I think it might therefore be an alternative for patients with prehypertension that may be more palpable.

Other similar products would be just as useful, provided they have been shown to reduce BP in good clinical trials. This approach is important because it presents an opportunity to institute some sort of intervention early in the disease process. It is very difficult, understandably, to persuade patients to take a tablet for a condition that is confusing and to get them to think of as abnormal. It may be easier to get patients to take a natural product if they think of it as a healthy thing.

ACE inhibitors are antihypertensives that were originally developed from the toxin of a South American viper snake, so they, too, came from a natural source. This is similar to developing peptides from the fermentation process of milk, a mechanism that I understand and therefore can make judgment about it.

What would you advise primary care physicians?

It is important to remember that we now have good evidence to suggest that prehypertensive patients already have some target-organ damage and are therefore at increased risk of developing CV disease. Certainly if the patient has other CV risk factors, you have to be much more aggressive in the treatment of prehypertension.

And as physicians at least we have to be more aware of instituting diet and exercise, and perhaps some alternative approaches to the management of prehypertension. A new avenue we should consider is the use of the nutraceutical products we discussed, if good studies show the product to be effective. As soon as patients become just mildly hypertensive, we have to be much more aggressive in our approach to treating their BP.

Finally, are you still a strong proponent of combination therapy for hypertension?

There is no question that combination therapy is the way to go. I think we are going to see some 3-drug combinations in a single tablet in the future. This reflects the realization that this is a disease that requires a multifactorial approach, and you have to simplify things for your patients as much as you can to enhance compliance and improve BP control.


1. Julius S, et al, for the Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006; 354:1685-1697.

2. Mizuno S, et al. Antihypertensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild hypertension. Br J Nutr. 2005; 94:84-91.

3. Aihara K, et al. Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension. J Am Coll Nutr. 2005; 24:257-265.

4. Mizushima S, et al. Randomized controlled trial of sour milk on blood pressure in border-line hypertensive men. Am J Hypertens. 2004; 17:701-706.

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