An Interview with Dr. John Laragh

Director of the Cardiovascular Center at the
New York Presbyterian Hospital-Cornell Medical Center and Weill Medical College and
Editor-in-Chief of the American Journal of Hypertension
By Paul J. Rosch, MD, F.A.C.P.

The first part of this interview referred to a recent survey finding that of the approximately 60 million Americans with hypertension, “30% were unaware of their illness, 42% were not being treated, and at the time that their BP was measured, 69% did not have their hypertension controlled!” Another reported that 97% of patients taking antihypertensive medications had suffered from significant side effects at some time 17% continued to do so, and Four out of five had serious concerns about side effects they had not been informed of or possible long term dangers. According to a September Reuters news release, “half of the people with high blood pressure who are at risk of a stroke are not identified, half who are identified are not treated, and half who are treated aren’t treated properly.” Many authorities believe that the reason for this is the government’s failure to recognize that there are two basic types of hypertension that vary in terms of prognosis and that require explicit corrective treatment with two very different classes of drugs.

The ALLHAT Trial – As Yogi Berra Said, It’s Déjà Vu All Over Again

The ALLHAT (Anti-hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) was a randomized double-blind controlled five-year study of over 42,000 hypertensives that began in 1994 at 623 centers in North America. Among other things, it was designed to determine whether the choice of first line treatment for hypertension influenced cardiovascular outcomes. This was assessed by comparing the thiazide diuretic hygroton with three other classes of antihypertensive drugs; an ACE inhibitor, calcium channel blocker and an alpha-adrenergic–receptor inhibitor (ARB). The preliminary findings were reported in the December 18, 2002 issue of the Journal of the American Medical Association. This was accompanied by a massive media blitz that resembled the premiere of a Hollywood production more than the presentation of a scientific report by a government agency. This began the day before at a carefully orchestrated and coordinated conference held at the National Press Club in Washington during which NHLBI Director Dr. Claude L’Enfant proudly proclaimed “ALLHAT shows that diuretics are the best choice to treat hypertension and reduce the risk of its complications, both medically and economically.” Cronies like Jeffrey Cutler also touted thiazide-like diuretics as being “unsurpassed in lowering blood pressure, reducing clinical events, and tolerability” and kept reemphasizing that thiazides “should be considered first for pharmacologic therapy in patients with hypertension.” The ALLHAT report would be appearing as a “JAMA express” contribution that is reserved for submissions with major health implications. To expedite publication, the peer-review process time is cut to 24-48 hours and the time for all authors to respond with any changes is 72 hours. It seems doubtful that the findings of both the blood pressure and lipid papers could have been thoroughly reviewed in the time allotted and almost inconceivable that all of the close to 60 authors involved would have been able to respond within 72 hrs, so some corners must have been cut.

PJR:The editorial you and Jean wrote was highly critical of the ALLHAT design and conclusions and other hypertension experts also objected to this as well as how the findings had been promoted to physicians and the public. However, nobody seems to have challenged the allegations that thiazides would save billions because they are more or just as effective and much cheaper than other antihypertensive drugs. I doubt that either of these allegations are true.

JHL: Despite the design of ALLHAT that favored thiazide diuretics, they couldn’t demonstrate with their data that hygroton was better than any of the other drugs in the study. This was because it was impossible to draw conclusions about first step therapy responses since the protocol made no provision for recording initial baseline blood pressures! The patients’ previous medications were never stopped until the switch day to the trial drug. With respect to saving billions, the low cost of hygroton is not germane because at the same time the government is advocating more and more multiple (2-4) drug regimens. But this claim too is doubtful when you think about how many patients on thiazide diuretics have to take potassium supplements. This is an additional expense, not to mention the antacids and/or other medications that are often required because of gastrointestinal side effects they cause. A very sizeable number of ALLHAT patients required potassium supplementation therapy and a very large proportion had dangerously low potassium levels in spite of that supplementation. Hygroton consistently produces losses of potassium and magnesium and many people do not realize that when there is significant potassium deficiency, cardioprotection is lost even when blood pressure is maintained at satisfactory low levels. We know from other large trials that hygroton causes low potassium ischemic electrocardiographic changes and is also impressively associated with new onset diabetes. In ALLHAT, there was an 11.6% incidence of new diabetes for every 4 years of hygroton so one might anticipate even a more alarming increase in diabetes in patients taking thiazides for ten or twenty years. Spirolactone, which has come off patent, is also quite inexpensive. In addition to being safer, spirolactone is as effective as thiazide or loop diuretics in lowering elevated blood pressure and does not cause potassium and magnesium loss or induce diabetes. The RALES (Randomized Aldactone Evaluation Study), found that in heart failure patients who were already being treated with thiazides, also blocking aldosterone by adding spirolactone produced such dramatic reductions in heart failure symptoms and mortality rates that the trial had to be stopped prematurely. There is also good evidence from numerous studies that thiazide diuretics can increase risk of cardiovascular and renal complications, all of which can dramatically increase the costs of long term thiazide therapy.³

Diabetes, Kidney Disease And Other Complications of Thiazides

PJR:I would like to discuss another important point that needs to be reemphasized. Basing conclusions on a study lasting a few years does not allow you to consider long term effects in patients doomed to take a drug for the rest of their life, which could be another few decades. As you suggest, it is possible that over half of patients who take thiazides for 20 years may develop diabetes, which poses a large risk for heart attack of the same magnitude as having primary coronary artery disease. An editorial in the August Journal of The Royal Society of Medicine entitled “Type 2 Diabetes is Cardiovascular Disease” noted,

“The day of ‘wait and see’ is past, and the term mild diabetes should be buried forever. Gaining ground is the idea that diabetes mellitus (especially type 2 diabetes) is a ‘state of accelerated cardiovascular disease that just happens to be associated with hyperglycemia’. People with type 2 diabetes are between two and six times more likely than those without diabetes to have cardiovascular disease and are more than twice as likely to die from it. Among diabetologists there is a widely held belief that cardiovascular risk reduction should take precedence over reduction of blood glucose.”

This is consistent with your contention that the primary goal of hypertension therapy should be to prevent its renin mediated vasculotoxic complications rather than simply trying to lower an elevated blood pressure regardless of how many medications are required.
It is also estimated that one third of patients with diabetes will eventually develop chronic kidney failure requiring dialysis or a kidney transplant. In addition to diabetes, diuretics can cause acute interstitial nephritis and their overuse is the most common cause of dehydration in patients with diabetic nephropathy. Since diuretics are contraindicated in chronic renal failure they could really wreak havoc in hypertensive diabetics who would continue to take them under the latest guidelines. JNC-VII makes no mention of the significantly increased incidence of new diabetes in ALLHAT compared to those started on an ACE inhibitor or calcium antagonist. Isn’t it totally irresponsible and inexcusable for JNC-VII not to warn about this potential problem?

JHL: Definitely. Thiazide induced diabetes is a permanent consequence of this class of drugs that should be emphasized rather than swept under the carpet as NHLBI has done. The same applies to administering thiazides to patients with impaired renal function, which has also been glossed over. It is important to correct hypertension in patients with diabetic nephropathy, but unlike thiazides, the antirenin drugs (ACE inhibitors, ARB’s and beta blockers) have been shown to have salutary effects on proteinuria that cannot be achieved with other antihypertensives like thiazides and calcium channel blockers. Thus, the angiotensin II receptor blockers losartan and irbesartan were recently approved for the treatment of diabetic nephropathy in hypertensives with type 2 diabetes. One of the earliest signs of diabetic nephropathy is albuminuria, which becomes greater as the disorder progresses. Screening for microalbuminuria is essential for all patients with diabetes since aggressive intervention can delay and possibly arrest the progression of symptomatic diabetic nephropathy. This is an example of the intermediate endpoints of subclinical organ damage such as microscopic albuminuria the Europeans wisely included as a tool for the assessment of long-term therapeutic benefits of antihypertensive drugs.
A number of clinical studies have clearly demonstrated that blockade of the renin-angiotensin system by an ACE inhibitor or an ARB not only reduces albuminuria but retards the progressive loss in renal function and improves survival. ACE inhibitors reduce albumin excretion in both normotensive and hypertensive patients with type 1 or type 2 diabetes and losartan, another ARB has now also been shown to reduce albuminuria in type 2 diabetes. Yet, JNC VII does not consider diabetes or impaired kidney function to be a contraindication to thiazide therapy and does not mention the potential benefits of ACE inhibitors or ARB’s in this regard. This is another reason why hypertensive patients must be treated on an individual basis rather than assuming they are a homogeneous group for whom no antihypertensive drug selectivity is relevant, as ALLHAT and JNC-VII routinely have continued to do.

PJR:An illustration of how well the JNC propaganda has been promoted and the potential for diabetes has been ignored can be found in the August 30 issue of the British Medical Journal, which emphasizes that, “Current evidence clearly supports using diuretics as first line treatment for hypertension in most patients, including those with diabetes” and cites JNC-VII as a reference. The JNC-VII media blitz made its debut at a special session of the American Society of Hypertension annual meeting in New York on May 14 along with an NHLBI Press Conference held in Washington with much fanfare and the premature publication of the JNC “Express Report” on the Journal of The American Medical Association web site – all on the same day. As with ALLHAT, officials made a point of reiterating that using diuretics as the first choice would save Americans billions of dollars since the newer drugs were much more expensive without being any more effective or safer. What they conveniently failed to mention was that it was not simply a case of either taking a diuretic or some other drug. So, while the public perception was that the government was saving them money by rejecting expensive drugs that offered no advantages, this was far from the truth. Pharmaceutical companies were far from upset by what most people assumed would augur a sharp decline in sales of their antihypertensive drugs. A Novartis spokesperson lavishly praised the report in a prepared press release the very same day noting that “Inadequate control of blood pressure has become a public health crisis. We are encouraged that new approaches recommended by JNC-VII will provide impetus for improvement.” That’s hardly surprising. Novartis, with its U.S. sales of $21 billion/year has all the hypertension treatment bases covered. They manufacture Diovan, a leading angiotensin receptor blocker Lopressor, a beta blocker, Lotensin, an ACE inhibitor, Lotrel, a combination ACE inhibitor and calcium channel blocking agent as well as products combining most of all the above with a thiazide diuretic to cover all contingencies. Other drug companies also have their own thiazide concoctions. As with ALLHAT, you and many other hypertension experts disputed this as well as other JNC-VII recommendations. For example, 6 months ago if you were to ask anyone, including physicians, what a normal or good blood pressure should be, the most likely response would be 120/80. According to JNC-VII, anyone with a blood pressure of 120/80 will now be labeled as “prehypertensive” and presumably requires treatment, which also provides a picnic for the drug companies. In contrast, the European Society of Hypertension and European Society of Cardiology guidelines published a few months later completely rejected this and continues to consider 120/80 as “optimal” blood pressure. Giuseppe Mancia, the Chair of the ESH/ESC Guidelines Committee, who disapproved of the term “prehypertensive,” asked “Would we, for example, call a healthy subject ‘prediseased’? It is difficult to tell a patient, ‘You are prehypertensive, but don’t do anything about it.’ Of course the patient is going to think that something is wrong and that he should see the doctor more frequently. He is going to go around asking for medical exams more frequently and he may want to have drugs anyway.” Do you agree with this?

JHL: Absolutely. I couldn’t say it any better. Nobody knows if this JNC-VII category of prehypertension really exists since there is no proof that it is predictive of anything. As a result, the only thing this new capricious classification accomplishes is to create 45 million more patients by instilling fear. The latest European guidelines also reject thiazides as the first and always drug to treat hypertension. As Professor Mancia noted, “We should not forget that guidelines deal with the disease and physicians deal with individual patients, and these can be quite different situations.” Thus, the European guidelines delineate the major indications for which a benefit has been demonstrated in clinical trials and then allows the treating physician to make a choice from a large number of diuretics, beta-blockers, calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers that appear to be most appropriate based on the presence of different risk factors. The guidelines also recognize that the results of therapeutic trials lasting four to six years may have limited value since the life expectancy for middle-aged hypertensive patients is more likely to be 20 to 30 years when other side effects may surface or efficacy may wane. As a result, they have included intermediate endpoints, to detect sub-clinical organ damage such as albuminuria, as tools for the assessment of long-term therapeutic benefits and differences between benefits of various drug classes. This is quite consistent with our contention that the primary goal in treating all hypertension is not to correct the blood pressure levels per se, but rather to avoid the future occurrence of MI, stroke, renal failure, or heart failure that shorten productive life. The only drugs proven to protect against these complications are the three anti-renin system drug classes, i.e. ACE inhibitors, angiotensin receptor blockers (ARBs), and the beta-blockers. All of these agents lower or block renin activity to lower blood pressure while providing measurable and prompt protection from such vasculotoxic effects as heart attack, stroke, heart failure and kidney failure. In the LIFE study, losartan, an angiotensin receptor blocker, when combined with a diuretic, was 25% more effective in preventing stroke compared to a beta-blocker combined with a diuretic, which was the winning combination in ALLHAT. JNC-VII also conveniently but reprehensibly ignored this study even though losartan was recently approved for the prevention of stroke. Some of the main differences between their conception of treating hypertension and ours include:

Our approach is based on decades of scientific research designed to delineate the various positive and negative influences on the renin-angiotensin-aldostersone system as illustrated in the following diagram taken from the cover of my book¹:

Our conclusions based on this may be summarized as follows:

 Our research has concentrated on the roles of renin, angiotensin and aldosterone but the cornerstone for understanding salt-volume hypertension was the demonstration of desoxycorticosterone – salt induced hypertension in rats by your close friend and mentor, Hans Selye. Since telling you about Selye’s research would be like bringing coals to Newcastle, let’s switch positions so I can ask you a few questions.

The Stress – Hypertension Connection And Conundrum

JHL:What do you think Selye’s take on all this might be were he alive today with respect to hypertension and its complications as an example of one of his “Diseases of Adaptation” due to stress?

PJR: I was hoping we might get around to this. Let me start by saying that Selye was very familiar with your hypothesis and devoted a half page to reproducing one of your diagrams showing the synergism of the angiotensin II vasoconstrictor and sodium-volume components in sustaining blood pressure in his massive tome, Stress in Health and Disease, published in 1976. He also cited several studies showing increases in renin and angiotensin ll in stressful human situations such as surgical procedures or severe burns. Elevation of blood pressure following infusion of angiotensin ll in monkeys was much greater in animals that were under stress and in rats exposed to repeated electroshocks “the marked rises in plasma concentrations of renin and corticosterone coincided.” These elevations were not inhibited by hypophysectomy but were blocked by dexamethasone and propanolol and increased by phentolamine.
Selye concluded that stress-induced renin release was mediated via beta-adrenergic receptors and that corticoids could modify this response. Much of his discussion was devoted to evidence that the pressor effects of catecholamines and corticoids released during stress acted synergistically and that the hypertensive actions of mineralocorticoids were augmented by a high sodium diet. The therapeutic efficacy of propanolol and aldactone seemed to support his stress theory but he was puzzled by “occasional instances of hypertension where plasma renin was below normal” He believed that this “hyporenimic hypertension” might be due to increased production of some mineralocorticoid that decreases renin secretion. As you suggest, Selye was much more interested in demonstrating that heart attacks, nephrosclerosis and other vasculotoxic complications of hypertension were Diseases of Adaptation since they could be readily induced during his General Adaptation Syndrome response to stress.
Selye was undoubtedly the leading endocrinologist of his era and was responsible for classifying the several dozen steroid hormones secreted by the adrenal cortex into three main categories – glucorticoids, mineralocorticoids and testoids. Glucorticoids like cortisone raised blood sugar and had catabolic and anti-inflammatory effects. Mineralocorticoids like desoxycorticocosterone (DOC) caused sodium retention and had “prophlogistic” activities that promoted inflammation while testoids acted like weak androgens and had anabolic activities. Selye went to great lengths to demonstrate a teleological basis for this, as Cannon had done for his “fight or flight” responses. ACTH clearly stimulated the production of glucocorticoids and STH augmented mineralocorticoid activities either by increasing production or exaggerating these effects. This suggested that there were checks and balances between ACTH and STH in the pituitary and between glucocorticoids and mineralocorticoids in the adrenal. ACTH and glucocorticoids had strong anti-inflammatory effects whereas STH and mineralocorticoids stimulated inflammatory and proliferative connective tissue responses in his animal studies.
Administration of cortisone to patients with rheumatoid arthritis dramatically reduced painful inflammation and when DOC was used to treat patients with adrenal insufficiency there were reports of focal areas of necrosis in the heart and skeletal muscle, evidence of periarteritis nodosa, nephrosclerosis, and even the development of incapacitating arthritis as had been seen in experimental animals. The tendency to develop hypertension even with very small doses of DOC was also a frequent problem encountered during the treatment of adrenal insufficiency. This supported Selye’s theories but DOC is not manufactured in any appreciable amount in humans. When aldosterone, the naturally occurring human mineralocorticoid, became available, attempts to demonstrate its ability to counter the anti-inflammatory effects of cortisone or produce the DOC changes observed in experimental animals were disappointing. It therefore seemed unlikely that aldosterone caused significant pathology in humans.

JHL:However, when aldosterone is present with increased renin-angiotensin levels it’s a different story. Recent studies do support Selye concepts since researchers have now confirmed that aldosterone can contribute to cardiovascular and renal pathology as well as to fibrosis and collagen formation by promoting sodium influx and potassium efflux and hypertrophy in vascular smooth muscle cells, generation of oxygen free radicals, stimulation of growth factors, the plasminogen activator system and via potentiating the pressor effects of angiotensin II.

PJR: Like angiotensin II, aldosterone stimulates inflammation, which many believe plays a more important role in the pathogenesis of coronary atherosclerosis than hyperlipidemia.

JHL:In that regard, I sent you a recent article by a respected cardiologist who suggested that “statin therapy should be routinely considered, even in those hypertensive patients whose cholesterol levels are apparently normal.” You have written a great deal about statins and I wanted your opinion.

PJR: Statins have also been recommended for all diabetics, regardless of lipid levels, and are allegedly effective for reducing everything from Alzheimer’s disease and atrial fibrillation to emotional stress. Statins may be effective medications but it is increasingly clear that their cardioprotective and other benefits are really due to their anti-inflammatory activities rather than lowering lipids. Therefore, the statin therapy goal of lowering LDL to an arbitrary level that is usually difficult to achieve is not only inappropriate but also dangerous. This can only lead to higher doses and longer duration of therapy, both of which are associated with increased side effects, which are much more common and diverse than generally recognized. C-reactive protein (CRP), a marker of inflammation has been shown to be superior to LDL levels for predicting coronary events and could be a more effective and certainly safer way to monitor statin therapy. In addition, I would remind you that the lipid reduction arm of the ALLHAT study showed absolutely no reduction in mortality from statins.

JHL:There is also increased interest in the possible role of inflammation in the pathogenesis of essential hypertension. I recognize there are conflicting opinions but do any of these research studies tend to support Selye’s contentions about the contribution of stress?

PJR: Yes and perhaps some comments about aldosterone and the plasminogen activator system (PAS) will illustrate the complex contributions of stress to hypertension and its complications. The plasminogen activator system is best known for its ability to dissolve clots but it also plays other important roles in blood vessel wall and tissue activities that are pertinent. It is inhibited by PAI-1, which has been shown to contribute directly to hypertension and perivascular fibrosis in a variety of different animal models. In humans, PAI-1 is increased in acute MI, disseminated intravascular coagulation and glomerulonephritis so perhaps it can contribute to these as well.
Aldosterone drives PAI-1 into the plasma and aldosterone concentrations correlate with PAI-1levels in hypertensive patients. Although hydrochlorothiazide shrinks intravascular volume the associated activation of the renin-angiotensin-aldosterone system increases plasma PAI-1 by 50% to 80% after a month depending on dosage. This could contribute to some of the adverse effects noted with long term thiazide therapy. Spirolactone obliterates aldosterone and PAI-1 relationships in hypertensives under basal conditions as well as on diuretics, which supports your observation about its superiority over thiazides.
The PAI-1 gene is “up regulated” or activated by mental stress. PAI-I is one of the most highly induced stress proteins and the magnitude of stress induced PAI-I increases with abdominal obesity. This suggests that visceral fat is its primary source, as it is for other inflammatory cytokines that contribute to the metabolic syndrome that includes hypertension and diabetes. A very recent study showing that visceral adiposity increases hypertension risk independent of insulin levels suggests that PAI-I activation plays a key role. Both animal and human studies confirm that stress promotes the development of visceral fat via increased cortisol secretion. Abdominal fat, hypertension and diabetes disappear in Cushing’s disease when the condition is corrected and high cortisol levels return to normal. I could go on in greater detail about this but am afraid that we have strayed quite a bit from our original objective, which was to highlight the fallacies of the ALLHAT study and the dangers of implementing its recommendations for treating hypertension as JNC-VII now advocates. I think we have accomplished that mission and perhaps we should close on what you see for the future of renin and its role in hypertension and cardiovascular disease.

Does Renin Cause Cardiovascular & Kidney Disease In Non-hypertensive Patients ?

PJR:As Hans Selye was fond of reminding me, theories are not important, only facts are. Some theories are meritorious for their heuristic value, in that they encourage others to discover new facts that lead to improved theories. In that regard, the existing facts confirm your hypothesis about the role of renin in essential hypertension. Studies now show that antirenin drugs are effective in treating or preventing cardiovascular and kidney disease not only in hypertensive patients but others with normal blood pressure. Doesn’t this imply a much larger role for renin in these disorders than is currently recognized?

JHL: You are absolutely correct. The antirenin R drugs (ACE inhibitors, ARB’s and beta blockers) have been shown to have salutary effects on the proteinuria due to kidney disease that are not achieved with other antihypertensives like thiazides and calcium channel blockers. Thus, the angiotensin II receptor blockers losartan and irbesartan were recently approved for the treatment of diabetic nephropathy in hypertensives with type 2 diabetes. As you pointed out, ACE inhibitors reduce albumin excretion in both normotensive and hypertensive patients with type 1 or type 2 diabetes and angiotensin II receptor blockers have also been shown to reduce albuminuria in type 2 diabetes. A recently published double-blind, randomized crossover trial reported that adding the ARB candesartan to treatment with maximal recommended doses of ACE inhibitors provided superior renoprotection in diabetic nephropathy that was completely independent of blood pressure changes. Candesartan has also been shown to reduce cardiovascular mortality and hospital admissions for congestive heart failure in a broad spectrum of patients already receiving “best treatment” with other drugs. The EUROPA study just reported that the ACE inhibitor perindopril reduced the risk of myocardial infarction and death in patients with stable coronary artery disease, including those with a history of a past myocardial infarction and angina so significantly that it should be considered for chronic therapy in all patients with coronary disease. Perindopril has also been suggested to prevent stroke recurrence in normotensive patients. It seems quite possible that we have only scratched the surface with respect to the role of renin in the pathophysiology of vasculotoxic events in normotensive patients at increased risk from diabetes, cardiovascular or renal disease. Gaining insight into what induces overactivity of the renin-angiotensin-aldosterone cascade in all these events could be the key to learning how to prevent or treat essential hypertension. Meanwhile, recognition of the renin factor in patients with (R) hypertension and early use of antirenin R drugs could extend useful life for millions by preventing or delaying fatal heart attack, stroke, or heart and kidney failure.

PJR: A recent study showed enhanced adrenocortical responses to stress as measured by salivary cortisol levels in hypertension prone men and women compared to controls. Increased aldosterone secretion during stress has also been reported. In addition, emotional stress increases levels of homocysteine, which has been shown to be a significant risk factor for heart attacks and accelerated atherosclerosis and possibly hypertension. My guess is that the primary stimulus for renin angiotensin aldosterone activation will be found to originate in the brain and possibly the cerebral cortex. If this proves true, stress could play a crucial role in hypertension, as Hans Selye always alleged.

1. Laragh, JH (2002): Laragh’s Lessons in Renin System Pathophysiology for Treating Hypertension and its Fatal Cardiovascular Consequences. Elsevier Science Inc., New York, NY (To order, 1-800-545-2522; www.us.elsevierhealth.com, www.amazon.com, or www.barnesandnoble.com)
2. Laragh JH, Sealey JE. Relevance of the plasma renin hormonal control system that regulates blood pressure and sodium balance for treating hypertension and for evaluating ALLHAT. 2003; American Journal of Hypertension, 16:407-415.
3. Laragh JH, Sealey JE. K+ depletion and the progression of hypertensive disease or heart failure. The pathogenic role of diuretic induced aldosterone secretion. 2001; Hypertension, 47 [part 2]:806-810.

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