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Metabolic changes with antihypertensive therapy of the salt-sensitive patient
MetabolicChangeswith AntihypertensiveTherapy of the Salt-SensitivePatient 0. BRYAN HOLLAND,
MD, and PETER E. POOL, MD
Recent evidence suggests that metabolic changes that occur with antihypertensive agents may infiuence cardiovascular risk. Diuretic therapy is particularly appropriate for the salt-sensitive hypertensive patient. However, diuretic-induced electrolyte abnormalities may lead to ventricular arrhythmias, even in patients with uncom~ikated essential hypertension. Antihypertensive drugs may change circulating lipoprotein levels, which may infiuence the development of atheroecieroeis. Therefore, serum cholesteroi and triglyceride ieveis should be monitored when antihypettensive drugs are administered that can cause hyperiipidemia. Weight reduction and diet therapy should be used because these may have a greater effect on reducing hyperiipidemia,
though choke of antihypertensive agents is important. in addition, glucose toierance may women wtth thiazide therapy, perhaps because newer evidence suggesk that insulin resistance is common in essential hypertension. This glucose intoierance may be corrected with potassium repletion or substitution of bumetanide for thiazide. The calcium antagonists may be substituted for diuretic therapy, or other classes of antihymensive drugs may be used with a reduced dose of diuretk drug if these metabolic changes persist. Thus, attention to metaboik changes may be as important as blood pressure reduction in treatment of the salt-sensitive hypertensive patient. (Am J Cardioi 1988;81:53H49H)
I
n recent years new evidence has suggested that metabolic changes resulting from antihypertensive drug therapy may be important as cardiovascular risk factors. In the salt-sensitive hypertensive patient, these metabolic changes largely pertain to diuretic-induced electrolyte abnormalities and hyperlipidemia and glucose intolerance occurring with a variety of antihypertensive agents. The Multiple Risk Factor Intervention Trial (MRFIT),l more than any other recent study, changed the attitude that blood pressure reduction is the only goal of antihypertensive therapy. In this study, the group of patients [special intervention group) who had an active treatment program to decrease cardiovascular risk had more reduction in serum cholesterol levels, better blood pressure control, and a greater reduction in smoking than did the control group. However, despite the favorable changes in these 3 risk factors for coronary artery disease, this group of patients
did not have a significant reduction in the incidence of myocardial infarction during this study, and indeed patients who had electrocardiographic (ECG) abnormalities at the time of entry into the study had a greater incidence of death from myocardial infarction. Thus, the investigators concluded that there appeared to be something about the antihypertensive therapy used in this study that acted to increase cardiovascular risk. Treatment of the special intervention patients was characterized by the use of higher dosages of diuretic drugs and less correction of hypokalemia. Thus, diuretic therapy has received the greatest blame for the failure to see a reduction in deaths due to myocardial infarction in the MRFIT study.
Diuretic-InducedVentricularArrhythmias It is reasonable to consider diuretic therapy for the salt-sensitive hypertensive patient because of its consistent effect in reducing blood pressure. Thus, it is of interest to review several metabolic abnormalities that can occur with diuretic therapy. The excess mortality among patients exhibiting ECG abnormalities at enrollment in the MRFIT study was attributable to an increase in sudden death during the first few years of the Y-year study.z At the time that the MRFIT study
From the Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, and the North County Cardiology Research Laboratory, Encinitas, California. Address for reprints: 0. Bryan Holland, MD, 4.174 OJSH, E 68, University of Texas Medical Branch, Galveston, Texas 77550.
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A SYMPOSIUM: THE SALT-SENSITIVE HYPERTENSIVE PATIENT
Baseline IVEA 0;1
Hydrochlorothiazide
1 K+ Repletion FIGURE 1. Development of ventricular ectoplc actlvlty (VEA) in 7 of 21 patlents wlth uncomplicated essential hypertenslon and normal basellne 24hour ambulatory monltorlng treated wlth hydrochlorothlarlde (50 mg twice a day) and the subsequent therapeutic response to potassium (K+) repletlon wlth splronolactone. The level of plasma potasslum noted at the time of ambulatory monltorlng durlng hydrochlorothlazlde treatment Is Indlcated. The grades of ventricular ectoplc actlvlty attained and the number of hours of that grade durlng 24-hour ambulatory monltorlng Is deplcted. VPB = ventricular premature beats. (Reprlnted wlth permlsslon from Am J Med.“)
#6
II = >30 Unifocal VPBlhr. or >l VPBlmin. VEA GRADE I = 530 Unifocal VPBlhr. IVA = Couplets IVB =Ventricular Tachycardia BG = Bigeminy Ill = Multifocal *Hr./24 hr. of VEA of that grade
was done, it was commonly believed that diureticinduced hypokalemia had few adverse cardiovascular effects in patients with uncomplicated hypertension.3 However, several studies have indicated that diureticinduced hypokalemia, even in patients without clinically evident underlying cardiac disease, may cause ventricular arrhythmias. In 1 of the studies,4 21 patients with histories of diuretic-induced hypokalemia underwent ambulatory ECG monitoring during an initial placebo phase to document that they had normal ambulatory ECG monitoring. They were then treated with 100 mg/day of hydrochlorothiazide for 4 weeks, at which time the ambulatory ECG monitoring was repeated. One-third of these patients had an increase in ventricular ectopic activity with hydrochlorothiazide treatment, and these ventricular arrhythmias were largely reversed by adding spironolactone to the hydrochlorothiazide to induce potassium repletion [Fig. 1). This study has been criticized in that the results might have been explained by spontaneous variation in the ambulatory ECG monitoring pattern. However, patients had ventricular ectopic activity significantly more often during the hypokalemic than during the normokalemic period.4 To obtain better evidence that ventricular ectopic activity occurring with diuretic-induced hypokalemia is not explained by spontaneous variation during the ambulatory ECG monitoring, another study5 of 21 patients was performed in which at least z ambulatory ECG monitorings were done in each treatment phase, and a control group was used that received diuretic treatment with a combination of hydrochlorothiazide and amiloride to determine the effects of normokalemic diuretic therapy on the genesis of ventricular ectopic activity. In this study, those patients in whom hypokalemia developed during treatment with hydrochlorothiazide alone had a significant increase in ventricular ectopic activity, and more ominous ventricular ectopic activity such as ventricular tachycardia was again observed. In addition, 1 patient died and autopsy findings were compatible with sudden death due to
ventricular arrhythmia. In contrast, patients who remained normokalemic with hydrochlorothiazide/ amiloride therapy did not have a significant increase in ventricular ectopic activity. In hydrochlorothiazidetreated patients in whom ventricular ectopic activity developed, subsequent potassium repletion with amiloride and potassium chloride resulted in a significant reduction in ventricular ectopic activity. Thus, the results of both of these studies suggest that ventricular ectopic activity can be induced with diuretic-induced hypokalemia, even in patients without evident underlying cardiac disease. Other studie#-* have also confirmed this finding. The large Medical Research Council trial8 deserves particular comment because this large trial has been interpreted as evidence both for and against ventricular ectopic activity with diuretic therapy. In this study, a clear increase in ventricular ectopic activity was noted in a select group of patients who became hypokalemic with diuretic therapy, whereas diuretic therapy in general (with most patients normokalemic) was not as clearly a predisposing factor for the genesis of ventricular ectopic activity. The investigators concluded that long-term diuretic therapy was associated with an increased incidence of ventricular arrhythmias, but that potassium depletion could not satisfactorily explain the genesis of the arrhythmias. However, several limitations of. this study9 appear to preclude this conclusion. Recent studies in both humans’O and experimental animals11-13 suggest that electrolyte changes associated with diuretic therapy cause ventricular ectopic activity, and the concomitant administration of a potassium-sparing diuretic, which also spares magnesium, has a significant beneficial effect in reducing this ventricular ectopic activity. The major electrolyte disturbance responsible for ventricular ectopic activity appears to be potassium depletion, though magnesium depletion14 or other electrolyte changes may also be important. Some investigators have speculated that catecholamine stimulation resulting from diuretic therapy might predispose patients to having ventricu-
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lar ectopic activity, but this did not appear to be the mechanism in 1 study in which plasma catecholamine levels were determined.lO The minimal occurrence of ventricular ectopic activity in normokalemic diuretictreated patients 5~8also suggests the etiologic role of electrolyte disturbances. Thus, electrolyte abnormalities should be avoided during long-term diuretic therapy. Other studies15J6have failed to find an increase in ventricular ectopic activity with diuretic-induced hypokalemia. However, all of these studies have included patients in the baseline placebo phase who have ventricular ectopic activity. These types of patients have been shown to have greater spontaneous variation during ambulatory ECG monitoring,17 and thus it becomes more difficult to distinguish ventricular ectopic activity resulting from diuretic therapy from ventricular ectopic activity resulting from other factors. This factor makes it more difficult to evaluate the contribution of diuretic-induced hypokalemia alone as a factor leading to ventricular ectopic activity, so it is not surprising that these studies have not been able to demonstrate statistically significant increases in ventricular ectopic activity. In 1 of these studies by Madias et alI6 in which the results of ambulatory ECG monitoring have been reported in sufficient detail so that changes in each patient could be evaluated, it appears that several of the patients [Nos. 8, 13, 15 and 17 in Table 3 by Madias et al) may have had an increase in ventricular ectopic activity with diuretic-induced hypokalemia. Thus, almost all evidence suggeststhat diuretic-induced hypokalemia can be associated with ventricular ectopic activity. There are other logical reasons for maintaining normokalemia with chronic diuretic therapy? (1) Hypokalemia is a known factor predisposing to glucose intolerance; and (2) hypokalemia in association with a myocardial infarction greatly increases the chance of ventricular fibrillation developing.laJg This interaction of hypokalemia with myocardial infarction may have explained the inability of the MRFIT study to note a clear association of serum potassium levels with sudden death. Struthers et alI9 showed that minimal diuretic-induced hypokalemia can lead to a striking reduction in serum potassium levels, with epinephrine infusion sufficient to achieve circulating levels that would be present during the time of a myocardial infarction. Thus, the combination of this stress-related factor with minimal diuretic-induced hypokalemia may greatly decrease the patient’s ability to survive a myocardial infarction, and it may have explained the excess in mortality due to sudden death in the MRFIT study. Also, it is difficult to be certain that an individual hypertensive patient does not have underlying heart disease. Occult coronary disease is difficult to detect clinically, and studies of young soldiers dying in the Korean and Vietnam wars have indicated a significant incidence of occult coronary atherosclerosis even in these physically fit young menzoJ1 Furthermore, newer studies indicate that diastolic dysfunction is often associated with hypertensionz2 Therefore, cardiac dysfunction appears to occur often in hyperten-
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sive patients, so it may be unrealistic to think that these patients are protected against diuretic-induced ventricular ectopic activity because they have “normal” hearts.
Hyperlipidemia A second metabolic factor that may have adverse cardiovascular effects is the induction of hyperlipidemia with antihypertensive drug therapy.i3z24 Hypercholesterolemia is clearly established as a risk factor for atherosclerosis, and hypertension and hypercholesterolemia appear to have a synergistic effect in enhancing atherosclerosis. In the Lipid Research Clinics Coronary Primary Prevention Trialz5 a group of men with Type 2 hyperlipoproteinemia received a cholesterol-lowering diet plus either cholestyramine or placebo. Those receiving cholestyramine had a significantly lower incidence of nonfatal and fatal myocardial infarction over a treatment period that averaged 7.4 years, to the extent that a 1% reduction in serum cholesterol levels produced approximately a 2% reduction in myocardial infarction. Diuretic therapy with both thiazide and loop diuretics leads to consistent increases in serum cholesterol and triglyceride levels. These changes are most prominent within the first few months of diuretic therapy, but they may regress significantly with diuretic therapy lasting for several years2Q7 The increase in serum cholesterol levels may result from increases in low-density lipoprotein (LDL), very low density lipoprotein (VLDL) or highdensity lipoprotein (HDL) levels, or a combination23J4 Therefore, the atherogenic potential will depend on the change in the LDL/HDL ratio in a given patient. Similarly, because elevations in serum triglyceride levels are of somewhat less importance as a cardiovascular risk factor,28 the atherogenic effects of thiazide diuretics remain somewhat uncertain. However, it is clear that treatment of mild hypertension with diuretic drugs has, in general, not been associated with a significant reduction in myocardial infarction. Whether this simply reflects the fact that mild hypertension is not a particularly important risk factor for coronary artery disease or whether adverse metabolic effects of the diuretics cancel the beneficial effects of blood pressure reduction is unclear. Unfortunately, the thiazide diuretics do not appear to exhibit a dose-response relation in causing hyperlipidemia. Thus, hyperlipidemia has been reported with doses of hydrochlorothiazide as low as 12.5 mg/dayezg The /3blockers, other than those with intrinsic sympathomimetic activity, have been associated with an increase in serum triglyceride levels and a decrease in HDL cholesterol, with little change in total cholesterolz3J4 Though these changes may favor the development of atherosclerosis, other factors could counterbalance the adverse effect of the lipid changes. First, experimental studies in rabbits fed a high-cholesterol diet have shown that even though the ,6 blocker propranolol caused typical worsening in the serum lipid profile, the incidence of atherosclerotic lesions was reduced, and a reduction in aortic cholesterol levels and cholesterol esters was founds30 In addition, the
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A SYMPOSIUM:
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0 Not on Diuretics n On Diuretics 26 24 = ? E
n
22 20
620
By a-way ANOVA p (AM) <.OOl P (Diuretic) < ,001 P (Interaction) -c .05
n
l6-
a
&I iz s 0 6
149 777
;
12=
i! a .G
lo-
I 8 6 0”
r 305
16’
551 8*
312
r
6= 42. Gain 210
Gain 5-9
Little Change
332
1
LOSS 5-9
Weight Change (Ibs.) FIGURE 2. Relation of weight change to reduction In plasma cholesterol from baseline to 72 months In Special lnterventlon men recelvlng diuretics and those not recelvlng dluretlcs adjusted for basellne plasma cholesterol, dlastollc blood pressure, and cigarettes per day. Figures above bars represent sample sire. ANOVA = analysls of variance. (Reprlnted wlth permlsslon from Am J Med.*‘)
Medical Research Council trial of treatment of mild hypertension noted a reduction in myocardial infarction in nonsmoking patients treated with propranolol compared with those treated with placebo.31 Thus, there are several reasons for questioning whether the adverse serum lipid level changes produced by the ,B blockers have a significant atherogenic potential. Other antihypertensive agents may have lesser tendencies to cause hyperlipidemia. The calcium channel antagonists cause essentially no change in serum cholesterol and triglyceride levels,23v24,32-34 and they may be used successfully as monotherapy in hypertensive patients vyith low-renin levels.35 In these patients, other classes of antihypertensive agents often require the concomitant use of a diuretic to provide adequate blood pressure control, so their intrinsic effects on serum lipid profiles are modified by diuretic treatment. The angiotensin-converting enzyme (ACE] inhibitors do not cause hyperlipidemia, and a variety of sympatholytic agents (peripheral (~1antagonists, centrally acting (Yagonists, catecholamine depletors and combined cu/p blockers] may be associated with no change or a reduction in serum cholesterol and triglyceride levels.23e24 In addition, dietary and other nonpharmacologic therapy may have far more influence on changes in the lipid profile then the choice of antihypertensive agents. For example, Lasser et a1,27in an analysis of the MRFIT study, showed that changes in body weight during the study had far more effect on changes in plasma total and HDL cholesterol levels than did diuretic therapy, though diuretic therapy consistently reduced the effect of diet (Fig. 21.Thus, the
reasons antihypertensive agents lead to changes in lipid levels are poorly understood at this time, and studies have not been done that establish that lipid changes with antihypertensive agents will lead to adverse cardiovascular effects. Hyperlipidemia, per se, is not invariably associated with enhanced atherosclerosis. For example, familial lipoprotein lipase deficiency is associated with both elevated serum cholesterol and triglyceride levels but not with atherosclerosis28Accu mulation of larger forms of VLDL, which may be associated with decreased clearance of VLDL, will lead to an increase in serum triglyceride levels and a slight increase in total serum cholesterol levels because of the cholesterol content of VLDL. However, these larger forms of VLDL do not appear to be particularly atherogenic.28 Thus, until more is understood about the basic pathophysiology of atherosclerosis and until the atherogenic effects of antihypertensive agents have been better studied, it is premature to assume that hyperlipidemia with antihypertensive agents will invariably enhance the rate of atherosclerosis, but it would be prudent to consider this possibility in the choice of treatment. In summary, the following conclusions may be made about the problem of hyperlipidemia with antihypertensive therapy in the salt-sensitive hypertensive patient. 1. In overweight patients, weight reduction is probably more important than medication effects in determining the lipid profile, but a significant proportion of the effect of diet may be vitiated by a drug that adversely affects serum lipid levels.
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2. Serum cholesterol and triglyceride levels should be determined as part of the baseline evaluation of all hypertensive patients and monitored when drug therapy that could cause hyperlipidemia is administered. 3. For those hypertensive patients who have a significant increase in serum cholesterol and triglyceride levels with diuretic therapy, the calcium channel antagonists may be administered because these agents do not appear to cause hyperlipidemia, and they are frequently effective as monotherapy in these patients. Other classes of drugs can be administered if the blood pressure is not controlled satisfactorily.
GlucoseIntolerance Another metabolic complication with antihypertensive therapy of the salt-sensitive patient is glucose intolerance. Diuretic drugs are known to lead to glucose intolerance.36 This glucose intolerance can frequently be explained by the effects of potassium depletion to diminish the insulin response to a glucose stimulus. Using the hyperglycemic clamp technique in normal subjects, Helderman et a13’ noted that the diabetogenic effect of 100 mg/day of hydrochlorothiazide could be explained by the potassium depletion that was induced with hydrochlorothiazide. However, some evidence suggests that thiazide diuretic drugs may cause glucose intolerance by other effects that do not depend on potassium depletion. Diuretic drugs have been shown to cause an increase in renin and catecholamine release, and angiotensin has been demonstrated in vitro to enhance gluconeogenesis38 and glycogenolysis .3gSimilarly, norepinephrine may stimulate pancreatic (Y~receptors to suppress insulin release40and may also stimulate gluconeogenesis.38 As a reflection of concern about metabolic effects of diuretic drugs, hypertensive patients are now usually being treated with much smaller doses of diuretics than in the past, and this leads to less renin and catecholamine stimulation. One recent study41 noted that lowdose hydrochlorothiazide did not have any diabetogenie effect. In that study, glucose homeostasis was evaluated by determining changes in fasting blood sugar levels, hemoglobin A1c, serum insulin levels, hepatic glucose output, insulin sensitivity with the euglycemic clamp technique and monocyte insulin binding. None of these factors changed significantly in Type 2 diabetic patients as therapy was changed from placebo to hydrochlorothiazide therapy (25 mg/day). Another study has shown that low-dose diuretic therapy for 10 years did not have a diabetogenic effect.42Thus, glucose tolerance should be unusual with low-dose diuretic therapy in the salt-sensitive hypertensive patient. It appears that in persons in whom glucose intolerance develops with hydrochlorothiazide or furosemide, bumetanide can be administered as an alternative diuretic agent. This diuretic was noted to have little effect on the glucose transporter in comparison with furosemide and hydrochlorothiazide43and no effect on in vitro stimulation of pancreatic insulin, glucagon and somatostatin.44 If glucose intolerance persists with low-dose hydrochlorothiazide or bumetanide therapy, other classes of antihypertensive agents may be substituted for diuret-
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ic therapy or combined with a reduced dose of a diuretic drug. The calcium channel antagonists may substitute as monotherapy in these patients. However, questions have been raised about their influence on glucose tolerance because insulin release has been shown in vitro to be dependent on an increase in cytosolic calcium.45 In vivo studies have shown impairment, no change, and improvement in insulin release.33v46-50 Some studies suggest that glucose tolerance may improve secondary to effects on the liver or by other mechanisms that do not affect insulin secretion.4g During clinical use of the calcium channel antagonists for the treatment of hypertension, fasting blood sugar levels remain unchanged33 or increase so slightly3* that it would not appear to be of clinical significance. However, occasional hyperglycemia has been noted.51952 Thus, further study of this area would be helpful, though the calcium channel antagonists appear to be relatively free of adverse effects on glucose homeostasis. An additional class of drugs that may be helpful when glucose intolerance develops is the ACE inhibitors. These agents have no adverse effect on glucose tolerance, and they may actually improve glucose tolerance slightly. Dominguez et aP3 noted that patients with Type 2 diabetes and hypertension had a significant decrease in hemoglobin A1c levels as well as a lower glucose response to an oral glucose tolerance test after 1 month of captopril treatment. However, a significant weight loss, which may have contributed to the improvement in glucose tolerance, was noted during this same time. Similarly, Matthews et a154demonstrated that treatment of hypertensive noninsulin-dependent diabetics with captopril was not associated with changes in fasting blood sugar levels or overall response to a glucose tolerance test. However, there was a significant decrease in the 120-minute plasma glucose value after the oral glucose challenge in these patients. Helgeland et a155reported that enalapril led to a significant reduction in fasting blood glucose levels in a large group of nondiabetic hypertensive subjects There have been anecdotal reports of diabetic subjects requiring a dosage reduction in either an oral agent or insulin with the addition of an ACE inhibitor.56,57Furthermore, a recent study41in Type 2 diabetic patients noted a slight decrease in hemoglobin A1c levels during enalapril treatment, without adverse effects on glucose homeostasis as assessedby changes in serum insulin levels, hepatic glucose output, insulin sensitivity determined with the euglycemic clamp technique and monocyte insulin binding. The mechanism of any beneficial effect on glucose tolerance remains unclear. Some studies indicate that enhanced insulin responsiveness occurs, perhaps secondary to decreased kinin degradation.58 In addition, angiotensin production may increase gluconeogenesiG* and glycogenolysis.3g Thus, ACE inhibitors appear to improve slightly or not worsen glucose tolerance, so they can be administered if glucose intolerance is encountered with other antihypertensive agents. Their ability to have a synergistic effect in reducing the blood pressure in combination with a low-dose diuretic may further obviate problems with glucose intoIerance.5g
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PATIENT
Othei- classes of antihypertensive agents have little effect on glucose homeostasis, though occasional problems may be encountered. The centrally acting CYagonists, in general, do riot provoke glucose intolertince.60 However, because insulin release is inhibited by cyzreceptor stimulation, glucose intolerance has been noted to develop in some patients, presumably secondary to a direct peripheral effect of these drugs.40Alphal-receptor antagonists such as prazosin and the primary vasodilators such as hydralazine and minoxidil have no adverse effects on glucose homeostasis. However, they usually must be given in combination with other antihypertensive agents, And these other drtigs may lead to worsening of glucose tolerance. The ,8 blockers, particularly when they are used in combination with.diuretic therapy, may worsen glucose tolerance.61Thus, a number of factors must be considered in selecting antihypertensive therapy in the diabetic patient, in the hypertensive patient with a strong family history of diabetes, and in the patient in whom glucose intolerance develops with initial antihypertensive therapy. Glucose intolerance with antihypertensive agents may be explained, in part, by the recent demonstratiorP2 that itisulin resistance is a common abnormality in patients with essential hypertension. In this study, young normoglycemic hypertensive patients, age- and weight-matched with a group of normal subjects, were ndted to have impaired insulin sensitivity. Specifically, insulin-mediated nonoxidative glucose disposal was markedly impaired. This study has thus provided evidence that essential hypertension is often accompanied by insulin resistance. It is uriclear at this time if this is a primary abnormality or if it is secondary to some other metabolic abnormality characteristic of hypertension, such as a hyperadrenergic state. In the future, some initial assessment of insulin resistance may be helpful for the hypertensive patient in order to select chronic drug therapy that would be less likely to predispose toward the development of glucose intolerance and eventually lead to overt diabetes. In summary, control of blood pressure is no longer the only goal of antihypertensive therapy. A number of recent sttidies have suggested that metabolic complications of antihypertensiire therapy may cause adverse cardiovascular effects. These considerations may be particularly important in salt-sensitive hypertensive patients in whom diuretic and other antihyperterisive agents can cause electrolyte abnormalities, hyperlipidemia or glucose intolerance, or any combination of these conditions.
References 1. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial. Risk factor changes and mortality results. JAMA 1982;248:1465-1477, 2. Multiple Risk Factor Intervention Trial Research Group. Baseline rest electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J CardioI1985;55:1-15. 3. Gifford RW. A guide to the practical use of diuretics. JAMA 1976;235:18901983. 4. Holland OB. Nixon JV, Kuhnert L. Diuretic-induced ventricular ectopic activity. Am J Med 1981;70:762-768. 5. Holland OB, Kuhnert L, Pollard J, Anderson RJ, Blomqvist G. Ventricular
ectopic activity with diuretic-induced
hypokalemia (absir). Clin Res 1984;
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6. Hollifield JW, Slaton PE. Thiazide diuretics, hypokalemia and cardiac arrhythmias. Acto Med Stand 1981;suppI 647:67-73. 7. Caralis PV, Materson BR, Pefez-Stable E. Potassium and diuretic-induced ventricular arrhythmias in ambulatory hypertensive patients. Miner Electrolyte Metab 1984;!0:148-154. 6. Medical Research Council Working Party on Mild to Mod&ate Hypertension. Ventricular extrasystofes during thiazide treatment: substudy of MRC Mild Hypertension Trial. Br Med J 1983;287:1249-1253. 9. Holland OB. Potassium loss, ventricular irritability, and the risk of sudden death in hypertensive patients. Drugs 1986;31:suppl 4:78-84. 10. Stewart DE, Ikram H. Espiner EA, Nicholls MG. Arrhythomogenic potential of diuretic-induced hypokalemia in patients with mild hypertension and ischemic heart disease. Br Heart J 1985;54:290-297. 11. Rabkin SW, Roob 0. Effect of chronic diuretics on epinephrine-induced ventriculpr arrhythmias: a comparison of hydrochlorothiazide and hmiloride in the rat. J Cardiovasc Pharmacol 1986;10:238-245. 12. Winslow E, Marshall RJ, Hdpe FG. Effects of diet-induced hypokalemia on the antiarrhythmic and ejectrophysiological actions of prolonged oral treatment with either omiodaione or disopyromide in the anaesthetised rat. J Cardiovasc Pharmacol 1986;9:267-275. 13. Winslow E. Marshall RJ, Campbell JK, Muir AW. Effects of diet-induced hypokalemia on the efficacy of antiarrhythmic drugs against ventricular arrhythmias evoked by coronary artery ligation in the anoesthetised rat. J Cardiovasc Pharmacof 1986;9:257-266. 14. Dyckner T, Wester PO. Intracellular magnesium ,%ssafter diuretic administration. Drugs 1984;28:suppI1:161-166. 15. Papademetriou V, Prince M, Notargiacomo A, Gottdiener J, Fletcher RD. Freis ED. Effect of diuretic therapy on ventricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am J Cardiol 1985;110:595-599. 16. Madias JE, MadiaS NE, Gavras HP. Nonarrhythmogenicity of diureticinduced hypokalemia. Its evidence in patients with uncomplicated hypertbnsion. Arch Intern Med 1964;144:2171-2176. 17. Calvert A. Lown B, Gorlin R. Ventricular premaiure beats and anatomically defined corimory heart disease. Am J Cardiol 1977;39:627-633. 16. Holland OB. Mild hypokajemia in non-edematous non-digitalized Patients. The case for routinely normalizing serum potassium. Ih: Narins RG, ed. Controversies in Nephrology and Hypertension. New York: Churchill Livingstone, Inc. 1984:345-358. 19. Struthers AD, Whitesmith R. Reid JL. Prior thiazide diuretic treatment increases adrenaline-induced hypokalemio. Lancet 1984;1:1358-1361. 20. Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea: preliminary report. JAMA 1953:152:10901093.
21. McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary artery disease among combat casualties in Vietnam. JAMA 1971;216:1185-1187. 22. Dianzumba SB, DiPette DJ, Corhman C. Weber E, Joyner CR. Left ventriculor filling characteristics in mild untreated hypertension. Hypertension 1986:8:suppI 1:1-156-I-160. 23. Weidmann P, Uehlinger DE, Gerber A. Antihypertensive treatment and serum Iipoproteinb. J Hypertens 1985;3:297-306. 24. Weinberger M. Antihypertensive therapy and lipids. Arch Intern Med 1985;145:1102-1105. 25. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results: reduction in incidence of coronary heart disease. JAMA 1984:251:351-374. 26. Frohlich ED. Diuretics in hypertension. J Hypertens 1987;5:suppI3:S-43s-49. 27. Lasser NL. Grandits G, CaggIula AW, Cutler JA, Grimm RH Jr, Kuller LH, Sherwin RW, Stamler J. Effects ofantihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984;76:suppf2A:52-66. 26. Grundy SM. Hyperlipoproteinemia: metabolic basis and rationale for therapy. Am J Cardiol 1984:54:2OC-26C’. 29. McKenney JM, Goodman RP. Wright JT Jr, Rifai N. Aycock DG, King ME. The effects of low-dose hydrochlqrothiazide on blood pressure, serum potossium, and lipoproteins. Pharmacotherapy 1986;6:179-184. 30. Chobanian AV. Brecher P, Chan C. Effects of propranolol on atherogenesis in the cholesterol-fed rabbit. Circ Res 1985;56:755-762. 31. Medical Research Council Working Party. MRC trial of treatment of mild hypertension. Principal results. Br Med J 1985;291:97-104. 32. Pool PE, Seagren SC, Sale1 AF. Skalland ML. Effects of diltiazem on serum lipids. exercise performance and blood pressure: randomized, doubleblind, placebo-controlled evaluation for systemic hypertension. Am J Cardiol 1985:56:88H-91H. 33. Schulte KL, Meyer-Sabellek WA, Haertenberger A, Thiede HM, Roecker L, Distler A, Gotzen R. Antihypertensive and metabolic effects of diltiazem and nifedipine. Hypertension 1988;8:859-885. 34. Massie B, MacCarthy EP, Ramanathan KB, Weiss RJ, Anderson M, Eidelson BA, Labreche DG. Tubau JF, Ulep D, Bartels D. Diltiazem and propranolo1in mild to moderate essential hypertension as monotherapy or with hydrochlorothiazide. Ann Intern Med 1987;107:150-157, 35. Buhler FR. Kiowski W. Calcium antagonists in hypertension. J Hypertens
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1967;5(suppl 3]:S-3-s-10. 36. Murphy MB, Lewis PJ,Kohner E, Schumer B, Dollery CT. Glucose intolerance in hypertensive patients treated with diuretics; a fourteen year fallow up. Lancet 1962;2:1293-1295, 37. Helderman JH. Elahi D, Andersen DK, Raizes GS, Tobin JD, Shocken D, Andres R. Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes 1963;32:106-111. 38. Kneer NM, Lardv HA. Regulation of gluconeagenesis by norepinephrine. vasapressin, and angiotension II. A comparative-study in the ibse&e and nresence of extracellular Ca2+. Arch Biochem Bioohvs 1963:225:167-195. !i9. Dewitt iM, Putney JN Jr. Stimulotion of glycogenoiysis in hepatocytes by angiotensin 11 may involve both calcium release and calcium influx. FEBS 1983:X0:259-263. 40. DiTullio NW, Cieslinski L, Matthews WD, Storer 8. Mechanisms involved in the hvoerelvcemic resoonse induced bv clonidine and other alnha-2 adrenoreceit;; agonists. J’Phormacal Exp ?her 1964:226:166-173. ’ 41. Holland OB, Prince MJ, Padia M, Bandi 2, Stuart C. Beneficial effects of enalapril for treatment of-hypertensive diabetic patients. Program abstracts of the second annual meeting. American Society of Hypertension. New York:1967:A312. 42. Berglund G. Anderson 0, Widgren B. Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10 year contrajled trial with bendroflumethiazide. Acta Med Stand 1966;220:419-424. 43. ]acobs DB, Mookejee BK. Jung CY. Furasemide inhibits glucose transport in isolated rat adipocytes via direct inactivation of carier proteins. J Clin Invest 1964;74:1679-1665. 44. Hermansen K, Schmitz 0. Mogensen CE. Effects of a thiazide diuretic (hydroflumethiazide) and a loop diuretic (bumetonide) on the endocrine pancreas: studies in vitro. Metabolism 1965:34:764-769. 45. Wollheim CB, Kikuchi M, Renald’ AE. Sharp GWG. The roles of intracellular and extracellular Co++ in glucose-stimulated biphasic in&in release by rat islets. J Clin Invest 1976;62:%-456. 46. Shamaon H, Baylor P, Kambosos D, Charlap S. Plawes S, Fri.&man WH. Influence of oral verapamil on glucaregulatary hormones in man. J Clin Endocrinol Metab 1965;60:536-541. 47. Giunliano D, Torella R, Cacciapuoti F, Gentile S. Verza M, Varricchio M. Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol 1960:16:395-396. 48. Donnelly T. Harrower ADB. Effect of nifedipine on glucose tolerance and insulin secretion in diabetic and non-diabetic patients. Curr Med Res Opin
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1960;6:suppl !0:690-693. 49. Andersson DEH, Rojdmark S. Improvement of glucose tolerance by verapamil in patients with non-insulin-dependent diabetes mellitus. Acta Med Stand 1961;216:27-33. 50. Segrestaa JM. Caulia C, Dahan R. Houlbert D, Thiercelin JF, Herman P. Sauvapet JP. Larribaud J. Effect of diltiazem on plasma glucose, insulin and glucagon dqring ah oral glucose tolerance test in healthy volunteers. Eur J Cfin Pharmacol 1964;26:461-463. bl. Charles S. Ketleslegers JM, Buysschaert M, Lambert A. Hyper,glycoemic effeci af nifedipine. B; M&d J 1981;263:19-20. 52. Pershadsingh HA, Grant N. McDonald JM. Association of diltiazem therapy with increased insulin resistonce in a patient with type 1 diabetes mellitus. JAMA 1967;257:930-932. 53. Dominnuez IR. de la Calle H. Hurtado A. Robles RG, Sancho-Rof J. Effect of converting enzyme inhibitors in hypertensive patients with nonlin&ndependent diabetes mellitus. Postgrad Med J 1966;62:suppl 1:66-66. 54. Matthews DM, Wathen CG, Bell D, Collier A, Muir AL, Clarke BF. The effect of captopril on blood pressure and glucose tolerance in hypertensive non-insulin dependent diabetics. Postgrad Med J 1966;62:suppl I:73-75. 55. Helgeland A, Hagelund CH, Stromtner R. Tretli S. Enalapril, atenolol, and hydrochlorothiazide in mild to moderate hypertension. Lancet 1966;1:672675. 56. Ferrieri M, Lachkar H. Richard JL, Bringer J, Orsetti A, Mirouze J. Captoprif and insulin sensitivity. Ann Intern Med 1965;102:134-135, 57. McMurray J, Fraser DM. Captopril. enalapril, and blood glucose. Lancet 1966;1:1035. 58. Jauch KW. Hart1 W, Guenther B, Wicklmayr M, Rett K, Dietze G. Captoprii enhances insulin respansjveness of forearm muscle tissue in non-insulindependent diabetes mellitus. Eur I Clin Invest 1967:17:446-454. 59: Holland OB, Kuhnert LV, Campbell WB, Anderson RJ. Synergistic effect of captopril with hydrochlorothiazide for the treatment of low-renin hypertensive black patients. Hypertension 1963;5;235-239. 60. Struthers AD. The choice of antihypertensive therapy in the diabetic uatient. Pas&rod Med I 1965:61:563-569. 61. Dornhorz A, Poweli SH, Pensky J. Aggravation by propranolol of hyperglycaemic effect of hydrochlorothiazide in type II diabetics without alteration of insulin secretion. -Lancet 1965;1:123-126. 62. Ferrannini E, Buzzigali G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R. Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med 1967;6:350-379.
MD, and PETER E. POOL, MD
Recent evidence suggests that metabolic changes that occur with antihypertensive agents may infiuence cardiovascular risk. Diuretic therapy is particularly appropriate for the salt-sensitive hypertensive patient. However, diuretic-induced electrolyte abnormalities may lead to ventricular arrhythmias, even in patients with uncom~ikated essential hypertension. Antihypertensive drugs may change circulating lipoprotein levels, which may infiuence the development of atheroecieroeis. Therefore, serum cholesteroi and triglyceride ieveis should be monitored when antihypettensive drugs are administered that can cause hyperiipidemia. Weight reduction and diet therapy should be used because these may have a greater effect on reducing hyperiipidemia,
though choke of antihypertensive agents is important. in addition, glucose toierance may women wtth thiazide therapy, perhaps because newer evidence suggesk that insulin resistance is common in essential hypertension. This glucose intoierance may be corrected with potassium repletion or substitution of bumetanide for thiazide. The calcium antagonists may be substituted for diuretic therapy, or other classes of antihymensive drugs may be used with a reduced dose of diuretk drug if these metabolic changes persist. Thus, attention to metaboik changes may be as important as blood pressure reduction in treatment of the salt-sensitive hypertensive patient. (Am J Cardioi 1988;81:53H49H)
I
n recent years new evidence has suggested that metabolic changes resulting from antihypertensive drug therapy may be important as cardiovascular risk factors. In the salt-sensitive hypertensive patient, these metabolic changes largely pertain to diuretic-induced electrolyte abnormalities and hyperlipidemia and glucose intolerance occurring with a variety of antihypertensive agents. The Multiple Risk Factor Intervention Trial (MRFIT),l more than any other recent study, changed the attitude that blood pressure reduction is the only goal of antihypertensive therapy. In this study, the group of patients [special intervention group) who had an active treatment program to decrease cardiovascular risk had more reduction in serum cholesterol levels, better blood pressure control, and a greater reduction in smoking than did the control group. However, despite the favorable changes in these 3 risk factors for coronary artery disease, this group of patients
did not have a significant reduction in the incidence of myocardial infarction during this study, and indeed patients who had electrocardiographic (ECG) abnormalities at the time of entry into the study had a greater incidence of death from myocardial infarction. Thus, the investigators concluded that there appeared to be something about the antihypertensive therapy used in this study that acted to increase cardiovascular risk. Treatment of the special intervention patients was characterized by the use of higher dosages of diuretic drugs and less correction of hypokalemia. Thus, diuretic therapy has received the greatest blame for the failure to see a reduction in deaths due to myocardial infarction in the MRFIT study.
Diuretic-InducedVentricularArrhythmias It is reasonable to consider diuretic therapy for the salt-sensitive hypertensive patient because of its consistent effect in reducing blood pressure. Thus, it is of interest to review several metabolic abnormalities that can occur with diuretic therapy. The excess mortality among patients exhibiting ECG abnormalities at enrollment in the MRFIT study was attributable to an increase in sudden death during the first few years of the Y-year study.z At the time that the MRFIT study
From the Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, and the North County Cardiology Research Laboratory, Encinitas, California. Address for reprints: 0. Bryan Holland, MD, 4.174 OJSH, E 68, University of Texas Medical Branch, Galveston, Texas 77550.
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A SYMPOSIUM: THE SALT-SENSITIVE HYPERTENSIVE PATIENT
Baseline IVEA 0;1
Hydrochlorothiazide
1 K+ Repletion FIGURE 1. Development of ventricular ectoplc actlvlty (VEA) in 7 of 21 patlents wlth uncomplicated essential hypertenslon and normal basellne 24hour ambulatory monltorlng treated wlth hydrochlorothlarlde (50 mg twice a day) and the subsequent therapeutic response to potassium (K+) repletlon wlth splronolactone. The level of plasma potasslum noted at the time of ambulatory monltorlng durlng hydrochlorothlazlde treatment Is Indlcated. The grades of ventricular ectoplc actlvlty attained and the number of hours of that grade durlng 24-hour ambulatory monltorlng Is deplcted. VPB = ventricular premature beats. (Reprlnted wlth permlsslon from Am J Med.“)
#6
II = >30 Unifocal VPBlhr. or >l VPBlmin. VEA GRADE I = 530 Unifocal VPBlhr. IVA = Couplets IVB =Ventricular Tachycardia BG = Bigeminy Ill = Multifocal *Hr./24 hr. of VEA of that grade
was done, it was commonly believed that diureticinduced hypokalemia had few adverse cardiovascular effects in patients with uncomplicated hypertension.3 However, several studies have indicated that diureticinduced hypokalemia, even in patients without clinically evident underlying cardiac disease, may cause ventricular arrhythmias. In 1 of the studies,4 21 patients with histories of diuretic-induced hypokalemia underwent ambulatory ECG monitoring during an initial placebo phase to document that they had normal ambulatory ECG monitoring. They were then treated with 100 mg/day of hydrochlorothiazide for 4 weeks, at which time the ambulatory ECG monitoring was repeated. One-third of these patients had an increase in ventricular ectopic activity with hydrochlorothiazide treatment, and these ventricular arrhythmias were largely reversed by adding spironolactone to the hydrochlorothiazide to induce potassium repletion [Fig. 1). This study has been criticized in that the results might have been explained by spontaneous variation in the ambulatory ECG monitoring pattern. However, patients had ventricular ectopic activity significantly more often during the hypokalemic than during the normokalemic period.4 To obtain better evidence that ventricular ectopic activity occurring with diuretic-induced hypokalemia is not explained by spontaneous variation during the ambulatory ECG monitoring, another study5 of 21 patients was performed in which at least z ambulatory ECG monitorings were done in each treatment phase, and a control group was used that received diuretic treatment with a combination of hydrochlorothiazide and amiloride to determine the effects of normokalemic diuretic therapy on the genesis of ventricular ectopic activity. In this study, those patients in whom hypokalemia developed during treatment with hydrochlorothiazide alone had a significant increase in ventricular ectopic activity, and more ominous ventricular ectopic activity such as ventricular tachycardia was again observed. In addition, 1 patient died and autopsy findings were compatible with sudden death due to
ventricular arrhythmia. In contrast, patients who remained normokalemic with hydrochlorothiazide/ amiloride therapy did not have a significant increase in ventricular ectopic activity. In hydrochlorothiazidetreated patients in whom ventricular ectopic activity developed, subsequent potassium repletion with amiloride and potassium chloride resulted in a significant reduction in ventricular ectopic activity. Thus, the results of both of these studies suggest that ventricular ectopic activity can be induced with diuretic-induced hypokalemia, even in patients without evident underlying cardiac disease. Other studie#-* have also confirmed this finding. The large Medical Research Council trial8 deserves particular comment because this large trial has been interpreted as evidence both for and against ventricular ectopic activity with diuretic therapy. In this study, a clear increase in ventricular ectopic activity was noted in a select group of patients who became hypokalemic with diuretic therapy, whereas diuretic therapy in general (with most patients normokalemic) was not as clearly a predisposing factor for the genesis of ventricular ectopic activity. The investigators concluded that long-term diuretic therapy was associated with an increased incidence of ventricular arrhythmias, but that potassium depletion could not satisfactorily explain the genesis of the arrhythmias. However, several limitations of. this study9 appear to preclude this conclusion. Recent studies in both humans’O and experimental animals11-13 suggest that electrolyte changes associated with diuretic therapy cause ventricular ectopic activity, and the concomitant administration of a potassium-sparing diuretic, which also spares magnesium, has a significant beneficial effect in reducing this ventricular ectopic activity. The major electrolyte disturbance responsible for ventricular ectopic activity appears to be potassium depletion, though magnesium depletion14 or other electrolyte changes may also be important. Some investigators have speculated that catecholamine stimulation resulting from diuretic therapy might predispose patients to having ventricu-
June 15, 1988
lar ectopic activity, but this did not appear to be the mechanism in 1 study in which plasma catecholamine levels were determined.lO The minimal occurrence of ventricular ectopic activity in normokalemic diuretictreated patients 5~8also suggests the etiologic role of electrolyte disturbances. Thus, electrolyte abnormalities should be avoided during long-term diuretic therapy. Other studies15J6have failed to find an increase in ventricular ectopic activity with diuretic-induced hypokalemia. However, all of these studies have included patients in the baseline placebo phase who have ventricular ectopic activity. These types of patients have been shown to have greater spontaneous variation during ambulatory ECG monitoring,17 and thus it becomes more difficult to distinguish ventricular ectopic activity resulting from diuretic therapy from ventricular ectopic activity resulting from other factors. This factor makes it more difficult to evaluate the contribution of diuretic-induced hypokalemia alone as a factor leading to ventricular ectopic activity, so it is not surprising that these studies have not been able to demonstrate statistically significant increases in ventricular ectopic activity. In 1 of these studies by Madias et alI6 in which the results of ambulatory ECG monitoring have been reported in sufficient detail so that changes in each patient could be evaluated, it appears that several of the patients [Nos. 8, 13, 15 and 17 in Table 3 by Madias et al) may have had an increase in ventricular ectopic activity with diuretic-induced hypokalemia. Thus, almost all evidence suggeststhat diuretic-induced hypokalemia can be associated with ventricular ectopic activity. There are other logical reasons for maintaining normokalemia with chronic diuretic therapy? (1) Hypokalemia is a known factor predisposing to glucose intolerance; and (2) hypokalemia in association with a myocardial infarction greatly increases the chance of ventricular fibrillation developing.laJg This interaction of hypokalemia with myocardial infarction may have explained the inability of the MRFIT study to note a clear association of serum potassium levels with sudden death. Struthers et alI9 showed that minimal diuretic-induced hypokalemia can lead to a striking reduction in serum potassium levels, with epinephrine infusion sufficient to achieve circulating levels that would be present during the time of a myocardial infarction. Thus, the combination of this stress-related factor with minimal diuretic-induced hypokalemia may greatly decrease the patient’s ability to survive a myocardial infarction, and it may have explained the excess in mortality due to sudden death in the MRFIT study. Also, it is difficult to be certain that an individual hypertensive patient does not have underlying heart disease. Occult coronary disease is difficult to detect clinically, and studies of young soldiers dying in the Korean and Vietnam wars have indicated a significant incidence of occult coronary atherosclerosis even in these physically fit young menzoJ1 Furthermore, newer studies indicate that diastolic dysfunction is often associated with hypertensionz2 Therefore, cardiac dysfunction appears to occur often in hyperten-
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sive patients, so it may be unrealistic to think that these patients are protected against diuretic-induced ventricular ectopic activity because they have “normal” hearts.
Hyperlipidemia A second metabolic factor that may have adverse cardiovascular effects is the induction of hyperlipidemia with antihypertensive drug therapy.i3z24 Hypercholesterolemia is clearly established as a risk factor for atherosclerosis, and hypertension and hypercholesterolemia appear to have a synergistic effect in enhancing atherosclerosis. In the Lipid Research Clinics Coronary Primary Prevention Trialz5 a group of men with Type 2 hyperlipoproteinemia received a cholesterol-lowering diet plus either cholestyramine or placebo. Those receiving cholestyramine had a significantly lower incidence of nonfatal and fatal myocardial infarction over a treatment period that averaged 7.4 years, to the extent that a 1% reduction in serum cholesterol levels produced approximately a 2% reduction in myocardial infarction. Diuretic therapy with both thiazide and loop diuretics leads to consistent increases in serum cholesterol and triglyceride levels. These changes are most prominent within the first few months of diuretic therapy, but they may regress significantly with diuretic therapy lasting for several years2Q7 The increase in serum cholesterol levels may result from increases in low-density lipoprotein (LDL), very low density lipoprotein (VLDL) or highdensity lipoprotein (HDL) levels, or a combination23J4 Therefore, the atherogenic potential will depend on the change in the LDL/HDL ratio in a given patient. Similarly, because elevations in serum triglyceride levels are of somewhat less importance as a cardiovascular risk factor,28 the atherogenic effects of thiazide diuretics remain somewhat uncertain. However, it is clear that treatment of mild hypertension with diuretic drugs has, in general, not been associated with a significant reduction in myocardial infarction. Whether this simply reflects the fact that mild hypertension is not a particularly important risk factor for coronary artery disease or whether adverse metabolic effects of the diuretics cancel the beneficial effects of blood pressure reduction is unclear. Unfortunately, the thiazide diuretics do not appear to exhibit a dose-response relation in causing hyperlipidemia. Thus, hyperlipidemia has been reported with doses of hydrochlorothiazide as low as 12.5 mg/dayezg The /3blockers, other than those with intrinsic sympathomimetic activity, have been associated with an increase in serum triglyceride levels and a decrease in HDL cholesterol, with little change in total cholesterolz3J4 Though these changes may favor the development of atherosclerosis, other factors could counterbalance the adverse effect of the lipid changes. First, experimental studies in rabbits fed a high-cholesterol diet have shown that even though the ,6 blocker propranolol caused typical worsening in the serum lipid profile, the incidence of atherosclerotic lesions was reduced, and a reduction in aortic cholesterol levels and cholesterol esters was founds30 In addition, the
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A SYMPOSIUM:
THE SALT-SENSITIVE
HYPERTENSIVE
PATIENT
0 Not on Diuretics n On Diuretics 26 24 = ? E
n
22 20
620
By a-way ANOVA p (AM) <.OOl P (Diuretic) < ,001 P (Interaction) -c .05
n
l6-
a
&I iz s 0 6
149 777
;
12=
i! a .G
lo-
I 8 6 0”
r 305
16’
551 8*
312
r
6= 42. Gain 210
Gain 5-9
Little Change
332
1
LOSS 5-9
Weight Change (Ibs.) FIGURE 2. Relation of weight change to reduction In plasma cholesterol from baseline to 72 months In Special lnterventlon men recelvlng diuretics and those not recelvlng dluretlcs adjusted for basellne plasma cholesterol, dlastollc blood pressure, and cigarettes per day. Figures above bars represent sample sire. ANOVA = analysls of variance. (Reprlnted wlth permlsslon from Am J Med.*‘)
Medical Research Council trial of treatment of mild hypertension noted a reduction in myocardial infarction in nonsmoking patients treated with propranolol compared with those treated with placebo.31 Thus, there are several reasons for questioning whether the adverse serum lipid level changes produced by the ,B blockers have a significant atherogenic potential. Other antihypertensive agents may have lesser tendencies to cause hyperlipidemia. The calcium channel antagonists cause essentially no change in serum cholesterol and triglyceride levels,23v24,32-34 and they may be used successfully as monotherapy in hypertensive patients vyith low-renin levels.35 In these patients, other classes of antihypertensive agents often require the concomitant use of a diuretic to provide adequate blood pressure control, so their intrinsic effects on serum lipid profiles are modified by diuretic treatment. The angiotensin-converting enzyme (ACE] inhibitors do not cause hyperlipidemia, and a variety of sympatholytic agents (peripheral (~1antagonists, centrally acting (Yagonists, catecholamine depletors and combined cu/p blockers] may be associated with no change or a reduction in serum cholesterol and triglyceride levels.23e24 In addition, dietary and other nonpharmacologic therapy may have far more influence on changes in the lipid profile then the choice of antihypertensive agents. For example, Lasser et a1,27in an analysis of the MRFIT study, showed that changes in body weight during the study had far more effect on changes in plasma total and HDL cholesterol levels than did diuretic therapy, though diuretic therapy consistently reduced the effect of diet (Fig. 21.Thus, the
reasons antihypertensive agents lead to changes in lipid levels are poorly understood at this time, and studies have not been done that establish that lipid changes with antihypertensive agents will lead to adverse cardiovascular effects. Hyperlipidemia, per se, is not invariably associated with enhanced atherosclerosis. For example, familial lipoprotein lipase deficiency is associated with both elevated serum cholesterol and triglyceride levels but not with atherosclerosis28Accu mulation of larger forms of VLDL, which may be associated with decreased clearance of VLDL, will lead to an increase in serum triglyceride levels and a slight increase in total serum cholesterol levels because of the cholesterol content of VLDL. However, these larger forms of VLDL do not appear to be particularly atherogenic.28 Thus, until more is understood about the basic pathophysiology of atherosclerosis and until the atherogenic effects of antihypertensive agents have been better studied, it is premature to assume that hyperlipidemia with antihypertensive agents will invariably enhance the rate of atherosclerosis, but it would be prudent to consider this possibility in the choice of treatment. In summary, the following conclusions may be made about the problem of hyperlipidemia with antihypertensive therapy in the salt-sensitive hypertensive patient. 1. In overweight patients, weight reduction is probably more important than medication effects in determining the lipid profile, but a significant proportion of the effect of diet may be vitiated by a drug that adversely affects serum lipid levels.
June 15, 1988
2. Serum cholesterol and triglyceride levels should be determined as part of the baseline evaluation of all hypertensive patients and monitored when drug therapy that could cause hyperlipidemia is administered. 3. For those hypertensive patients who have a significant increase in serum cholesterol and triglyceride levels with diuretic therapy, the calcium channel antagonists may be administered because these agents do not appear to cause hyperlipidemia, and they are frequently effective as monotherapy in these patients. Other classes of drugs can be administered if the blood pressure is not controlled satisfactorily.
GlucoseIntolerance Another metabolic complication with antihypertensive therapy of the salt-sensitive patient is glucose intolerance. Diuretic drugs are known to lead to glucose intolerance.36 This glucose intolerance can frequently be explained by the effects of potassium depletion to diminish the insulin response to a glucose stimulus. Using the hyperglycemic clamp technique in normal subjects, Helderman et a13’ noted that the diabetogenic effect of 100 mg/day of hydrochlorothiazide could be explained by the potassium depletion that was induced with hydrochlorothiazide. However, some evidence suggests that thiazide diuretic drugs may cause glucose intolerance by other effects that do not depend on potassium depletion. Diuretic drugs have been shown to cause an increase in renin and catecholamine release, and angiotensin has been demonstrated in vitro to enhance gluconeogenesis38 and glycogenolysis .3gSimilarly, norepinephrine may stimulate pancreatic (Y~receptors to suppress insulin release40and may also stimulate gluconeogenesis.38 As a reflection of concern about metabolic effects of diuretic drugs, hypertensive patients are now usually being treated with much smaller doses of diuretics than in the past, and this leads to less renin and catecholamine stimulation. One recent study41 noted that lowdose hydrochlorothiazide did not have any diabetogenie effect. In that study, glucose homeostasis was evaluated by determining changes in fasting blood sugar levels, hemoglobin A1c, serum insulin levels, hepatic glucose output, insulin sensitivity with the euglycemic clamp technique and monocyte insulin binding. None of these factors changed significantly in Type 2 diabetic patients as therapy was changed from placebo to hydrochlorothiazide therapy (25 mg/day). Another study has shown that low-dose diuretic therapy for 10 years did not have a diabetogenic effect.42Thus, glucose tolerance should be unusual with low-dose diuretic therapy in the salt-sensitive hypertensive patient. It appears that in persons in whom glucose intolerance develops with hydrochlorothiazide or furosemide, bumetanide can be administered as an alternative diuretic agent. This diuretic was noted to have little effect on the glucose transporter in comparison with furosemide and hydrochlorothiazide43and no effect on in vitro stimulation of pancreatic insulin, glucagon and somatostatin.44 If glucose intolerance persists with low-dose hydrochlorothiazide or bumetanide therapy, other classes of antihypertensive agents may be substituted for diuret-
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ic therapy or combined with a reduced dose of a diuretic drug. The calcium channel antagonists may substitute as monotherapy in these patients. However, questions have been raised about their influence on glucose tolerance because insulin release has been shown in vitro to be dependent on an increase in cytosolic calcium.45 In vivo studies have shown impairment, no change, and improvement in insulin release.33v46-50 Some studies suggest that glucose tolerance may improve secondary to effects on the liver or by other mechanisms that do not affect insulin secretion.4g During clinical use of the calcium channel antagonists for the treatment of hypertension, fasting blood sugar levels remain unchanged33 or increase so slightly3* that it would not appear to be of clinical significance. However, occasional hyperglycemia has been noted.51952 Thus, further study of this area would be helpful, though the calcium channel antagonists appear to be relatively free of adverse effects on glucose homeostasis. An additional class of drugs that may be helpful when glucose intolerance develops is the ACE inhibitors. These agents have no adverse effect on glucose tolerance, and they may actually improve glucose tolerance slightly. Dominguez et aP3 noted that patients with Type 2 diabetes and hypertension had a significant decrease in hemoglobin A1c levels as well as a lower glucose response to an oral glucose tolerance test after 1 month of captopril treatment. However, a significant weight loss, which may have contributed to the improvement in glucose tolerance, was noted during this same time. Similarly, Matthews et a154demonstrated that treatment of hypertensive noninsulin-dependent diabetics with captopril was not associated with changes in fasting blood sugar levels or overall response to a glucose tolerance test. However, there was a significant decrease in the 120-minute plasma glucose value after the oral glucose challenge in these patients. Helgeland et a155reported that enalapril led to a significant reduction in fasting blood glucose levels in a large group of nondiabetic hypertensive subjects There have been anecdotal reports of diabetic subjects requiring a dosage reduction in either an oral agent or insulin with the addition of an ACE inhibitor.56,57Furthermore, a recent study41in Type 2 diabetic patients noted a slight decrease in hemoglobin A1c levels during enalapril treatment, without adverse effects on glucose homeostasis as assessedby changes in serum insulin levels, hepatic glucose output, insulin sensitivity determined with the euglycemic clamp technique and monocyte insulin binding. The mechanism of any beneficial effect on glucose tolerance remains unclear. Some studies indicate that enhanced insulin responsiveness occurs, perhaps secondary to decreased kinin degradation.58 In addition, angiotensin production may increase gluconeogenesiG* and glycogenolysis.3g Thus, ACE inhibitors appear to improve slightly or not worsen glucose tolerance, so they can be administered if glucose intolerance is encountered with other antihypertensive agents. Their ability to have a synergistic effect in reducing the blood pressure in combination with a low-dose diuretic may further obviate problems with glucose intoIerance.5g
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A SYMPOSIUM:
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HYPERTENSIVE
PATIENT
Othei- classes of antihypertensive agents have little effect on glucose homeostasis, though occasional problems may be encountered. The centrally acting CYagonists, in general, do riot provoke glucose intolertince.60 However, because insulin release is inhibited by cyzreceptor stimulation, glucose intolerance has been noted to develop in some patients, presumably secondary to a direct peripheral effect of these drugs.40Alphal-receptor antagonists such as prazosin and the primary vasodilators such as hydralazine and minoxidil have no adverse effects on glucose homeostasis. However, they usually must be given in combination with other antihypertensive agents, And these other drtigs may lead to worsening of glucose tolerance. The ,8 blockers, particularly when they are used in combination with.diuretic therapy, may worsen glucose tolerance.61Thus, a number of factors must be considered in selecting antihypertensive therapy in the diabetic patient, in the hypertensive patient with a strong family history of diabetes, and in the patient in whom glucose intolerance develops with initial antihypertensive therapy. Glucose intolerance with antihypertensive agents may be explained, in part, by the recent demonstratiorP2 that itisulin resistance is a common abnormality in patients with essential hypertension. In this study, young normoglycemic hypertensive patients, age- and weight-matched with a group of normal subjects, were ndted to have impaired insulin sensitivity. Specifically, insulin-mediated nonoxidative glucose disposal was markedly impaired. This study has thus provided evidence that essential hypertension is often accompanied by insulin resistance. It is uriclear at this time if this is a primary abnormality or if it is secondary to some other metabolic abnormality characteristic of hypertension, such as a hyperadrenergic state. In the future, some initial assessment of insulin resistance may be helpful for the hypertensive patient in order to select chronic drug therapy that would be less likely to predispose toward the development of glucose intolerance and eventually lead to overt diabetes. In summary, control of blood pressure is no longer the only goal of antihypertensive therapy. A number of recent sttidies have suggested that metabolic complications of antihypertensiire therapy may cause adverse cardiovascular effects. These considerations may be particularly important in salt-sensitive hypertensive patients in whom diuretic and other antihyperterisive agents can cause electrolyte abnormalities, hyperlipidemia or glucose intolerance, or any combination of these conditions.
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