Treatment of obesity-associated hypertension

Treatment of ObesityHAssociatedHypertension Harriet P. Dustan, MD, and Roland L. Weinsier,

MD, DrPH

Many obese people are hypertensiwe either because of obesity-associated hypertension or because the two conditions coexist. Weight loss is recommended fm all obese hypertensiues as some patients benefit by concomitant reductions of arterial pressure and/or decreased requirements fur antihypertensive drugs. Since obesity-associated hypertension cannot be diagnosed as a separate entity, available evidence was rewiewed to determine the antihypertensive effectiveness of weight loss and effects of weight loss on antihypertensive drug requirements. Generally speaking, patients with mild hypertension appear to respond better to weight reduction than those with moderate and severe hypertension. However, a substantial percentage of patients with mild hypertension may be unresponsive. Weight loss also seems to have potential for lessening requirements for antihypertensive drug therapy. Beneficial effects for both blood pressure and drug requirements are due to weight loss and not caloric restriction, per se. Mechanisms of the beneficial effects are related to consequences of weight loss and appear to involve decreased cardiac output and blood volume. The issue of salt sensitivity of obesity-associated hypertension is unresolved. Ann Epidemiol 1991;1:371-379 KEY WORDS:

Hypertension,

obesity, hypertension

therapy, obesity-diet therapy.

INTRODUCTION

Obesity plays a large role in the prevalence of hypertension: Weight gain in young adults is a powerful factor for the subsequent development of hypertension ( 1, 2)) and obese people are far more often hypertensive than are nonobese people (3). Therefore, it is logical to assume that weight reduction in obese hypertensives would decrease arterial pressure and eliminate their hypertension altogether. While there is ample evidence that a substantial percentage of obese hypertensives experience blood pressure reduction with weight loss, not everyone benefits because obesity and hypertension surely can coexist as separate entities in some people. At the present time there is no way of knowing which obese hypertensives will benefit from weight loss; therefore, it becomes important to review the available information for possible indications of true obesity-associated hypertension in contrast to obesity coexistent with hypertension. Conventional wisdom holds that weight reduction by obese hypertensives can decrease or eliminate the need for antihypertensive drug therapy. If true, the potential benefit could promote participation in weight loss programs because the expense of therapy with the newer antihypertensive drugs is often considerable and the possibility of avoiding such costs, a realistic goal. Thus, the effects of weight loss on drug requirements is reviewed. The mechanisms of obesity-associated hypertension are not understood and have been variously ascribed to hypervolemia causing increased cardiac output with failure of an appropriate reduction in systemic vascular resistance (4, 5), hyperinsulinemia (6, 7), increased activity of the sympathetic nervous system (8), and an aberration of

From the Departments of Medicine (H.P.D.) and Nutrition Sciences (R.L.W.), Birmingham, Birmingham, AL. Address reprint requests to: Harriet P. Dustan, MD, 28 Hagan Drive, Essex, Received August 6, 1990; revised November 20, 1990. 0 1991 Elsevm Science Puhhshing Co., Inc.

University

of Alabama

at

VT 05452. 1047-2797/91/$03.50

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aldosterone-renin relationships (9). A study of all these factors, as weight is lost, has provided useful information that, along with results of a recent study at our institution, is summarized here.

THE ANTIHYPERTENSIVE

EFFECTIVENESS

OF WEIGHT

LOSS

Arterial pressure of both normotensives and hypertensives is variably responsive to weight reduction, and from the available information, hypertensives do not appear to respond more often than normotensives, although the actual magnitude of the response is greater. In 1952, Martin reported the blood pressure effects of weight loss in 18 normotensives and 19 hypertensives (10). Five of the normotensives had a decrease in systolic pressure and in only one of these did diastolic pressure decrease as well. In 7 of the hypertensives, both systolic and diastolic pressures decreased but in only 4 of the 7 were values of 140/90 mm Hg or less achieved. Salzano and colleagues followed 16 obese, young normotensive adults (age range, 22 to 35 years) while they lost I I to 27% of their prediet weight (11). Nine had decreases in systolic pressure of 10 mm Hg or more and in 4 of these diastolic pressure fell as well by at least 5 mm Hg. The Minnesota semistarvation study done during World War II gave sriking results in regard to the variation in response of normal blood pressure to weight reduction (12). Thirtytwo young men who were conscientious objectors were studied after 24 weeks of semistarvation during which they lost 25% of their body weight. For the entire group, control blood pressure averaged 107/70 mm Hg and after weight loss it averaged 95/64 mm Hg. These means obscure marked differences in individual responses: 5 men had no change in systolic arterial pressure; 10 experienced a decrease in systolic blood pressure to 90 mm Hg or less, while in one it rose strikingly from 93 mm Hg at the beginning of the semistarvation study to 113 mm Hg at the end. Rocchini and associates examined the effects of diet and diet plus exercise in a group of obese adolescents who were followed over a period of 6 months and compared the results with those obtained in a group similarly overweight but who received no diet or exercise advice (13). The control group had an increase in blood pressure over the period of observation while both the diet and diet plus exercise groups had a significant decrease. Exercise did not have an antihypertensive effect that was additional to that of weight reduction alone. In judging the variations in blood pressure response to weight reduction, the earlier studies are particularly helpful because all raw data are available for review (10, 11, 14). For example, the report of Adlersberg and coworkers gave detailed information about blood pressure effects of weight reduction in 54 hypertensive patients who were followed for an average of 8.2 months, during which mean weight loss was 24 lbs (52.91 kg) (14). Wh ereas all patients lost weight, only 39 (Group I) experienced a decreased blood pressure and 15 (Group II) failed to have any response. Means for Group I were 188009 mm Hg before weight loss and 172/98 mm Hg afterward. For Group II, these means were 196/l 14 and 198/l 10 mm Hg, respectively. Inspection of the individual values for Group I patients shows extraordinary variation in blood pressure responses. In 10 patients, blood pressure fell to normal, averaging 127177 mm Hg at the end of the weight loss period. If one analyzes the data of those 10 separately from the 29 who had a lesser response, the picture is changed considerably. The 10 had a blood pressure change from 169/97 to 127/77 mm Hg, representing a 23% decrease in mean arterial pressure. In contrast, the 29 had a baseline pressure of 195/ 112 mm Hg, with a decrease to 167/97 mm Hg after weight loss; the mean pressure decrease was only 14%. This suggests that the milder the hypertension, the more likely

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the response to weight reduction. That was the conclusion of Adlersberg and colleagues because the blood pressure level of the relatively unresponsive Group II patients was somewhat higher than that of the responsive Group I patients. As attractive as that suggeston is, it is not supported by more recent information. Haynes and colleagues measured the blood pressure response of 30 mildly hypertensive (blood pressure, 135/91 mm Hg) obese subjects to a restricted calorie intake over a 6month period and compared results obtained to those of a control group of similar age, gender, degree of overweight, and blood pressure ( 15). The experimental group lost 4.1 kg as compared with the 0.8skg loss of the controls, but arterial pressure did not change in either group. Also, we studied 24 mildly hypertensive, obese women during a lo- to 12-week weight loss program until they were of normal weight (between 100 and 120% of ideal) and had lost at least 10 kg. Supine blood pressure was not affected, although standing blood pressure fell significantly; that decrease, however, represented only a 7 mm Hg decrease in mean arterial pressure (16). In summary: A review of the available information indicates that hypertension associated with obesity is often, but not always, ameliorated or abolished by weight reduction. Generally speaking, it appears that mild to moderate hypertension is more responsive than are higher levels, but that has not been a universal finding. Thus, weight reduction is indicated as adjunctive therapy for severe hypertension because it may occasionally be beneficial by itself and, failing that, may allow lower doses of antihypertensive drugs.

EFFECTS OF WEIGHT LOSS ON ANTIHYPERTENSIVE DRUG REQUIREMENTS Although the belief is widely held that weight reduction of obese-associated hypertensives allows drug therapy to be lessened, there is little firm fact in support. Tyroler and associates carried out a community-based diet experiment in overweight hypertensives recruited from the total Evans County Cardiovascular Survey population (17). Of the 127 patients who qualified, 64 served as controls and 63 received a low-calorie, lowsalt diet. The two groups were similar as to age, race and gender, blood pressure, weight indices, and drug therapy, with 27 control and 28 treatment group subjects taking antihypertensive drugs. After 1 year, it was found that the treatment group had sustained a greater decrease in systolic blood pressure than did the control group ( - 18 versus - 12 mm Hg, P < .05) in spite of the fact that fewer of the subjects in the diet group were receiving drugs than at the beginning (8 versus 28). During that same interval, the number of control subjects on drug treatment had increased from 27 to 36. Ramsay and coworkers examined the relationship of weight loss to antihypertensive drug requirements in 46 patients who were followed for 1 year after receiving weight loss instructions (18). The group was equally divided into those who lost less than 3 kg and those, more than 3 kg. Those who lost more than 3 kg had a greater decrease in arterial pressure ( 16.7/8.4 mm Hg) than those who lost less (2.2/1.5 mm Hg) (P < .Ol ). This greater decrease in blood pressure occurred in the group that lost more than 3 kg in spite of the fact that medications were more often reduced and less frequently increased, compared to the group that lost less weight. A different tack was taken by some of the investigators of the Hypertension Detection and Follow-up Program (HDFP) at its end (19). They enrolled 496 participants in the Dietary Intervention Study in Hypertension (DISH) to determine if

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dietary measures (weight reduction and salt restriction) sion when treatment

could delay return of hyperten-

was discontinued

after prolonged good blood pressure control in the Stepped Care arm of the HDFP (20). Th ose who were at or above 120% of ideal weight (overweight, 325 subjects) were randomized into four groups: (1) continuation of HDFP drug treatment. of hypertension,

(2) discontinuation

(3) discontinuation

of medications

of medications

to observe rate of return

and dietary sodium restriction

with a goal of 70 mEq/d, and (4) d’ rscontinuation of medications and weight reduction. 171 subjects) were divided into three groups, the same

The nonobese (not overweight, as for the overweight baseline,

subjects

but eliminating

the weight reduction

protocol.

the overweight group was taking more drugs than the nonoverweight

At

group

(P = .025). The period of observation

was 56 weeks and success was judged by persistence of

a diastolic blood pressure of less than 95 mm Hg. Of the overweight (i.e.,

without medication

or dietary intervention),

35.3%

control group

remained normotensive.

For those restricting sodium or having lost weight, the rates were 44.9% respectively.

In the nonoverweight

preventing return of hypertension, opposed to 44.9%

and 59.5%,

group, sodium restriction was even more helpful in with 53.4% of that group remaining normotensive

as

of the overweight group.

In summary: The evidence presented certainly suggests that significant weight loss (e.g.,

at least 5% of initial weight) can reduce the need for antihypertensive

drugs.

Further, when drugs are discontinued after a long period of good blood pressure control, weight reduction of the obese or weight control for the nonobese

can postpone the

return of hypertension.

MECHANISMS FOR THE ANTIHYPERTENSIVE EFFECTIVENESS OF WEIGHT LOSS Decreases in blood pressure produced by weight reduction have been variously ascribed to a decreased blood volume and cardiac output, suppression of sympathetic system activity,

diminished

insulin resistance

creased body sodium stores, and normalization the present time,

interest

a combination

(NIDDM),

of aldosterone-renin

relationships.

At

is focused on excess serum insulin levels and/or insulin

resistance (6, 7). It seems an attractive with

nervous

with decreased insulin levels and de-

of hypertension,

and hyperinsulinemia,

possibility because obesity is often associated non-insulin-dependent diabetes mellitus

all ofwhich are reversible in some patients by weight

loss. The question is whether the enthusiasm for this hypothesis exceeds the evidence in support of it. Before proceeding made concerning

to a discussion of proposed mechanisms,

the relative contributions

comment

should be

of calorie restriction and weight reduction

to the antihypertensive

effectiveness

of weight loss.

Calorie Restriction

versus Weight Reduction

To investigate possible differences between these two conditions, we studied 24 moderately obese (120 to 150% of ideal body weight) women with mild hypertension (mean blood pressure for the group, 157/93 mm Hg) and normal glucose tolerance (16). The study lasted for 5 months and consisted of several phases. First, subjects had an outpatient adaptation, during which calorie intake was adjusted until weight varied less than 1% over 10 days. Phase I came next: Subjects were hospitalized in the General

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Clinical Research Center (GCRC) for a lo-day period of study during stable weight. Phase II followed immediately and also lasted for 10 days, during which energy intake was reduced to 800 kcal/d. Subjects then left the hospital; the 800-kcal diet was continued until at least 10 kg had been lost and body weight was between 100 and 120% of ideal. This required 10 to 12 weeks. When that goal was achieved, subjects were readmitted to the GCRC for two consecutive lo-day periods. In Phase III, the 800-kcal diet was continued and studies carried out to determine the effects of weight reduction. In the subsequent Phase IV, calorie intake was increased to maintain weight, thus mirroring Phase I except that subjects were of normal weight. Throughout the entire study, regardless of the number of calories consumed, the diet provided a fixed proportion of carbohydrate (55%), fat (22%), and protein (23%) and sodium and potassium intakes of 174 and 115 mEq/d, respectively. The conclusions that follow are based on a comparison of the decreased-calorie Phases II and III with the eucalorie Phases I and 1V. Calorie restriction had no independent effect on either supine or standing arterial pressure, although there were statistically significant decreases in resting metabolic rate, heart rate, sodium and potassium balances, serum insulin concentration, and the ratio of serum T,/rT,. Weight reduction, as distinct from calorie restriction, resulted in the following significant changes: decreases in metabolic rate, heart rate, standing blood pressure, cardiac output, plasma volume, plasma renin activity, and urinary dopamine; systemic vascular resistance was increased. From the statistical analyses performed, we concluded that weight loss had an effect of lowering blood pressure that was not dependent on calorie restriction but was related to decreases in blood volume and cardiac output. The conclusion that the effect of lowering blood pressure was related to weight loss is similar to that of an earlier report by Domfield and colleagues (21), who described blood pressure and body weight relationships in 218 obese individuals. These individuals were studied at various times during weight reduction achieved through a protein supplemented fast with a dietary formula that provided 320 kcal/d with 45 g of protein and 30 g of carbohydrate. Their analyses showed that changes in arterial pressure correlated with changes in body weight.

The Hemodynamic

Consequences

of Weight Reduction

It is not surprising that weight loss has marked hemodynamic effects because it represents loss of tissue with an associated decrease in blood volume and blood flow. Alexander and Peterson studied 9 grossly overweight people who lost an average of 54 kg over periods of 4 to 34 months (22). They found that weight loss resulted in a decrease in oxygen consumption, a decrease in blood volume on the average of 1.7 L, a decrease in cardiac output of 1.7 L/min, and a decrease in arterial pressure from 102 to 87 mm Hg, although vascular resistance was not changed. Similarly, Reisin and colleagues (5) found that weight reduction reduced arterial pressure because of a decrease in cardiac output and blood volume, whereas total peripheral resistance was unchanged. Thus, it seems that patients with obesity-associated hypertension have a decrease in blood pressure with weight reduction because cardiac output falls while total peripheral resistance remains the same. This seems to be in contrast to those patients in whom weight loss does not reduce arterial pressure (i.e., those in whom obesity and hypertension are separate entities). Such individuals would be expected to have the same reduction in cardiac output, but in them the hypertension would be maintained because of a rise in vascular resistance.

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Weight Reduction and Sympathetic Nervous System Activity Fasting and refeeding influence catecholamine metabolism in rats. For example, Landsberg and Young found a reduced cardiac norepinephrine turnover in rats fasted for 2 days and a substantial increase in turnover with 3 days of glucose refeeding (23). Some of the studies of weight reduction of obese people have described a decrease in plasma norepinephrine levels (24, 25) but this is not always the case. As described above, in our study we failed to find any change in plasma norepinephrine level, although mild decreases in standing pressure, as well as decreases in heart rate, were found ( 16). Also, Amatruda and coworkers, who studied 5 obese patients for 40 days with a verylow-calorie (420skcal) diet that resulted in a 10% weight loss, found a reduction in plasma norepinephrine levels in only 2 of the 5 (26). J ames and colleagues looked for other evidence of changed noradrenergic activity by measuring the urinary excretion rate of the catecholamine metabolite, 4-hydroxy-3-methoxymandelic acid (HMMA) (27). When normotensive obese women lost weight, they not only had decreases in arterial pressure and heart rate but also a decreased excretion rate of HMMA, which returned promptly to pretreatment levels with carbohydrate refeeding. However, obese hypertensives, although losing weight, did not have a decrease in the excretion of HMMA to the extent found in the normotensive obese subjects. Thus it seems that whereas sympathetic activity is influenced by calorie restriction and weight reduction, a decrease is unlikely to be the sole reason for the change in arterial pressure with weight loss.

Correction of Hyperinsulinemia

by Weight Reduction

Obese people, whether hypertensive or normotensive, tend to have hyperinsulinemia and insulin resistance. Several studies indicated a significant association between insulin and blood pressure, which is thought to function through body sodium stores and activity of the sympathetic nervous system. A case in point is the study by Rocchini and colleagues on the effect of weight loss on insulin and blood pressure in obese adolescents (13). They studied 50 young people before and after a 20-week weight loss program. Before the subjects lost weight, a significant correlation of systolic and diastolic blood pressures was found for body weight, fasting insulin, and the sum of insulin values during a glucose tolerance test. Subsequent weight loss significantly decreased arterial pressure, serum insulin levels, and the sum of insulin. The change in pressure brought on by weight loss correlated significantly with a change in both insulin and body weight. The relationship between blood pressure and serum insulin levels does not seem so simple as this. In the first place, although obesity is routinely associated with hyperinsulinemia and insulin resistance, hypertension does not always occur and a substantial percentage of overweight people are normotensive. Also, if insulin does play a key role in obesity-associated hypertension, arterial pressure should follow serum insulin levels in weight loss programs. In our study (16), serum insulin levels decreased with energy restriction (Phase II), but arterial pressure was affected only by weight reduction. Further, when caloric intake was increased (Phase IV), serum insulin levels rose but pressure fell. A major postulated role for hyperinsulinemia in the hypertension of obesity is through renal sodium retention. DeFronzo and associates found that insulin infusion, determined by hyperinsulinemic, euglycemic clamp method, reduced urinary sodium excretion (28). This study was done in normal subjects so that if such a mechanism exists in hyperinsulinemic, insulin-resistant subjects, it must be shown that the kidney does not share in the insulin resistance of other peripheral tissues. A recent article by

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Rocchini and colleagues investigated this in obese, young people, 14 to 19 years old, comparing results with nonobese subjects, 18 to 21 years old (29). They used the hyperinsulinemic, euglycemic clamp method and found that the obese young people, although exhibiting a reduced glucose uptake in response to the insulin (i.e., insulin resistance), had the same degree of sodium retension as did the nonobese control subjects. Another report by Rocchini and his colleagues indicated that obese, mildly hypertensive adolescents have blood pressure that is reduced by salt restriction, thus adding evidence for the role of sodium in the blood pressure changes of obesity (30). However, there have been no reports of increased sodium stores in uncomplicated hypertension in obese, insulin-resistant individuals ( 31, 32). Dahl and colleagues studied a group of obese patients whose blood pressure decreased with weight reduction only if sodium was restricted as well (33). Similarly, Fagerberg and coworkers found that weight loss normalized blood pressure of hypertensive obese men only when sodium restriction was added to calorie reduction (34). However, other studies clearly indicated that some obese hypertensives who do not restrict sodium intake have a decrease in blood pressure with weight loss alone (16, 35, 36).

CONCLUSIONS It seems reasonable to conclude that a major part of the mechanisms underlying the arterial pressure reduction with weight loss operates through a reduction in body mass, blood volume, and cardiac output. Other factors may influence that decrease, depending on the individual. There is clear evidence that in some obese people, weight reduction reduces indices of sympathetic activity. In addition, there is also evidence that some obese hypertensives may have a degree of salt-sensitive hypertension. It is likely that th e h ypertension of obesity will be found to be as heterogeneous in its mechanisms as is essential hypertension.

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