(Hypertension. 1995;26:950-956.)
© 1995 American Heart Association, Inc.
Articles |
Combinations of Potassium, Calcium, and Magnesium Supplements in Hypertension
From the Channing Laboratory (F.M.S., L.E.B., D.E.), Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass; Welsh Center for Prevention, Epidemiology, and Clinical Research (L.A., P.W.), Departments of Medicine and Epidemiology, The Johns Hopkins Medical Institutions, Baltimore, Md; and the Department of Family and Community Medicine (N.O.B.), University of Nevada (Reno).
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Abstract Dietary intakes of potassium, calcium, and magnesium have each been reported to lower blood pressure, but the extent of blood pressure reduction in epidemiological studies and clinical trials has tended to be small and inconsistent. We hypothesized that combinations of these mineral supplements would lower blood pressure and that the reductions would be greater than that usually reported in studies of each cation alone. One hundred twenty-five patients (82 men and 43 women) with untreated mild or borderline hypertension were randomly assigned to daily treatment with one of the following four regimens: 60 mmol potassium and 25 mmol (1000 mg) calcium, 60 mmol potassium and 15 mmol (360 mg) magnesium, calcium and magnesium, or placebo. Standardized clinic blood pressure measurements were obtained on 3 days at baseline and after 3 and 6 months of treatment. At baseline, systolic and diastolic blood pressures (mean±SD) were 139±12 and 90±4 mm Hg, respectively, and dietary intakes of potassium, calcium, and magnesium were 77±32, 19±13, and 12±52 mmol/d, respectively. The mean differences (with 95% confidence intervals) of the changes in systolic and diastolic blood pressures between the treatment and placebo groups were not significant: -0.7 (-4.3 to +2.9) and -0.4 (-2.9 to +2.1) for potassium and calcium, -1.3 (-4.4 to +1.8) and 0.4 (-2.5 to +3.3) for potassium and magnesium, and +2.1 (-1.8 to +6.0) and +2.2 (-1.0 to +5.4) for calcium and magnesium. In conclusion, this trial provides little evidence of an important role of combinations of cation supplements in the treatment of mild or borderline hypertension.
Key Words: diet • blood pressure • potassium • magnesium • calcium • food, fortified
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Introduction |
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Dietary potassium, calcium, and magnesium have each been inversely associated with blood pressure and the incidence of hypertension in a variety of epidemiological studies.1 2 3 4 5 6 7 Uncertainty exists, however, as to which of these cations has the strongest association and the extent to which there is an interaction between the effects of different cations. Because these cations exist together in commonly eaten foods such as fruits, nuts, vegetables, cereals, and dairy products, their intakes are highly correlated. This collinearity makes it difficult in observational studies to distinguish the individual effects of dietary cations on blood pressure.5 Meta-analysis of clinical trials reveals a significant hypotensive effect of moderate size (-5.9/-3.4 mm Hg) for potassium supplementation,8 a significant but lesser effect (1.8 mm Hg) on systolic but not on diastolic blood pressure for calcium supplements,1 and an inconsistent pattern for magnesium supplementation.2 9 10 11 12
One explanation for the divergence between the observational epidemiological studies that suggest that these dietary cations may play an important role in blood pressure control and trials that, particularly for calcium and magnesium, do not show important effects is that these nutrients act in concert. Very slight effects on blood pressure from individual nutrients could acquire clinical importance through additivity. Alternatively, synergism may exist so that two nutrients that are ineffective alone have a hypotensive effect when ingested together. A prospective study of 58 218 US nurses found that the protective associations of calcium and magnesium with incidence of hypertension were approximately additive.4 Also, metabolic studies have identified biologically plausible mechanisms for an interactive effect of these cations on blood pressure. For example, potassium decreases urinary calcium excretion and increases body calcium balance, probably by increasing renal calcium resorption.13 14 15 Magnesium administration, concomitant with potassium, assists tissue replenishment of potassium.16 17 Therefore, we hypothesized that combinations of these cations would lower blood pressure. Our research strategy was to test three combinations of potassium, calcium, and magnesium and, if one or more combinations were hypotensive, to study in subsequent trials the nature of the interaction.
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Methods |
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Subjects
Men and women of any race or ethnic background who were 21 to 70 years of age and had an average diastolic blood pressure of 85 to 99 mm Hg over three screening visits were potentially eligible for the study. Exclusion criteria included obesity (body mass index >36 kg/m2), insulin-dependent diabetes, angina pectoris, myocardial infarction, congestive heart failure, stroke, intermittent claudication, chronic renal failure, abnormal serum potassium or creatinine level, chronic gastrointestinal disease that could interfere with absorption of the nutritional supplements, pregnancy or intent to become pregnant, treatment during the preceding 3 months with medications that affect blood pressure, dietary therapy to lose weight, and use of nutritional supplements of calcium, magnesium, or potassium, including antacid preparations.
A total of 140 subjects were enrolled—95 at The Johns Hopkins University and 45 at the University of California, Davis. Mass mailing of brochures was the primary recruitment strategy at The Johns Hopkins University. From a total of 581 persons who responded by postcard, 44 (8%) could not be contacted, 59 (10%) were not interested, 51 (7%) could not be withdrawn from their antihypertensive medications, and 95 (16%) met one or more of the exclusion criteria. The remaining 332 (57%) participated in one or more of the three screening visits, and 95 (16%) of them were enrolled. At the University of California, Davis site, participants were recruited by mailings to local communities and to the employees of several large companies located nearby. Invitations were mailed to 93 097 persons; 3901 (5%) responded, 190 (0.2%) participated in the first screening visit, and 45 (0.05%) were randomized. This study was approved by the institutional review boards at Johns Hopkins Medical Institutions, University of California, Davis, and Brigham and Women's Hospital; the subjects gave informed consent; and procedures followed institutional guidelines.
Study Design
The study was a randomized, parallel-group, double-blind
trial with three groups receiving combinations of dietary supplements
and a fourth group receiving placebo. The duration of supplementation
was 6 months. Before randomization, enrollees participated in a series
of three screening visits to determine eligibility and in a run-in
period to test adherence. At the first screening visit, subjects gave a
medical history and had three measurements of blood pressure taken. If
the average diastolic blood pressure was 82 to 105 mm
Hg and the participant met other eligibility requirements, second
and third screening visits were conducted. The mean duration between
the screening visits was 14 days. If an average of the blood pressures
at all three visits was 85 to 99 mm Hg, the participant was determined
to be eligible. At the end of the third screening visit, potentially
eligible participants were enrolled in a 4- to 6-week run-in phase,
during which placebo pills (two magnesium-placebo capsules BID)
were prescribed. Only those with a pill count suggesting consumption of
>80% of their assigned pills were considered eligible for
randomization. Randomization was conducted by opening a sealed envelope
provided by the Coordinating Center to each clinical center.
Randomization was stratified by center. The 140 enrollees were
randomized into four approximately equal-sized groups: 35 received
calcium and magnesium, 34 received calcium and potassium, 36 received
potassium and magnesium, and 35 received placebo. Follow-up visits
were conducted at the approximate midpoint (3 months) and at the end of
the 6-month supplementation period. The mean follow-up time was 12
weeks at the midpoint and 24 weeks at the end of the trial. The
participants were not counseled to restrict sodium intake.
The dietary supplements were potassium chloride sustained-release tablets (20 mmol per tablet, K-Dur; Schering-Plough), magnesium diglycine chelate (3.7 mmol [90 mg] magnesium per capsule, Chelasomes; Albion), and calcium carbonate (12.5 mmol [500 mg] calcium per tablet, Os-Cal; Marion-Merrell-Dow). The daily amount of the supplement for potassium was 60 mmol (2 tablets in the morning, 1 in the evening); magnesium, 15 mmol (360 mg) (2 capsules BID); and calcium, 25 mmol (1000 mg) (1 tablet BID). Participants were given their assigned pills in "blister" packs.
Blood pressure was measured at three clinic visits occurring an average of 12 to 14 days apart at baseline screening, midpoint, and closing, according to a standardized protocol used in other multicenter trials.11 18 Stringent quality control criteria were applied to the selection and certification of the blood pressure observers. On each day of measurement, three readings were taken in succession. The participants provided urine samples over a 24-hour period on the day before the third screening visit, the randomization visit, the second midpoint visit, and the second closing visit. Urine samples from the screening and randomization visits were pooled for an average baseline measurement. Urine samples were analyzed for calcium and magnesium content by atomic absorption spectrophotometry at the Channing Laboratory and for sodium, potassium, and creatinine content by autoanalyzer at the Core Laboratory of the Clinical Research Center, Brigham and Women's Hospital. Customary nutrient intake was measured by a food frequency questionnaire19 at baseline and closing. The participants were asked not to change their diets during the trial. A pill count was conducted at the midpoint and closing visits. A follow-up health questionnaire was administered by clinic staff at the first midpoint and closing visits. A questionnaire on side effects was administered at each follow-up visit. Patients whose diastolic blood pressure averaged >102 mm Hg for the three midpoint visits were withdrawn from the trial and referred to their physicians for treatment.
The data were analyzed at the Coordinating Center using the STATISTICAL ANALYSIS SYSTEM.20 The primary outcome variable was change in diastolic blood pressure from the baseline screening visits to the average of the midpoint and closing visits. Patients who withdrew from the study after the midpoint were included in the primary analysis. Blood pressure for each subject at baseline, midpoint, and closing was the average of nine measurements (three measurements on each of 3 days). The trial was designed to have at least 80% power to detect a change in blood pressure of 3 mm Hg diastolic with two-sided P<.05. The actual sensitivity of the trial for the effect of each cation combination was determined from the 95% confidence intervals of the differences in the blood pressure changes between supplement and placebo groups (for an example, see "Results"). Multiple regression analyses determined the effect of each treatment compared with placebo using treatment group as an independent variable. Additional analyses were conducted on systolic blood pressure and on the changes at midpoint and closing, separately. Covariates were added to the multiple regression model to assess the effects of treatment in various subgroups of the patients, eg, baseline urinary electrolyte excretion. The model included treatment group, baseline urinary excretion, and the interaction term, treatmentxurinary excretion. The effects of the treatments were also examined in subgroups with urinary electrolyte excretion levels above and below the median.
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Results |
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The 125 patients who form the primary analysis group completed at least the midpoint blood pressure measurements. Eight patients were withdrawn from the trial because of a diastolic blood pressure >102 mm Hg (7 before and 1 after the midpoint measurements); 2 of them were receiving placebo, 3 were receiving calcium and potassium, 2 were receiving potassium and magnesium, and 1 was receiving calcium and magnesium. Eight patients left the trial for personal reasons before the midpoint, and 5 additional patients left before providing closing measurements. There were 82 (66%) men and 43 (34%) women; 81 (65%) were white, 34 (27%) were black, 4 (3%) were Hispanic, and 6 (5%) were Asian. Their mean age was 53 years (range, 25 to 66 years) (Table 1). There were no significant differences among the treatment groups in sex, race, age, body mass index, or smoking (Table 1). One patient in the calcium and magnesium group, 1 patient in the potassium and magnesium group, and none in the other two groups had previously taken antihypertensive medication.
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At baseline, mean daily dietary intake was 782±477 mg (19±13 mmol) calcium, 284±79 mg (12±5 mmol) magnesium, and 2770±802 mg (77±32 mmol) potassium. Reported intake of all three nutrients as well as of energy tended to decrease mildly during the trial in all groups with no significant difference among the four groups (Table 2). Baseline urinary excretion of calcium, magnesium, and potassium was similar across the four treatment groups (Table 3). Urinary excretion of calcium increased significantly in the two groups who received calcium in comparison with the placebo group. Likewise, potassium excretion increased significantly in the two groups who received potassium supplements, and magnesium excretion increased significantly in the calcium and magnesium group (Table 3). The rise in magnesium excretion in the potassium and magnesium group did not achieve statistical significance. According to pill counts, the patients took approximately 95% of their assigned pills throughout the trial.
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Mean blood pressure at baseline was 139±12 mm Hg systolic and 90±4 mm Hg diastolic for the patients who finished the trial and was similar among the four groups (Table 4). Blood pressure decreased significantly by 3 to 5 mm Hg in the groups assigned to placebo, potassium and magnesium, and calcium and potassium, whereas the blood pressure reduction in the calcium and magnesium group, approximately 1 mm Hg, was nonsignificant. There were no significant differences in change in blood pressure between each treatment group and the placebo group. The results were unaffected by adjusting the blood pressure differences for nonsignificant discrepancies in baseline characteristics, including dietary intake and urinary electrolyte excretion.
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The minimum detectable effect on blood pressure of each combination of cations was determined by computing the 95% confidence interval for the difference between the treatment group and the control group in mean blood pressure changes. For example, in the calcium and magnesium group, systolic blood pressure decreased at the close of the trial by 0.6 mm Hg compared with 4.3 mm Hg in the placebo group, with the difference being a relative increase of +3.7 mm Hg (Table 4). The 95% confidence interval (-1.1 to 8.5) indicates that the true effect of calcium and magnesium on systolic blood pressure, estimated as +3.7 mm Hg, could range between a decrease of 1.1 mm Hg and an increase of 8.5 mm Hg. Therefore, the trial had a 95% chance of detecting a systolic blood pressure–lowering effect of calcium and magnesium supplements of >1.1 mm Hg. For potassium and magnesium supplementation, the confidence intervals excluded hypotensive effects of >3.4 mm Hg systolic and >1.2 mm Hg diastolic at the closing visits, and for potassium and calcium supplementation, the confidence intervals excluded hypotensive effects of >3.8 mm Hg systolic and >2.9 mm Hg diastolic.
Subgroup analysis showed no differences in the effects of any of the supplements in men versus women; whites versus blacks; persons with a baseline systolic or diastolic blood pressure above versus their counterparts with a pressure below the mean; baseline dietary potassium, calcium, or magnesium intake above versus those below the mean; baseline urinary sodium, potassium, calcium, or magnesium excretion above versus below the median; or change in urinary sodium, potassium, calcium, or magnesium. These variables defining subgroups were also studied as continuous covariates in multiple regression analyses and showed no significant interaction with treatment.
There were no differences between the groups in the frequency of medical or psychological symptoms except for a greater frequency of urination in each treatment group compared with the control group.
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Discussion |
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We found that combinations of the dietary cations potassium, magnesium, or calcium did not significantly lower blood pressure in patients with mild or borderline hypertension. This finding is surprising because observational epidemiological studies show inverse relations of these cations with blood pressure,1 4 5 6 7 and clinical trials demonstrate significant blood pressure lowering with supplements of either potassium or calcium.1 8 21 Because hypotensive drugs have additive effects on blood pressure, we anticipated significant effects of cation combinations.
Blood pressure levels in the patients in our study declined significantly from baseline in all groups except for those receiving calcium and magnesium. We believe that these declines are the result of accustomization, or placebo effects, a common finding in blood pressure trials, particularly in newly diagnosed hypertensives identified by community screening.22 23 Another contributing factor to a placebo effect is that the baseline blood pressure was the mean of measurements taken on the initial three clinic visits rather than after the 4- to 6-week run-in on placebo. The magnitudes of the mean changes from baseline (3 to 4 mm Hg in our study) are comparable to or less than those reported in the placebo groups in other well-designed trials.22 23 24 A placebo response could add variability to blood pressure changes and therefore decrease the sensitivity of a study. The sensitivity analysis for this trial presented in "Results" takes into account this source of variability by using the actual variability in the measurements.
In 13 trials with hypertensives, Cappuccio and MacGregor8 estimated that potassium supplementation lowered blood pressure significantly by -8.2 mm Hg systolic and -4.5 mm Hg diastolic. In a later meta-analysis restricted to 16 randomized controlled trials, Whelton21 found a more conservative result, -5.1 mm systolic and -3.0 mm diastolic. In the present study, the confidence intervals for the mean differences in blood pressure changes between the potassium-supplemented groups and the control group exclude these effect sizes, indicating that the present study could have detected the average effect found in these meta-analyses. Among previous trials, a higher pretreatment blood pressure correlated with a greater hypotensive effect of potassium.8 Compared with the hypertensive populations in previous potassium-supplementation trials,8 our group had lower baseline blood pressure levels—139/90 versus 152/96 mm Hg. In contrast, trials of potassium in normotensive persons, with a range of average blood pressures of 117 to 136 mm Hg systolic and 61 to 81 mm Hg diastolic, found little evidence for a blood pressure–lowering effect.8 11 21 Perhaps the blood pressure levels in the present study, although higher than in the normotensive trials, were not high enough for potassium supplementation to be effective. It is also possible that potassium supplementation with magnesium or calcium had a very small blood pressure–lowering effect, ie, 1 to 2 mm Hg, that could not have been detected.
We discounted other explanations for the lack of effect of potassium supplementation in our trial. First, other than for baseline blood pressure levels, the characteristics of the patients in our trial are similar to those of the hypertensive patients included in previous trials.8 21 Second, the 6-month duration of the present trial was much longer than the 40-day average duration of the other trials. Among these trials of short duration, potassium was more effective as duration increased.8 In contrast, we found no tendency toward a stronger treatment effect at 6 versus 3 months, with the trends being in the opposite direction. Similarly, in a 6-month trial of potassium in persons with high normal blood pressure, a trend toward lower blood pressure at 3 months was no longer present at 6 months.11 It would appear unlikely that extending the duration of our study would have revealed a hypotensive action of the supplements. Third, the amount of potassium supplementation was less in the present than in the average of previous trials—60 versus 86 mmol. We therefore estimated the effect on blood pressure of potassium (60 mmol) by considering the seven trials in hypertensives25 26 27 28 29 30 31 (excluding an outlier32 ) that tested a range of potassium doses from 48 to 65 mmol. Blood pressure decreased on average in these trials -8.2/-6.1 mm Hg from a baseline average of 156/99 mm Hg. The present trial could easily have detected this magnitude of blood pressure lowering if potassium, administered with either calcium or magnesium, lowered blood pressure as much as potassium administered without the other cations. Only one previous trial studied cation combinations. Patki et al30 found that the addition of magnesium (20 mmol) to potassium (60 mmol) did not augment or diminish the hypotensive effect of potassium.
Cutler and Brittain1 estimated that calcium supplementation lowers systolic blood pressure significantly by 1.8 mm (95% confidence interval, -3.0 to -0.6) and diastolic blood pressure nonsignificantly by 0.7 mm (95% confidence interval, -1.5 to +0.2). For the trials in hypertensive persons, the estimated effects were -2.1 (-3.6 to -0.6) systolic and -0.1 (1.3 to 1.0) diastolic. The average daily dose of calcium was approximately 1 g, the same as in the present trial. Six trials of dietary calcium and blood pressure published after this report have provided mixed results.11 33 34 35 36 37 Five of these trials showed a diastolic blood pressure change of approximately 0 mm Hg,11 34 35 36 37 and one showed a significant fall of 5 mm Hg.33 The systolic blood pressure differences were -14 mm Hg,33 -3 mm Hg,36 and 0 mm Hg in the remaining four trials.11 34 35 37 The trial that had by far the largest sample size, 237, found a null difference.11 Therefore, we do not think that calcium had the potential to contribute much of a hypotensive effect in our study. Interestingly, Weinberger et al37 found that calcium supplements decreased blood pressure in patients identified a priori as being salt sensitive but not in the general population.
Magnesium sulfate, administered parenterally, has been used as a treatment for severe hypertension in preeclampsia38 39 and glomerulonephritis.40 41 Proposed mechanisms involve stimulation of vascular prostacyclin release,39 42 renal vasodilation,42 vascular responsiveness,38 acceleration of the cell membrane sodium pump,43 44 and antagonism of arterial calcium uptake.45 Low dietary magnesium raises blood pressure levels in the rat,46 47 but it is unknown whether a similar effect occurs in humans. In healthy humans, experimental magnesium depletion increases the hypertensive effect of intravenous angiotensin II.42 Whelton and Klag2 reviewed seven trials of dietary magnesium supplementation reported through 1988. Trials that did not use a randomized control group showed decreases in blood pressure. The four controlled trials produced mixed results, although a trend toward a hypotensive effect was suggested. Six controlled trials published since the review9 10 11 12 48 49 provide little evidence that magnesium, in amounts similar to those used in the present study, lowers blood pressure. One trial found that after 6 months blood pressure decreased significantly by 3 mm Hg, but there was no effect at 3 months.49
Epidemiological studies that report significant inverse relations between blood pressure levels and potassium, calcium, and magnesium intakes1 4 5 6 7 21 50 51 contrast with the largely negative clinical trials of potassium, calcium, and magnesium in normotensive persons. It could be that foods such as fruits or vegetables rather than specific constituent minerals have the true hypotensive action, as suggested by a recent trial of guava fruit.52 Alternatively, other nutrients in these foods (eg, fiber, vitamins, vegetable protein) that are not well studied may lower blood pressure. In US nurses4 and health professionals,7 intake of fruits was an independent predictor of blood pressure levels and risk of hypertension even after the adjustment for the effects of potassium, magnesium, and calcium. Vegetarians whose diets are rich in fruits and vegetables have substantially lower blood pressure levels than do nonvegetarians.53 Clinical trials of specific food groups and of dietary patterns are needed and are in progress.54
Finally, we speculate that persons who are relatively deficient due to a low intake of cations may be particularly responsive to supplementation. Epidemiological studies tend to include those in the lowest category of intake in a control group, which serves as a point of reference for the effects of average and high intake. In contrast, most trials test the effect of increasing an average to a high intake, which was true for the present trial. Also, a deficiency in one nutrient could enhance the sensitivity to another.55 For example, in a US population sample, the ratio of dietary sodium to potassium appeared to affect blood pressure levels only in persons with a low calcium intake.56 A clinical trial in persons with habitually low intake of one or more cations would be needed to address the question of selective responsiveness.
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Acknowledgments |
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This work was supported by grants from the National Heart, Lung, and Blood Institute (RO1-HL-34593, NCRR GCRC MO1-RR-02635) and an Established Investigator Award from the American Heart Association (Dr Sacks). We thank Jeanne Charleston, RD; Dolores Kaidy, LPN; the staff at the Johns Hopkins Pro Health Facility; and Patricia Borhani, Trina Guly, RN; and Amy Merchant, University of California, Davis, for their conscientious conduct of the study protocol. We acknowledge our gratitude to the dedicated study participants.
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Footnotes |
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Reprint requests to Dr Frank M. Sacks, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail fsacks@hsph.harvard.edu.
Received May 31, 1994; first decision July 27, 1994; accepted July 21, 1995.
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