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Effect of Soybean Protein on Blood Pressure: A Randomized, Controlled Trial
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Jiang He, MD, PhD; Dongfeng Gu, MD, MS; Xigui Wu, MD; Jichun Chen, MSc; Xiufang Duan, MD; Jing Chen, MD, MSc; and Paul K. Whelton, MD, MSc
Annals of Internal Medicine
5 July 2005 | Volume 143 Issue 1 | Pages 1-9
ABSTRACT
Background: Epidemiologic studies suggest that vegetable protein intake is inversely related to blood pressure.
Objective: To examine the effect of soybean protein supplementation on blood pressure in persons with prehypertension or stage 1 hypertension.
Design: Randomized, double-blind, controlled trial.
Setting: Three communities in the People's Republic of China.
Patients: 302 participants 35 to 64 years of age with an initial untreated systolic blood pressure of 130 to 159 mm Hg, diastolic blood pressure of 80 to 99 mm Hg, or both.
Intervention: Study participants were randomly assigned to receive 40 g of isolated soybean protein supplements per day or complex carbohydrate control for 12 weeks; 91.4% completed the intervention.
Measurements: Blood pressure measurements were obtained by using random-zero sphygmomanometers at baseline and at 6 and 12 weeks.
Results: At baseline, the mean systolic and diastolic blood pressures were 135.0 mm Hg (SD 10.9) and 84.7 mm Hg (SD 6.9), respectively. Compared with the control group, the net changes in systolic blood pressure and diastolic blood pressure were -4.31 mm Hg (95% CI, -2.11 to -6.51 mm Hg; P < 0.001) and -2.76 mm Hg (CI, -1.35 to -4.16 mm Hg; P < 0.001), respectively, after the 12-week intervention. The net changes in systolic and diastolic blood pressure reductions were -7.88 mm Hg (CI, -4.66 to -11.1 mm Hg) and -5.27 mm Hg (CI, -3.05 to -7.49 mm Hg), respectively, in persons with hypertension and -2.34 mm Hg (CI, 0.48 to -5.17 mm Hg) and -1.28 mm Hg (CI, 0.52 to -3.07 mm Hg), respectively, in those without hypertension.
Limitations: This trial did not examine whether the blood pressure reduction was due to protein or isoflavones in soybean.
Conclusions: Soybean protein supplementation resulted in a reduction in systolic and diastolic blood pressure. These findings suggest that increased intake of soybean protein may play an important role in preventing and treating hypertension.
Hypertension has become a global public health challenge, affecting approximately 50 million individuals in the United States and 1 billion individuals worldwide (1, 2). The prevalence of hypertension has increased dramatically in developing countries during the past several decades (1, 3) and has increased slightly in the United States according to a recent national survey (4). Hypertension is not only very common but is also an important major modifiable risk factor for cardiovascular disease, stroke, and chronic kidney disease (5-7). Lifestyle modification, including nutritional intervention, provides an important approach for preventing and treating hypertension (2, 8). Clinical trials have documented that weight loss, exercise, alcohol restriction, sodium reduction, and potassium supplementation reduce blood pressure in both hypertensive and prehypertensive persons (2, 8). The effect of dietary macronutrients on blood pressure has not been well studied, although clinical trials indicate that diets rich in fruits, vegetables, and low-fat dairy products and with reduced saturated and total fat (Dietary Approaches to Stop Hypertension [DASH] diet) lower blood pressure (9).
Several epidemiologic studies have observed an inverse relationship between dietary protein intake and blood pressure (10-14). The few clinical trials that examined the effect of an increased intake of dietary protein on blood pressure produced conflicting results (10, 15, 16). In most of these trials, change in blood pressure was not the primary outcome of interest, the sample size was small, and only a single blood pressure measurement was obtained at the baseline and termination visits (10). We conducted a randomized, double-blind, controlled multicenter trial to test the effect of soybean protein supplementation on systolic and diastolic blood pressure among individuals with prehypertension or stage 1 hypertension in 3 samples of community residents in the People's Republic of China.
Study Participants
Trial participants were men and women 35 to 65 years of age who had an average systolic blood pressure of 130 to 159 mm Hg, diastolic blood pressure of 80 to 99 mm Hg, or both based on an average of 9 readings (3 observations at each of 3 screening visits). The criteria for exclusion were self-reported use of antihypertensive medications in the previous 2 months; a history of cardiovascular disease, diabetes mellitus, cancer, chronic obstructive pulmonary disease, psychiatric disease, or any other serious life-threatening illness that required regular medical treatment; serum creatinine level of 150.3 µmol/L or greater (≥1.7 mg/dL) at the screening examination; or alcohol intake of 21 drinks or more per week or at least 40 g/d. We also excluded women who were pregnant or who intended to become pregnant during the study.
The study sites conducted community-based blood pressure prescreening to recruit the trial participants. We invited 862 persons who met blood pressure and other criteria at prescreening and who were willing to participate in the trial to the study clinics for screening visits. Of them, 302 persons met all eligibility criteria and were randomly assigned (Figure 1). Of the 302 trial participants, 150 were recruited from Beijing, 84 were recruited from Hebei province, and 68 were recruited from Hubei province.
Study participants who were assigned to the intervention group received 40 g of isolated soybean protein supplement per day in cookies for 12 weeks, while those in the control group received 40 g of complex carbohydrate from wheat in cookies during the same period. The Sanjiang Food Company (Heilongjiang province, People's Republic of China) provided the isolated soybean protein supplements. The soybean protein and control cookies were prepared centrally in Beijing and had the same appearance and taste. The daily nutritional content of the cookies was similar for those in the soybean protein supplement group and the control group, except for dietary protein and carbohydrate content: total energy (594.0 kcal vs. 577.1 kcal), protein (49.0 g vs. 12.9 g), carbohydrate (64.8 g vs. 95.3 g), fat (15.4 g vs. 16.1 g), saturated fat (2.4 g vs. 2.6 g), monounsaturated fat (6.2 g vs. 6.3 g), polyunsaturated fat (7.0 g vs. 7.2 g), and sodium (145.3 mg vs. 145.8 mg). The Food Science and Human Nutrition Laboratory of Iowa State University, Ames, Iowa, and Ralston Analytical Laboratories, St. Louis, Missouri, measured isoflavones in duplicate. The measurements were almost the same between the 2 laboratories, and we report the average. The daily portion of the soybean protein cookies contained 76.4 mg of total isoflavone, 44.9 mg of genistein, 26.5 mg of daidzein, and 4.9 mg of glycitein.
During the intervention, a study dietitian instructed study participants to reduce other food intake so that the total energy intake would be constant during the course of the trial. Most study participants consumed study cookies in place of their usual breakfast, and a few study participants consumed study cookies in place of their usual lunch. Participants were also instructed to maintain their usual level of physical activity, alcohol intake, and dietary sodium intake. We monitored each participant's body weight biweekly during the study and provided dietary consultation when we observed more than a 2-kg weight gain.
The study participants returned unconsumed cookies at their 6- and 12-week follow-up visits after randomization. The study coordinator counted the number of cookies returned, and we used this to assess the participants' adherence to their assigned intervention.
Discussion
Our study contributes important information on the role of a nutritional intervention in lowering blood pressure. First, we demonstrated that soybean protein supplementation reduced blood pressure in persons with an average systolic blood pressure of 130 to 159 mm Hg, diastolic blood pressure of 80 to 94 mm Hg, or both. Several small clinical trials previously reported inconsistent findings regarding the effect of soybean protein on blood pressure (10, 15, 16). Washburn and colleagues (15) compared the effect of 20 g of soybean protein containing 34 mg of phytoestrogens given either in 1 dose or in 2 doses with that of 20 g of complex carbohydrates on cardiovascular disease risk factors and menopausal symptoms among 51 women in a randomized, controlled trial. They observed a statistically significant reduction in diastolic blood pressure in the twice-daily soybean protein diet compared with the carbohydrate control diet (Table 3). Burke and colleagues (16) examined the effects of soybean protein on 24-hour ambulatory blood pressure among 41 treated hypertensive patients in a randomized, controlled trial. Compared with the controls, mean 24-hour systolic and diastolic blood pressure statistically significantly decreased in those assigned to soybean protein supplementation (Table 3). Our study, with the largest sample size and several measurements of blood pressure, indicated that soybean protein supplementation reduced both systolic and diastolic blood pressure.
Second, our trial documented that the blood pressure reduction associated with soybean protein supplementation was greater than that of the carbohydrate control. Conventionally, increased intake of complex carbohydrate has been recommended as a replacement for saturated fat intake to reduce cardiovascular risk (19). Our findings suggest that vegetable protein, such as soybean protein, may be an ideal replacement for saturated fat because of its apparent capacity to reduce cardiovascular disease risk.
Third, we consistently noted blood pressure reduction in men and women, in younger and older participants, and in obese and nonobese individuals, suggesting that the results might be broadly applicable to the general population. In the participants with hypertension, the reduction in blood pressure with soybean protein supplementation was greater than that noted with most other currently recommended lifestyle modification interventions, except for a combined dietary intervention with changes in several micronutrients and macronutrients (DASH diet) (9, 20-23). As such, soybean protein supplementation should probably be recommended as an effective approach for reducing blood pressure in persons with stage 1 hypertension. The blood pressure reduction did not achieve a conventional level of statistical significance in persons without hypertension in our trial. Our study was not designed, however, to have sufficient statistical power to test for a blood pressure reduction effect within subgroups.
The average intake of dietary protein at baseline was 69 g/d in our study participants. This is similar to the corresponding intake in general Chinese adult populations (24, 25). On the basis of data from the Third National Health and Nutrition Examination Survey (NHANES III), the average intake of dietary protein is 79 g/d in the U.S. general adult population (26). Dietary protein is mainly from plant foods in the People's Republic of China but from animal foods in the United States (24-26). Given these differences, whether our study findings can directly apply to the U.S. general population is unclear. Additional soybean protein supplementation trials in the U.S. general population would help resolve this area of uncertainty.
A limitation of our study was that dietary nutrient intake was not as strictly controlled as is possible in a feeding study. During the intervention, we instructed study participants to reduce their intake of other foods to balance their total energy intake. On average, dietary protein intake accounted for 12% of participants' calories at baseline. Consumption of soybean protein cookies reduced dietary protein from other foods by 18 g/d. According to the 24-hour dietary recall data, the net increase in dietary protein intake was 26 g, less than the targeted 40 g/d. Reduced protein intake from other foods might have biased the blood pressure-lowering effect of soybean protein toward the null. Another limitation of our study was that we did not examine whether the blood pressure reduction was due to soybean protein or isoflavones. Future research is needed to compare the effect of blood pressure reduction among different dietary proteins and to study the effect of isoflavones on blood pressure.
Few observational epidemiology studies have noted an increased risk for bladder cancer associated with soy consumption in Asian populations (27, 28). For example, compared with the lowest quartile of energy-adjusted total soy intake (<36.9 g/1000 kcal), the highest quartile of total soy intake (≥92.5 g/1000 kcal) was associated with a 2.3-fold (CI, 1.1-fold to 5.1-fold) higher risk for bladder cancer after adjustment for cigarette smoking and level of education in the Singapore Chinese Health Study (27). The Shanghai Cohort Study (28) reported similar results. Compared with men consuming soy less than once per week, the relative risks for those who consumed soy 1 to fewer than 3 times per week, 3 to fewer than 7 times per week, and daily were 2.05 (CI, 0.80 to 5.29), 2.45 (CI, 0.89 to 6.76), and 4.61 (CI, 1.57 to 13.51) (P = 0.004 for trend), respectively, after adjustment for age, cigarette smoking, and level of education. Because these studies observed few bladder cancer cases, additional investigations are warranted to confirm or refute these findings and to explore the causality of any such association.
The underlying mechanisms by which dietary protein may influence blood pressure are not entirely clear. One plausible hypothesis is that dietary protein supplementation may result in a higher concentration of proteins rich in specific amino acids in regions of the brain or blood vessel wall, triggering a vasodilatory response (29). Soybean protein contains high levels of arginine, the metabolic precursor of the potent vasodilator nitric oxide (30). Intravenous injection of arginine in humans substantially decreases blood pressure and total peripheral resistance (31, 32). In addition, protein intake leads to increased sodium, water, and urinary-free dopamine excretion levels in humans (33, 34). The dopamine-mediated, protein-induced natriuresis may play a role in the blood pressure-lowering effect of protein (34). Compared with normotensive patients, patients with hypertension were found to have a decreased urinary-free dopamine response in the postabsorptive state after protein ingestion (35). Furthermore, animal experiments suggest that soybean protein may improve insulin sensitivity and glucose tolerance (36, 37). Lavigne and colleagues (36) found that soybean protein-fed rats had lower fasting plasma glucose and insulin concentrations and higher glucose disposal rates than casein-fed animals. Dietary soybean protein may increase insulin-receptor gene expression in Wistar fatty rats and reduce insulin resistance due to a defect of insulin-receptor gene expression (37). Insulin resistance and the concomitant compensatory hyperinsulinemia may be a major underlying pathogenetic mechanism of hypertension (38).
Soybean protein supplementation has been shown to decrease serum concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglycerides in randomized, controlled trials and has been recommended as way to decrease serum lipid levels (39, 40). Our study, a randomized, double-blind, controlled trial in Chinese adults, documented a statistically significant blood pressure reduction related to soybean protein supplementation. Results from our study provide new evidence supporting dietary soybean protein supplementation to prevent and treat hypertension.
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