The Trials of Hypertension Prevention (TOHP) II study addressed the issue of whether weight loss is effective in preventing the onset of hypertension in people with borderline blood pressure. This was a multi-center, randomized clinical trial where subjects were randomized to four different treatment groups: 1)weight loss alone, 2) sodium restriction alone, 3) combination of weight loss and sodium restriction, or 4) usual care (control). Inclusion criteria were men and women 30 to 54 years old, body mass index (BMI) of 26.1 to 37.4 kg/m2 for men and 24.4 to 37.4 kg/m2 for women (110% to 165% of ideal body weight), diastolic blood pressure of 83 to 89 mmHg and systolic blood pressure of less than 140 mmHg (Table 1.)

     Exclusion criteria included: current pharmacological treatment that could affect blood pressure, any cardiovascular disease, diabetes mellitus, significant renal insufficiency, and current or planned pregnancy.
     Subjects who were randomized to the weight loss group had a target weight loss of 4.5 kg (10 lb) during the first 6 months of the intervention. The program consisted of an initial individual counseling session followed by 14 weekly group meetings led by dietitians or health educators. Afterwards, the participants attended 6 biweekly meetings and then monthly meetings. The program consisted of behavioral changes, nutrition education, information on physical activity, and social support system to aid in these lifestyle changes. The duration of the trial was 3 years.
     The weight loss group had mean decrease in weight of 4.4 kg at 6 months, 2.0 kg at 18 months and 0.2 kg at 36 months. The control group had a mean increase in weight of 0.1, 0.7, and 1.8 kg, respectively (Table 2).

     The investigators further categorized the weight loss group into 3 sub-groups based on degree of weight loss maintenance (Table 3).

     Of the 3 sub-groups, only participants in the first tertile maintained a significant decrease in blood pressure. The other groups eventually regressed to their baseline blood pressure at 36 months. The effect on blood pressure was greatest in the group that lost the most weight and the group that maintained the weight loss for the longest period of time. The overall effect was noted to be a 0.35 mmHg reduction in diastolic blood pressure and a 0.45 mmHg reduction in systolic blood pressure per kg of weight loss.
     A secondary outcome of the TOHP II study was to determine if there was an effect on the onset of hypertension (defined as systolic blood pressure >140 or diastolic blood pressure > 90) in these sub-groups. The investigators compared the various sub-groups and the relative risk in developing hypertension (Figure 1). The only sub-group that had a statistically significant risk reduction was the successful maintenance sub-group.
     On the surface, these results are promising. However, it is important to note 13% of the participants in the study could maintain the weight loss for 36 months despite the intensive nature of the intervention. Certainly, this is a low number considering the support these people received during the trial. There was a direct correlation between the number of meetings the participants attended and the amount of weight loss. Another troubling result is that even the sub-group that successful maintained their weight loss, the blood pressure readings trended upwards after the initial 6 month weight loss period. This may indicate that weight loss alone will not prevent the onset of hypertension over the long term.

     Furthermore, although we have sufficient evidence that the pharmacological treatment of hypertension can reduce events, it is not known whether the risks of cardiovascular disease and stroke are reduced by these preventative methods. Further studies are needed to evaluate this possibility. Interestingly, there are a few studies which indicate that changes in weight, either an increase or decrease, can increase the risk of cardiovascular events. The rationale is that weight cycling can be deleterious and is commonly seen in obese patients.

The Treatment in Obese Patients with Hypertension (TROPHY) Study
     Since many obese patients will develop hypertension and may not be able to make the necessary lifestyle modifications, medications are a vital part to the treatment plan for obese hypertensives. The JNC VI recommends thiazide diuretics and beta-blockers as first-line medications since they are the only drug classes which have been shown to decrease cardiovascular events in large-scale prospective randomized trials. However, the paradigm for treating hypertension continues to evolve, and the primary care physician needs to realize that the optimal treatment for each patient is different based on a number of individual patient characteristics including: ethnicity, gender, co-morbid medical conditions, etc.
     The Treatment in Obese Patients with Hypertension (TROPHY) study group compared patients treated with an ACE inhibitor, lisinopril, versus patients treated with HCTZ. This was a 12 week, multicenter, double-blind, randomized clinical trial monitoring 232 obese patients with hypertension. Patients were enrolled in the study with a BMI range of 28 to 40 kg/m2 for men and 27 to 40 kg/m2 for women. These patients also had to have diastolic blood pressure readings of between 90 and 109 mmHg at two consecutive visits and at the final visit before randomization. Patients were then randomized to receive lisinopril or HCTZ. At 4 week intervals, blood pressures were recorded and medication regimens were titrated to the next highest dose if response did not meet pre-determined criteria.
     The results of the study showed that 57% of the patients had an adequate response to the low dose of lisinopril (10 mg/d), but only 29% of the patients had an adequate response to the low dose of HCTZ (12.5 mg/d). Additionally, 46% of patients on HCTZ needed the highest does (50 mg/d). There were variations in the response to treatment by race. Black patients had a better response with HCTZ (52%) than to lisinopril (33%). On the other hand, white patients responded better to lisinopril (43%) than to HCTZ (20%). Younger patients also had a better response to lisinopril. These results may be explained by the fact that black patients tend to have a low renin hypertension and lisinopril may not have dramatic effects in such a setting. The greater overall effectiveness of lisinopril may have been at least partially secondary to the fact that the majority of TROPHY subjects were Caucasians.

     Other hypertension medications have been studied with regards in obese patients. Patients on beta-blockers have been shown to have less weight reduction after caloric restriction when compared to HCTZ and placebo. The mechanism of this phenomenon is unclear and further studies are needed to address this question, as well as the relative effectiveness of other anti-hypertensive classes including calcium channel blockers and angiotensin receptor blockers.

Conclusion:
     Both hypertension and obesity continue to be a major problem for patients and health care workers alike. As the people in the United States get older and more obese, prevention of hypertension becomes a more important task. Based on data from the TOHP II Trial, it appears that with appropriate diet and weight loss, it is possible for obese people to avoid developing hypertension, along with its complications and the side effects of the medications used to treat it. This non-pharmacological therapy should be approached as a continuing endeavor, with the help of a multidisciplinary team, patients must be encouraged to adopt beneficial lifestyle modifications. However, even in the most ideal circumstances such as were present in the TOHMS Study, patient compliance with long-term behavior modification tends to fall short. Given this fact, it seems unlikely that we can prevent the development of hypertension in the majority of obese persons through weight loss alone.
     As such, many of our obese patients will go on to develop hypertension, and medications will be needed in addition to lifestyle modification. The primary care physician must be cognizant of the dynamic world of hypertension treatment and must consider the effects of obesity on hypertension and tailor medicine regimens with this in mind. In the TROPHY Study, an ACE-inhibitor was found to be somewhat more effective in controlling blood pressure than a diuretic in a cohort of obese subjects with mild to moderate hypertension. Nonetheless, there was significant variability in individual response, especially as pertains to race. In light of the fact that many of our obese patients are at high cardiovascular risk due to other concomitant risk factors (such as diabetes) combination anti-hypertensive therapy will likely be needed in a majority of cases to achieve aggressive blood pressure lowering goals.

References:

1. Thompson D; Edelsberg J; Colditz GA; Bird AP; Oster G. Lifetime health and economic consequences of obesity. Arch Intern Med 1999 Oct 11;159(18):2177-83.

2. Stevens, V., Obarzanek, E., et. al., Long-Term Weight Loss and Changes in Blood Pressure: Results of the Trials of Hypertension Prevention, Phase II. Ann Intern Med. 2001; 134:1-11.

3. Blair, SN, Shaten, J, Brownell, K, et. Al. Body weight change, all-cause mortality, and cause-specific mortality in the Multiple Risk Factor Intervention Trial. Ann Intern Med 1993; 119:749

4. Reisin, E, Weir, M, et. al. Lisinopril Versus Hydrochlorothiazide in Obese Hypertensive Patients. Hypertension. 1997; 30:140-145.

5. Davis, BR, Oberman, A, Blaufox, MD, et. al. Effect of Antihypertensive Therapy on Weight Loss. Hypertension 1992; 19:393.

6. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1993; 153:598-615.