JAMA March 18, 1998

Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE)

P K Whelton, L J Appel, M A Espeland, W B Applegate, W H Ettinger Jr, J B Kostis, S Kumanyika, C R Lacy, K C Johnson, S Folmar, J A Cutler; TONE Collaborative Research Group

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Bottom Line

In older adults with hypertension controlled by a single medication, dietary sodium reduction and weight loss interventions successfully improved blood pressure control and facilitated the safe withdrawal of antihypertensive therapy.

Key Findings

1. The primary composite endpoint (return of high blood pressure, resumption of antihypertensive medication, or a cardiovascular event) was significantly less frequent among participants assigned to reduced sodium intake compared to those who were not (relative hazard ratio, 0.69; 95% CI, 0.59-0.81; P < .001).

2. Among obese participants, the primary endpoint was significantly lower for those assigned to weight loss compared to those not assigned to weight loss (relative hazard ratio, 0.70; 95% CI, 0.57-0.87; P < .001).

3. Relative to usual care, obese participants demonstrated the greatest benefit from a combined intervention, with hazard ratios of 0.60 (95% CI, 0.45-0.80) for sodium reduction alone, 0.64 (95% CI, 0.49-0.85) for weight loss alone, and 0.47 (95% CI, 0.35-0.64) for combined sodium reduction and weight loss.

4. At the end of the trial, approximately 30% of all participants successfully remained off their antihypertensive medications without experiencing a cardiovascular event or a return of high blood pressure.

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

975

Patients

Duration

29 mo

Median

Setting

4 academic centers, US

Population Men and women aged 60 to 80 years with hypertension controlled (systolic BP < 145 mm Hg and diastolic BP < 85 mm Hg) on a single antihypertensive medication. The cohort included 585 obese and 390 nonobese participants.

Intervention Reduced dietary sodium intake (target ≤80 mmol/d), weight loss (target ≥4.5 kg), or a combination of both, followed by supervised withdrawal of baseline antihypertensive medication 3 months after intervention onset.

Comparator Usual care, followed by the identical supervised withdrawal of baseline antihypertensive medication.

Outcome A composite of the diagnosis of high blood pressure at one or more follow-up visits, the resumption of antihypertensive medication, or a cardiovascular event following medication withdrawal.

Study Limitations

• The median follow-up of 29 months was relatively short, limiting the ability to assess the long-term impact of these interventions on cardiovascular morbidity and hard mortality endpoints.

• The study population was restricted to older adults whose blood pressure was already well-controlled on a single antihypertensive agent, limiting generalizability to patients with severe or treatment-resistant hypertension.

• The intensive behavioral and dietary interventions utilized in the trial may be difficult to replicate, scale, and maintain long-term in routine clinical practice.

• Due to the nature of lifestyle modifications, participants and interventionists could not be blinded, which could introduce performance bias, though objective blood pressure parameters and blinded adjudication of adverse events were utilized.

Clinical Significance

The TONE trial provided definitive, landmark evidence that lifestyle modifications—specifically sodium restriction and weight loss—are highly effective and safe in older adults with hypertension. It demonstrated that targeted nonpharmacologic therapy can allow a substantial proportion of elderly patients to successfully discontinue antihypertensive medication, thereby reducing the risks of polypharmacy and medication-related side effects in the geriatric population.

Historical Context

Published in 1998, TONE emerged during a pivotal era for lifestyle medicine, coinciding closely with the publication of the DASH diet trials. While the benefits of salt restriction and weight loss were generally accepted for younger populations, there was prevailing skepticism regarding the safety, feasibility, and efficacy of these interventions in older adults. TONE dispelled these doubts, cementing lifestyle modification as a foundational first-line and adjunctive strategy for hypertension management in the elderly.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the physiological mechanisms by which age-related vascular changes make older adults particularly sensitive to dietary sodium reduction for blood pressure control?

Key Response

Older adults often develop increased arterial stiffness, endothelial dysfunction, and decreased renal sodium excretory capacity, leading to volume-dependent, salt-sensitive hypertension. Understanding this pathophysiology explains why the TONE study found sodium reduction to be so highly effective in facilitating medication withdrawal in this specific demographic.

Resident

When considering a trial of deprescribing antihypertensives in an older adult as demonstrated in the TONE study, what clinical criteria and monitoring parameters should guide your decision to safely taper and stop the medication?

Key Response

Residents must balance the risks of polypharmacy with the necessity of hypertension management. The TONE study highlights that patients controlled on a single agent who adhere to rigorous lifestyle modifications (sodium restriction, weight loss) are ideal candidates, but close outpatient BP monitoring is required to detect rebound hypertension and prevent cardiovascular events.

Fellow

How does the combination of weight loss and sodium reduction interact synergistically at the level of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, and why is this relevant for managing resistant hypertension in older adults?

Key Response

Obesity drives sympathetic overdrive and RAAS activation, while high sodium intake expands intravascular volume and blunts RAAS suppression in salt-sensitive individuals. Combining these interventions targets both volume and neurohormonal pathways, offering a powerful non-pharmacologic foundation before escalating to complex, multi-drug regimens in difficult-to-control older patients.

Attending

As an attending physician aiming to reduce polypharmacy, how can we practically implement and sustain the intensive behavioral modifications used in the TONE study within a standard primary care clinic where resources for dietitians and frequent follow-ups are limited?

Key Response

The TONE study utilized rigorous, intensive behavioral interventions. The attending-level challenge is translating trial efficacy into real-world effectiveness, utilizing multidisciplinary teams, remote monitoring, and community resources to sustain lifestyle changes and safely maintain the deprescribing of antihypertensives.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The TONE trial utilized a 2x2 factorial design for its obese cohort to evaluate sodium reduction, weight loss, both, or usual care. What are the statistical advantages and limitations of this design for assessing the interaction between two lifestyle interventions, and how might incomplete adherence skew the interaction term?

Key Response

Factorial designs efficiently evaluate two interventions simultaneously and their interaction. However, in lifestyle trials, differential non-adherence across groups can reduce statistical power to detect an interaction effect, complicating the interpretation of whether weight loss and sodium reduction are truly additive or synergistic.

Journal Editor

Given that the primary endpoint involved the necessity to restart antihypertensive medication or the occurrence of a cardiovascular event, how might the unblinded nature of the behavioral interventions introduce ascertainment bias in the treating physician's decision to restart medications?

Key Response

A critical reviewer would flag that since patients and their treating physicians knew their lifestyle group assignment, there could be a higher threshold to restart medications in the active intervention arms due to subconscious bias or patient reluctance, potentially threatening the internal validity of the time-to-endpoint analysis.

Guideline Committee

Based on the findings of the TONE study, should current ACC/AHA guidelines formally incorporate specific, algorithmic protocols for deprescribing antihypertensives in older adults who achieve targeted lifestyle modification metrics, and what level of evidence supports this?

Key Response

Current guidelines heavily emphasize initiating therapy and lifestyle changes for BP control but offer less standardized guidance on deprescribing. The TONE trial provides high-quality evidence that deprescribing is safe and effective in older adults controlled on monotherapy who adopt strict lifestyle changes, suggesting guidelines could formally recommend a trial of deprescribing to minimize polypharmacy and adverse events in this specific phenotype.

Clinical Landscape

Noteworthy Related Trials

1997

DASH Trial

n = 459 · NEJM

Tested

DASH diet rich in fruits, vegetables, and low-fat dairy

Population

Adults with high-normal blood pressure or stage 1 hypertension

Comparator

Typical American control diet

Endpoint

Change in systolic and diastolic blood pressure

Key result: The DASH diet significantly lowered systolic and diastolic blood pressure compared to the typical American diet.

1997

TOHP II Trial

n = 2,382 · Arch Intern Med

Tested

Weight loss and sodium reduction interventions

Population

Overweight adults with high-normal blood pressure

Comparator

Usual care control group

Endpoint

Incidence of clinical hypertension

Key result: Weight loss and sodium reduction independently and jointly reduced the incidence of hypertension over a follow-up of multiple years.

2001

DASH-Sodium Trial

n = 412 · NEJM

Tested

Low dietary sodium intake combined with the DASH diet

Population

Adults with prehypertension or stage 1 hypertension

Comparator

Higher sodium intake levels on a control diet

Endpoint

Change in systolic blood pressure

Key result: Reducing sodium intake significantly lowered blood pressure, with the greatest reductions observed when combined with the DASH diet.

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