BPROAD

Published

Bi Y, et al. "Intensive blood-pressure control in patients with type 2 diabetes". The New England Journal of Medicine. 2024. e-pub 2024-11-6:1-13.
PubMed • PDF • ClinicalTrials.gov

Clinical Question

Among adults with type 2 diabetes and hypertension at elevated CVD risk, does intensive BP control (targeting SBP <120 mm Hg) lower risk of nonfatal stroke, nonfatal MI, HF events, or CVD mortality when compared to standard BP control (SBP <140 mm Hg?).

Bottom Line

In this large Chinese RCT, adults with type 2 diabetes and hypertension at elevated CVD risk who were randomized to intensive BP control (SBP <120 mm Hg) had lower risk of nonfatal stroke, nonfatal MI, HF events, or CVD mortality when compared to persons randomized to standard BP control (SBP <140 mm Hg).

Major Points

Diabetes and hypertension are major CVD risk factors. Among persons without diabetes, there is evidence that SBP targets below the JNC7 threshold of 140 mm Hg are associated with lower CVD and HF events. For example, SPRINT (2015) found a 25% lower risk of first ACS, stroke, HF, or CV death among persons with certain CVD risk factors who were randomized to intensive BP control (SBP <120) in comparison to standard BP control (SBP 135-139). Importantly, SPRINT excluded persons with diabetes. Largely because of the findings of SPRINT, the 2017 ACC/AHA-led hypertension guidelines lowered the hypertension threshold from 140/90 mm Hg (of JNC7 era) to 130/80 mm Hg, and recommended initiation of antihypertensive therapies at 130/80 mm Hg for persons at higher CVD risk and 140/90 mm Hg in all.

SPRINT excluded persons with diabetes primarily because of the negative ACCORD BP trial (2010). ACCORD BP was part of the larger ACCORD trial, which randomized intensive BP control among persons with DM. There were numerically fewer CVD events in the intensive BP control arm of ACCORD BP relative to the standard BP arm, but the comparison between the arms did not reach statistical significance (1.87 vs. 2.09%/yr; P=0.20). ACCORD BP had fewer than expected CVD events and might have been too small to detect a difference between BP targets (N=4,733). In the post-SPRINT era, there was interest in determining if intensive BP control among persons with diabetes might lead to similar benefits as persons without diabetes.

Published in 2024, the Blood Pressure Control Target in Diabetes (BPROAD) trial randomized 12,821 Chinese men and women with diabetes and also additional CVD risk factors to an intensive BP target (<120 mm Hg) or a standard BP target (<140 mm Hg). With a median follow-up of 4.2 years, there was a 21% lower risk of the composite CVD endpoint among persons randomized to the intensive BP arm (1.65 vs. 2.09/100 P-Y; HR 0.79; 95% CI 0.69-0.90; P<0.001). Intensive BP control was generally well tolerated, but there were more persons with symptomatic hypotension and also high potassium in this arm. Taken together with ACCORD BP and SPRINT, BPROAD confirms that intensive BP control is associated with lower risk of CVD events among persons with diabetes at elevated CVD risk.

Guidelines

As of November 2024, no guidelines have been published that reflect the results of this trial.

Design

• Open label, multicenter RCT
• N=12,821
  • Intensive BP treatment (n=6414)
  • Standard BP treatment (n=6407)
• Setting: 145 sites in China
• Enrollment: 2019-2021
• Median follow-up: 4.2 years
• Analysis: Intention-to-treat
• Primary outcome: Nonfatal stroke, Nonfatal MI, HF hospitalization or treatment, or CVD mortality

Population

Extended details are in the protocol.

Inclusion Criteria

• Men and women aged ≥50y
• Diabetes defined as:
  • Self-report diagnosis by health professionals on diabetes medications
  • FPG ≥126 mg/dL
  • OGTT 2-hour PG ≥200 mg/dL
  • Hgb A1c ≥6.5%
  • For lab diagnosis, the confirmatory test must be repeated on a subsequent day.
• SBP at a threshold:
  • ≥140 mm Hg on no meds
  • 130-180 mm Hg on 1 meds
  • 130-170 mm Hg on 2 meds
  • 130-160 mm Hg on 3 meds
  • 130-150 mm Hg on 4 meds
• At elevated CVD risk with ≥1 of the following:
  • Prior clinical CVD more than 3 months prior
    • Stroke
    • MI
    • PCI/CABG
    • CEA or carotid stent
    • PAD with revascularization
    • ACS, ECG on graded exercise test, positive cardiac imaging study
  • Subclinical CVD in prior 3 years:
    • Microalbuminuria
    • ≥50 stenosis of coronary artery, carotid artery, or lower extremity artery
    • CAC ≥400 Agatson units
    • ABI ≤0.90
    • LVH (unclear criteria for this)
  • ≥2 CVD risk factors
    • Current smoker
    • BMI &Ge;28 kg/m² or waist circumference ≥90 cm in men or ≥85 cm in women
    • Current lipid-lowering medication or LDL-c ≥130; HDL-C <40 mg/dL; tg ≥150 mg/dL
• eGFR 30-59 mL/min/1.73 m²

Exclusion Criteria

• T1DM
• Secondary hypertension
• Orthostatic hypotension
• CVD event (including UA) or procedure in prior 3 months
• Symptomatic HF in prior 6 months or LVEF <35%
• ALT or AST >2x ULN
• Proteinuria (e.g., 24h protein ≥1g/d, 24h albumin ≥600 mg/d, spot protein/creatinine ≥1 g/g, or albumin/creatinine ≥600 mg/g)
• PCKD or glomerulonephritis
• Cancer diagnosis and treated in prior 2 years
• Organ transplant
• Survival <5y
• Issues likely to limit adherence
• Usual pregnancy/breast feeding exclusions

Baseline Characteristics

From the intensive BP treatment arm.

• Demographics: Female sex 46%, age 64 years, high school diploma or greater 48%
• Hypertension details: BP 140/76 mm Hg, duration 12 years, any antihypertensive 99%
  • BP meds: ACE inhibitor 14%, ARB 44%, CCB 59%, diuretic 7%, alpha blocker 1%, beta blocker 15%, other 3%
• Diabetes details: Duration 10 years, fasting glucose 149 mg/dL, A1c 7.6%
  • Any hypoglycemic medication: 99%
    • Hypoglycemic meds: Insulin 49%, metformin 66%, TZD 3%, sulfonylurea 15%, alpha-glucosidase inhibitor 34%, GLP1 agonist 4%, DPP-4 antagonist 10%, SGLT2 inhibitor 10%
• CVD details: Prior CVD 23%, subclinical CVD 34%
  • CVD meds: Statin 65%, aspirin 50%
• Anthropometrics: 27 kg/m2, waist circumference 95 cm
• Other labs: LDL 158, HDL 40, TG 130 mg/dL; eGFR 89 ml/min/1.73 m² (eGFR <60 8%), ACR ≥30 40

Interventions

• Participants were randomized to a BP target in open label fashion
  • Intensive treatment - Systolic BP <120 mm Hg
  • Standard treatment - Systolic BP <140 mm Hg
• BP medications followed a standard algorithm in section 4.3 of the protocol The backbone of therapy was ACE-i/ARB, CCB, or diuretics.

Outcomes

Shown as intensive vs. standard BP treatment.

Primary Outcome

Components of the primary outcome that are themselves secondary outcomes are shown here for simplicity.

Nonfatal stroke, Nonfatal MI, HF hospitalization or treatment, or CVD mortality

1.65 vs. 2.09/100 P-Y (HR 0.79; 95% CI 0.69-0.90; P<0.001)

Fatal or nonfatal MI: 0.28 vs. 0.33/100 P-Y (HR 0.84; 0.60-1.16)

Fatal or nonfatal stroke: 1.19 vs. 1.50/100 P-Y (HR 0.79; 0.67-0.92)

HF hospitalization or treatment: 0.13 vs. 0.19/100 P-Y (HR 0.66; 0.41-1.04)

CVD mortality: 0.24 vs. 0.32/100 P-Y (HR 0.76; 0.55-1.06)

Secondary Outcomes

All-cause mortality

0.69 vs. 0.73/100 P-Y (HR 0.83; 0.74-0.94)

Primary outcome or all-cause mortality

2.07 vs. 2.48/100 P-Y (HR 0.83; 0.74-0.94)

CKD progression

1.61 vs. 1.11/100 P-Y (HR 1.36; 0.71-2.59)

CKD development

1.14 vs. 1.05/100 P-Y (HR 1.11; 0.92-1.34)

Incident albuminuria

11.29 vs. 13.84/100 P-Y (HR 0.87; 0.77-0.97)

Additional Outcomes

Mean (median) SBP at 1 year

122 (118) vs. 133 (135) mm Hg

Subgroup Analysis

There was a similar effect size for the primary outcome when stratified by age, sex, prior CVD, prior CKD, baseline SBP level, baseline A1c, duration of DM, and duration of hypertension.

Adverse Events

Serious

36.5% vs. 36.3% (HR 1.00; 0.94-1.06; P=0.96)

Conditions of interest

Arrhythmia: 1.1% vs 1.1% (P=0.95)

Electrolyte abnormality: 0.6% vs. 0.6% (P=0.91)

Injurious fall: 1% vs. 1% (P=0.74)

Symptomatic hypotension: 0.1% vs. <0.1% (HR 7.92; 95% 0.99-63.34 P=0.05 - presumably >0.05)

Syncope: 0.2% vs. 0.2% (P=0.99)

Acute renal failure: 0.1% vs. 0.1% (P=0.73)

Clinical safety alerts

Sodium

<130 mmol/L: 0.7% vs. 0.8% (P=0.89)

>150 mmol/L: 0.4% vs. 0.4% (P=0.65)

Potassium

<3 mmol/L: 0.5% vs. 0.5% (P=0.90)

>5.5 mmol/L: 2.8% vs. 2.0% (HR 1.41; 1.12-1.17; P=0.003)

Criticisms

• Open label
• This trial occurred during the heyday of the Covid-19 pandemic and some of the assessments transitioned away from in-person.
• ~40% of the intensive treatment group met their targets at 1 year.
• Occurred in China, possibly limiting generalizability
• Inclusion criteria did not consider an existing risk prediction model, such as the Pooled Risk Equation, Framingham Risk Score, or Reynold's Risk Score

Funding

Various public and university funding sources in China.