Weekly Journal Scan: the (BP)ROAD to optimal blood pressure control in type-2 diabetes

This comment refers to ‘Intensive Blood-Pressure Control in Patients with Type 2 Diabetes’, published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2412006. The Blood Pressure Control Target in Diabetes (BPROAD) is a parallel-design, publicly funded, randomized clinical trial to evaluate the efficacy of an intensive treatment regimen [targeting a systolic blood pressure (BP) of <120 mmHg] in reducing the risk of cardiovascular disease (CVD) among patients with type 2 diabetes (T2D), as compared with standard treatment (targeting a systolic BP of <140 mmHg). The primary outcome was a composite of non-fatal stroke, non-fatal myocardial infarction (MI), treatment or hospitalization for heart failure (HF), or death from cardiovascular causes. Secondary outcomes included fatal or non-fatal stroke, fatal or non-fatal MI, treatment or hospitalization for HF, death from cardiovascular causes, death from any cause, and an expanded composite of the primary outcome or death from any cause, development of chronic kidney disease (CKD) or progression of the disease in patients with CKD at baseline.1 Patients with T2D aged 50 years or older were considered eligible if they had an elevated systolic BP (defined as 130–180 mmHg in patients taking antihypertensive medications or at least 140 mmHg in patients not taking medications) and an increased risk of CVD (defined as having one or more of the following: a history of clinical CVD at least 3 months before enrolment, subclinical CVD within 3 years before enrolment, two or more risk factors, and CKD with an estimated glomerular filtration rate of 30 to <60 mL per minute per 1.73 m2 of body surface area). A total of 12 821 patients with T2D (6414 in the intensive-treatment group and 6407 in the standard-treatment group) were enrolled at 145 sites across China from February 2019 through December 2021. The mean age was 64 years, with 45% of female patients and 22% with a history of cardiovascular events. Glycated haemoglobin level (mean 7.6%) body mass index, waist circumference, and lipid levels were similar in the two groups. There were no differences in antihypertensive and glucose-lowering drugs used in the two groups at baseline, and BP was 140 mmHg in both groups. At 1 year, the mean systolic BP was 121 mmHg in the intensive-treatment group (with more antihypertensive drugs used) and 133 mmHg in the standard-treatment group. Approximately 60% of patients in the intensive-treatment group met the systolic BP target within 1 year. During a median follow-up of 4.2 years, 393 patients in the intensive-treatment group (1.7 events per 100 person-years) experienced a primary outcome event vs. 492 patients (2.1 events per 100 person-years) in the standard-treatment group [hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.69–0.90; P < .001] (number needed to treat to prevent one event, 250 patients). Fatal or non-fatal stroke occurred in 284 patients (1.2 events per 100 person-years) in the intensive-treatment group vs. 356 patients (1.5 events per 100 person-years) in the standard-treatment group (HR, 0.79; 95% CI, 0.67–0.92). No differences were found for fatal or non-fatal MI (0.3 events per 100 person-year in both groups), treatment or hospitalization for HF, death from cardiovascular causes, death from any cause, and CKD development/progression. Data were consistent across the prespecified subgroups. There was no significant between-group difference in the incidence of serious adverse events. However, symptomatic hypotension and hyperkalaemia rates were higher with intensive treatment. Patients with diabetes often have elevated BP or hypertension, and the natural history of the concomitance of these conditions is reflected by a high risk of major cardiovascular events.2 Hypertension is the most important modifiable cardiovascular risk factor, and its prevalence steadily increases with ageing.3 Substantial evidence supports the beneficial role of BP-lowering therapy in reducing CVD and mortality. However, the timing and thresholds of the BP-lowering pharmacological intervention, as well as the optimal targets, have been long debated and still remain uncertain.4,5 Studies in patients with T2D have described a J-shaped association between BP and the risk of CVD, and the lack of a clear benefit of the treatment on cardiac outcomes for the lower BP levels reported in some meta-analyses has led to cautious recommendations for more intensive management of BP levels.6–8 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial compared an intensive BP-lowering treatment with the standard of care in patients with T2D, and failed to show any benefit on CV outcomes.9 In the Systolic Blood Pressure Intervention Trial (SPRINT), which enrolled patients at high cardiovascular risk but excluded patients with diabetes or prior stroke, an intensive BP-lowering treatment strategy was associated with a significant 27% lower risk of major cardiovascular events.10 According to this and other evidence, current guidelines consistently recommend a tighter BP control, targeting BP levels below 130/80 mmHg in most hypertensive patients aged ≤65.3,11 More recently, the Effects of Intensive Systolic Blood Pressure Lowering Treatment in Reducing Risk of Vascular Events (ESPRIT) trial further supported the benefits of ‘the lower–the better’ strategy, showing a significant reduction in the risk of major vascular events among patients with and without diabetes who received intensive BP treatment.12 In the wake of these studies, the findings of BPROAD provide support to the efficacy of a more intensive treatment strategy targeting a BP of <120 mmHg in preventing major cardiovascular events in patients with T2D. The discrepancy with the ACCORD trial could be explained by different factors, such as the higher statistical power, the selected composite primary endpoint, the differences in the frequency of stroke/MI in the two populations (US/Canada vs. China), and the better glycaemic control of patients, which may suggest that the beneficial effects of antihypertensive treatment may be partially offset in patients with poorly controlled diabetes. Some important limitations of BPROAD need to be considered. First, the BP target selected for the standard-treatment group appears somewhat obsolete, and it is not in line with the current recommendations of the major international guidelines.3,11 The choice of a BP cut-off value of <130 rather than 140 mmHg would have provided more meaningful evidence to define the benefits of a more intensive strategy in comparison to what is already recommended in the current guidelines. In fact, in the standard-treatment group, systolic BP remained well above the recommended target of 130 mmHg throughout the trial. In addition, diastolic BP levels were significantly different between the treatment groups, which makes it difficult to dissect the independent effect of systolic BP impact on the results. The open-label design involving both physicians and patients and the use of telephone interviews to collect data during the COVID-19 pandemic should not be neglected in interpreting the results, though the outcome assessors were blinded to treatment allocation. Finally, the study was performed in a Chinese population, and the results obtained should be extended with caution to other ethnic populations, especially since the benefits on the primary endpoint were largely driven by the reduction of stroke, which is the most common CVD among Chinese people. In spite of these limitations, BPROAD is a large study which provides additional proof to the mounting evidence supporting the potential benefits of tighter BP control in diabetic patients, addressing a clinically relevant aspect, as these patients are at higher risk of CVD and may derive a greater absolute benefit from more intensive BP control. Further studies across non-Chinese cohorts are needed to support the generalizability of the results of ESPRIT and BPROAD. D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from, Astra Zeneca, Bayer, GSK, Menarini Int, Novartis Pharma, Novo Nordisk, Pfizer, Sanofi Pasteur, and Servier. M.V. is supported by a research grant from Italian Ministry of Health (‘Ricerca corrente’).