Stratified medicine for blood pressure targets in type 2 diabetes mellitus

Major guidelines agree that blood pressure (BP) targets should be similar for people with or without type 2 diabetes mellitus (T2DM). The 2023 European Society of Hypertension (ESH) guideline, endorsed by the European Renal Association (ERA), and the most recent 2024 European Society of Cardiology (ESC) guideline set systolic blood pressure (SBP) targets of 120–129 mmHg and diastolic blood pressure (DBP) targets of 70–79 mmHg for people with T2DM [1, 2]. A major contributor to this recommendation was the ACCORD trial (NCT00000620), which recruited 4733 participants with T2DM and hypertension and compared an SBP target of <120 mmHg with a target of <140 mmHg. The ACCORD trial did not observe statistically significant differences in a primary composite outcome of non-fatal myocardial infarction (MI), non-fatal stroke or death from cardiovascular causes over a mean follow-up of 4.7 years {annual rates 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group; hazard ratio [HR] with intensive therapy 0.88 [95% confidence interval (CI) 0.73–1.06]; P = .20} [3]. There was a difference in the risk of total stroke favouring the intensive target [HR 0.59 (95% CI 0.39–0.89)] and a lower mean urine albumin:creatinine ratio (UACR; 11 versus 13.3 mg/g in the two groups; P < .001), but with simultaneously increased the risk of an estimated glomerular filtration rate (eGFR) decrease of <30 ml/min/1.73 m2 at any point (4.2% versus 2.2% of participants; P < .001) and identical rates of any dialysis or kidney failure (1.2% versus 1.2% of participants; P = .91). The larger BPROAD trial (NCT03808311) has enrolled 12 821 participants with T2DM and hypertension to compare similar SBP targets and found a reduced incidence of the primary composite outcome of non-fatal stroke, non-fatal MI, treatment or hospitalization for heart failure or death from cardiovascular causes in the intensive therapy group over 4.2 years [1.65 events/100 person-years versus 2.09 events/100 person-years; HR 0.79 (95% CI 0.69–0.90); P < .001] [4]). Furthermore, while ACCORD emphasized an increased risk of serious adverse events attributed to antihypertensive treatment (3.3% in the intensive-therapy group and 1.3% in the standard-therapy group; P < .001), BPROAD did not observe differences for overall serious adverse effects (36.5% versus 36.3%). At first sight, the results of the two trials appear to differ, but an in-depth analysis suggests that similar results were obtained in two populations that differed for the baseline risk of specific cardiovascular events. BPROAD and ACCORD recruited participants in different countries (China and the USA/Canada, respectively), which resulted in different ancestries (Asian and 85% White/Black, respectively), and at different time points (2019–2021 and 2003–2005, respectively), which resulted in different background treatments, as sodium–glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists were part of the diabetic regime in BPROAD in ≈25% of participants [3, 4]. The number of medications needed to achieve the targeted BP was lower in BPROAD than in ACCORD (2.2/1.4 versus 3.4/2.1, respectively, for intensive/standard arms at 3 years). There were also differences in specific antihypertensive agents (e.g. beta-blockers 14–15% at entry and 20–30% at 48 months in BPROAD versus 25% at entry and 43–61% at study end in ACCORD). However, key baseline demographic characteristics were similar, including age, sex, duration of diabetes and baseline SBP and DBP (Supplementary Table S1). While mean body mass index (BMI) was lower in BPROAD (26.7 ± 3.2 versus 32.1 ± 5.6 kg/m2), it was still in the obesity range for ancestry-adjusted thresholds. Different BMI thresholds have been proposed to diagnose overweight and obesity for Asians (overweight ≥23, obese class 1 25–29.9 kg/m2) and non-Asians (overweight ≥25, obese class 1 30–34.9 kg/m2), based on association with risk [5]. Still, the different BMIs may have impacted the results. BMI represents an actionable item given that some drugs (SGLT2 inhibitors, GLP1 receptor agonists) decrease kidney and cardiovascular (but not stroke) events and also body weight. Additionally, BPROAD participants were generally less educated and more frequently smokers. They also less frequently had a history of cardiovascular disease (CVD) and better metabolic control (glycaemia, haemoglobin A1C, low-density lipoprotein cholesterol levels). While kidney function was generally preserved, the UACR was slightly higher at baseline in BPROAD. Both trials were successful in achieving predefined mean SBP targets during the course of the trials [BPROAD: mean SBP 121.6 mmHg (median 118.3 mm Hg) in the intensive-treatment group and 133.2 mm Hg (median 135.0 mm Hg) in the standard-treatment group; ACCORD: mean SBP 119.3 mm Hg and 133.5 mm Hg, respectively]. The primary outcome definition was similar in both trials [3, 4], although BPROAD also incorporated treatment or hospitalization for heart failure. Cardiovascular deaths and heart failure were uncommon in both trials, accounting for <100 events in each arm. The most common events were stroke events in BPROAD (72.4% of events for 26.2% in ACCORD) and MI in ACCORD (Figure 1A and B). Both trials concurred in the significant protection offered from stroke to participants in the intensive-treatment arm, which was represented by a numerically higher HR in BPROAD than in ACCORD [HR 0.79 (95% CI 0.67–0.92) versus 0.59 (0.39–0.89)]. The HR for MI was very similar [HR 0.84 (95% CI 0.60–1.16) versus 0.87 (0.68–1.10), respectively] (Figure 1C). Thus, while atenolol was reported to be less protective against stroke than amlodipine in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm trial [6], the greater use of beta-blockers in ACCORD than in BPROAD did not seem to impact the results. Overall, despite the totally differing conclusion regarding the primary endpoint, as BPROAD found a statistically significant decrease in cardiovascular risk while ACCORD did not, both trials reproduced very similar results for stroke and MI and the different conclusion may have been driven by the larger sample size of BPROAD and, crucially, by the higher baseline risk of stroke in its study population. Cardiovascular outcomes in the BPROAD and ACCORD clinical trials of intensive BP control in people with T2DM. (A) Incidence of the primary outcome, its individual components and all-cause death in BPROAD. The pie chart represents the percentage of strokes among primary outcome events in the standard SBP target arm. (B) Incidence of the primary outcome, its individual components, heart failure and all-cause death in ACCORD. The pie chart represents the percentage of strokes among primary outcome events in the standard SBP target arm. (C) Hazard ratio (95% confidence interval) for these outcomes in the BPROAD and ACCORD clinical trials. Although BPROAD had secondary kidney outcomes, they are difficult to interpret, since they did not follow standard definitions of chronic kidney disease (CKD) based on eGFR and UACR thresholds [7] and there were too few CKD progression events. However, there was a suggestion of protection from albuminuria progression (UACR ≥10 mg/g) in those with baseline UACR <10 mg/g [HR 0.87 (95% CI 0.77–0.97)]. In this regard, albuminuria progression was the most common endpoint analysed, occurring in 14/100 person-years in the standard-treatment arm. Meta-analyses are planned that include both BPROAD and ACCORD and will be useful for guideline developers. However, they may be less informative than the trials themselves, as both trials enrolled different populations with very different background cardiovascular risks but obtained similar results regarding protection from stroke by intensive SBP control. A major lesson from BPROAD and ACCORD is that lower SBP targets protect from stroke and this protection acquired relevance regarding overall CVD protection in populations at high risk for stroke. Future guidelines should incorporate this information when setting SBP targets for people with T2DM and hypertension. In other words, stratified medicine should be incorporated in the decision-making process for BP targets in T2DM. Stratified medicine refers to subpopulations rather than individuals. For individuals, the terms precision or personalized medicine may apply. Similar to China, stroke is also the first overall cause of death and disability-adjusted life years (DALYs) in other Asian countries such as South Korea and also in European countries including Portugal, Georgia, North Macedonia and Montenegro [8]. Indeed, nearly 60% of the world population lives in countries with age-standardized stroke incidence rates >110/100 000 people, including most of Eastern Europe and Turkey, while in the USA and many Western European countries, rates are 56.7–76.3/100 000 people [9]. At least 15 countries have higher stroke incidence rates than China, including Bulgaria and North Macedonia. A similar stratified medicine approach is already recommended by the 2021 ESC guidelines on CVD prevention in clinical practice, which incorporate the country of origin to estimate the risk of CVD in the decision-making process regarding initiation of primary prevention interventions [10]. The Systemic Coronary Risk Estimation-2 (SCORE2) algorithm estimates an individual's 10-year risk of fatal and non-fatal CVD events (MI, stroke) in apparently healthy people ages 40–69 years with risk factors that are untreated or have been stable for several years. SCORE2-OP (older people) applies to people ≥70 years of age. Portugal is considered a moderate-risk country and Georgia, Bulgaria and North Macedonia very-high-risk countries in this guideline. This classification applies to persons not already having TD2M or CKD, since ESC guidelines already assign a high or very high risk of CVD to persons with moderate to severe CKD [11]. Countries with very different risks for MI and stroke may choose to assign greater priority to stroke when establishing SBP targets, if this is the main local cardiovascular health issue, lowering the threshold to initiate treatment of hypertension or lowering the target SBP. Eventually, different SBP targets may be applied to individuals at increased risk of stroke (e.g. because of combined clinical and polygenic risk scores) within the same country. The EURECAm working group is an official body of the European Renal Association. Funding was received from Comunidad de Madrid en Biomedicina (P2022/BMD-7223, CIFRA_COR-CM), Instituto de Salud Carlos III (ISCIII) (PI22/00469, PI22/00050, PI21/00251, PI23/00627), ERA-PerMed-JTC2022 (SPAREKID AC22/00027), ERAPERMED2022-248-SIGNAL (AC22/00028), RICORS program to RICORS2040 (RD21/0005/0001, RD24/0004/0001) co-funded by the European Union and SPACKDc PMP21/00109, FEDER funds, COST Action PERMEDIK CA21165, supported by COST (European Cooperation in Science and Technology), PREVENTCKD Consortium (Project ID 101101220, Programme EU4H DG/Agency: HADEA), KitNewCare (Project ID: 101137054, Call: HORIZON-HLTH-2023-CARE-04, Programme: HORIZON, DG/Agency: HADEA.PICKED (Project ID: 101168626 HORIZON-MSCA-2023-DN-01-01 MSCA Doctoral Networks 2023). BFF and AO wrote a draft of the manuscript. JMV, LV and PS worked in the draft. All authors reviewed the final version. No original data was used in the present manuscript. A.O. has received grants from Sanofi and consultancy, speaker fees or travel support from Astellas, AstraZeneca, Bioporto, Boehringer Ingelheim, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Sobi, Menarini, Lilly, Chiesi, Otsuka, Novo Nordisk, Sysmex, Vifor Fresenius Medical Care Renal Pharma and Spafarma and is Director of the Catedra UAM-AstraZeneca of chronic kidney disease and electrolytes. He has stock in Telara Farma.

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