What is the most appropriate target SBP in persons with hypertension and diabetes mellitus?

In this issue, Ó Hartaigh et al.[1] use data from the action to control cardiovascular risk in diabetes blood pressure (ACCORD BP) trial to test whether achieving target SBP less than 120 mmHg (intensive group) or less than 140 mmHg (standard group) lowers the risk of major adverse cardiovascular events (MACE) in persons with hypertension and diabetes mellitus [2]. The major finding was that, after adjustment for other statistically significant predictors of MACE, there was no significant reduction in the risk of MACE in those in the intensive group who achieved SBP less than 120 mmHg versus those who did not, whereas in the standard group, those who achieved the target SBP less than 140 mmHg had a significant (35–53%) reduction in the risk of MACE compared with those who maintained SBP more than 140 mmHg. The authors conclude that achieving a SBP goal of 120–140 mmHg is beneficial in reducing the risk of cardiovascular disease (CVD) outcomes in persons with hypertension and diabetes mellitus, whereas achieving SBP less than 120 mmHg does not further mitigate the risk of CVD outcomes. The study by Ó Hartaigh et al.[1] is limited by differences in baseline characteristics of the participants, including characteristics that are significant predictors of MACE, between those who achieved the SBP targets versus those who did not. Individuals who achieved SBP less than 120 mmHg or less than 140 mmHg were younger, more likely to be White, had a higher level of education, less evidence of renal complications, and a lower baseline SBP, whereas persons who did not achieve either target had an overall higher CVD risk profile (higher baseline SBP, higher percentage of smoking, increased prevalence of Blacks). There was a two-fold or greater increased risk of cardiovascular events, including cardiovascular death, in those who did not achieve either SBP target, and initial univariate Cox regression analyses based on data that were unadjusted for predictors of MACE showed significant reduction in MACE with achievement of target BP in both the intensive and standard treatment groups. However, after adjusting for predictors of MACE (including age, education, DBP, hemoglobin A1c, high/low density lipoprotein, intensive glycemic arm, and urine albumin to creatinine ratio), multivariable Cox regression analyses no longer showed significant reductions in CVD outcomes in the intensive group, but continued to show significant reductions in those who achieved a target of SBP less than 140 mmHg. Randomized controlled trials (RCTs) providing evidence for an appropriate SBP target in persons with both hypertension and diabetes mellitus are limited. Early clinical trials did not consistently show a reduction in CVD outcomes with intensive BP treatment in hypertensive patients with diabetes mellitus [3,4]. The more recent ACCORD BP trial randomly assigned hypertensive patients with diabetes mellitus and a history of CVD or two or more risk factors for CVD to either standard BP treatment (target SBP <140 mmHg, mean achieved SBP 134 mmHg) or intensive BP treatment (target SBP <120 mmHg, mean achieved SBP 119 mmHg) [2]. A nonsignificant 12% reduction in the annual rate of the primary composite endpoint (nonfatal myocardial infarction (MI), nonfatal stroke, or CVD associated mortality) was observed in the intensive treatment group compared with the standard treatment group at a mean follow-up of 4.7 years, but with a 95% confidence interval (CI) that included the possibility of a much larger reduction (27%). ACCORD BP lacked statistical power, which likely contributed to the nonsignificant difference in outcomes between the two treatment groups. Further, the primary outcome included events that were relatively insensitive to BP reduction (nonfatal MI, and CVD associated mortality, including unexpected death presumed to be because of ischemic CVD and presumed cardiovascular death). In addition, ACCORD BP had a two-by-two factorial design in which persons were randomized to either intensive or standard glycemic control, in addition to different BP treatment targets [5]. There was a 26% reduction in the primary endpoint in the intensive BP and standard glycemic control group, indicating benefit of intensive BP lowering. Ó Hartaigh et al.[1] attribute the lack of statistically significant reduction in cardiovascular outcomes with intensive BP treatment reported in ACCORD BP to not analyzing the results by achieved SBP. Based on their analysis of individuals who achieved the SBP targets, they conclude that a SBP less than 120 mmHg does not mitigate risk for MACE. Meta-analyses evaluating the effect of different SBP targets on CVD events in persons with diabetes mellitus offer inconsistent conclusions. Some find maximal benefit from a target BP less than 140/90 mmHg based on findings that treating to lower targets in individuals with baseline SBP less than 140 mmHg worsens CVD outcomes, suggesting a J-shaped association between CVD risk and SBP [6,7]. Other studies show increased rates of adverse effects associated with intensive BP lowering coupled with no CVD benefit, except for stroke reduction [8,9]. A meta-analysis limited to hypertensive patients with diabetes mellitus showed decreased rates of stroke and all-cause mortality when a target SBP 135 mmHg or less was achieved [10]. Thomopoulos et al. in a meta-analysis of 41 RCTs limited to persons with hypertension and DM showed no additional benefit in reduction of non-fatal CVD outcomes, all-cause death, and end stage renal disease related to achieving SBP <130 mmHg [11]. A very recent analyses by the same investigators in persons with DM and high CVD risk (>5% risk of CVD associated death in 10 years) confirmed the findings of the prior study [12]. The authors acknowledged that, in patients with DM and hypertension, data with achieved SBP <130 mmHg are few, and more evidence is needed. Few RCTs of antihypertensive treatment have been designed to analyze results based on achieved BP, rather than treatment to a specific target. Bundy et al.[13] recently carried out a meta-analysis of 42 RCTs (30 RCTs including participants with diabetes mellitus; n = 144 220) that analyzed results according to mean achieved SBP to assess the relationship between achieved SBP levels and CVD risk. The lowest risk of CVD and all-cause mortality occurred at SBP 120–124 mmHg (hazard ratio CVD 0.71, 95% CI 0.60–0.83; hazard ratio all-cause mortality 0.73, 95% CI 0.58–0.93) compared with mean SBP 130–134 mmHg, SBP 140–144 mmHg, SBP 150–154 mmHg, and SBP ≥160 mmHg). No evidence of a J-shaped association between SBP and CVD outcomes was observed. Eryd et al.[14] in a large population-based cohort study (n = 187 106) of men and women with hypertension and diabetes mellitus, but no prior history of CVD, compared CVD risk among six levels of achieved SBP (110–119 mmHg, 120–129 mmHg, 130–139 mmHg, 140–149 mmHg, 150–159 mmHg, ≥160 mmHg). Participants with SBP 110–119 mmHg had significantly lower risk of nonfatal acute MI, total acute MI, nonfatal CVD, total CVD, and nonfatal coronary heart disease compared with those with SBP 130–139 mmHg. Interestingly, those with SBP 110–119 mmHg had the highest rate of total mortality, which the authors attributed to underlying concomitant disease. Thus, recent observational and RCT data provide evidence that achieving a SBP less than 120 mmHg may be associated with reduction in CVD outcomes. The Ó Hartaigh et al. study [1] addresses an area of controversy that has been the topic of many recent analyses, commentaries, as well as deliberations of BP guideline committees. It is well documented that lowering BP in persons with hypertension, with or without diabetes mellitus, reduces CVD risk. Large scale population studies have shown a strong, log-linear relationship between SBP and CVD-associated mortality down to SBP of 115 mmHg [15]. However, optimal BP targets in persons with both hypertension and diabetes mellitus remain debated as discussed above. Further, there are inconsistencies in consensus guidelines regarding BP targets for patients with hypertension and diabetes mellitus. The Eight Joint National Committee and European Societies of Hypertension and Cardiology guidelines recommend a BP target of less than 140/90 mmHg in persons with both diabetes mellitus and hypertension [16,17]. The American Diabetes Association, while endorsing the recommendation for a BP target less than 140/90 mmHg, specifically advocates for achieving lower BP (130/80 mmHg) in those with diabetes mellitus who are at high risk for CVD [18]. The Canadian Cardiovascular Society recommends a lower BP target of less than 130/80 mmHg, whereas the National Heart Foundation of Australia recommends a BP target of less than 140/90 mmHg in these patients, except for those in whom the prevention of stroke is prioritized, in which case a SBP target less than 120 is recommended [19,20]. Guidelines from the United States regarding the management of hypertension in persons with diabetes mellitus are currently under development and will carefully consider the presence of diabetes mellitus as a possible determinant of target SBP. The study by Ó Hartaigh et al.[1] further raises the question of SBP targets in various patient subgroups, particularly the elderly and those with chronic kidney disease (CKD). They reported that elderly individuals (65 years or older) with diabetes mellitus did not benefit significantly from achieving either the intensive SBP target (hazard ratio 0.99, 95% CI 0.63–1.50) or the standard SBP target (hazard ratio 0.76, 95% CI 0.50–1.20). The lack of statistical significance in this analysis is likely because of the small number of clinical events observed. Older individuals have been shown to benefit from more intensive SBP targets in previous studies. The Systolic Blood Pressure Intervention Trial enrolled a large subpopulation of elderly individuals without diabetes mellitus (mean age 68 years, 2636 ≥ 75 years of age) and showed a significant reduction in the primary composite endpoint (first occurrence of nonfatal MI, other acute coronary syndrome, stroke, heart failure hospitalization, or cardiovascular-related death) in the intensive treatment group compared with the standard group (hazard ratio 0.67, 95% CI 0.49–0.91) that was even greater than that seen in the trial as a whole (hazard ratio 0.75, 95% CI 0.64–0.89) [21,22]. Further, Bavishi et al.[23] in a meta-analysis of four RCTs (n = 10 857) assessed the safety and efficacy of SBP lowering in individuals aged 65 years and older with and without diabetes mellitus. The results showed a significant reduction in CVD events [relative risk (RR) 0.71, 95% CI 0.60–0.84] and mortality (RR 0.67, 95% CI 0.45–0.98) with target SBP less than 140 mmHg. The ACCORD BP trial, on which the Ó Hartaigh study [1] was based, excluded persons with CKD (creatinine >1.5 mg/dl) and the estimated glomerular filtration rate (GFR) in study participants in the Ó Hartaigh et al. study averaged ∼90 ml/min per 1.73 m2. In the United States, the prevalence of CKD in individuals with diabetes mellitus is estimated at 44% overall, with 43% of diabetic individuals 65 years and older having a GFR of less than 60/ml/min/1.73 m2[24]. Systolic Blood Pressure Intervention Trial was enriched with participants (28%, n = 2646) with baseline CKD (GFR 20–59 ml/min per 1.73 m2). Intensive BP treatment reduced cardiovascular outcomes (hazard ratio 0.81, 95% CI 0.63–1.05) and mortality (hazard ratio 0.72, 95% CI 0.53–0.99) in the CKD subgroup, indicating that these patients benefit from stringent SBP lowering compared with standard lowering [21]. The recent Chronic Renal Insufficiency Cohort study enrolled men and women (n = 3708) with or without diabetes mellitus and with mild-to-moderate CKD to investigate the relationship between BP and CKD progression [25]. Participants were followed over a median of 5.7 years and the progression of CKD was assessed according to baseline SBP and time-updated SBP. There was a 2.6-fold increased risk of progression to end-stage renal disease in those with SBP at least 130 mmHg compared with those with SBP less than 120 mmHg. These data provide evidence that achievement of a strict SBP target in those with CKD provides improved clinical outcomes long term. The study by Ó Hartaigh et al.[1] addresses what SBP target should be achieved to prevent CVD outcomes in those with hypertension and diabetes mellitus. The authors conclude that achieving SBP less than 120 mmHg does not reduce the risk of CVD outcomes more than achieving SBP less than 140 mmHg. They postulate that the presence of diabetes mellitus results in underlying vascular damage, which may not be reversible with aggressive BP lowering and may be associated with intolerance of aggressive BP lowering strategies, a hypothesis that must be tested in future RCTs. The findings of their study are limited by its being a post hoc analysis of a treatment to target study, as opposed to a prespecified analysis of the comparative results of achieving two different BP goals. Overall, clinicians need to weigh the risks and benefits of aggressive BP lowering for individual patients, including those with diabetes mellitus. A SBP less than 120 mmHg may be feasible and beneficial long term; however, this approach needs to be tempered by the risk of adverse effects associated with hypotension and multiple antihypertensive agents. A personalized approached balancing the patient's comorbidities and risks/benefits with aggressive BP lowering should be considered. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

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