Uncertainty about the systolic blood pressure target in people with diabetes

Results of ABCD NT

The ABCD NT trial is the only randomized controlled trial (RCT) cited by the CDA guideline to support a target SBP of less than 130 mm Hg.⁵ This small study randomized 480 patients with type 2 diabetes to different DBP targets. The intensive therapy group received nisoldipine or enalapril to achieve a DBP reduction of 10 mm Hg from the baseline measurement. The moderate therapy group received placebo and aimed for a DBP of 80 to 89 mm Hg. After a mean of 5.3 years, the achieved BPs were 128/75 mm Hg and 137/81 mm Hg in the intensive and moderate therapy groups, respectively. There was no statistically significant difference in the primary outcome of change in creatinine clearance. However, there was benefit in some secondary outcomes including stroke, proteinuria, and retinopathy.

The CDA acknowledges the limitations of ABCD NT and gives the recommendation to achieve an SBP of less than 130 mm Hg a grade C evidence level, indicating it is based on a non-randomized clinical trial or cohort study. The CDA also cites 2 cohort studies supporting an SBP target of less than 130 mm Hg.^14,15 However, while these 2 observational studies indicate fewer microvascular and macrovascular outcomes with lower SBP, they do not prove that lowering SBP with antihypertensive medication will lead to fewer such outcomes and do not provide definitive evidence for a specific treatment target. Again, family physicians might not be aware of the low quality of evidence supporting the recommended SBP target of less than 130 mm Hg.

Results of ACCORD BP

The publicly funded ACCORD BP (Action to Control Cardiovascular Risk in Diabetes—Blood Pressure) trial was designed to address this lack of RCT evidence¹⁶ and, according to the CDA guidelines, would provide stronger evidence for an optimal SBP treatment target.⁵ The ACCORD BP trial was a large study (N = 4733) that randomized patients with type 2 diabetes to a target SBP of less than 120 mm Hg or less than 140 mm Hg.¹⁶ Mean baseline BP was 139/76 mm Hg. Both groups were allowed to take the same medications. After a mean of 4.7 years, mean BPs were 119/64 mm Hg and 134/71 mm Hg in the intensive and moderate treatment groups, respectively. There was no significant difference between the 2 groups in the primary composite outcome of myocardial infarction (MI), stroke, and death. There was a statistically significant reduction in the risk of stroke (2.6% vs 1.5%, absolute risk reduction 1.1%, number needed to treat 92 [95% CI 53 to 356]). However, there was also an increase in serious adverse events with a number needed to harm of 50 (95% CI 35 to 87) (Table 1).^16,17 While ACCORD BP did not test an SBP target of less than 140 mm Hg against a target of less than 130 mm Hg, it is unlikely that a target of 130 mm Hg would be preferable, as even a target of 120 mm Hg did not provide beneft.¹⁶ An SBP target of less than 120 mm Hg might lead to a small reduction in stroke, and some patients might wish to incur the extra costs and possible adverse effects of intensive BP lowering if they place a high value on stroke prevention.¹⁸

Evidence for identifying an SBP target

The RCT evidence for and against an SBP target of less than 130 mm Hg revolves around 2 studies, ABCD NT¹¹ and ACCORD BP.¹⁶ The CDA and the Canadian Hypertension Education Program have not changed their recommendations since ACCORD BP was published and presumably are basing their recommendations on ABCD NT. Table 2^4,5,11,16 summarizes the key features of the 2 RCTs.

Uncertainty about efficacy is not the only factor to consider when identifying an appropriate SBP target. It is also important to consider the safety and practicality of reaching the target. Osher et al aimed to reduce BP in 257 patients with type 2 diabetes to less than 130/85 mm Hg, as was recommended when the study was conducted.¹⁹ Initial mean BP was 159/86 mm Hg, reflecting that most patients were already taking antihypertensive medications. An SBP of 130 mm Hg was reached by only 33% of patients, and DBP was lowered to 70 mm Hg or lower in 57% of patients. Lower DBPs were associated with advancing age, higher initial SBPs, and pre-existing coronary artery disease. The decline in DBP was not associated with any drug class or combination of drugs. The authors concluded that attempted lowering of SBP to less than 130 mm Hg is associated with inordinate lowering of DBP in a substantial number of patients. They also questioned if the benefits of tight SBP control to less than 130 mm Hg outweighed the risks of excessive diastolic reduction, especially in older patients with diabetes or those with coronary artery disease and diabetes.

The question of harm from excessive lowering of DBP remains unanswered. A recent meta-analysis of 31 BP-lowering trials in 73 913 persons with diabetes found no evidence of increased risk of MI from excessive lowering of DBP.²⁰ However, this finding was not based on individual patient data but on meta-regression, which is like an epidemiologic study of the included RCTs. Therefore, results might have been affected by unknown confounding variables.^18,21

A secondary analysis of INVEST (International Verapamil-Trandolapril Study) did find evidence of harm. The original INVEST trial randomized 22 576 patients with hypertension and coronary artery disease to antihypertensive therapy based on either a calcium channel blocker or a β-blocker.²² After a mean of 2.7 years, there was no significant difference in the primary composite outcome of all-cause death, nonfatal MI, and nonfatal stroke between the 2 treatment groups. The secondary analysis explored the relationship between achieved SBP and DBP and the primary outcome and its individual components.²³ The primary outcome, total MI, and total stroke occurred more frequently with a DBP lower than 70 mm Hg than with a DBP of 70 to 90 mm Hg (Table 3).^17,23 Although the analysis was based on patient-level data, it has limitations, as it was a post hoc observational study of an RCT and included only 6400 patients with diabetes. Nevertheless, physicians should be aware of the possibility of harm from excessive lowering of DBP when trying to achieve a target SBP of 130 mm Hg or less.

Summary

Patients with diabetes benefit from antihypertensive treatment. The uncertainty is in the recommended target of 130 mm Hg or lower. Achieving such a target can be difficult and there is the possibility of harm. The 2013 American Diabetes Association has updated its target SBP position statement. It states there is level B evidence from well-conducted cohort studies that “People with diabetes and hypertension should be treated to a systolic blood pressure goal of < 140 mm Hg.”²⁴ It also states there is level C evidence from poorly controlled or uncontrolled studies that “Lower systolic targets, such as < 130 mm Hg, may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden.”²⁴