The goal of treating hypertension in patients with diabetes is to prevent associated macrovascular and microvascular morbidity and mortality. Although for almost 20 years guidelines have recommended lower BP goals in patients with diabetes,2
there is a paucity of evidence supporting this recommendation, particularly for lower systolic BP.11,20
In this observational study, we have shown for the first time, to our knowledge, that decreasing systolic BP to lower than 130 mm Hg in patients with diabetes and CAD was not associated with further reduction in morbidity beyond that associated with systolic BP lower than 140 mm Hg, and, in fact, was associated with an increase in risk of all-cause mortality. Moreover, the increased mortality risk persisted over the long term.
The HOT study, which assigned participants to 3 different diastolic BP goals, showed that patients overall and those assigned to the subgroup of patients with diabetes who were assigned to the 80 mm Hg or less group had significantly reduced adverse outcomes compared with those assigned to higher diastolic BP groups.3
However, although achieved BPs were not reported for the diabetes subgroup, overall, patients assigned to the 80 mm Hg or lower diastolic BP group actually achieved a mean (SD) BP of 139.7 (11.7)/81.1 (5.3) mm Hg, and only approximately 6% of the HOT population had CAD at entry.3
The UKPDS, which enrolled only patients with diabetes, showed that patients assigned to the tight BP control group (<150/85 mm Hg) actually achieved a mean (SD) BP of 144 (14)/82 (7) mm Hg over 9 years of follow-up, which was associated with a significant reduction in microvascular and macrovascular events.4
Although both of these landmark trials provided evidence to support benefits for the patients assigned to lower BP goals, it is important to note that on average, in neither trial was the goal met, and the systolic BP associated with the benefit observed in these trials was significantly higher than what is currently recommended (~140 vs <130 mm Hg) for patients with diabetes.11
In fact, many of the major hypertension clinical trials published in the last decade have shown benefit with regard to cardiovascular and nephropathy risk reduction despite mean systolic BP higher than 130 mm Hg.23
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study24
randomized 4733 patients with hypertension to antihypertensive therapy that was considered either intensive (targeting a systolic BP of <120 mm Hg) or standard (targeting a systolic BP of <140 mm Hg) and evaluated risk for nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes over a mean follow-up of 4.7 years. Unlike HOT and UKPDS for which achieved BP exceeded the randomized target BP, ACCORD after a year of follow-up achieved a mean systolic BP in the intensive group of 119 mm Hg (95% CI, 118.9–119.7 mm Hg) and 133.5 mm Hg (95% CI, 133.1–133.8 mm Hg) in the standard group. This provided the first opportunity in a large randomized clinical trial to assess effects of achieving lower systolic BP in patients with diabetes. For the primary outcome, there was no difference comparing the intensive and standard therapy groups (HR, 0.88; 95% CI, 0.73–1.06; P
=.20). Similarly, there was no difference comparing the groups with all-cause mortality and cardiovascular mortality. There was, however, reduction in risk of total stroke and non-fatal stroke observed in the intensive therapy group, although the overall annual stroke rate was very low (0.32% in the intensive group and 0.53% in the standard group). Importantly, the intensive therapy group had signficantly higher rates of serious adverse events attributed to antihypertensive therapy.24
The ACCORD results are somewhat surprising, particularly in light of the favorable results observed in UKPDS with regard to lower BP targets. However, in ACCORD, patients had lower systolic BP at baseline than was achieved in UKPDS,4
suggesting the benefit observed in the tight-control group of UKPDS was likely based on reducing systolic BP from a mean 160 mm Hg at baseline to 144 mm Hg, and there is less benefit going from an average baseline systolic BP of 139 to 119 mm Hg as was observed in ACCORD.24
In the Appropriate Blood Pressure Control in Diabetes (ABCD) trial,25
patients with diabetes were randomized to intensive vs moderate BP control groups. The mean BP achieved was 132/78 mm Hg in the intensive group and 138/86 mm Hg in the moderate BP control groups.25
The ABCD investigators found that after 5 years, no difference existed between the intensive and moderate groups in the progression of diabetic retinopathy or neuropathy. They also reported no difference in the rate of myocardial infarction, cerebrovascular events, or heart failure comparing the BP control groups. However, unlike in the present study, the ABCD participants in the intensive group had a significant reduction in all-cause mortality.25
This may be explained by ABCD patients being on average a decade younger than those in our study and that only half had any history of cardiovascular disease; whereas all INVEST participants had documented CAD and thus were a higher-risk cohort and were more susceptible to the adverse effects of lower BP. The overall all-cause mortality rate in ABCD was 8% compared with 12.2% in the diabetes cohort of INVEST.
Results from the Irbesartan Diabetic Nephropathy Trial (IDNT) suggested that after a mean follow-up of 2.6 years, in patients with diabetic nephropathy, 60% of whom had a history of heart disease, achieving a systolic BP of 120 mm Hg or less was associated with an increase in all-cause mortality and cardiovascular mortality risk compared with those achieving systolic BP higher than 120 mm Hg.26
The IDNT investigators concluded that BP of 120/85 mm Hg or less may be associated with an increase in cardiovascular events.26
Although patients with creatinine levels of 4 mg/dL (to convert to μmol/L, multiply by 88.4) or more were excluded in INVEST, many had a diagnosis of renal impairment, and we observed a similar and significant increased mortality risk at systolic BP of less than 115 mm Hg.
The UKPDS performed an additional 10 years of follow-up that included in-person and questionnaire visits but no attempt to maintain previously assigned BP-lowering therapies. This long-term follow-up revealed a loss of the benefit realized in the tight-control group within the first 2 years after the study closed. When evaluating the 20-year period encompassing study and poststudy follow-up, there was no significant difference in the rate of any diabetes-related end point, myocardial infarction, microvascular disease, or all-cause mortality comparing the tight-control and less-tight control groups.27
Our long-term follow-up data in the cohort of INVEST participants enrolled in the United States indicate that the increased risk of mortality observed in patients achieving tight control during study follow-up persisted in extended follow-up. Even though we have no BP data during extended follow-up, it is likely that patients were continued on the same or similar antihypertensive regimens and our data raise the possibility that continued maintanence of systolic BP lower than 130 mm Hg could be hazardous over the long term.
Our study has some limitations. This is a post hoc analysis and as such, represents observational data generated from a randomized, controlled clinical trial. We did not randomize a priori to the different systolic BP groups but rather categorized patients according to their achieved systolic BP within the context of the study. This could lead to possible sources of confounding. Individual patient characteristics over and above study treatment play a role in lowering BP. However, after adjustment for differences in baseline characteristics, there remained no difference in the risk of the primary outcome, nonfatal myocardial infarction, and nonfatal stroke comparing the tight-control with the usual-control group. Additionally, our data cannot be generalized to the population of patients with diabetes without CAD. However, as seen with ACCORD, conducting a randomized controlled trial to assess effects of lower systolic BP can also lead to possible sources of bias, including a priori sample selection with regard to level of BP and degree of cardiovascular risk at entry, which may play a role in the outcomes observed.
In conclusion, our data from this post hoc analysis in the cohort of patients with diabetes enrolled in INVEST indicate that tight control of systolic BP was not associated with improved cardiovascular outcomes compared with usual control. At this time, there is no compelling evidence to indicate that lowering systolic BP below 130 mm Hg is beneficial for patients with diabetes; thus, emphasis should be placed on maintaining systolic BP between 130 and 139 mm Hg while focusing on weight loss, healthful eating, and other manifestations of cardiovascular morbidity to further reduce long-term cardiovascular risk.