Keywords
The two major trials of intensive blood pressure control to reduce cardiovascular disease in patients with type 2 diabetes, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Systolic Blood Pressure Intervention Trial (SPRINT), reported seemingly opposite results. ACCORD, conducted exclusively in individuals with type 2 diabetes, showed that targeting a systolic blood pressure <120 mmHg was not associated with cardiovascular benefits. SPRINT, which included people without diabetes, showed that targeting a systolic blood pressure <120 mmHg was beneficial, and raises a critical question: Should blood pressure targets for people with and without diabetes be different?
ACCORD, published in 2010, remains the only large randomized controlled trial of intensive blood pressure control conducted exclusively in people with type 2 diabetes. ACCORD tested the hypothesis that targeting a systolic blood pressure <120 mmHg would reduce major cardiovascular disease events in people with type 2 diabetes.
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Participants were randomized to receive intensive or standard glycemic control; 4733 participants were also randomized to receive intensive or standard blood pressure control (<120 mmHg systolic). The mean systolic blood pressure on enrollment was 139 mmHg. Within 1 year, the intensive-therapy group had a mean systolic blood pressure of 119 mmHg, compared with 134 mmHg for the standard-therapy group. The intensive-therapy group required an average of 3.4 medications for blood pressure compared with 2.1 for the standard-therapy group.The primary outcome, a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, was not significantly different between groups (per year, 1.87% in the intensive-therapy group compared with 2.09% in the standard-therapy group). No subgroup interactions were identified and none of the individual secondary outcomes favored the intensive-treatment group. The rates of serious adverse events (hypokalemia and elevations in serum creatinine level) were significantly higher in the intensive-treatment group.
In 2015, the findings of another large randomized controlled trial, SPRINT, countered those of ACCORD. Importantly, SPRINT excluded people with type 2 diabetes.
2
Like ACCORD, the target systolic blood pressure for the intensive-treatment group was <120 mmHg. The mean systolic blood pressure on enrollment was 140 mmHg. Within 1 year, the intensive-therapy group had a mean systolic blood pressure of 121 mmHg, compared with 136 mmHg for the standard-therapy group. The intensive-therapy group required an average of 2.8 medications for blood pressure compared with 1.8 for the standard-therapy group.Unlike ACCORD, SPRINT was terminated early because of the marked benefit of intensive treatment—a 25% reduction in the primary endpoint of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes, with 1.65% events per year in the intensive-treatment group vs. 2.19% for the standard-treatment group. All-cause mortality was 27% lower in the intensive-therapy group, but the rate of serious adverse events, including hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, was higher.
2
Subsequent guidelines adopted a middle ground for individuals with diabetes, endorsing a systolic blood pressure target of <130 mmHg—a level that no trial evidence has determined to be a more suitable “intensive” target compared with the <120 mmHg targets in ACCORD and SPRINT. The most recent American College of Cardiology/American Heart Association hypertension guidelines recommend a blood pressure target of <130/80 mmHg in individuals with elevated risk for cardiovascular disease, defined as >10% probability of a cardiovascular disease event in the next 10 years as calculated by the American Heart Association/American College of Cardiology Pooled Cohort Equations for Atherosclerotic Cardiovascular Disease (ASCVD). The guideline notes that most patients with diabetes would qualify by cardiovascular disease risk score for the lower 130/80 mmHg target.
3
The 2022 American Diabetes Association guidelines recommend a target of <140/90 mmHg for most patients with type 2 diabetes, with a caveat that <130/80 mmHg would be the target for patients with increased ASCVD risk score (10-year ASCVD risk >15%).- Whelton PK
- Carey RM
- Aronow WS
- Casey DE
- Collins KJ
- Dennison Himmelfarb C
- DePalma SM
- Gidding S
- Jamerson KA
- Jones DW
- MacLaughlin EJ
- Muntner P
- Ovbiagele B
- Smith SC
- Spencer CC
- Stafford RS
- Taler SJ
- Thomas RJ
- Williams KA
- Williamson JD
- Wright JT.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Hypertension. 2018; 71: e13-e115
4
The question remains whether there is an effect of a lower target in individuals with type 2 diabetes. Prior guidelines historically suggested a lower target for such individuals assuming their relative risk reduction was equivalent to those without the condition, and the absolute risk reduction would be greater.The key question is why the presence of type 2 diabetes would nullify the benefit of the lower blood pressure target seen in SPRINT. The National Institutes of Health made both trials’ data publicly available, an open science approach that provided the opportunity for secondary analyses. Many hypotheses were generated, including differences in the study populations, primary outcomes, and number of medications used.
5
Secondary analyses that were made publicly available show that the trials had differences in achieved blood pressure and that in ACCORD, the blood pressure intervention effect differed by glycemic control arm—insights that could influence the studies’ interpretations.A study comparing ACCORD and SPRINT found that the mean achieved blood pressure differences in the trial groups obscured an important difference in the distribution of blood pressure in the trials’ arms.
6
In both trials, the mean blood pressures were similar at baseline, with the intervention, and the systolic difference after intervention was about 15 mmHg, with ACCORD having a slightly smaller between-group difference. However, ACCORD had larger standard deviations of the achieved blood pressures compared with SPRINT (40% versus 20% overlap between the lower and higher target groups, respectively). The achieved blood pressure had a similar relationship with risk in the trials; when split into tertiles (<122, 122–133, >134 mmHg) of systolic blood pressure at 1 year, there was no significant difference in the SPRINT and ACCORD primary outcome composites, or heart failure, between each tertile of SPRINT and ACCORD patients.- Huang C
- Dhruva SS
- Coppi AC
- Warner F
- Li SX
- Lin H
- Nasir K
- Krumholz HM.
Systolic blood pressure response in SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD (Action to Control Cardiovascular Risk in Diabetes): a possible explanation for discordant trial results.
J Am Heart Assoc. 2017; 6e007509
6
This suggests that the reduction in blood pressure had a similar effect but the ACCORD intervention had much more variability in blood pressures (perhaps due to how the intervention was applied), which caused the overall negative result.- Huang C
- Dhruva SS
- Coppi AC
- Warner F
- Li SX
- Lin H
- Nasir K
- Krumholz HM.
Systolic blood pressure response in SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD (Action to Control Cardiovascular Risk in Diabetes): a possible explanation for discordant trial results.
J Am Heart Assoc. 2017; 6e007509
Another nuance of the ACCORD design was the layering of the blood pressure and glycemia interventions. An analysis of ACCORD data for the combinations of blood pressure and glycemia arms revealed a statistically significant risk reduction effect on the primary cardiovascular disease outcome in the intensive blood pressure/standard glycemia arm, but no incremental benefit combining intensive glycemia and intensive blood pressure treatments.
7
One study comparing the ACCORD standard glycemia and intensive glycemic control arms with SPRINT found that the intensive blood pressure intervention in the ACCORD standard glycemia group had a similarly sized positive, statistically significant effect on the composite cardiovascular disease primary outcome as SPRINT. Meanwhile, the effect of intensive blood pressure intervention in the ACCORD intensive glycemia group was not positive.- Margolis KL
- O'Connor PJ
- Morgan TM
- Buse JB
- Cohen RM
- Cushman WC
- Cutler JA
- Evans GW
- Gerstein HC
- Grimm Jr., RH
- Lipkin EW
- Narayan KMV
- Riddle Jr., MC
- Sood A
- Goff Jr., DC
Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial.
Diabetes Care. 2014; 37: 1721-1728
8
In a survival-time analysis of ACCORD data, intensive blood pressure control was found to increase the mean event-free survival of the original cardiovascular disease endpoint only in the standard glycemic control arm.- Beddhu S
- Chertow GM
- Greene T
- Whelton PK
- Ambrosius WT
- Cheung AK
- Cutler J
- Fine L
- Boucher R
- Wei G
- Zhang C
- Kramer H
- Bress AP
- Kimmel PL
- Oparil S
- Lewis CE
- Rahman M
- Cushman WC.
Effects of intensive systolic blood pressure lowering on cardiovascular events and mortality in patients with type 2 diabetes mellitus on standard glycemic control and in those without diabetes mellitus: reconciling results from ACCORD BP and SPRINT.
J Am Heart Assoc. 2018; 7e009326
9
These secondary analyses highlight the difficulties in comparing randomized controlled trials with complex interventions, even those with a similar hypothesis.The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, published in 2021, examined intensive blood pressure control for older Chinese patients with and without diabetes to determine whether intensive treatment (systolic blood pressure target 110 to <130 mmHg) would reduce cardiovascular risk more than standard treatment (target 130 to <150 mmHg).
10
STEP enrolled 8511 patients aged 60–80 years. Average participant age was 66 years and 53% were women. The mean systolic blood pressure on enrollment was 146 mmHg. Within 1 year, the intensive-therapy group had a mean systolic blood pressure of 128 mmHg compared with 135 mmHg for the standard-therapy group. The intensive-therapy group required an average of 1.9 blood pressure medications compared with 1.5 for the standard-therapy group.Like SPRINT, the STEP trial demonstrated cardiovascular disease benefits in the intensive-treatment group—a significant 26% reduction in the primary endpoint of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. The mean achieved systolic blood pressure was 127.5 mmHg in the intensive-treatment group and 135.3 mmHg in the standard-treatment group. Safety outcomes were not worse in the intensive-therapy group. Importantly, the results were approximately the same for individuals with or without diabetes, with no evidence of an interaction—though the trial was not powered to specifically detect a difference in the subgroup of individuals with diabetes.
The combined evidence from ACCORD, SPRINT, and STEP suggests that individuals with type 2 diabetes do not have a different response to blood pressure lowering beyond traditional targets. However, there is evidence that we are not treating patients according to these targets, or even the older targets. A nationally representative dataset in the United States from 2015–2018 showed 52.3% of patients with type 2 diabetes with blood pressure >130/80 mmHg and 29.6% with blood pressure >140/90 mmHg.
11
There is work to do to address the gaps in old targets, and evidence that for people with type 2 diabetes, we should be aiming for lower targets as indicated in the current guidelines.Role of the Funding Source
This work did not receive direct funding.
ACKNOWLEDGMENT
Conflict of Interest Statement
In the past three years, Kasia Lipska received support from the National Institutes of Health and the Patient-Centered Outcomes Research Institute, royalties from UpToDate to write and edit content, and other support from the Centers for Medicare & Medicaid Services to develop and evaluate publicly reported quality measures. In the past three years, Harlan Krumholz received expenses and/or personal fees from UnitedHealth, Element Science, Aetna, Reality Labs, Tesseract/4Catalyst, F-Prime, New England Journal of Medicine, the Siegfried and Jensen Law Firm, Arnold and Porter Law Firm, and Martin/Baughman Law Firm. He is a co-founder of Refactor Health and HugoHealth, and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare & Medicaid Services and through Yale University from Johnson & Johnson. Cindy Du, Chenxi Huang, Yuan Lu, and Erica Spatz report no potential conflicts of interest.
REFERENCES
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- Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial.Diabetes Care. 2014; 37: 1721-1728
- Effects of intensive systolic blood pressure lowering on cardiovascular events and mortality in patients with type 2 diabetes mellitus on standard glycemic control and in those without diabetes mellitus: reconciling results from ACCORD BP and SPRINT.J Am Heart Assoc. 2018; 7e009326
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