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Intensive systolic blood pressure control and incident chronic kidney disease in people with and without diabetes mellitus: secondary analyses of two randomised controlled trials

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Summary

Background

Guidelines, including the 2017 American College of Cardiology and American Heart Association blood pressure guideline, recommend tighter control of systolic blood pressure in people with type 2 diabetes. However, it is unclear whether intensive lowering of systolic blood pressure increases the incidence of chronic kidney disease in this population. We aimed to compare the effects of intensive systolic blood pressure control on incident chronic kidney disease in people with and without type 2 diabetes.

Methods

The Systolic Blood Pressure Intervention Trial (SPRINT) tested the effects of a systolic blood pressure goal of less than 120 mm Hg (intensive intervention) versus a goal of less than 140 mm Hg (standard intervention) in people without diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial tested a similar systolic blood pressure intervention in people with type 2 diabetes. Our study is a secondary analysis of limited access datasets from SPRINT and the ACCORD trial obtained from the National Institutes of Health. In participants without chronic kidney disease at baseline (n=4311 in the ACCORD trial; n=6715 in SPRINT), we related systolic blood pressure interventions (intensive vs standard) to incident chronic kidney disease (defined as >30% decrease in estimated glomerular filtration rate [eGFR] to <60 mL/min per 1·73 m2). These trials are registered with ClinicalTrials.gov, numbers NCT01206062 (SPRINT) and NCT00000620 (ACCORD trial).

Findings

The average difference in systolic blood pressure between intensive and standard interventions was 13·9 mm Hg (95% CI 13·4–14·4) in the ACCORD trial and 15·2 mm Hg (14·8–15·6) in SPRINT. At 3 years, the cumulative incidence of chronic kidney disease in the ACCORD trial was 10·0% (95% CI 8·8–11·4) with the intensive intervention and 4·1% (3·3–5·1) with the standard intervention (absolute risk difference 5·9%, 95% CI 4·3–7·5). Corresponding values in SPRINT were 3·5% (95% CI 2·9–4·2) and 1·0% (0·7–1·4; absolute risk difference 2·5%, 95% CI 1·8–3·2). The absolute risk difference was significantly higher in the ACCORD trial than in SPRINT (p=0·0001 for interaction).

Interpretation

Intensive lowering of systolic blood pressure increased the risk of incident chronic kidney disease in people with and without type 2 diabetes. However, the absolute risk of incident chronic kidney disease was higher in people with type 2 diabetes. Our findings suggest the need for vigilance in monitoring kidney function during intensive antihypertensive drug treatment, particularly in adults with diabetes. Long-term studies are needed to understand the clinical implications of antihypertensive treatment-related reductions in eGFR.

Funding

National Institutes of Health.

Introduction

Hypertension is strongly associated with stroke, heart failure, sudden death, end-stage renal disease, and death from all causes.1, 2, 3, 4, 5 Findings of the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive lowering of systolic blood pressure (target <120 mm Hg, vs standard lowering to <140 mm Hg) reduced the risk of death and major cardiovascular events in people without diabetes, but at high cardiovascular risk.6, 7 However, the SPRINT Research Group also reported that people undergoing intensive lowering had a 3·5-fold higher risk of incident chronic kidney disease,6, 8 defined a priori in the protocol as a reduction in estimated glomerular filtration rate (eGFR) of 30% or higher with a second confirmed eGFR below 60 mL/min per 1·73 m2.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial in people with type 2 diabetes tested the same systolic blood pressure intervention as in SPRINT (intensive vs standard lowering) in addition to intensive versus standard glycaemic control (HbA1c <6% [42 mmol/mol] vs 7·0–7·9% [53–64 mmol/mol]) in a 2 × 2 factorial design.9 Compared with the standard systolic blood pressure intervention, participants who underwent intensive lowering of systolic blood pressure had lower mean eGFR at the final study visit (74·8 mL/min per 1·73 m2 [SD 25·0] vs 80·6 mL/min per 1·73 m2 [24·8]), with a similar prevalence of a prespecified primary microvascular outcome composite of renal failure and retinopathy (11·4% vs 10·9%) and end-stage renal disease (2·5% vs 2·4%).9, 10

Research in context

Evidence before this study

The 2017 American College of Cardiology and American Heart Association blood pressure guidelines based on systematic review and meta-analysis, recommended a systolic blood pressure goal of less than 130 mm Hg in people with and without diabetes. Findings of the Systolic Blood Pressure Intervention Trial (SPRINT) in individuals without diabetes showed a lower risk of cardiovascular disease events and all-cause mortality but a higher risk of incident chronic kidney disease with intensive lowering of systolic blood pressure (goal <120 mm Hg) compared with standard systolic blood pressure control (goal <140 mm Hg). Whether the magnitude of increased incidence of chronic kidney disease with intensive lowering of systolic blood pressure is higher in people with type 2 diabetes compared with those without diabetes is not known.

Added value of this study

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial in people with type 2 diabetes, a systolic blood pressure intervention was tested similar to that assessed in SPRINT. Despite a clinically similar reduction in systolic blood pressure in both the ACCORD trial and SPRINT, at 3 years, the absolute risk difference between the intensive and standard interventions for incident chronic kidney disease was 5·9% (95% CI 4·3–7·5) in the ACCORD trial and 2·5% (1·8–3·2) in SPRINT (p=0·0001 for interaction).

Implications of all the available evidence

The risk of incident chronic kidney disease was higher in people with type 2 diabetes than in those without this disease with intensive systolic blood pressure lowering. Chronic kidney disease is known to be a risk factor for future cardiovascular events. However, it is unclear whether incident chronic kidney disease due to intensive lowering of systolic blood pressure increases the risk of future cardiovascular events. Further studies are warranted to ascertain whether the higher risk of incident chronic kidney disease with intensive lowering of systolic blood pressure is outweighed by the expected reductions in cardiovascular disease and all-cause mortality in type 2 diabetes in the long term.

To our knowledge, a detailed analysis of the effects of intensive systolic blood pressure lowering in people with type 2 diabetes on incident chronic kidney disease has not been published. Examination of the magnitude of the effect of systolic blood pressure lowering on kidney outcomes in individuals with type 2 diabetes and without chronic kidney disease is highly relevant, because most people with type 2 diabetes do not have chronic kidney disease, particularly in the early years of their condition. Therefore, we aimed to investigate the effects of intensive systolic blood pressure control on incident chronic kidney disease in the ACCORD trial and compared the magnitude of these effects with those noted in SPRINT.

Section snippets

Participants

We did a secondary analysis of limited-access ACCORD trial and SPRINT datasets obtained from the National Heart, Lung, and Blood Institute's Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Details of study population, interventions, and study procedures for the ACCORD trial9, 11 and SPRINT6, 12 are published elsewhere.13, 14 In brief, 4733 participants with type 2 diabetes were randomly assigned in the ACCORD trial (2 × 2 factorial design) to either intensive

Results

The current analysis included 4311 individuals from the ACCORD trial and 6715 people from SPRINT; all participants had a baseline eGFR of 60 mL/min per 1·73 m2 or higher (ie, they did not have chronic kidney disease; appendix). Baseline demographic, clinical, and laboratory characteristics were similar for people allocated the intensive and standard systolic blood pressure interventions within the ACCORD trial and SPRINT (table). However, compared with the SPRINT population who did not have

Discussion

Our analyses show that intensive systolic blood pressure lowering increased the risk of incident chronic kidney disease in people both with and without type 2 diabetes. Furthermore, for a clinically similar level of systolic blood pressure lowering, the absolute risk increase for incident chronic kidney disease was higher in ACCORD trial participants with type 2 diabetes than in SPRINT participants without type 2 diabetes.

Incident chronic kidney disease was one of the prespecified secondary

References (26)

  • E Rapsomaniki et al.

    Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people

    Lancet

    (2014)
  • F Ismail-Beigi et al.

    Combined intensive blood pressure and glycemic control does not produce an additive benefit on microvascular outcomes in type 2 diabetic patients

    Kidney Int

    (2012)
  • KT Mills et al.

    Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries

    Circulation

    (2016)
  • PA James et al.

    2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)

    JAMA

    (2014)
  • CY Hsu et al.

    Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease

    Arch Intern Med

    (2005)
  • S Lewington et al.

    Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

    Lancet

    (2002)
  • A randomized trial of intensive versus standard blood-pressure control

    N Engl J Med

    (2015)
  • JD Williamson et al.

    Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: a randomized clinical trial

    JAMA

    (2016)
  • S Beddhu et al.

    Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial

    Ann Intern Med

    (2017)
  • Effects of intensive blood-pressure control in type 2 diabetes mellitus

    N Engl J Med

    (2010)
  • Effects of intensive glucose lowering in type 2 diabetes

    N Engl J Med

    (2008)
  • WT Ambrosius et al.

    The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT)

    Clin Trials

    (2014)
  • Systolic Blood Pressure Intervention Trial (SPRINT): protocol version 4.0

  • Cited by (0)

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