Association between cumulative systolic blood pressure load and MACE in T2DM

Cumulative Systolic Blood Pressure Load and Cardiovascular Risk in Patients With Diabetes

Literature - Wang N, Harris K, Hamet P, et al. - J Am Coll Cardiol. 2022 Sep 20;80(12):1147-1155. doi: 10.1016/j.jacc.2022.06.039

Introduction and methods


As standard measures of blood pressure (BP) do not acknowledge that BP fluctuates over time, the most recently recorded BP measurement may not reflect previous BP control. Therefore, a measure that accounts for both the magnitude and duration of exposure to elevated BP is needed. An example of such a measure is the cumulative BP load, which has been associated with target organ damage [1].

Previously, the effects of BP lowering and intensive blood glucose–lowering treatment on vascular outcomes were evaluated in patients with T2DM in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron - Modified Release Controlled Evaluation) trial [2-4].

Aim of the study

The authors sought to assess the association between the cumulative systolic BP (SBP) load over 24 months and the occurrence of MACE in the ADVANCE trial and its post-trial follow-up study, ADVANCE-ON.


The ADVANCE trial was an international, 2 × 2 factorial RCT in which 11,140 T2DM patients at high risk of CV events were randomly assigned to either perindopril/indapamide 4 mg/1.25 mg or matching placebo and to either an intensive glucose control regimen based on gliclazide modified release (aiming to achieve HbA1c ≤6.5%) or standard glucose control based on local guidelines of participating countries. Post-trial follow-up data were obtained from 8494 patients of a total of 10,082 patients who were alive when the randomized treatment phase of the ADVANCE trial was completed [5].

For the current post-hoc analysis, data from 9338 patients with SBP measures at 3, 4, 6, 12, 18, and 24 months were collected. Based on BP measurements at these 6 clinic visits, cumulative SBP load, mean BP, SBP TITRE, and visit-to-visit variability in SBP were calculated. Cumulative SBP load was defined as the area under the curve (AUC) for SBP values ≥130 mmHg divided by the AUC for all measured SBP values. SBP TITRE (TIme at TaRgEt) was calculated as the percentage of time a patient spent at SBP target (defined as <130 mmHg) over the exposure period. Visit-to-visit variability in SBP was calculated as the SD of the SBP values at the 6 clinic visits.


The primary endpoint was MACE, defined as the composite outcome of CV death, nonfatal MI, and nonfatal stroke. Secondary endpoints were components of the primary endpoint and all-cause mortality.

Main results

Effects of SBP measures on CV outcomes

  • During a median follow-up period of 7.6 years, MACE were observed in 1469 patients, 1615 patients died (of whom 660 were CV deaths), 491 patients had an MI, and 674 patients experienced a stroke.
  • After adjustment for traditional CVD risk factors, the risk of MACE increased log-linearly with an increasing cumulative SBP load (P for trend<0.001). The highest quarter of SBP load was associated with a 24% increase in MACE risk compared with the lowest quarter (hazard ratio (HR): 1.24; 95%CI: 1.06–1.44).
  • Similar associations were observed between cumulative SBP load and all-cause mortality (P for trend=0.001), CV death (P for trend<0.001), and MI (P for trend<0.001) but not stroke (P for trend=0.492).
  • Each 1-SD increase in cumulative SBP load was associated with a 14% increase in MACE (HR: 1.14; 95%CI: 1.09–1.19; P<0.001), a 13% increase in all-cause mortality (HR: 1.13; 95%CI: 1.08–1.18; P<0.001), a 21% increase in CV death (HR: 1.21; 95%CI: 1.13–1.29; P<0.001), a 19% increase in MI (HR: 1.19; 95%CI: 1.10–1.29; P<0.001), and a 10% increase in stroke (HR: 1.10; 95%CI: 1.02–1.19; P=0.012).
  • For mean SBP, SBP TITRE, and visit-to-visit variability in SBP, each 1-SD increase was also associated with a significantly higher risk of the 5 endpoints, except for SBP TITRE with MACE, all-cause mortality, and stroke, and for visit-to-visit variability in SBP with stroke.

Independent association of cumulative SBP load or visit-to-visit variability in SBP with CV outcomes

  • After adjustment for visit-to-visit variability in SBP and traditional CVD risk factors, cumulative SBP load remained an independent predictor of the primary and secondary endpoints. Each 1-SD increase in cumulative SBP load was associated with a 12% increase in MACE (HR: 1.12; 95%CI: 1.06–1.18; P<0.001), a 9% increase in all-cause mortality (HR: 1.09; 95%CI: 1.04–1.15; P<0.001), a 18% increase in CV death (HR: 1.18; 95%CI: 1.10–1.27; P<0.001), a 15% increase in MI (HR: 1.15; 95%CI: 1.05–1.25; P=0.002), and a 9% increase in stroke (HR: 1.09; 95%CI: 1.01–1.18; P=0.036).
  • When the Cox regression model was adjusted for cumulative SBP load and traditional CVD risk factors, visit-to-visit variability in SBP was an independent predictor of all-cause mortality (HR: 1.09; 95%CI: 1.04–1.14; P<0.001) and MI (HR: 1.09; 95%CI: 1.00–1.19; P=0.050) but not MACE (HR: 1.06; 95%CI: 1.00–1.11; P=0.052), CV death (HR: 1.05; 95%CI: 0.97–1.13; P=0.237), or stroke (HR: 95%CI: 1.03; 0.95–1.11; P=0.651).

Prognostic value of SBP measures compared with traditional CVD risk factors

  • As for the risk of MACE, the addition of any of the SBP measures to the base model with traditional CVD risk factors significantly improved the C-statistic and continuous net reclassification improvement. However, addition of cumulative SBP load to the base model was associated with the largest improvement in C-statistic (difference in C statistic: 0.0052; 95%CI: 0.0009–0.0095) and the lowest Akaike information criterion—which indicated it was the overall best model—compared with the addition of any of the other SBP measures.
  • Largely similar patterns were seen for the prediction of the risk of one of the 4 secondary endpoints, with cumulative SBP load outperforming the other SBP measures.


In a post-hoc analysis of the ADVANCE trial and its follow-up study, a higher cumulative SBP load was associated with CV events and death in T2DM patients independent of traditional CVD risk factors. Cumulative SBP load was a independent predictor of CV events. In addition, cumulative SBP load was a better predictor of MACE than mean SBP, SBP TITRE, or visit-to-visit variability in SBP.

As cumulative SBP load encompasses both duration (similar to SBP TITRE) and magnitude (similar to mean SBP) of SBP exposure, the authors believe their study “reinforces not only the importance of treating the degree of SBP elevation, but also the need for early intervention to minimize the duration of elevated SBP exposure.”


1. Zhou B, Li C, Shou J, Zhang Y, Wen C, Zeng C. The cumulative blood pressure load and target organ damage in patients with essential hypertension. J Clin Hypertens (Greenwich). 2020;22:981–990.

2. Committee AM. Study rationale and design of ADVANCE: action in diabetes and vascular disease–preterax and diamicron MR controlled evaluation. Diabetologia. 2001;44:1118–1120.

3. Patel A, MacMahon S, Chalmers J, et al. for the ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–840.

4. Patel A, MacMahon S, Chalmers J, et al. for the ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572.

5. Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371:1392–1406.

Find this article online at J Am Coll Cardiol.

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