Cardiovascular Outcomes According to Urinary Albumin and Kidney Disease in Patients With Type 2 Diabetes at High Cardiovascular Risk: Observations From the SAVOR-TIMI 53 Trial

JAMA Cardiol. 2018 Feb 1;3(2):155-163. doi: 10.1001/jamacardio.2017.4228.

Abstract

Importance: An elevated level of urinary albumin to creatinine ratio (UACR) is a marker of renal dysfunction and predictor of kidney failure/death in patients with type 2 diabetes. The prognostic use of UACR in established cardiac biomarkers is not well described.

Objective: To evaluate whether UACR offers incremental prognostic benefit beyond risk factors and established plasma cardiovascular biomarkers.

Design, setting, and participants: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study was performed from May 2010 to May 2013 and evaluated the safety of saxagliptin vs placebo in patients with type 2 diabetes with overt cardiovascular disease or multiple risk factors. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years).

Interventions: Patients were randomized to saxagliptin vs placebo plus standard care.

Main outcomes and measures: Baseline UACR was measured in 15 760 patients (95.6% of the trial population) and categorized into thresholds.

Results: Of 15 760 patients, 5205 were female (33.0%). The distribution of UARC categories were: 5805 patients (36.8%) less than 10 mg/g, 3891 patients (24.7%) at 10 to 30 mg/g, 4426 patients (28.1%) at 30 to 300 mg/g, and 1638 patients (10.4%) at more than 300 mg/g. When evaluated without cardiac biomarkers, there was a stepwise increase with each higher UACR category in the incidence of the primary composite end point (cardiovascular death, myocardial infarction, or ischemic stroke) (3.9%, 6.9%, 9.2%, and 14.3%); cardiovascular death (1.4%, 2.6%, 4.1%, and 6.9%); and hospitalization for heart failure (1.5%, 2.5%, 4.0%, and 8.3%) (adjusted P < .001 for trend). The net reclassification improvement at the event rate for each end point was 0.081 (95% CI, 0.025 to 0.161), 0.129 (95% CI, 0.029 to 0.202), and 0.056 (95% CI, -0.005 to 0.141), respectively. The stepwise increased cardiovascular risk associated with a UACR of more than 10 mg/g was also present within each chronic kidney disease category. The UACR was associated with outcomes after including cardiac biomarkers. However, the improvement in discrimination and reclassification was attenuated; net reclassification improvement at the event rate was 0.022 (95% CI, -0.022 to 0.067), -0.008 (-0.034 to 0.053), and 0.043 (-0.030 to 0.052) for the primary end point, cardiovascular death, and hospitalization for heart failure, respectively.

Conclusions and relevance: In patients with type 2 diabetes, UACR was independently associated with increased risk for a spectrum of adverse cardiovascular outcomes. However, the incremental cardiovascular prognostic value of UACR was minimal when evaluated together with contemporary cardiac biomarkers.

Trial registration: clinicaltrials.gov Identifier: NCT01107886.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / therapeutic use
  • Albuminuria / diagnosis*
  • Biomarkers / urine
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / urine*
  • Diabetic Cardiomyopathies / urine*
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / urine
  • Dipeptides / therapeutic use
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Double-Blind Method
  • Female
  • Glomerular Filtration Rate / physiology
  • Heart Failure / etiology
  • Hospitalization / statistics & numerical data
  • Humans
  • Incretins / therapeutic use
  • Male
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / urine

Substances

  • Biomarkers
  • Dipeptides
  • Dipeptidyl-Peptidase IV Inhibitors
  • Incretins
  • saxagliptin
  • Adamantane

Associated data

  • ClinicalTrials.gov/NCT01107886