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

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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Scirica reports research grants from AstraZeneca, Eisai, Merck, and Poxel; consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr Reddy’s Laboratory, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, NovoNordisk, Sanofi, St. Jude's Medical; and equity in Health[at]Scale. Dr Mosenzon is on the advisory board of Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Jansen and Jansen, Novartis, and AstraZeneca; receives grants paid to institution as study physician by AstraZeneca and Bristol-Myers Squibb; receives research grant support through Hadassah Hebrew University Hospital and Novo Nordisk; and is on the speaker’s bureau for AstraZeneca, Bristol-Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Novartis, Merck, Sharp & Dohme, and Boehringer Ingelheim. Dr Bhatt is on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; is on the board of directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; is a chair for the American Heart Association Quality Oversight Committee; is on the data monitoring committees for Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and Population Health Research Institute; receives honoraria from the American College of Cardiology (senior associate editor), Clinical Trials and News, ACC.org, Belvoir Publications (editor, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (continuing medical education steering committees); is deputy editor of Clinical Cardiology; chair of National Cardiovascular Data Registry-ACTION Registry Steering Committee and VA CART Research and Publications Committee (Chair); has received research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company; receives royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); is a site co-investigator at Biotronik, Boston Scientific, and St. Jude Medical (now Abbott); is a trustee at American College of Cardiology; and has unfunded research with FlowCo, Merck, PLx Pharma, and Takeda. Dr Udell reports grants from AstraZeneca and Bristol-Myers Squibb; personal fees/honoraria for advisory board participation from Janssen, Merck, Sanofi Pasteur, and Novartis outside the submitted work; and grants from Novartis for participation as a site investigator in a clinical trial. Dr Steg reports grants from Merck, Sanofi, and Servier; personal fees from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, Regeneron, Roche, Sanofi, Servier, and the Medicines Company, outside the submitted work. Dr McGuire reports receiving personal fees for clinical trial leadership from Boehringer-Ingelheim, Janssen Research and Development LLC, Merck Sharp and Dohme, Lilly USA, Novo Nordisk, GlaxoSmithKline, Takeda Pharmaceuticals North America, AstraZeneca, Lexicon, Eisai, and Akebia Pharmaceuticals; and personal consulting fees from Sanofi-Aventis Group, Merck Sharp and Dohme, Novo Nordisk, Lilly USA, and Regeneron. Dr Im and Ms Kanevsky report research funding via the TIMI Study and Brigham and Women’s Hospital from AstraZeneca. Drs Stahre and Sjöstrand are employees of AstraZeneca. Dr Raz reports being on the advisory board of AstraZeneca/Bristol-Meyers Squibb, Eli Lilly and Company, Merck Sharp and Dohme Limited, Novo Nordisk, Inc, Sanofi, Orgenesis, SmartZyme Innovation Ltd, Labstyle Innovations Ltd, and Boehringer Ingelheim; consulting for AstraZeneca/Bristol-Meyers Squibb, Insuline Medical, Gili Medical, Kamada Ltd, FuturRx Ltd, Nephrogenex Inc, and Diabetes Medical Center (Tel Aviv, Israel); being on the speaker’s bureau for AstraZeneca/Bristol-Meyers Squibb, Eli Lilly and Company, Johnson & Johnson, Merck Sharp and Dohme Limited, Novartis Pharma AG, Novo Nordisk, Inc, Sanofi, Teva, and Boehringer Ingelheim; being a stock shareholder of Insuline Medical, Labstyle Innovations, SmartZyme Innovation Ltd, Orgenesis, and Glucome Ltd. Dr Braunwald reports grants from AstraZeneca, Daiichi-Sankyo, GlaxoSmithKline, Merck, and Novartis; personal fees from the Medicines Company, Theravance, Daiichi Sankyo, Menarini International, and Medscape; and uncompensated consultancies and lectures from Merck and Novartis.

Figures

Figure 1.. Kaplan-Meier (KM) Estimates According to Baseline Urinary Albumin to Creatinine Ratio Levels

Figure 2.. Risk of Primary End Point, Cardiovascular Death, Myocardial Infarction, and Hospitalization for Heart Failure, by Urinary Albumin to Creatinine Ratio (UACR) as Continuous Variable

The solid dark blue line indicates the adjusted hazard ratio; dotted dark blue line, 95% CI; and the solid light blue line, a reference when the adjusted hazard ratio for UACR is 1.