Cardiovascular Outcomes of Patients in SAVOR-TIMI 53 by Baseline Hemoglobin A1c

Accepted Manuscript Cardiovascular Outcomes of Patients in SAVOR-TIMI 53 by Baseline Hemoglobin A1c Matthew A. Cavender, MD, MPH, Benjamin M. Scirica, MD, MPH, Itamar Raz, MD, Ph. Gabriel Steg, MD, Darren K. McGuire, MD, MHSc, Lawrence A. Leiter, MD, Boaz Hirshberg, MD, Jaime Davidson, MD, Avivit Cahn, MD, Ofri Mosenzon, MD, KyungAh Im, PhD, Eugene Braunwald, MD, Deepak L. Bhatt, MD, MPH PII:

S0002-9343(15)01017-7

DOI:

10.1016/j.amjmed.2015.09.022

Reference:

AJM 13226

To appear in:

The American Journal of Medicine

Received Date: 5 September 2015 Revised Date:

26 September 2015

Accepted Date: 28 September 2015

Please cite this article as: Cavender MA, Scirica BM, Raz I, Steg PG, McGuire DK, Leiter LA, Hirshberg B, Davidson J, Cahn A, Mosenzon O, Im K, Braunwald E, Bhatt DL, Cardiovascular Outcomes of Patients in SAVOR-TIMI 53 by Baseline Hemoglobin A1c, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.09.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Cardiovascular Outcomes of Patients in SAVOR-TIMI 53 by Baseline Hemoglobin A1c Running Title: HbA1c and CV Events in SAVOR-TIMI 53

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Matthew A. Cavender MD, MPH,1 Benjamin M. Scirica MD, MPH,1

Itamar Raz MD,2 Ph. Gabriel Steg MD,3 Darren K. McGuire MD, MHSc,4

Lawrence A. Leiter MD,5 Boaz Hirshberg MD,6 Jaime Davidson MD,7 Avivit Cahn

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MD,2 Ofri Mosenzon MD,2 KyungAh Im PhD,1 Eugene Braunwald MD,1 Deepak L. Bhatt MD, MPH1

TIMI Study Group, Heart and Vascular Center, Brigham and Women’s Hospital, and

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Harvard Medical School, Boston, MA, USA 2

Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital,

Jerusalem, Israel 3

FACT, DHU FIRE, Université Paris-Diderot, Sorbonne Paris-Cité, LVTS INSERM U-

1148, Hôpital Bichat, HUPNVS, AP-HP, Paris, France and NHLI, Imperial College, Royal Brompton Hospital, London, UK

Division of Cardiology, Department of Internal Medicine, University of Texas

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Southwestern Medical Center, Dallas, TX, USA 5

Division of Endocrinology and Metabolism, Keenan Research Centre in the Li Ka Shing

Knowledge Institute of St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

AstraZeneca Research and Development, Gaithersburg, MD, USA

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Division of Endocrinology, Department of Internal Medicine, University of Texas

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Southwestern Medical Center, Dallas, TX, USA

Corresponding Author: Deepak L. Bhatt, MD, MPH 75 Francis Street

Boston, MA 02115

75 Francis Street, Boston, MA 02115 Phone: 617-278-0145 Fax: 1-888-249-5261 [email protected] Manuscript Word Count: 2141

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Abstract: Objective: The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we

saxagliptin vs. placebo according to baseline HbA1c.

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analyzed the SAVOR-TIMI 53 trial to compare the cardiovascular effects of

Research Design and Methods: A total of 16,492 patients with type 2 diabetes,

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HbA1c 6.5%-12.0% in the 6 months prior to randomization, and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis

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were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke. Results: Patients were stratified by HbA1c at randomization into the following

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prespecified groups: <7%, 7-<8%, 8-<9%, ≥9%. Baseline HbA1c ≥7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (HRadj 1.35, 95%CI 1.17,1.58) but not hospitalization for heart

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failure (HRadj 1.09, 95%CI 0.88,1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic

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stroke in patients with HbA1c <7% (HR 1.01, 95%CI 0.78,1.31), 7-<8% (HR 0.98, 95%CI 0.80,1.20), 8-<9% (HR 1.09, 95%CI 0.85,1.39), ≥9% (HR 0.95, 95%CI 0.77,1.18) (p-int=0.89). Conclusions: Baseline HbA1c is associated with increased risk of macrovascular events, but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline

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HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values. Abstract Word Count: 244

assay, randomized clinical trials

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Key Words: diabetes mellitus, coronary artery disease, glycated hemoglobin

Subject Codes: Diabetes: Type 2, Chronic ischemic heart disease

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Trial registration: NCT01107886 (www.clinicaltrials.gov)

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ABBREVIATIONS ACR: albumin to creatinine ratio ADA: American Diabetes Association

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CI: confidence interval CKD: chronic kidney disease

DPP-4: dipeptidyl peptidase-4 eGFR: estimated glomerular filtration rate

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CVA: ischemic stroke

ESRD: end-stage renal disease

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EASD: European Association for the Study of Diabetes

FDA: Food and Drug Administration HR: hazard ratio

MG: milligram

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HbA1c: glycated hemoglobin

MI: myocardial infarction

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mL: milliliter

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TZD: thiazolidinedione

ACRONYMS

SAVOR: Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus

TIMI: Thrombolysis in Myocardial Infarction

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In patients with type 2 diabetes, hemoglobin A1c (HbA1c) reflects the degree of glycemic control over the preceding weeks to months. The American Diabetes Association (ADA)/ European Association for the Study of Diabetes

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(EASD) guidelines endorse a patient-centered approach that recommends most patients be treated to a goal HbA1c of <7.0% with less stringent criteria for

HbA1c targets in selected high-risk patients.(1; 2) While the benefit of glycemic

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control in patients with type 2 diabetes on microvascular events such as retinopathy, neuropathy, or nephropathy is well established, no anti-

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hyperglycemic agent or strategy has clearly been demonstrated to reduce macrovascular events.(3; 4) In fact, some studies have suggested more intensive glycemic control may be associated with increased cardiovascular risk, particularly in patients with established cardiovascular disease.(5) Prior studies

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have demonstrated associations between increasing levels of HbA1c and increased risk of death, myocardial infarction, stroke, and coronary revascularization; yet, there are few studies evaluating whether cardiovascular

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outcomes differ with particular agents based on the HbA1c at the time in which therapy is initiated. (6-11) Thus, evaluating the cardiovascular safety and efficacy

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of different anti-hyperglycemic regimens according to glycemic control at baseline is important to define optimal medical strategies for patients with type 2 diabetes.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients

with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial evaluated the cardiovascular safety and efficacy of saxagliptin, a selective

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dipeptidyl peptidase-4 (DPP-4) inhibitor, versus placebo in 16,492 patients with type 2 diabetes.(12-14) Saxagliptin neither increased nor decreased the risk of the primary composite endpoint (cardiovascular death, myocardial infarction, or

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ischemic stroke) or the secondary composite endpoint (primary composite

endpoint plus hospitalization for unstable angina, coronary revascularization or

hospitalization for heart failure). However, treatment with saxagliptin did increase

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the risk of hospitalization for heart failure, a component of the secondary end point.(15) In the present analyses, we sought to add to pre-existing data by

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describing the relationship between baseline HbA1c and cardiovascular outcomes in the SAVOR-TIMI 53 trial and evaluate whether the effects of saxagliptin on cardiovascular events differ based upon the HbA1c at baseline. Research Design and Methods

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Study Design and Oversight

SAVOR-TIMI 53 was a double-blind, placebo-controlled trial that randomized patients with type 2 diabetes to either saxagliptin or placebo while all other diet

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and lifestyle modifications, background anti-hyperglycemic therapies (except incretin-based therapies), and cardiovascular therapies were left to the discretion

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of the treating provider.(14) The trial was designed by the TIMI Study Group and Hadassah Medical Organization in conjunction with the sponsors. The TIMI Study Group and Hadassah Medical Organization have complete access to the data and assume responsibility for the accuracy and completeness of the data in this manuscript.

Study Population

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The full eligibility criteria of the trial have been reported previously.(12) In brief, eligible patients had a history of documented type 2 diabetes, HbA1c between 6.5% and ≤12.0% in the 6 months prior to randomization, and either a history of

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established cardiovascular disease (n=12,959, 79%) or multiple risk factors (n=3,533, 21%) for vascular disease. To be included in the established

cardiovascular disease cohort, patients had to be at least 40 years old and have

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a history of a clinical event secondary to atherosclerosis involving the coronary, cerebrovascular, or peripheral vascular systems. Patients in the multiple risk

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factor cohort had to be at least 55 years old (men) or 60 years old (women) and have at least one of the following risk factors for atherosclerosis: dyslipidemia, hypertension, or active smoking. Patients were ineligible if they were currently or previously (within 6 months) treated with an incretin-based therapy or had end-

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stage renal disease (chronic dialysis and/or renal transplant and/or a serum creatinine >6.0 mg/dL). The Institutional Review Board or Ethics Committee for each participating institution reviewed and approved the trial. All patients

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provided written informed consent.

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Randomization and Study Treatment

Eligible patients were randomly assigned in a 1:1 fashion to receive either saxagliptin 5 mg daily (or 2.5 mg daily in patients with an estimated glomerular filtration rate (eGFR) of 50 mL/min or less) or placebo. Randomization was stratified by prevalent cardiovascular disease (established cardiovascular disease or multiple risk factors for cardiovascular disease) and renal function

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(normal function/mild renal impairment [eGFR >50mL/min] vs. moderate renal impairment [30 to 50 mL/min] or severe renal impairment [eGFR <30ml/min). HbA1c was measured in a central core lab for 16,199 patients at randomization

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(HPLC, Quintiles Laboratories Worldwide, Durham, North Carolina).

Endpoints

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A clinical events committee made up of cardiovascular specialists who were unaware of the study-group assignments adjudicated all components of the

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primary and secondary efficacy endpoints. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The key secondary endpoint included the components of primary composite endpoint plus hospitalization for heart failure, coronary revascularization, or unstable

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angina.

Statistical Analysis

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For the present pre-specified analyses, subjects were stratified based on the HbA1c at the time of randomization into the following groups: <7%, 7-<8%, 8-

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<9%, ≥9%. Patients with HbA1c <7% were considered the reference group. Patients in whom baseline HbA1c was not available were excluded from the analysis. Categorical variables were compared using the chi-squared test and continuous variables were compared with either a t-test or Wilcoxon rank sum test, as appropriate. The associations between different groups of baseline HbA1c and clinical events were examined using a Cox proportional hazards model stratified by baseline renal impairment category and baseline

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cardiovascular risk group, and with treatment as a model term together with potential confounders (age, sex, duration of type 2 diabetes, eGFR, urinary albumin: creatinine ratio). Comparisons between saxagliptin and placebo were

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made using a Cox proportional hazards model, stratified by baseline renal

impairment category and baseline cardiovascular risk, which included terms for randomized treatment and an interaction between treatment and baseline

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HbA1c. Events rates are presented as 2-year Kaplan-Meier estimates. Analyses were performed with SAS version 9.3 (SAS Institute, Cary, North Carolina) and

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were made in the intention-to-treat population.

Results

The mean HbA1c at baseline was 8.0±1.4%. The proportion of patients in

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each of the prespecified categories were: <7% (n=4119, 25.4%), 7-<8% (n=5416, 33.4%), 8-<9% (n=3139, 19.4%), ≥9% (n=3525, 21.8%). In general, patients with lower HbA1c were older and had shorter duration of diabetes (Table 1). The

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proportion of patients with established cardiovascular disease was higher in patients with baseline HbA1c ≥9% (81.8%) than in patients with baseline HbA1c

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<7% (73.4%). Renal dysfunction (defined as GFR <50 ml/min) was not statistically different among the groups although patients with higher baseline HbA1c were more likely to have evidence of micro- or macroalbuminuria. Cardiovascular medications were utilized with high frequency in all baseline HbA1c groups, while patients with higher baseline HbA1c were more likely to be

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using insulin and sulfonylureas and less likely to be using metformin or a thiazolidinedione. There was a stepwise relationship between the risk of cardiovascular

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death, myocardial infarction, or ischemic stroke at 2 years and baseline HbA1c: <7% (5.3%), 7-<8% (6.7%), 8-<9% (8.0%), ≥9% (9.9%) (Figure 1). After

adjusting for potential confounders, baseline HbA1c ≥7% was associated with an

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increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (HRadj 1.35, 95% CI 1.17, 1.58) when compared to patients with HbA1c <7%. A

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similar association between increasing HbA1c and increased risk was seen for each of the individual components of the primary endpoint including cardiovascular death, myocardial infarction, and ischemic stroke (Figure 2), however, there was no relationship between HbA1c ≥7% and hospitalization for

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heart failure (HRadj 1.09, 95% CI 0.88, 1.36). A baseline HbA1c >9% was associated with a significantly increased risk of non-cardiovascular death (HRadj 1.48, 95% CI 1.02-2.16). Patients with HbA1c 7-<8% and 8-<9% were at

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increased likelihood of undergoing coronary revascularization when compared to patients with HbA1c <7%. There was no association between baseline HbA1c

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and hospitalization for unstable angina (Supplemental Table 1). Consistent with the overall trial results, saxaglipitin, when compared to

placebo, neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in each of the baseline HbA1c groups (p-value for interaction=0.89, Figure 3). Similar results were found when examining the effects of saxagliptin on the secondary composite endpoint

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(cardiovascular death, myocardial infarction, ischemic stroke, hospitalization for unstable angina/revascularization, or hospitalization for heart failure), as well as key individual components of the endpoint, such as cardiovascular death or

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myocardial infarction.

Saxagliptin increased the risk of hospitalization for heart failure in the

subgroup of patients with baseline HbA1c<7% (3.5% vs. 2.1%, HR 1.70, 95% CI

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1.17-2.50, p=0.01). There was a similar relationship in patients with a baseline HbA1c >7% (3.6% vs. 3.0%, HR 1.19, 95% CI 0.98-1.46, p-interaction=0.11).

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Conclusion

Our findings from the SAVOR-TIMI 53 trial show that the degree of glycemic control in a contemporary cohort of patients with diabetes at high risk of ischemic events is associated with increased risk of cardiovascular events

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despite therapy. Secondly, treatment with saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke regardless of the HbA1C at baseline providing further support for the

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cardiovascular safety of saxagliptin. Thirdly, despite the known association between diabetes and heart failure,(16) the degree of HbA1c elevation at

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baseline in SAVOR-TIMI 53 was not associated with observed heart failure events. Finally, there was no clear, directional relationship between baseline HbA1c and the risk of hospitalization for heart failure in patients treated with saxagliptin but the increased risk of heart failure with saxagliptin was seen regardless of baseline glycemic control.

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Prior studies have suggested that some anti-hyperglycemic drugs and strategies of intensive glycemic control may increase the risk of cardiovascular events or death.(5; 17) Thus, it is possible that the degree of glycemic control at

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the time in which a drug is initiated could modify either the benefit or risk

associated with that particular drug. For example, in the ACCORD trial, patients with baseline HbA1c ≤8.0% treated with intensive glycemic control were at lower

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risk of cardiovascular death, myocardial infarction, or stroke compared with patients treated with standard glycemic therapy. A similar benefit was not

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observed in patients with baseline HbA1c >8%.(18) Current ADA/EASD guidelines recommend treating patients to an individualized HbA1c target and suggest adding anti-hyperglycemic agents in patients who fail to meet their target after 3-6 months of therapy.(1; 2) Most patients will first be initiated on metformin,

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but eventually many will require additional therapy. The choice of the secondand third-line agents remains unclear. With the growing number of therapeutic options, the decision to choose one agent over another should incorporate not

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only patient characteristics and the ultimate glycemic goal, but also the mechanism by which the agent improves glycemic control and the overall risk

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and benefit of that drug at different levels of HbA1c. The present analyses expand upon the initial findings of SAVOR-TIMI 53 and demonstrate that the effect of saxagliptin on cardiovascular events is similar irrespective of baseline HbA1c.

Prior studies have shown that the risk of cardiovascular events increases in patients with an elevated HbA1c.(6-11; 19) Our findings expand upon these

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observations and show that in a contemporary population of patients with diabetes, of whom a large proportion were treated with evidence based medications, HbA1c remains an independent and stepwise predictor of

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macrovascular events. However, we found no relationship between baseline

HbA1c and hospitalization for heart failure. Type 2 diabetes has been associated with the development of heart failure; however, prior studies on the association

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between HbA1c and heart failure have had conflicting results.(19-21) In contrast to our findings, Iribarren et al found that every 1% increase in the HbA1c was

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associated with an 8% increased risk of heart failure in a cohort with diabetes but no known heart failure.(19) Prior studies have also not found a consistent association between the intensity of glycemic control and the risk of hospitalization for heart failure.(22) The relationship between diabetes, glycemic

evaluation.(23)

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control, and the development or exacerbation of heart failure warrants further

Our study should be taken in the context of its limitations. First, the

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potential anti-hyperglycemic effects of saxagliptin were blunted due to the design of the SAVOR-TIMI 53 trial that encouraged additional measurements of HbA1c

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levels and up-titration of non-study related anti-hyperglycemic therapy. Secondly, given that the median follow-up was 2.1 years, the study does not exclude the possibility of either benefit or risk with a longer duration of saxagliptin. In conclusion, HbA1c level at baseline is independently correlated with

macrovascular events. Treatment with saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic

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stroke but increased risk of hospitalization for heart failure irrespective of HbA1c at baseline. Identifying the optimal target of HbA1c to prevent macrovascular complications and determining the optimal strategy reduce cardiovascular events

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remains challenging. However, saxagliptin provides a therapeutic option for lowering HbA1c in patients with diabetes who are at increased risk for

cardiovascular disease that has proven cardiovascular safety regardless of

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glycemic control at the time in which treatment is initiated.

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Acknowledgements These data were previously reported in abstract form at the Scientific Sessions of the American Heart Association.

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Data were obtained by M.A.C., B.M.S., I.R., B.H., O.M., E.B., D.L.B. The statistical analyses was performed by K.I. M.A.C wrote the first draft of the manuscript. All authors reviewed/edited the manuscript and approved the final draft.

Drs. Cavender, Scirica, Raz, Im, Braunwald, and Bhatt take full responsibility for the contents of the manuscript.

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Executive Committee:

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Eugene Braunwald (Study Chair), Deepak L. Bhatt (Co-Principal Investigator), Itamar Raz (Co-Principal Investigator), Jaime A. Davidson, Robert Frederich (non-voting), Boaz Hirshberg (non-voting), Ph. Gabriel Steg Funding: SAVOR-TIMI 53 was funded by AstraZeneca and Bristol-Myers Squibb.

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Conflicts of Interest: The TIMI Study Group has received significant research grant support from Amgen, Astra-Zeneca, Athera, Beckman Coulter, BG Medicine, Bristol-Myers Squibb, Buhlmann Laboratories, Daiichi Sankyo, Eli Lilly and Co, Eisai, Glaxo Smith Kline, Johnson & Johnson, Merck and Company, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, Singulex.

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Dr. Cavender reports consulting fees from AstraZeneca and Merck.

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Dr. Scirica reports consulting fees from AstraZeneca, Gilead, GE Healthcare, Lexicon, Arena, Eisai, St. Jude's Medical, Bristol-Myers Squibb, Forest Pharmaceuticals, Boston Clinical Research Institute, University of Calgary, Elsevier Practice Update Cardiology, Forest Pharmaceuticals. Dr. Raz reports grants from Astra Zeneca, grants from Bristol Myers Squibb, during the conduct of the study; scientific board membership from Novo Nordisk, MSD, Eli Lilly, Sanofi, Medscape, Andromeda, Insuline; Payment for lectures including service on speakers bureaus for lectures from Eli Lilly, Novo Nordisk, Johnson and Johnson, Sanofi, MSD, Novartis; stock options in Insuline. Dr. Steg reports personal fees from AstraZeneca during the conduct of the study; personal fees from Amarin, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck-Sharpe-Dohme, Novartis, Otsuka, Pfizer, Roche, The Medicines Company, and Vivus. He has received grants and

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personal fees from Sanofi and Servier.

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Dr. McGuire reports personal fees from Brigham and Women’s Hospital during the conduct of the study; personal fees from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi Aventis Groupe, Genentech, Inc., Merck Sharp and Dohme Corp., Medscape Cardiology, Pri-Med Institute, The Brigham and Women's Hospital, Duke Clinical Research Institute, The Cleveland Clinic Coordinating Center for Clinical Research, The University of Oxford, Daiichi Sankyo, Lilly USA, Novo Nordisk, F. Hoffmann La Roche, Axio Research, Premier Research, INC Research LLC, Glaxo Smith Kline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, Astra Zeneca, Lexicon Pharmaceuticals, GlaxoSmithKline, Eisai, Omthera, and Regeneron. He reports non-financial support from Gilead Sciences.

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Dr. Leiter reports receiving research funding from, having provided CME on behalf of, and/or have acted as a consultant to: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novo Nordisk, Sanofi, Servier, and Takeda. Dr. Hirshberg reports employment by AstraZeneca and having stock/stock options in AstraZeneca. Dr. Davidson reports personal fees from the TIMI Study Group during the conduct of the study.

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Dr. Mosenzon reports grants from AstraZeneca and Bristol-Myers Squibb during the conduct of the study; consulting fees from AstraZeneca and Bristol-Myers Squibb; support for travel to meetings for the study from AstraZeneca and BristolMyers Squibb; scientific advisory board membership from Novo Nordisk, Eli Lilly, sanofi, Norvartis, speakers bureaus for Novo Nordisk, Eli Lilly, sanofi, Norvartis, Mercj, Sharpe and Dohme. Dr. Im reports no conflicts.

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Dr. Braunwald reports grants from Duke University, personal fees from Eli Lilly, Merck, CVRx, CV Therapeutics (now Gilead), Daiichi Sankyo, Menarini International, Medscape, Bayer, Genzyme, The Medicines Company, Sanofi Aventis. Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior

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Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, 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), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Site Co-Investigator: Biotronik, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda.

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Figure Legends Figure 1 – Baseline hemoglobin A1c and the risk of cardiovascular death, myocardial infarction, or ischemic stroke.

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Figure 2 – Association of baseline hemoglobin A1c with cardiovascular events.

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Figure 3 – Primary and secondary efficacy endpoints by baseline hemoglobin A1c in patients treated with saxagliptin or placebo.

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Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI

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Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I, Committee S-TS,

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Investigators: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-1326

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Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL, Committee S-TS, Investigators*: Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130:1579-1588

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Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559 19. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV:

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Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. The Lancet Diabetes & Endocrinology

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23. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA: Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. The Lancet

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Diabetes & Endocrinology 2014;2:843-851

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Table 1 – Baseline demographics by baseline hemoglobin A1c. HbA1c <7% (n=4,119)

HbA1c 7 - <8% (n=5,416)

HbA1c 8 - <9% (n=3,139)

HbA1c ≥9% (n=3,525)

P-value

66.0 (61.0 - 72.0)

66.0 (61.0 - 72.0)

64.0 (59.0 - 70.0)

62.0 (57.0 - 68.0)

<0.001

Male, n (%)

2,804 (68.1%)

3,715 (68.6%)

2,107 (67.1%)

2,214 (62.8%)

<0.001

White, n %)

3,279 (79.6%)

4,254 (78.5%)

2,332 (74.3%)

2,296 (65.1%)

<0.001

30.3 (27.2 - 34.1)

30.5 (27.4 - 34.4)

30.7 (27.4 - 34.7)

30.4 (26.9 - 34.6)

0.02

Established Cardiovascular Disease, n (%)

3,024 (73.4%)

4,254 (78.5%)

2,562 (81.6%)

2,885 (81.8%)

<0.001

Duration of Diabetes (years), Median (IQR)

7.2 (3.1 - 13.4)

10.3 (5.3 - 16.9)

11.9 (6.8 - 19.1)

11.6 (6.9 - 18.6)

<0.001

1,527 (37.1%)

1,247 (23.0%)

5 - <10 yrs

996 (24.2%)

1,331 (24.6%)

10 - <15 yrs

714 (17.3%)

1,133 (20.9%)

2

Body mass index (kg/m ), Median (IQR)

<5 yrs

15 - <20 yrs

385 (9.4%)

≥ 20 yrs

495 (12.0%)

GFR > 50 ml/min, n (%)

3,481 (84.5%)

Urine Albumin/Creatinine Ratio (mg/g), n (%) <30

2,903 (72.7%) 856 (21.4%)

≥ 300

234 (5.9%)

Anti-Hypoglycemic Medications Metformin, n (%) Sulfonylurea, n (%) Thiazolidinedione, n(%) Insulin, n (%)

Aspirin, n (%)

ADP Antagonist, n (%)

807 (22.9%)

722 (23.0%)

874 (24.8%)

690 (12.7%)

493 (15.7%)

511 (14.5%)

708 (22.6%)

767 (21.8%)

4,554 (84.1%)

2,630 (83.8%)

3,008 (85.3%)

0.30 <0.001

3,374 (64.3%)

1,737 (57.1%)

1,643 (48.1%)

1,391 (26.5%)

945 (31.0%)

1,218 (35.7%)

485 (9.2%)

362 (11.9%)

554 (16.2%)

3,881 (71.7%)

2,130 (67.9%)

2,374 (67.3%)

<0.001

1,447 (35.1%)

2,255 (41.6%)

1,291 (41.1%)

1,527 (43.3%)

<0.001

295 (7.2%)

348 (6.4%)

140 (4.5%)

180 (5.1%)

<0.001

875 (21.2%)

2,103 (38.8%)

1,729 (55.1%)

2,030 (57.6%)

<0.001

3,011 (73.1%)

4,080 (75.3%)

2,392 (76.2%)

2,698 (76.5%)

0.002

687 (16.7%)

984 (18.2%)

546 (17.4%)

601 (17.0%)

0.26

3,222 (78.2%)

4,319 (79.7%)

2,469 (78.7%)

2,675 (75.9%)

0.003

ACE Inhibitor, n (%)

2,232 (54.2%)

2,930 (54.1%)

1,696 (54.0%)

1,927 (54.7%)

0.95

Beta-Blocker, n (%)

2,509 (60.9%)

3,382 (62.4%)

1,971 (62.8%)

2,113 (59.9%)

0.04

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Statin, n (%)

703 (22.4%)

<0.001

2,900 (70.4%)

EP

Cardiovascular Medications

565 (16.0%)

1,011 (18.7%)

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30 - <300

508 (16.2%)

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Duration of Diabetes, n (%)

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Age (years), Median (IQR)

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Demographic Characteristics

1

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10

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Adjusted for age, sex, duration of diabetes, eGFR, established cardiovascular disease vs. primary prevention, microalbuminuria: creatinine ratio

8

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4 2

6

12 Months

18

24

HRadj (95% CI)

≥9%

1.77 (1.48-2.12)

8-<9%

1.38 (1.14-1.66)

7-<8%

1.14 (0.96-1.35)

<7%

D

6

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CV Death, MI or Ischemic Stroke

12

Reference

Event Rate HRadj, (95% CI)

CVD, MI, CVA

5.3% 6.7% 8.0% 9.9%

CVD, MI, CVA, Hosp for HF, UA, or Revasc HbA1c <7% HbA1c 7-≤8%

10.2%

Reference

12.5%

1.12 (0.99-1.27)

13.9%

1.26 (1.10-1.44)

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HbA1c 8-≤9% HbA1c ≥9%

CV Death

M AN U

HbA1c <7%

HbA1c 7-≤8% HbA1c 8-≤9% HbA1c ≥9%

Myocardial Infarction

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HbA1c <7% HbA1c 7-≤8%

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HbA1c 8-≤9% HbA1c ≥9%

EP

Ischemic Stroke

AC C

HbA1c <7% HbA1c 7-≤8% HbA1c 8-≤9% HbA1c ≥9%

Reference 1.14 (0.96-1.35) 1.38 (1.14-1.66) 1.77 (1.48-2.12)

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HbA1c <7% HbA1c 7-≤8% HbA1c 8-≤9% HbA1c ≥9%

14.7%

1.33 (1.16-1.52)

2.2%

Reference

2.7%

1.04 (0.80, 1.35)

3.6%

1.44 (1.10, 1.91)

4.1%

1.80 (1.38, 2.37)

2.3%

Reference

3.4%

1.38 (1.07, 1.78)

3.2%

1.27 (0.95, 1.69)

4.5%

1.75 (1.33, 2.30)

1.4% 1.4% 2.2% 2.6%

Reference 1.03 (0.73, 1.47) 1.59 (1.10, 2.29) 1.96 (1.38, 2.80)

2.8% 3.5% 3.0% 3.1%

Reference 1.14 (0.90, 1.44) 1.03 (0.78, 1.36) 1.06 (0.80, 1.41)

Hosp for Heart Failure HbA1c <7% HbA1c 7-≤8% HbA1c 8-≤9% HbA1c ≥9%

0.7

0.8 0.9

1.0

1.2

1.6

2.0

Hazard Ratio Increased Risk as compared to Baseline HbA1c <7%

CV DEATH, MI, OR ISCHEMIC STROKE

RI PT

Saxagliptin (%) Placebo (%) HR, (95% CI)

HbA1c <7% HbA1c 7-≤8%

SC

HbA1c 8-≤9%

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HbA1c ≥9% Overall

5.3

5.3

1.01 (0.78, 1.31)

6.6

6.8

0.98 (0.80, 1.20)

8.5

7.5

1.09 (0.85, 1.39)

9.8

10.0

0.95 (0.77, 1.18)

7.3

7.2

1.00 (0.89, 1.12)

10.5

9.8

1.07 (0.89, 1.30)

12.4

12.6

0.98 (0.85, 1.14)

15.1

12.8

1.18 (0.98, 1.43)

14.3

15.1

0.91 (0.76, 1.08)

12.8

12.4

1.02 (0.94, 1.11)

p (int)=0.89

CV DEATH, MI, ISCHEMIC STROKE, HOSPITALIZATION FOR UNSTABLE ANGINA, REVASCULARIZATION OR HEART FAILURE

D

HbA1c <7%

TE

HbA1c 7-≤8% HbA1c 8-≤9%

EP

HbA1c ≥9%

0.7

0.8

AC C

Overall

0.9

1.0

Hazard Ratio

p (int)=0.23

1.2

1.6

ACCEPTED MANUSCRIPT

•

In patients with diabetes randomized in the SAVOR-TIMI 53 trial, baseline HbA1c ≥7% was associated with an increased risk of CV death, MI, or

•

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ischemic stroke when compared to patients with baseline HbA1c <7%.

Baseline HbA1c ≥7% was not associated with increased risk of

•

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hospitalization for heart failure in the SAVOR-TIMI 53 trial.

The effect of saxagliptin on cardiovascular events, including heart failure,

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is similar irrespective of baseline HbA1c.

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Hospitalization for Unstable Angina N HRadj (95% CI)

N

HRadj (95% CI)

N

HRadj (95% CI)

165

Ref

62

Ref

65

236

1.06 (0.87-1.31)

87

1.11 (0.79-1.56)

65

170

1.35 (1.08-1.69)

53

1.18 (0.80-1.74)

31

206

1.69 (1.36-2.10)

61

1.48 (1.02-2.16)

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Coronary Revascularization N HRadj (95% CI)

Ref

177

Ref

1.10 (0.74-1.67)

311

1.26 (1.04-1.52)

0.86 (0.53-1.39)

192

1.29 (1.05-1.60)

0.94 (0.59-1.49)

187

1.13 (0.91-1.40)

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<7% (n=4119) 7-<8% (n=5416) 8-<9% (n=3139) ≥9% (n=3525)

Non-CV Death

SC

Death

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Supplemental Table 1 – Association between baseline HbA1c and other cardiovascular events.*

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*Adjusted for age, gender, duration of diabetes, GFR, established cardiovascular disease, microalbuminuria:creatinine ratio.

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