Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Moderate or Severe Renal Impairment: Observations From the SAVOR-TIMI 53 Trial

Patients with concomitant type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are at high risk for atherothrombotic events and heart failure (1,2). Progressive albuminuria and decrements in estimated glomerular filtration rate (eGFR) are each independent predictors of adverse renal outcomes in patients with T2DM (3), as well as cardiovascular (CV) death and all-cause mortality (4–6). Therefore, patients with T2DM and CKD represent a patient population in which strategies to reduce CV risk are needed (7).

There are few evidence-based treatments of hyperglycemia available for patients with T2DM and advanced renal impairment, who are particularly susceptible to adverse reactions such as severe hypoglycemia and reduced drug elimination (8–10). Moreover, these high-risk patients have been relatively under-represented in large clinical outcomes trials. As a result, there are limited data on the CV safety and efficacy of glycemic control strategies or interventions aimed at the prevention of incident or progressive atherosclerotic disease in patients with concomitant T2DM and CKD (10,11).

Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is primarily eliminated by the kidneys (12,13). The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized 16,492 patients with T2DM who were at risk for CV events to receive saxagliptin or placebo for a median period of 2 years (14). In the trial as a whole, saxagliptin had no detectable effect on CV events, improved glycemic control, and reduced the development and progression of albuminuria. However, saxagliptin was associated with a small but statistically significant increase in the risk of hospitalization for heart failure. The present prespecified secondary analysis evaluated the efficacy and safety of saxagliptin compared with placebo according to baseline renal function in patients with T2DM.

The design, baseline characteristics, and primary results of the SAVOR-TIMI 53 trial have been reported previously (14–17). Briefly, this was an international, multicenter, double-blind, event-driven, randomized, controlled trial in stable patients with T2DM who were at moderate-to-high risk for CV events based on either a history of established CV disease or multiple vascular risk factors. Patients were randomly assigned to receive saxagliptin or matching placebo. Other background glucose-lowering and CV therapies, and recommendations for diet and lifestyle, were at the discretion of the responsible physician (18). Open-label initiation and/or titration of glucose-lowering therapies was allowed throughout the trial in both arms, excluding the use of DPP-4 inhibitors or GLP-1 analogs. All participants provided written informed consent, and the study protocol was approved by the relevant institutional review board at each participating site and the coordinating center.

Patients were excluded from SAVOR-TIMI 53 if they had either a history of end-stage renal disease (ESRD) on long-term dialysis, renal transplantation, or a serum creatinine level of >6.0 mg/dL. The eGFR was determined according to the Modification of Diet in Renal Disease formula (19). Randomization was stratified by baseline renal function category (normal or mildly impaired renal function [eGFR >50 mL/min/1.73 m²] vs. moderate renal impairment [eGFR 30–50 mL/min/1.73 m²] or severe renal impairment [eGFR <30 mL/min/1.73 m²]) (20) and CV disease status (primary or secondary prevention). At least 800 patients with moderate-to-severe renal impairment were targeted for enrollment and randomization into the trial. Once ∼300 patients with severe renal impairment were randomized, enrollment of this group was capped.

Saxagliptin is metabolized by the liver into its main active metabolite, and both are primarily eliminated by the kidney. Based upon prior studies, patients with moderate-to-severe renal impairment (eGFR ≤50 mL/min/1.73 m²) have maximal serum concentrations of saxagliptin that are 40–100% higher than those patients with preserved renal function (21). As a result, one-half the usual dose of saxagliptin is recommended for patients with moderate-to-severe renal impairment or ESRD (12,21). Patients were assigned to receive the study drug dose at baseline based upon the eGFR calculated during the screening visit (5 mg daily or 2.5 mg daily in patients with an eGFR ≤50 mL/min/1.73 m²). There was a single dose adjustment to 2.5 mg daily in those patients in whom renal impairment developed (eGFR <50 mL/min/1.73 m²) during the study period. Patients were to continue receiving the study drug even if further renal impairment, ESRD, or initiation of long-term dialysis occurred.

The primary end point was the time to the first event of a composite of CV death, myocardial infarction (MI), or ischemic stroke. The major secondary end point included the primary composite plus hospitalization for heart failure, coronary revascularization, or unstable angina. Each component of the composite primary or secondary end point was adjudicated by an independent clinical events committee blinded to study group assignment, according to prespecified criteria that have been reported previously (14,17). A prespecified renal laboratory end point included the risk of progressive microalbuminuria, which was defined as the number and proportion of patients with worsening of, no change in, or improvement in urinary albumin-to-creatinine ratio (ACR), which was defined as a shift from baseline category (<3.4, ≥3.4 to ≤33.9, or >33.9 mg/mmol) to the end of treatment. Two prespecified clinical renal end points were defined as follows: 1) the composite of a doubling of serum creatinine level, initiation of long-term dialysis, renal transplantation, or serum creatinine level >6 mg/dL and 2) the prior composite renal end point together with death. Hypoglycemic end points included hospitalization for hypoglycemia and major hypoglycemic events, identified by the investigator if the event required intervention by a third party. Other adverse events and severe adverse events were also recorded, as previously described (14,16).

Baseline characteristics of patients were examined by categories of renal function. Aggregate and treatment-specific event rates across the three renal function groups are presented as 2-year Kaplan-Meier estimates. Cumulative event rates were also calculated for the primary end point by stratifying patients on the basis of renal function and established CV disease. The influence of renal function on outcomes was estimated using a Cox proportional hazards model with a restricted cubic spline function to derive hazard ratios (HRs) and 95% CIs for decrement in eGFR levels and for a threshold effect (22,23). Models were adjusted for clinical risk factors, including age, sex, current tobacco use, history of hypertension, presence of hypercholesterolemia, established CV disease, and heart failure. Models containing the aforementioned clinical variables were further adjusted for urinary ACR.

The statistical analysis plan prespecified testing the efficacy and safety of the randomized comparison in patients with moderate and severe renal dysfunction for consistency with the overall trial results (14,16). All analyses were conducted on an intention-to-treat basis among patients who underwent randomization. The homogeneity of treatment effects on the occurrence of the primary and secondary end points across subgroups of renal function status—categorized three-way (eGFR >50 mL/min/1.73 m², 30–50 mL/min/1.73 m², and <30 mL/min/1.73 m²) and dichotomously (eGFR >50 mL/min/1.73 m² and ≤50 mL/min/1.73 m²)—was examined using a Cox proportional hazards model stratified by baseline CV disease status, and included terms for randomized treatment and an interaction between treatment and renal function category. Comparisons of emergent adverse events by treatment assignment were calculated using either a χ² test or a Fisher exact test. The statistical software package SAS (version 9.3; SAS Institute, Cary, NC) was used for all analyses, with a two-sided P value <0.05 considered to be statistically significant. All analyses were performed by the TIMI Study Group. The academic authors take full responsibility for the integrity of the database and analyses.

Among the 16,492 patients with T2DM who were randomized, the median eGFR was 71.7 mL/min/1.73 m² (interquartile range 57.1–86.4). There were 13,916 (84.4%) patients with normal or mildly impaired renal function (eGFR >50 mL/min/1.73 m²), 2,240 patients (13.6%) with moderate renal impairment (eGFR 30–50 mL/min/1.73 m²), and 336 patients (2.0%) with severe renal impairment (eGFR <30 mL/min/1.73 m²) at baseline. Baseline characteristics between treatment groups were well balanced within each renal group.

Patients with more severe renal impairment were older and more frequently female and had a longer duration of diabetes, a higher prevalence of prior heart failure, a lower fasting serum glucose level, a higher urinary ACR, and higher levels of the N-amino terminal fragment of the prohormone B-type natriuretic peptide compared with patients with normal or mildly impaired renal function (Table 1). Additionally, patients with moderate and severe renal impairment were less frequently treated at baseline with metformin and sulfonylureas, and were more frequently treated with insulin (Supplementary Table 1).

Higher rates of all CV, renal, and hypoglycemic events were observed with progressive renal impairment. For instance, in aggregate, patients with normal or mildly impaired renal function (eGFR >50 mL/min/1.73 m²) had a 2-year risk of CV death, MI, or ischemic stroke of 6.4% (referent), compared with 11.2% in patients with moderate renal impairment (adjusted HR 1.48 [95% CI 1.28–1.71], P < 0.001) and 15.9% in patients with severe renal impairment (adjusted HR 2.52 [95% CI 1.90–3.26], P < 0.001) (Fig. 1A). Risk of hospitalization for heart failure among these three groups of patients was 2.2% (referent), 7.4% (adjusted HR 2.38 [95% CI 1.95–2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28–6.28], P < 0.001), respectively (Fig. 1B). A similar pattern was observed with regard to CV death (Fig. 1C). The risk associated with CV death, MI, or ischemic stroke and hospitalization for heart failure remained significant even after further adjustment for urinary ACR (Supplementary Table 2). When patients were further stratified by either the presence of moderate-to-severe renal impairment (eGFR ≤50 mL/min/1.73 m²) or a history of established CV disease, each group demonstrated a comparable elevated risk of ischemic CV events, with markedly elevated risk among patients presenting with both risk factors simultaneously (Supplementary Fig. 1).

Spline models demonstrated that the influence of eGFR on the risk of the primary end point was nonlinear; a nadir in risk was observed at an eGFR of ∼86 mL/min/1.73 m² (Supplementary Fig. 2). Progressively lower eGFR demonstrated a linear association with the risk of the primary end point independent of age, sex, current tobacco use, and history of hypertension, hypercholesterolemia, established CV disease, and heart failure. A more gradual relationship of risk with an increasing eGFR of >86 mL/min/1.73 m² was also observed. Patients with an eGFR of ≤86 mL/min/1.73 m² had a significantly higher adjusted risk of CV death, MI, or ischemic stroke compared with patients with normal renal function (adjusted HR 1.25 [95% CI 1.08–1.46], P = 0.003).

The relative risk of the primary end point and major secondary end point with saxagliptin relative to placebo was similar, irrespective of renal impairment (Table 2 and Fig. 2). Similarities in treatment effect were also observed for the other CV end points across renal categories (all P for interactions ≥0.19), though, given the small size of the severe renal impairment cohort (n = 336), the number of events was small. Results were similar when renal function was analyzed dichotomously at an eGFR of ≤50 mL/min. (Supplementary Table 3 and Supplementary Fig. 3).

The frequency of progressive diabetic nephropathy, as reflected in the urinary ACR, was significantly reduced with saxagliptin compared with placebo in all patients except those with severe renal impairment (Table 3). Specifically, patients with normal or mildly impaired renal function (P < 0.0001) and moderate-to-severe renal impairment (P = 0.041) randomized to saxagliptin had more improvement and less worsening of urinary ACR compared with the placebo group (Supplementary Table 4). Results in patients with severe renal impairment were not significant (P = 0.61). Other renal end points occurred at relatively balanced rates in patients treated with saxagliptin compared with placebo, irrespective of renal impairment (Fig. 2 and Supplementary Table 5).

Regarding glycemic end points, patients treated with saxagliptin had significantly lower HbA_1c levels compared with those treated with placebo at 1 year, irrespective of baseline renal status. For example, median HbA_1c at 1 year was lower in saxagliptin-treated patients with normal or mildly impaired renal function (7.3% [56 mmol/mol] vs. 7.6% [60 mmol/mol], P < 0.0001), moderate renal impairment (7.4% [57 mmol/mol] vs. 7.6% [60 mmol/mol], P = 0.0009), and severe renal impairment (7.1% [54 mmol/mol] vs. 7.7% [61 mmol/mol], P = 0.002), and these differences persisted throughout the follow-up period (data not shown). Similarly, the relative likelihood of patients treated with saxagliptin requiring the addition or increase of any new anti-hyperglycemic medication, including the initiation of insulin therapy, was lower compared with placebo, irrespective of renal impairment (both P for interactions ≥0.17) (Fig. 2).

Few hospitalizations for hypoglycemia occurred during the study, though the risk was highest in patients with moderate or severe renal impairment (Fig. 2). Similarly, the relative risk of major hypoglycemia with saxagliptin therapy compared with placebo was lowest in patients with severe renal impairment (4.84% vs. 6.39%, HR 0.65 [95% CI 0.26–1.58], P = 0.35) compared with patients with both normal or mildly impaired renal function (1.45% vs. 1.30%, HR 1.11 [95% CI 0.84–1.47], P = 0.46) and moderate renal impairment (5.73% vs. 3.31%, HR 1.91 [95% CI 1.27–2.92], P = 0.002, P for interaction = 0.03) (Fig. 2). When considered dichotomously, the absolute risk difference with saxagliptin was higher in patients with moderate-to-severe renal impairment (Supplementary Table 5).

The emergence of any adverse event or severe adverse event increased in patients with progressive renal impairment and occurred in similar proportions in patients with normal or mildly impaired renal function and moderate renal impairment, respectively (Supplementary Table 6). At least one adverse event occurred in 152 (88%) saxagliptin-treated patients with severe renal impairment compared with 126 (77%) patients treated with placebo (P = 0.006), with no significant difference in severe adverse events.

In this analysis of patients with T2DM in the SAVOR-TIMI 53 trial, there were four major findings. First, subjects with more advanced nephropathy in the form of progressive renal impairment had a significantly higher risk of CV events compared with patients with normal or mildly impaired renal function. Second, the CV effect of saxagliptin, including hospitalization for heart failure, in patients with moderate-to-severe renal impairment was consistent with that in patients with normal or mildly impaired renal function. Third, treatment with saxagliptin resulted in a modest, but significant, improvement in glycemic control, even though patients assigned to receive placebo had higher rates of add-on glycemic therapy, which may have attenuated any differences seen with saxagliptin (14). While saxagliptin also prevented progressive microalbuminuria in patients with moderate-to-severe renal impairment, it did not affect other renal end points. Fourth, major hypoglycemia, although infrequent, was approximately three times more frequent in patients with nephropathy, with higher rates in all patients treated with saxagliptin compared with placebo except those with severe renal impairment. This single finding of heterogeneity may be due to differences in concomitant anti-hyperglycemic medications such as sulfonylureas or the play of chance (12). To the best of our knowledge, this is the largest cohort of patients in a clinical outcomes trial to provide efficacy and safety data of an anti-hyperglycemic agent in patients with T2DM and CKD (10–12).

The presence of proteinuric nephropathy, including early microalbuminuria and decrement in eGFR, is considered an independent risk factor of future atherothrombotic events and CV death in patients with T2DM (3–6). In the present analyses, within each group of patients with stepwise worsening of renal function, atherothrombotic risk increased nearly threefold; whereas the risk was elevated threefold to sixfold for those with heart failure. These patients represent a growing population for targeting risk reduction with adequate glycemic control and prevention of progressive nephropathy (7,9,10). Whether improvement in levels of either serum glucose and/or urinary albumin may translate into a cardioprotective benefit remains controversial (24,25). Hypoglycemia, either major events or those requiring hospitalization, occurred infrequently in this population. Patients with moderate-to-severe renal impairment had higher overall rates of hypoglycemia, though the relative risk with saxagliptin was similar to that in patients with normal or mildly impaired renal function, likely reflecting the preferential use of insulin versus sulfonylureas in patients with worsening renal function.

The choice of anti-hyperglycemic agent in patients with renal impairment is challenging in light of the lack of outcomes data in patients with T2DM and CKD (9,10). For instance, metformin is typically recommended as first-line therapy in patients with mild renal impairment (8,26). Historically, caution has been advised with the use of metformin in patients with established CV disease or moderate-to-severe renal impairment because of concerns about lactic acidosis in patients with reduced renal clearance (27). However, large contemporary registries with metformin suggest no additional risk and relative effectiveness in CV protection and mortality in patients with T2DM and CKD or CV disease (28–30). There are limited CV outcomes data for the use of sulfonylureas and insulin in patients with T2DM and CKD, and these agents can increase susceptibility to hypoglycemia as a result of reduced renal clearance (9,10).

Among the therapies with outcomes data from large trials, glitazones reduce progressive microalbuminuria in patients with T2DM but increase weight and heart failure (31–35). Insulin glargine had a neutral effect on CV outcomes in the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial, but specific results in the 1,942 patients with albuminuria have yet to be reported (36). The DPP-4 inhibitor alogliptin had neutral effects on overall CV outcomes in patients with T2DM after an acute coronary syndrome event in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (37). However, among the 1,565 patients with moderate-to-severe renal impairment, there was a trend toward an increase in CV death, MI, or stroke (HR 1.15 [95% CI 0.91–1.46]) compared with 3,815 patients with normal or mildly impaired renal function (HR 0.84 [95% CI 0.68–1.04], P for interaction = 0.046). Details of whether this trend was observed for other CV end points, including hospitalization for heart failure, are yet to be reported (37).

The strength of the present analysis is that differences in saxagliptin effect were ascertained in a large, contemporary, randomized, placebo-controlled trial conducted in international centers with patients with T2DM and varying degrees of renal impairment. This analysis also has limitations: patients with moderate and severe renal impairment were subgroups, with predefined enrollment goals that alone were not powered to determine efficacy or safety. Thus, the number of events in the severe renal impairment group, in particular, was relatively small. Nevertheless, the treatment effect for various end points in patients with and without advanced renal impairment was consistent with the results of the overall trial. Second, this analysis was limited to a median of 2 years of follow-up, with no ability to determine the effects of saxagliptin on CV or renal outcomes beyond that time. Finally, data on baseline left ventricular function were not available.

In conclusion, patients with T2DM and CKD are a challenging group to treat with respect to hyperglycemia and prevention of progressive nephropathy. Intensive glucose management strategies and certain anti-hyperglycemic medications may confer inherent risks, including adverse CV, renal, and hypoglycemic events. In the SAVOR-TIMI 53 trial, we observed that the relative effects of saxagliptin on CV, renal, and glycemic end points were consistent in patients with moderate-to-severe renal impairment compared with patients with normal or mildly impaired renal function. These findings highlight the increased CV risk of patients with diabetic nephropathy, and provide data on the efficacy and safety of saxagliptin to inform clinicians when formulating treatment strategies for their patients with concomitant T2DM and renal impairment.

Acknowledgments. The authors gratefully acknowledge the patients, investigators, research coordinators, and committee members of the SAVOR-TIMI 53 trial for their efforts. SAVOR-TIMI 53 Executive Committee: Eugene Braunwald (study chair), Deepak L. Bhatt (co-principal investigator), Itamar Raz (co-principal investigator), Jaime A. Davidson, Robert Frederich (nonvoting), Boaz Hirshberg (nonvoting), and Ph. Gabriel Steg.

Funding and Duality of Interest. The SAVOR-TIMI 53 trial was funded by AstraZenecahttp://dx.doi.org/10.13039/100004325/Bristol-Myers Squibbhttp://dx.doi.org/10.13039/10.13039/100002491. J.A.U., M.A.C., K.I., A.A.U.-E., and P.H. report they are or were members of the TIMI Study Group, which received research grant support from AstraZeneca and Bristol-Myers Squibb. D.L.B. discloses the following relationships: advisory board for Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; chair of the American Heart Association Get With The Guidelines Steering Committee; data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; honoraria from the American College of Cardiology (editor, Clinical Trials, Cardiosource), 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), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), and WebMD (continuing medical education steering committees); Clinical Cardiology (associate editor); Journal of the American College of Cardiology (section editor, pharmacology); research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi, and The Medicines Company; and unfunded research for FlowCo, PLx Pharma, and Takeda. E.B. discloses research grants through the TIMI Study Group and Brigham and Women’s Hospital from AstraZeneca and Bristol-Myers Squibb. M.A.C. has received consulting fees from AstraZeneca and Merck Sharp & Dohme. O.M. discloses the following relationships: research grants through Hadassah Hebrew University Hospital from AstraZeneca and Bristol-Myers Squibb; consulting fees from AstraZeneca and Bristol-Myers Squibb; travel support for attendance at scientific meetings from AstraZeneca and Bristol-Myers Squibb; advisory board for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novartis, Novo Nordisk, and Sanofi; and speaker fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi. P.G.S. discloses the following relationships: speaker fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Roche, and The Medicines Company; consulting fees from Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, Servier, and Vivus; honoraria for clinical trial steering committee participation from AstraZeneca, Amarin, GlaxoSmithKline, Otsuka, Sanofi, Servier, and Vivus; and honoraria for preparation of educational material from Boehringer Ingelheim. J.A.D. discloses the following relationships: honoraria for advisory board participation from Aspire Bariatrics, AstraZeneca, Eli Lilly, Janssen, and Novo Nordisk; speaker fees from AstraZeneca, Janssen, Johnson & Johnson, and Novo Nordisk; President of WorldWIDE Diabetes, a not-for-profit foundation; The Executive Committee CME of The University of Texas Southwestern Medical Center; the editorial boards of The Journal of Diabetes and ALAD, the Journal of the Latin American Diabetes Association. J.C.N. discloses the following relationships: research grants through the Heart Institute (InCor) at the University of São Paulo Medical School from AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Johnson & Johnson, and Sanofi; advisory boards for AstraZeneca, Bayer, and Sanofi; consulting fees from AstraZeneca; travel support for attendance at scientific meetings from AstraZeneca; speaker fees from AstraZeneca, Bayer, and Sanofi; and honoraria for the preparation of educational material from AstraZeneca and Bayer. R.C. discloses honoraria through the Pontificia Universidad Católica de Chile from Brigham and Women’s Hospital during the conduct of this study and served on the Latin American Advisory Board. B.H. is employed by AstraZeneca. R.F. is employed by Bristol-Myers Squibb. D.K.M. discloses the following relationships: research grants and honoraria from Brigham and Women’s Hospital during the conduct of this study; personal fees from Boehringer Ingelheim, Janssen Research and Development LLC, Merck Sharp & Dohme, Brigham and Women's Hospital, Duke Clinical Research Institute, Cleveland Clinic Coordinating Center for Clinical Research, University of Oxford, Eli Lilly USA, Novo Nordisk, F. Hoffmann-La Roche, GlaxoSmithKline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, Omthera, AstraZeneca, and Regeneron; and nonfinancial research support from Gilead Sciences. L.A.L. discloses the following relationships: consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche, Sanofi, Servier, and Takeda; research grants through the Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche, and Sanofi; speaker fees from Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Sanofi, and Takeda; and honoraria for the preparation of educational material from AstraZeneca and Bristol-Myers Squibb. I.R. discloses the following relationships: consulting fees from Andromeda, AstraZeneca, Bristol-Myers Squibb, and Insuline; travel support for attendance at scientific meetings from AstraZeneca; advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi; speaker fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi; and equity stock ownership in Insuline. B.M.S. discloses the following relationships: research grants through the TIMI Study Group and Brigham and Women’s Hospital from AstraZeneca and Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Bayer Healthcare, Gilead, Eisai, and Merck Sharp & Dohme and consulting fees from Gilead, Lexicon, Arena, Eisai, St. Jude's Medical, Bristol-Myers Squibb, Forest Pharmaceuticals, Boston Clinical Research Institute, Decision Resources, University of Calgary, and Elsevier Practice Update Cardiology. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. J.A.U., D.L.B., E.B., P.G.S., J.A.D., B.H., R.F., I.R., and B.M.S. conceived and designed the study; helped to acquire, analyze, and interpret the data; helped to draft the manuscript and revise the manuscript for important intellectual content; and approved the final version of the manuscript submitted. M.A.C., O.M., J.C.N., R.C., K.I., A.A.U.-E., P.H., D.K.M., and L.A.L. helped to acquire, analyze, and interpret the data; helped to draft the manuscript and revise the manuscript for important intellectual content; and approved the final version of the manuscript submitted. J.A.U. and B.M.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.