egfr > 50 (n = 13,916)

Saxagliptin and Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus and Moderate or Severe Renal Impairment: Observations from the SAVOR-TIMI 53 Trial Supplementary Table 1. Characteristics according to Renal Function Characteristic egfr > 50 (n = 13,916) egfr 50 (n = 2,576) Demographic Characteristics Age years, Median (IQR) 64.0 (59.0-70.0) 70.0 (64.0-75.0) <.0001 Female sex, n(%) 4,355 (31.3%) 1,100 (42.7%) <.0001 Weight kg, Median (IQR) 86.1 (74.8-99.8) 85.0 (73.2-99.5) 0.03 Body-mass index - kg/m 2, Median (IQR) 30.4 (27.2-34.3) 31.0 (27.6-35.1) <.0001 Past Medical History Duration of diabetes, Median (IQR) 10.0 (4.9-15.8) 13.6 (7.8-20.7) <.0001 Established atherosclerotic disease, n(%) 10,809 (77.7%) 2,150 (83.5%) <.0001 Hypertension, n(%) 11,301 (81.2%) 2,191 (85.1%) <.0001 Dyslipidemia, n(%) 9,760 (70.1%) 1,979 (76.8%) <.0001 Prior myocardial infarction, n(%) 5,209 (37.4%) 1,028 (39.9%) 0.02 Prior heart failure, n(%) 1,577 (11.3%) 528 (20.5%) <.0001 Prior coronary revascularization, n(%) 5,900 (42.4%) 1,223 (47.5%) <.0001 Clinical and Laboratory Measurements Systolic blood pressure mmhg, Median (IQR) 136.5 (125.0-147.0) 137.0 (125.0-148.5) 0.18 Diastolic blood pressure mmhg, Median 80.0 (71.5-85.5) 77.0 (69.0-83.5) 0.0001 (IQR) HbA1c (%), Median (IQR) 7.6 (6.9-8.7) 7.6 (6.9-8.7) 0.24 HbA1c (mmol/mol), Median (IQR) 60 (52-72) 60 (52-72) 0.24 Fasting serum glucose (mg/dl), Median (IQR) 146.0 (120.0-183.0) 139.0 (110.0-178.0) <.0001 Estimated glomerular filtration rate ml/min, 75.6 (64.3-89.5) 41.4 (34.7-46.1) <.0001 Median (IQR) Albumin/creatinine ratio mg/mmol, Median 1.6 (0.7-6.0) 5.9 (1.4-38.1) <.0001 (IQR) Albumin/creatinine ratio, n(%) <.0001 < 3.4 mg/mmol 8,691 (65.3%) 1,005 (41.2%) 3.4-33.9 mg/mmol 3,624 (27.2%) 802 (32.9%) > 33.9 mg/mmol 1,004 (7.5%) 634 (26.0%) Baseline Cardiovascular Medications Aspirin, n(%) 10,501 (75.5%) 1,903 (73.9%) 0.09 Statins, n(%) 10,814 (77.7%) 2,103 (81.6%) <.0001 Beta-Blockers, n(%) 8,379 (60.2%) 1,783 (69.2%) <.0001 Diuretics, n(%) 5,503 (39.5%) 1,695 (65.8%) <.0001 ACE Inhibitors, n(%) 7,611 (54.7%) 1,329 (51.6%) 0.004 Angiotensin Receptor Blockers, n(%) 3,708 (26.6%) 887 (34.4%) <.0001 Calcium antagonists, n(%) 4,312 (31.0%) 1,066 (41.4%) <.0001 Baseline Anti-hyperglycemic Medications Metformin, n(%) 10,355 (74.4%) 1,118 (43.4%) <.0001 Sulfonylurea, n(%) 5,702 (41.0%) 931 (36.1%) <.0001 Thiazolidinediones, n(%) 831 (6.0%) 147 (5.7%) 0.60 Insulin, n(%) 5,380 (38.7%) 1,452 (56.4%) <.0001 None, n(%) 632 (4.5%) 103 (4.0%) 0.22 Abbreviations: egfr, estimated glomerular filtration rate, presented as ml/min/1.73m 2. P

Supplementary Table 2. Association of Renal Function and Cardiovascular Endpoints Adjusted for Clinical Findings and Urinary Albumin-to-Creatinine Ratio Outcome Hazard Ratio (95% CI) egfr > 50 egfr 30-50 P egfr < 30 P CV Death, MI, Ischemic Stroke Referent 1.17 (1.00-1.37) 0.042 1.53 (1.13-2.02) 0.004 Hosp. for HF Referent 1.78 (1.43-2.20) <0.001 2.56 (1.77-3.60) <0.001 Patients are categorized into normal or mildly impaired renal function (egfr >50 ml/min/1.73m 2 ); moderate renal impairment (egfr 30-50 ml/min/1.73m 2 ); or severe renal impairment (egfr <30 ml/min/1.73m 2 ). Covariates in the model include age, sex, current tobacco use, history of hypertension, history of hypercholesterolemia, prior cardiovascular disease, prior heart failure, and urinary albumin-to-creatinine ratio. Supplementary Table 3. Two-Year Cardiovascular Endpoints According to Renal Function Endpoint egfr > 50 ml/min/1.73m2 egfr 50 ml/min/1.73m 2 P Interaction Saxagliptin Placebo Hazard Ratio P Saxagliptin Placebo Hazard Ratio P 5 mg (n = 6986) (n = 6930) (95% CI) 2.5 mg (n = 1294) (n = 1282) (95% CI) CV Death, MI, Ischemic Stroke 6.55% 6.28% 1.01 (0.88-1.15) 0.93 11.5% 12.3% 0.97 (0.78-1.22) 0.82 0.82 CV Death, MI, Ischemic Stroke, Hosp. for HF, Coronary 11.7% 11.1% 1.03 (0.93-1.13) 0.61 19.0% 19.5% 1.00 (0.84-1.19) 0.98 0.80 Revascularization, UA CV Death 2.59% 2.28% 1.06 (0.86-1.31) 0.58 6.53% 6.53% 0.98 (0.73-1.31) 0.87 0.66 MI 2.74% 3.06% 0.88 (0.73-1.07) 0.21 5.67% 5.18% 1.16 (0.82-1.63) 0.40 0.17 Ischemic Stroke 1.94% 1.63% 1.12 (0.88-1.44) 0.36 1.79% 1.88% 1.03 (0.59-1.82) 0.91 0.79 Hosp. for HF 2.46% 1.97% 1.23 (0.99-1.55) 0.06 9.09% 7.22% 1.32 (1.00-1.74) 0.047 0.70 Abbreviations: CI indicates confidence interval; CV, cardiovascular; egfr, estimated glomerular filtration rate; Hosp., hospitalization; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

Supplementary Table 4. Frequency of Progressive Microalbuminuria by Completion of Follow-up According to Renal Function Total Worsened No Change Improved N (%) N (%) N (%) N (%) P-value* egfr > 50 ml/min/1.73m 2 (n = 10,621) <0.0001 Saxagliptin 5,380 (50.7%) 682 (12.7%) 4,139 (76.9%) 559 (10.4%) Placebo 5,241 (49.3%) 790 (15.1%) 4,003 (76.4%) 448 (8.5%) egfr 50 ml/min/1.73m 2 (n = 1739) 0.041 Saxagliptin 885 (50.9%) 151 (17.1%) 623 (70.4%) 111 (12.5%) Placebo 854 (49.1%) 179 (21.0%) 591 (69.2%) 84 (9.8%) The risk of progressive microalbuminuria was defined as a treatment difference in the number and proportion of patients with worsening, no change, or improvement in urinary albumin-to-creatinine ratio (ACR), defined as a shift from baseline category (<3.4, 3.4 to 33.9, or >33.9 mg/mmol) over the duration of follow-up among patients with complete data. *P-values based on chi-square or Fisher s exact test.

Supplementary Table 5. Frequency of Renal and Glycemic Endpoints According to Renal Function Endpoint egfr > 50 ml/min/1.73m 2 egfr 50 ml/min/1.73m 2 P Interaction Saxagliptin Placebo Hazard Ratio Saxagliptin Placebo Hazard Ratio 5 mg (n = 6986) (n = 6930) (95% CI) 2.5 mg (n = 1294) (n = 1282) (95% CI) Doubling of Serum Creatinine, Dialysis, Renal Transplant, 1.50% 1.22% 1.10 (0.83-1.44) 5.80% 6.16% 1.06 (0.78-1.44) 0.90 Serum Creatinine >6 mg/dl Doubling of Serum Creatinine, Dialysis, Renal Transplant, Serum Creatinine >6 mg/dl, Death 5.24% 4.41% 1.10 (0.95-1.27) 13.9% 13.7% 1.06 (0.86-1.29) 0.78 Hosp. for Hypoglycemia 0.44% 0.30% 1.44 (0.84-2.52) 1.65% 1.82% 0.99 (0.54-1.82) 0.36 Major Hypoglycemia 1.45% 1.30% 1.11 (0.84-1.47) 5.60% 3.70% 1.58 (1.10-2.30) 0.13 Initiation of Insulin Therapy 5.24% 7.66% 0.67 (0.59-0.77) 7.14% 8.60% 0.87 (0.66-1.16) 0.10 Addition or Increase of Any New Anti-Hyperglycemic Medication (including Insulin) 24.4% 30.1% 0.77 (0.72-0.82) 20.0% 24.9% 0.81 (0.69-0.96) 0.60 Abbreviations: CI indicates confidence interval; HR, hazard ratio; Hosp., hospitalization; egfr, estimated glomerular filtration rate. Interaction P-values based on categorical egfr groups. Supplementary Table 6. Frequency of Adverse Events According to Renal Function Safety Endpoint egfr > 50 ml/min/1.73m 2 egfr 30-50 ml/min/1.73m 2 egfr < 30 ml/min/1.73m 2 Saxagliptin Placebo P Value* Saxagliptin Placebo P Value* Saxagliptin Placebo P Value* 5 mg (n = 6930) 2.5 mg (n = 1118) 2.5 mg (n = 164) (n = 6986) (n = 1122) (n = 172) Any Adverse Event 5079 (72.7%) 5054 (72.9%) 0.76 869 (77.5%) 866 (77.5%) 0.996 152 (88.4%) 126 (76.8%) 0.006 Total Number of Events 24,797 24,815 5,448 4,770 749 764 Any Severe Adverse Event 1645 (23.5%) 1591 (23.0%) 0.41 403 (35.9%) 412 (36.9%) 0.65 81 (47.1%) 70 (42.7%) 0.42 Total Number of Events 2887 2858 866 807 156 185 *P-values based on chi-square or Fisher s exact test.

Supplementary Figure 1. Two-year event rates for the composite of cardiovascular death, myocardial infarction, or ischemic stroke in patients stratified by renal function and cardiovascular disease status. Patients are categorized dichotomously into moderate-to-severe renal impairment (egfr 50 ml/min/1.73m 2 ) or not (egfr >50 ml/min/1.73m 2 ); with or without a prior history of established cardiovascular disease. Abbreviations: CV indicates cardiovascular; egfr, estimated glomerular filtration rate; MI, myocardial infarction.

Supplementary Figure 2. Relationship between egfr and the risk of the composite of cardiovascular death, myocardial infarction, or ischemic stroke The solid lines represent the adjusted point estimates for the risk of the composite endpoint of cardiovascular death, MI, or ischemic stroke by egfr, presented as ml/min/1.73m 2 ; black represents all patients, red represents patients assigned to saxagliptin, and blue represents patients assigned to placebo. The y-axis represents the log hazard ratio of the composite outcome. The red dotted line represents the reference level of egfr 86 ml/min/1.73m 2. The cubic spline function was adjusted for age, sex, current tobacco use, and history of hypertension, hypercholesterolemia, established cardiovascular disease, and heart failure. Abbreviations: CV indicates cardiovascular; egfr, estimated glomerular filtration rate; MI, myocardial infarction.

Supplementary Figure 3. Effect of saxagliptin on the risk of cardiovascular outcomes in patients categorized by estimated GFR. Patients are categorized according to baseline renal function as normal or mildly impaired (egfr > 50 ml/min/1.73m 2 ; N=13,916) or moderate-tosevere renal impairment (egfr 50 ml/min/1.73m 2 ; N=2576). Patients are categorized according to baseline renal function as normal or mildly impaired (egfr > 50 ml/min/1.73m 2 ; N=13,916) or moderate-to-severe renal impairment (egfr 50 ml/min/1.73m 2 ; N=2576). Shown are Kaplan-Meier (KM) rate estimates of each cardiovascular endpoint through 2 years in saxagliptin (S) and placebo (P) arms, respectively. The squares indicate the point estimate, and horizontal lines indicate the 95% confidence interval (CI) for the effect in each subgroup. Abbreviations: CV indicates cardiovascular; Cor. Revasc., coronary revascularization; HF, heart failure; HR, hazard ratio; hosp., hospitalization; egfr, estimated glomerular filtration rate; MI, myocardial infarction; UA, unstable angina. Interaction P-values based on categorical egfr groups.