Variables analyzed as potential mediators of the effect of empagliflozin versus placebo on risk of CV death in the EMPA-REG OUTCOME trial
| Mechanistic category and variable . | . | . | . | Adjusted mean (SE) difference vs. placebo in change from baseline* . | |||
|---|---|---|---|---|---|---|---|
| Mean (SE) at baseline . | Week 12 or 28† . | Week 164 . | |||||
| Placebo . | Empa 10 mg . | Empa 25 mg . | Empa 10 mg . | Empa 25 mg . | Empa 10 mg . | Empa 25 mg . | |
| Glycemia | |||||||
| HbA1c (%) | 8.08 (0.02) | 8.08 (0.02) | 8.07 (0.02) | −0.54 (0.02) | −0.60 (0.02) | −0.31 (0.04) | −0.42 (0.04) |
| FPG (mg/dL) | 153.45 (0.91) | 153.23 (0.91) | 151.81 (0.90) | −20.36 (1.12) | −23.80 (1.12) | −8.24 (1.92) | −13.94 (1.91) |
| Vascular tone | |||||||
| SBP (mmHg) | 135.79 (0.36) | 134.91 (0.35) | 135.65 (0.35) | −4.01 (0.40) | −3.72 (0.40) | −3.33 (0.58) | −2.58 (0.58) |
| DBP (mmHg) | 76.83 (0.21) | 76.60 (0.20) | 76.68 (0.20) | −1.48 (0.23) | −1.24 (0.23) | −0.52 (0.34) | −0.19 (0.34) |
| Heart rate (bpm) | 68.41 (0.25) | 68.76 (0.24) | 68.27 (0.25) | −0.63 (0.26) | −1.12 (0.26) | −0.32 (0.39) | −0.60 (0.39) |
| Lipids (mg/dL) | |||||||
| LDL-C | 84.80 (0.74) | 86.29 (0.77) | 85.46 (0.74) | 2.17 (0.82) | 3.27 (0.83) | 0.49 (1.22) | 1.66 (1.22) |
| HDL-C | 44.04 (0.24) | 44.65 (0.25) | 44.49 (0.25) | 1.47 (0.22) | 1.98 (0.22) | 1.18 (0.32) | 2.00 (0.32) |
| TGs | 170.79 (2.53) | 168.49 (2.67) | 172.78 (2.77) | −7.32 (3.03) | −9.99 (3.04) | −2.46 (5.46) | −2.57 (5.43) |
| FFAs | 14.69 (0.15) | 14.50 (0.14) | 14.57 (0.15) | 0.70 (0.20) | 1.01 (0.20) | 1.09 (0.30) | 1.26 (0.30) |
| Renal | |||||||
| UACR (mg/g)‡ | 25.99 (477.32) | 25.51 (452.73) | 25.38 (439.71) | 0.86 (0.82, 0.90) | 0.82 (0.78, 0.87) | 0.78 (0.71, 0.85) | 0.81 (0.74, 0.88) |
| eGFR (MDRD) (mL/min/1.73 m2) | 73.80 (0.44) | 74.34 (0.45) | 74.08 (0.44) | −1.48 (0.31) | −1.96 (0.31) | 2.69 (0.52) | 2.70 (0.52) |
| eGFR (CKD-EPI) (mL/min/1.73 m2) | 75.45 (0.41) | 75.89 (0.41) | 75.68 (0.41) | −1.66 (0.26) | −1.96 (0.26) | 2.49 (0.44) | 2.38 (0.44) |
| Adiposity | |||||||
| Weight (kg) | 86.68 (0.40) | 85.97 (0.39) | 86.53 (0.40) | −1.20 (0.08) | −1.49 (0.08) | −1.60 (0.19) | −1.98 (0.19) |
| BMI (kg/m2) | 30.67 (0.11) | 30.59 (0.11) | 30.62 (0.11) | −0.43 (0.03) | −0.53 (0.03) | −0.56 (0.07) | −0.69 (0.07) |
| WC (cm) | 105.0 (0.3) | 104.8 (0.3) | 104.8 (0.3) | −1.0 (0.1) | −1.1 (0.1) | −1.5 (0.2) | −1.6 (0.2) |
| Volume status | |||||||
| Hematocrit (%) | 41.28 (0.09) | 41.29 (0.09) | 41.44 (0.09) | 2.18 (0.08) | 2.46 (0.08) | 2.57 (0.14) | 2.66 (0.14) |
| Hemoglobin (g/dL) | 13.72 (0.03) | 13.71 (0.03) | 13.76 (0.03) | 0.60 (0.02) | 0.69 (0.02) | 0.78 (0.04) | 0.80 (0.04) |
| Albumin (g/dL) | 4.41 (0.01) | 4.42 (0.01) | 4.43 (0.01) | 0.04 (0.01) | 0.06 (0.01) | 0.04 (0.01) | 0.05 (0.01) |
| Other | |||||||
| Uric acid (mg/dL) | 6.01 (0.03) | 5.91 (0.03) | 5.97 (0.03) | −0.34 (0.03) | −0.35 (0.03) | −0.29 (0.05) | −0.30 (0.05) |
| Mechanistic category and variable . | . | . | . | Adjusted mean (SE) difference vs. placebo in change from baseline* . | |||
|---|---|---|---|---|---|---|---|
| Mean (SE) at baseline . | Week 12 or 28† . | Week 164 . | |||||
| Placebo . | Empa 10 mg . | Empa 25 mg . | Empa 10 mg . | Empa 25 mg . | Empa 10 mg . | Empa 25 mg . | |
| Glycemia | |||||||
| HbA1c (%) | 8.08 (0.02) | 8.08 (0.02) | 8.07 (0.02) | −0.54 (0.02) | −0.60 (0.02) | −0.31 (0.04) | −0.42 (0.04) |
| FPG (mg/dL) | 153.45 (0.91) | 153.23 (0.91) | 151.81 (0.90) | −20.36 (1.12) | −23.80 (1.12) | −8.24 (1.92) | −13.94 (1.91) |
| Vascular tone | |||||||
| SBP (mmHg) | 135.79 (0.36) | 134.91 (0.35) | 135.65 (0.35) | −4.01 (0.40) | −3.72 (0.40) | −3.33 (0.58) | −2.58 (0.58) |
| DBP (mmHg) | 76.83 (0.21) | 76.60 (0.20) | 76.68 (0.20) | −1.48 (0.23) | −1.24 (0.23) | −0.52 (0.34) | −0.19 (0.34) |
| Heart rate (bpm) | 68.41 (0.25) | 68.76 (0.24) | 68.27 (0.25) | −0.63 (0.26) | −1.12 (0.26) | −0.32 (0.39) | −0.60 (0.39) |
| Lipids (mg/dL) | |||||||
| LDL-C | 84.80 (0.74) | 86.29 (0.77) | 85.46 (0.74) | 2.17 (0.82) | 3.27 (0.83) | 0.49 (1.22) | 1.66 (1.22) |
| HDL-C | 44.04 (0.24) | 44.65 (0.25) | 44.49 (0.25) | 1.47 (0.22) | 1.98 (0.22) | 1.18 (0.32) | 2.00 (0.32) |
| TGs | 170.79 (2.53) | 168.49 (2.67) | 172.78 (2.77) | −7.32 (3.03) | −9.99 (3.04) | −2.46 (5.46) | −2.57 (5.43) |
| FFAs | 14.69 (0.15) | 14.50 (0.14) | 14.57 (0.15) | 0.70 (0.20) | 1.01 (0.20) | 1.09 (0.30) | 1.26 (0.30) |
| Renal | |||||||
| UACR (mg/g)‡ | 25.99 (477.32) | 25.51 (452.73) | 25.38 (439.71) | 0.86 (0.82, 0.90) | 0.82 (0.78, 0.87) | 0.78 (0.71, 0.85) | 0.81 (0.74, 0.88) |
| eGFR (MDRD) (mL/min/1.73 m2) | 73.80 (0.44) | 74.34 (0.45) | 74.08 (0.44) | −1.48 (0.31) | −1.96 (0.31) | 2.69 (0.52) | 2.70 (0.52) |
| eGFR (CKD-EPI) (mL/min/1.73 m2) | 75.45 (0.41) | 75.89 (0.41) | 75.68 (0.41) | −1.66 (0.26) | −1.96 (0.26) | 2.49 (0.44) | 2.38 (0.44) |
| Adiposity | |||||||
| Weight (kg) | 86.68 (0.40) | 85.97 (0.39) | 86.53 (0.40) | −1.20 (0.08) | −1.49 (0.08) | −1.60 (0.19) | −1.98 (0.19) |
| BMI (kg/m2) | 30.67 (0.11) | 30.59 (0.11) | 30.62 (0.11) | −0.43 (0.03) | −0.53 (0.03) | −0.56 (0.07) | −0.69 (0.07) |
| WC (cm) | 105.0 (0.3) | 104.8 (0.3) | 104.8 (0.3) | −1.0 (0.1) | −1.1 (0.1) | −1.5 (0.2) | −1.6 (0.2) |
| Volume status | |||||||
| Hematocrit (%) | 41.28 (0.09) | 41.29 (0.09) | 41.44 (0.09) | 2.18 (0.08) | 2.46 (0.08) | 2.57 (0.14) | 2.66 (0.14) |
| Hemoglobin (g/dL) | 13.72 (0.03) | 13.71 (0.03) | 13.76 (0.03) | 0.60 (0.02) | 0.69 (0.02) | 0.78 (0.04) | 0.80 (0.04) |
| Albumin (g/dL) | 4.41 (0.01) | 4.42 (0.01) | 4.43 (0.01) | 0.04 (0.01) | 0.06 (0.01) | 0.04 (0.01) | 0.05 (0.01) |
| Other | |||||||
| Uric acid (mg/dL) | 6.01 (0.03) | 5.91 (0.03) | 5.97 (0.03) | −0.34 (0.03) | −0.35 (0.03) | −0.29 (0.05) | −0.30 (0.05) |
Mediation analyses adjusting for changes from baseline in covariates or updated mean covariate values were based on changes before CV death, not at week 12, 28, or 64. bpm, beats per minute; Empa, empagliflozin; FFA, free fatty acid; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; TG, triglyceride; WC, waist circumference.
*Mixed-model repeated-measures analysis using all data up to individual trial completion in treated patients who had a baseline and postbaseline measurement for the respective outcome. The model included baseline HbA1c and baseline of the outcome in question as linear covariates and baseline eGFR, region, BMI, the last week a patient could have had a measurement of the outcome in question, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction, and baseline of the outcome in question by visit interaction as fixed effects.
†Week 12 for variables other than heart rate, LDL-C, HDL-C, TGs, and FFAs (which were not measured at week 12).
‡Baseline data are geometric mean (geometric coefficient of variation); differences vs. placebo are adjusted geometric mean ratio (95% CI) obtained from mixed-model repeated-measures analysis applied on log-transformed data.