Effects of Lowering LDL Cholesterol on Progression of Kidney Disease Richard Haynes, David Lewis, Jonathan Emberson, Christina Reith, Lawrence Agodoa, Alan Cass, Jonathan C. Craig, Dick de Zeeuw, Bo Feldt-Rasmussen, Bengt Fellström, Adeera Levin, David C. Wheeler, Rob Walker, William G. Herrington, Colin Baigent and Martin J. Landray for the SHARP Collaborative Group J Am Soc Nephrol, 2014. doi: 10.1681/ASN.2013090965
Baseline characteristics by treatment allocation, among 6245 patients not on dialysis at randomisation Simvastatin plus ezetimibe (n=3116) (n=3129) Age at randomization (years)* 63 (12) 63 (12) Men 1953 (63%) 1929 (62%) Prior vascular disease* 473 (15%) 459 (15%) Diabetes* 718 (23%) 708 (23%) Current smoker* 383 (12%) 379 (12%) Systolic blood pressure (mm Hg)* 139 (21) 139 (21) Diastolic blood pressure (mm Hg)* 80 (12) 80 (12) Total cholesterol (mmol/l)* 5.01 (1.18) 5.01 (1.15) LDL cholesterol (mmol/l)* 2.87 (0.87) 2.86 (0.85) HDL cholesterol (mmol/l)* 1.14 (0.34) 1.12 (0.34) Triglycerides (mmol/l)* 2.31 (1.63) 2.34 (1.68) Body mass index (kg/m²)* 27.4 (5.5) 27.4 (5.4) Ethnicity # White 2248 (72%) 2235 (71%) Black 62 (2%) 57 (2%) Asian 748 (24%) 774 (25%) Other/not specified 58 (2%) 63 (2%) Co-medication *# Antiplatelet therapy 614 (20%) 617 (20%) Oral anticoagulant therapy 82 (3%) 93 (3%) ACE inhibitor or ARB 1912 (61%) 1902 (61%) Beta blocker 1119 (36%) 1202 (38%) Calcium channel blocker 1388 (45%) 1356 (43%) Diuretic 1397 (45%) 1384 (44%) Erythropoiesis stimulating agent 409 (13%) 359 (11%) Sevelamer 40 (1%) 24 (<1%) Data are n (%), mean (SD), or median (IQR). *Variables updated at 1 year for patients originally allocated simvastatin only who were rerandomised to ezetimibe/simvastatin or placebo. Percentages exclude participants for whom data were not available for that category. #Not a pre-specified category for subgroup analyses.
Baseline characteristics by treatment allocation, among 6245 patients not on dialysis at randomisation contd. MDRD-estimated GFR (ml/min/1.73m²)* Simvastatin plus ezetimibe (n=3116) (n=3129) Mean (SD) 26.6 (12.9) 26.6 (13.1) 60 44 (1%) 44 (1%) 30 to <60 1100 (37%) 1055 (35%) 15 to <30 1246 (41%) 1319 (44%) <15 613 (20%) 606 (20%) Not available 113 105 Urinary albumin:creatinine ratio (mg/g) Median (IQR) 217 (44-787) 196 (43-746) <30 545 (20%) 562 (20%) 30 to 300 1032 (37%) 1076 (39%) >300 1202 (43%) 1155 (41%) Not available 337 336 Renal diagnosis # Glomerulonephritis 528 (18%) 521 (17%) Diabetic nephropathy 445 (15%) 441 (15%) Hypertensive/renovascular 641 (21%) 661 (22%) Cystic kidney disease 329 (11%) 346 (12%) Pyelonephritis 198 (7%) 206 (7%) Other known cause 452 (15%) 434 (15%) Unknown cause 405 (14%) 383 (13%) Not available 118 137 Data are n (%), mean (SD), or median (IQR). *Variables updated at 1 year for patients originally allocated simvastatin only who were rerandomised to ezetimibe/simvastatin or placebo. Percentages exclude participants for whom data were not available for that category. #Not a pre-specified category for subgroup analyses.
Average use of study simvastatin plus ezetimibe or non-study statin among 6245 patients not on dialysis at randomisation, and average change in plasma LDL cholesterol from baseline, by period of follow-up LDL-cholesterol-lowering drug use LDL-cholesterol difference (mmol/l)* Follow-up (months) Simvastatin plus ezetimibe Absolute difference Simvastatin plus ezetimibe Absolute difference 8-13 79% 3% 76% -1.22 0.06 1.28 ± 0.07 26-31 73% 8% 65% -1.11-0.15 0.96 ± 0.02 44-49 71% 13% 57% -0.90-0.05 0.84 ± 0.07
Effect of allocation to simvastatin plus ezetimibe on annual reduction in egfr among 5037 patients not on dialysis at randomisation and with at least 3 follow-up egfrs Qualifying criteria for analysis Number INCLUDED in analysis Number EXCLUDED from analysis Estimated annual rate of change in egfr (ml/min/1.73m²) P- value S/E PBO S/E PBO S/E PBO Difference Main analysis Patients with average deviation from own fitted line <9.0 ml/min/1.73m² (p 99 ) 2492 2495 27 23-1.66 (0.07) -1.83 (0.07) 0.17 (0.10) 0.10 Sensitivity analyses Patients with average deviation from own fitted line <5.1 ml/min/1.73m² (p 95 ) 2388 2398 131 120-1.72 (0.07) -1.88 (0.07) 0.17 (0.10) 0.09 Patients with average deviation from own fitted line <3.9 ml/min/1.73m² (p 90 ) 2253 2281 266 237-1.78 (0.07) -1.94 (0.07) 0.15 (0.10) 0.12 Patients with average deviation from own fitted line <3.3 ml/min/1.73m² (p 85 ) 2143 2139 376 379-1.85 (0.07) -2.03 (0.07) 0.18 (0.10) 0.07 Number of patients or mean (SE) shown. S/E = simvastatin plus ezetimibe. PBO =. p x is the Xth percentile of the average deviations from individuals' fitted slopes.
Effects of allocation to simvastatin plus ezetimibe on renal outcomes among 6245 patients not on dialysis at randomisation Simvastatin plus ezetimibe (n=3116) (n=3129) Risk ratio (95% CI) p value Initiation of dialysis 975 (31.3%) 1016 (32.5%) 0.95 (0.87-1.03) 0.22 Renal transplantation 265 (8.5%) 242 (7.7%) 1.10 (0.93-1.31) 0.28 End-stage renal disease 1057 (33.9%) 1084 (34.6%) 0.97 (0.89-1.05) 0.41 Death 635 (20.4%) 635 (20.3%) 1.01 (0.90-1.12) 0.93 ESRD or death 1476 (47.4%) 1512 (48.3%) 0.97 (0.90-1.04) 0.34 Doubling of creatinine 370 (11.9%) 415 (13.3%) 0.89 (0.78-1.03) 0.11 ESRD or 2 x creatinine 1189 (38.2%) 1257 (40.2%) 0.93 (0.86-1.01) 0.09 0.5 0.75 1 1.5 2 Simvastatin plus better ezetimibe better
Effects of allocation to simvastatin plus ezetimibe on end stage renal disease by baseline egfr, among 6245 patients not on dialysis at randomisation Simvastatin plus ezetimibe better (n=3116) (n=3129) Risk ratio (95% CI) MDRD estimated egfr (ml/min/1.73m 2 2 ) ( c 1 =0.18; p=0.67) 60 2/44 (4.5%) 0/44 (0.0%) 14.41 (0.76-274.02) 30 <60 94/1100 (8.5%) 83/1055 (7.9%) 1.08 (0.80-1.44) 15 <30 454/1246 (36.4%) 489/1319 (37.1%) 0.96 (0.84-1.09) <15 471/613 (76.8%) 473/606 (78.1%) 0.98 (0.86-1.12) All patients not on dialysis 1057/3116 (33.9%) 1084/3129 (34.6%) 0.97 (0.89-1.05) 0.5 0.75 1 1.5 2 Simvastatin plus better ezetimibe better
Effect of allocation to simvastatin plus ezetimibe on rate of change in egfr among 5037 patients not on dialysis at randomisation and with at least 3 follow up egfrs, by baseline (a) egfr and (b) albuminuria Annual rate of change in egfr (±SE) (ml/min/1.73m 2 ) Annual rate of change in egfr (± SE) (ml/min/1.73m2) (a) Baseline MDRD egfr (ml/min/1.73m 2 ) 30 15 to <30 <15 0 (b) 0 Baseline albuminuria (mg/g) <30 30-300 >300-1 -1 =0.04 (0.18) -2 =0.00 (0.18) -2 =0.05 (0.13) -3-4 =0.24 (0.14) =0.30 (0.19) P for trend in across groups = 0.24 Simvastatin plus ezetimibe -3-4 P for trend in across groups = 0.13 Simvastatin plus ezetimibe =0.42 (0.20) Median time to ESRD No. (%) reaching ESRD >6 years ~6 years ~1 year 179 (8%) 943 (37%) 944 (77%) Median time to ESRD No (%) reaching ESRD >6 years >6 years ~4 years 141 (13%) 604 (29%) 1223 (52%)