Managing patients with renal disease Hiddo Lambers Heerspink, MD University Medical Centre Groningen, The Netherlands Asian Cardio Diabetes Forum April 23 24, 216 Kuala Lumpur, Malaysia
Prevalent cases, in millions, ± 95% CI Diabetic Kidney Disease is common 34% prevalence increase 8 6 4 18% prevalence increase All diabetic kidney disease Persistent albuminuria only (ACR 3 mg/g) Impaired egfr only (< 6 ml/min/1.73 m 2 ) Albuminuria and impaired egfr 2 1988 1994 1999 24 25 28 De Boer IH et al. JAMA 211;35:2532
Prevalence of kidney disease is projected to increase Estimated relative prevalence rate (per million population) Projection of CKD in patients with diabetes in 12 European countries* 2. 18. 16. 14. CKD3 12. 1. 8. 6. 4. 2. 21 215 22 225 Year 14. 12. CKD4 1. 8. 6. 4. CKD5 2. 21 215 22 225 Year CKD3, CKD stage 3; CKD4, CKD stage 4; CKD5, CKD stage 5 *Austria, Belgium, Denmark, Finland, Greece, Iceland, Italy, Netherlands, Norway, Spain, Sweden, UK Kainz A et al. Nephrol Dial Transplant 215;3:iv1113
Prevalence of ESRD around the world World Region Lynage Lancet 215
ESRD/Death (Event Rate, %) Despite RAAS blockade high residual risk for dialysis and mortality 16 14 12 1 Early Intermediate Late Intervention BP Prot + GFR Conventional treatment RAAS intervention 8 6 4 BP MA + 2 BP MA - BENEDICT ROADMAP IRMA-2 RENAAL IDNT ALL Cancers
New drugs for diabetic kidney disease Low Protein Diet (MDRD, no formal additive effect tested) NSAID s (proteinuria reduction, no hard endpoint trials) Combination ACEi/ARB (alb red, hard endpoints, NEPHRON; STOPPED) Renin-inhibitors (alb red, hard endpoints, ALTITUDE; CV/renal, STOPPED) Erythropoietin (Hb rise; hard endpoint trial; TREAT; CV/renal; NO EFFECT) GAG s(prot reduction; hard endpoint trial; SUN-Overt; renal; STOPPED) Statins (hard endpoint trial; SHARP;CV/renal; CV but NO RENAL EFFECT) Statins (prot reduction and GFR decline; PLANET trial; renal) Nrf2 agonist (rise in egfr; hard endpoint; BEACON; renal; STOPPED) Endothelin Antagonist (alb red; hard endpoint ; ASCEND; renal; STOPPED SONAR; ONGOING) SGLT2 inhibition (EMPAREG, CV benefit; CRENDENCE ongoing)
Day 1, ΔUGE -24h (g) Effects of SGLT2i on urinary glucose excretion depends on renal function 8 6 4 2 2 4 6 8 1 12 GFR (ml/min/1.73m 2 ) egfr Normal Renal Function (n=3) 9 ml/min/1.73m 2 egfr Mild Renal Impairment (n=1) 6 to 89 ml/min/1.73m 2 egfr Moderate Renal Impairment (n=9) 3 to 59 ml/min/1.73m 2 egfr Severe Renal Impairment (n=1) 15 to 29 ml/min/1.73m 2 y = -12.2 +.697 (r 2 adj:.783) 95% Confidence Band
Urinary glucose:creatinine ratio (mg/mg) Hba1c (%) change Effects of SGLT2i attenuates at lower egfr 45 to <6 ml/min/1.73m 6 6 to <9 ml/min/1.73m 2 9 ml/min/1.73m 2. 5 2 -.2 4 3 -.4 2 1 -.6 BL 4 8 12 16 2 24 -.8 BL 4 8 12 16 2 24 Study week Study week Heerspink et.al. ADA 216
Δ Hct (%) Effects of SGLT2i on volume related parameters independent of egfr Δ BW (Kg) Δ Systolic BP (mmhg) Δ UACR (%) Hematocrit Systolic BP 4 4 2 2 3 3 2 1 BL 4 8 12 16 2 24 Study week 45 to <6 ml/min 6 to <9 ml/min/ 9 ml/min/ 2 1 BL 4 8 12 16 2 24 Study week -1 Body Weight 4 2 Albuminuria -2-2 -4-3 -6-8 -4 BL 4 8 12 16 2 24 Study week BL 4 8 12 16 2 24 Study week Heerspink et.al. ADA 216
3-point MACE: subgroup analysis by egfr Empagliflozin Placebo All patients 4687 2333 Age, years.1 <65 2596 1297 65 291 136 Sex.81 Male 3336 168 Female 1351 653 Race.9 White 343 1678 Asian 16 511 Black/African-American 237 12 HbA1c, %.1 <8.5 3212 167 8.5 1475 726 Body mass index, kg/m 2.6 <3 2279 112 3 248 1213 egfr, ml/min/1.73m 2.2 9 15 488 6 to <9 2425 1238 <6 1212 67 Hazard ratio (95%CI) Zinman et.al. NEJM 215
EMPAREG CV death: subgroup analyses by egfr Empagliflozin Placebo All patients 4687 2333 Age, years.21 <65 2596 1297 65 291 136 Sex.32 Male 3336 168 Female 1351 653 Race.43 White 343 1678 Asian 16 511 Black/African-American 237 12 HbA1c, %.51 <8.5 3212 167 8.5 1475 726 Body mass index, kg/m 2.5 <3 2279 112 3 248 1213 egfr, ml/min/1.73m 2.15 9 15 488 6 to <9 2425 1238 <6 1212 67 Zinman et.al. NEJM 215
Diabetes causes glomerular hypertension Na+/glucose cotransport SGLT2 SGLT2 SGLT2 Afferent arteriole Glomerular pressure GFR PT Efferent arteriole Glucose PT: Proximal tubule GL: Glomerulus MD: Macula densa Loop of Henle Renal hemodynamics under hyperglycemia Adapted from: Cherney D et al. Circulation 214;129:587
Empagliflozin lowers intra-glomerular pressure SGLT inhibitor blocks SGLT2 SGLT2 SGLT2 SGLT2 Afferent arteriole Glomerular pressure GFR PT Efferent arteriole Glucose PT: Proximal tubule GL: Glomerulus MD: Macula densa Loop of Henle Renal hemodynamics with empagliflozin Adapted from: Cherney D et al. Circulation 214;129:587
Tubular Na reabsorption in T1 diabetes mellitus Pollock CA et al (1991) Am. J. Physiol. 26: F946-F952
Fractional Sodium delivery diatal tuble (%) GFR (ml/min/1g Normalisation in GFR after phlorizin treatment in type 1 diabetes experimental model 6 5 4 3 2 1 1,4 1,2 1,8,6,4,2 Control Diabetes D+Phlorizin Control Diabetes D+Phlorizin Pollock CA et al. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. (1991) Am. J. Physiol. 26: F946-F952
Mean intraglomerular pressure mmhg Empagliflozin reduces intra-glomerular pressure 8 7 ~6 8 mmhg 6 5 4 Euglycemia * Hyperglycemia *p<.1 Baseline Empagliflozin Intra-glomerular pressure recorded at baseline and after 8 weeks treatment with empagliflozin Glomerular pressure T1D-H (mmhg) Baseline EMPA p value Change from baseline Euglycaemia (mmhg) 67.4 ± 5.4 61. ± 5.2 <.1 9.5% Hyperglycaemia (mmhg) 69.3 ± 6.5 61.6 ± 6.3 <.1 11.1% Skrtic M et al. Diabetologia 214;57:2599
Empagliflozin attenuates glomerular hyperfiltration Mean GFR (ml/min/1.73 m 2 ) Type 1 Diabetes: 2 18 16 14 12 1 8 6 4 2 Glomerular filtration rate 172. * 139. GFR reduced by -33 ml/min/1.73 m 2 Baseline Empagliflozin *p<.1 T1D-H (Euglycemia) Type 1 diabetes patients with hyperfiltration. Mean GFR recorded at baseline and after 8 weeks treatment with empagliflozin 25 mg QD Cherney D et al. Circulation 214;129:587
Dapagliflozin causes a fall in mgfr in type 2 diabetes Mean GFR (ml/min/1.73m2) Mean GFR (ml/min/1.73m2) Type 2Diabetes: 12 Placebo 12 Dapagliflozin 1 1 GFR reduced by -1.1 ml/min/1.73m 2 8 8 6 baseline week 12 6 baseline week 12 Heerspink et al. DOM 213
SGLT2i causes an acute fall in egfr followed by a complete stabilization Change in egfr (ml/min/1.73m 2 ) egfr slope (ml/min/1.73m 2 /year 2-2 -4-2 -6-4 -8-1 -12 Glimepiride Canagliflozin 1 mg Canagliflozin 3 mg 26 52 78 14-6 -8 Glimepiride Cana 1 mg Cana 3 mg Time (weeks)
SGLT2i decreases risk of egfr decline endpoint Canagliflozin 1 mg vs glimepiride Overall population 3% egfr decline No. of events / patients Favors Favors Hazard Ratio Canagliflozin Glimepiride Canagliflozin Glimepiride (95% CI) p-value 3% egfr decline 32/477 46/475.66(.42-1.4).7 4% egfr decline 7/477 11/475.61(.24-1.57).3 UACR < 3 mg/g 25/43 29/4.83(.49-1.43).51 UACR 3 mg/g 7/74 17/75.37(.15-.9).28.2.5.8 1. 1.5 2. 3. Hazard Ratio (95%CI)
Iothalamate GFR (ml/min) Blood pressure lowering with ACEi or β-blocker causes an acute and reversible fall in GFR 58 56 54 52 5 48 46 5 1 15 2 Apperloo et.al. Kidney Int 1998
Long-term (3 years) egfr decline stratified by initial (3 months) egfr change Long-term egfr slope (ml/min/1.73m2/year) Tertiles of initial fall in egfr (-8.6) (-2.4) (+4.2) (-8.6) (-2.4) (+4.2) - 1-2 -3-4 -3.77-4.1-4.82-3.64-3.85-4.4-5 -6 p=.9 Unadjusted analysis p=.49 Adjusted analysis Holtkamp et.al. Kidney Int 211
Renoprotection by reducing intraglomerular pressure SGLT2i tubuloglomerular feedback, afferent arteriole tone and intraglomerular pressure ACEi and ARB efferent arteriole tone and intraglomerular pressure Initial in egfr followed by stabilization albuminuria Initial in egfr followed by stabilization albuminuria Renal Protection (to be determined) Renal Protection Increased intraglomerular pressure and hyperfiltration are key steps in the progression of diabetic kidney disease
EMPAREG: Empagliflozin lowers risk of acute kidney injury Placebo Empa 1 Empa 25 Empa pooled Acute Kidney Injury 37 (1.6) 26 (1.1) 19 (.8) 45 (1.)* *P<.5 vs. placebo
Conclusions Effects of SGLT2i on glycemic control attenuate at lower renal function Effects on other CV risk factors are independent of GFR EMPAREG trial showed that effects of empagliflozin on CV outcomes are consistent regardless of egfr Restoration of TGF, reduction in intra-glomerular pressure, and albuminuria contribute to long-term renoprotective effects Future trials in patients with diabetic kidney disease (CREDENCE) will provide definitive answers on efficacy and safety in this population