SGLT2-inhibition: A New Strategy to Protect the Heart and the Kidney?

Transcription

1 SGLT2-inhibition: A New Strategy to Protect the Heart and the Kidney? Hiddo Lambers Heerspink Department of Clinical Pharmacy and Pharmacology University Medical Center Groningen The Netherlands Disclosures: Consultancy for Abbvie, Astellas, Astra Zeneca, Boehringer Ingelheim, Janssen, Merck, ZS-Pharma. All honoraria paid to institution

2 Standardised 1-year cumulative incidence of mortality (95% CI) Mortality is more frequent present in diabetes and kidney disease than those without % % 23.9% Excess mortality % 7.7% No kidney disease Albuminuria Impaired GFR Albuminuria & impaired GFR No diabetes, no kidney disease Percentages indicate absolute excess mortality above the reference group (individuals with no diabetes or kidney disease) *No diabetes and no kidney disease; GFR, glomerular filtration rate; T2D, type 2 diabetes Afkarian M et al. J Am Soc Nephrol 213;24:32

3 Potential approaches and trials testing additive renal (cardiovascular) protection (on top of ACEi or ARB) ACEi+ARB (VA NEPHRON-D; prematurely stopped for safety; renal) ACEi + ARB (HALT-PKD; no effect; renal) ACEi/ARB + DRI (ALTITUDE; prematurely stopped for safety; CV/renal) Low Protein Diet (MDRD; completed, no additive effect? ) Erythropoietin (TREAT; completed; no effect CV/renal) GAG s (SUN-Overt; prematurely stopped; no effect renal) GAG s (SUN-Micro; completed; no effect renal) ET-A (Avosentan) (ASCEND; prematurely stopped for safety; renal) Statins (SHARP; completed; no renal effect?; CV/renal) Pentoxifylline (PREDIAN; completed; egfr protection) Nrf2 (Bardoxolone) (BEACON; stopped for safety; renal/cv outcome) Carbon Absorption (AST-12) (CAP-KD; completed no effect; renal outcome) Nrf2 (Bardoxolone) (Japanese study; ongoing; renal outcome) ET-A (Atrasentan) (SONAR; ongoing; renal outcome) SGLT2 (canagliflozin) (CREDENCE; starting; renal/cv outcome) SGLT2 (empagliflozin) (EMPA-REG; completed; CV and renal protection) Uric acid (allopurinol) (PERL; ongoing; renal outcome) GLP-1 mimetic (Liraglutide) (LEADER; ongoing; CV and renal outcome) DPP-4 (Linagliptin) (CARMELINA; ongoing; CV and renal) Pyridorin (PIONEER; ongoing, renal outcome) AngII/NEPi (LCZ696) (?) Prostacyclin (Beraprost) (CASSIOPEIR; ongoing; renal outcome; ASN submission) MCA (spironolactone) (PRIORITY; ongoing; renal outcome) MCA (fineronone) (FIGARO and FIDELIO-DKD; ongoing; renal/cv outcome)

4 The kidney plays an important role in glucose production and utilization The kidney contributes to glucose homeostasis through processes of: 1. Glucose release (gluconeogenesis) 2. Glucose utilisation for energy needs 3. Glucose filtration and reabsorption De Fronzo et al. Nat Rev Nephrol 217;1:11

5 The role of SGLT2 inhibitors in glucose reabsporption Reduced glucose and sodium reabsorption SGLT-2 SGLT-2 Glucose Sodium SGLT2-inhibitor Glucose filtration Proximal tubule Remaining glucose is reabsorbed by SGLT1 (1%) Increased urinary excretion of excess glucose By inhibiting SGLT2, these drugs remove excess glucose in the urine and lower HbA 1c 1 SGLT-2 inhibitors act on natriuretic mechanisms and are associated with a decrease in intracellular Na + concentration & Na + /K ATPase activity 1. Marsenic O. Am J Kidney Dis 29;53:875 85;

6 SGLT2 Mediates Glucose Reabsorption in the Kidney K + ATPase Blood Lumen SGLT2 Glucose Na + Na + S1 Proximal Tubule GLUT2 Glucose SGLT2: Major transporter of glucose in the kidney 1-3 Co-transports Na+ and glucose at 2:1 stoichiometry Responsible for majority of renal glucose reabsorption in the proximal tubule 1. Hediger and Rhoads. Physiol Rev. 1994;74:993; 2. Magen et al. Kidney Int. 25;67:34; 3. Kanai et al. J Clin Invest.1994;93:397.

7 SGLT2 inhibitors decrease the glucose excretion threshold Urinary glucose excretion (mg/min) 25 2 Canagliflozin 1mg Blood glucose (mg/dl) Untreated Polidori D et.al. Con Endorinol Metab 213;98:E867-E871

8 Placebo-subtracted LS Mean Change in HbA 1c (%) (95% CI) SGLT2 decreases HbA1c on top of other diabetic medications BL Mean HbA 1c (%), -,2 -,4 -,6 Monotherapy (DIA35) N =584 Metformin (DIA36) N = 1284 SU (DIA38) N = 127 Add-on Combinations with Met/SU (DIA32) N = 469 Met/Pio (DIA312) N = 342 Insulin (DIA38) N = Current Therapy in Older Subjects (DIA31) N = SU INS 31 -,8-1, -.62* -.77* -.71* -.62* -.76* -.65* -.73* -.57* -.7* -1,2-1,4 -.91* -1.16* -.74* -.83* -.92* -1,6 All at 26 weeks except 18 weeks DIA38 Insulin, SU sub-studies CANA 1 mg * p<.1 Based on ANCOVA models, data prior to rescue (LOCF) CANA 3 mg

9 EMPAREG: Empagliflozin is cardioprotective in patients with type 2 diabetes and established CV disease Primary CV endpoint CV death endpoint HR.86 (95% CI.74,.99); p=.4* HR.62 (95% CI.49,.77); p<.1* Primary CV endpoint composite of non-fatal MI, stroke or CV-death Patients were randomly assigned to empa 1 mg, empa 25 mg or placebo. Shown are the combined 1 and 25 mg doses versus placebo Zinman B et.al. N Engl J Med. 215 Nov 26;373(22):

10 EMPAREG: Empagliflozin is cardioprotective in patients with type 2 diabetes and established CV disease Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 49/ / (.74,.99)*.382 CV death 172/ / (.49,.77) <.1 Non-fatal MI 213/ / (.7, 1.9).2189 Non-fatal stroke 15/4687 6/ (.92, 1.67).1638 Heart Failure 95/ / (.5.85),25,5 1, 2, Favours empagliflozin Favours placebo Zinman B et.al. N Engl J Med. 215 Nov 26;373(22):

11 What could be the mechanisms of clinical benefit? Clinical benefit of SGLT2 inhibitors could be explained by: 1. Metabolic effects Improved β-cell function/ tissue insulin sensitivity Decrease in β-cell glucotoxicity Body weight loss effects on visceral subcutaneous fat 2. Diuretic / Natriuretic effects 3. Renal effects

12 SGLT2 inhibitors: Proximal tubular diuretics? 15 3 days cum Na excretion (mmol) Body weight change (kg) 1. Hematocrit (%) change placebo Dose dapagliflozin -2 placebo Dose dapagliflozin placebo Dose dapagliflozin Heerspink et al. World Congress Nephrology 211

13 Dapagliflozin diuretic effects: lower plasma volume, body weight, and 24-hr blood pressure Δ body weight (kg) Plasma volume Body Weight 24hr SBP Placebo HCTZ Dapagliflozin Time (weeks) -6 Dapagliflozin reduces plasma volume compared to placebo or HCTZ as measured by 51 Cr Albumin Reductions in body weight during the initial 4 weeks paralleled reductions in body weight during HCTZ Abbreviations: HCTZ, hydrochlorothiazide, SBP, systolic blood pressure Heerspink et al. Diabetes Obesity Metabolism 213;15(9):853-62

14 Meta-analysis of diuretic effects on CV outcomes Cardiovascular events RR (95% CI) Favors diuretic Favors Placebo Favors Empa Favors Placebo Thiazide-type.67 (.56.81) Thiazide-like.67 (.6.75) Cerebrovascular events.86 (.74.99) Thiazide-type.52 (.38.69) Thiazide-like.68 (.57.8) Heart Failure 1.24 ( ) Thiazide-type.36 (.16.84) Thiazide-like.47 (.36.61) All-cause Mortality.65 (.5.85) Thiazide-type.86 (.75 1.) Thiazide-like.84 (.74.96).68 (.57.82) Olde Egberink et.al. Hypertension Hazard ratio (95%CI)

15 What could be the mechanisms of clinical benefit? Clinical benefit of SGLT2 inhibitors could be explained by: 1. Metabolic effects 2. Diuretic / Natriuretic effects 3. Renal effects Restore tubulo-glomerular feedback Reduction Intraglomerular Pressure Reduction Albuminuria

16 High intraglomerular pressure causes renal damage Normal Glomerulus Glomerular Hypertension Afferent arteriole Normal endothelium Dilated afferent arteriole Loss of podocyte integrity Efferent arteriole Podocytes Constricted efferent arteriole Focal glomerulosclerosis Damaged endothelium

17 Estimated GFR (ml/min) Acute reduction in GFR during RAAS inhibition associated with subsequent stabile renal function egfr (ml/min/1.73m2) 4 P: -1.6 L: (95%CI -4.7 to -5.4) -4.2 (95%CI -3.9 to -4.6) 6 58 P: -1.6 A: (95%CI -3.4 to -3.9) -3.3 (95%CI -3.1 to -3.6) Placebo Losartan Time (months) Placebo Aliskiren Time (months) RENAAL: Type 2 diabetes and nephropathy randomized to losartan 1 mg/d or placebo. Holtkamp et al. Kidney Int 211: Heerspink et.al. Lancet Diabetes & Endocrinology 216 ALTITUDE: Selection of patients with type 2 diabetes and nephropathy randomized to aliskiren 3 mg/d or placebo on top of ACEI or ARB.

18 Initial fall in egfr is associated with less renal function decline during prolonged follow-up 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) p=.9 Unadjusted analysis p=.49 Adjusted analysis Holtkamp et al. Kidney Int 211

19 SGLT2 inhibitors restore tubulo-glomerular feedback GFR, glomerular filtration rate; SGLT, sodium glucose cotransporter; TGF, tubuloglomerular feedback Cherney D, et al. Circulation 214;129:

20 Mean RBV (ml/min/1.73 m 2 ) Mean GFR (ml/min/1.73 m 2 ) Mean GFR (ml/min/1.73m2) SGLT2 inhibitors decrease RPF and GFR Type 1 diabetes Type 2 diabetes RBF T1D-H (Euglycemia) 6 baseline week 12 Cherney D et al. Circulation 214:129; Heerspink et.al. DOM 213: 15:853-62

21 Adjusted Mean (SE) egfr (ml/min/1.73 m 2 ) EMPAREG: Empagliflozin slows egfr decline over time Empagliflozin 1 mg Empagliflozin 25 mg Week Placebo Placebo Empa 1 mg Empa 25 mg Wanner C et.al. N Engl J Med. 216 Jul 28;375(4):323-34

22 EMPAREG: Empagliflozin reduces renal risk in patients with type 2 diabetes and established CV disease Cumulative probability of event (%) In patients with egfr (MDRD) <6 ml/min/1.73 m 2 and/or macroalbuminuria (UACR >3 mg/g) at baseline, empagliflozin reduced the risk of incident or worsening nephropathy Empagliflozin Placebo HR.58 (95% CI.47,.71) P<.1 2 No. of patients Empagliflozin Placebo Months Wanner C et.al. N Engl J Med. 216 Jul 28;375(4):323-34

23 EMPAREG: Empagliflozin reduces renal risk N With Event/N Patients Empagliflozin Placebo HR (95% CI) P-value New onset/worsening of nephropathy 525/ / (.53,.7) <.1 New onset macroalbuminuria 459/491 33/ (.54,.72) <.1 Doubling of serumcreatinine* Initiation of renal replacement therapy 7/4645 6/ (.39,.79).9 13/ / (.21,.97).49 * Accompanied by estimated glomerular filtration rate (MDRD) 45 ml/min/1.73 m Favours empagliflozin 2. Favours placebo Wanner C et.al. N Engl J Med. 216 Jul 28;375(4):323-34

24 RAAS and SGLT2 inhibitors reduce intraglomerular pressure through different mechanisms 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

25 Cumulative probability of event (%) EMPAREG: Empagliflozin reduces risk of AKI Empagliflozin had a protective effect against acute renal failure and acute kidney failure vs placebo Empagliflozin Placebo 1 Acute renal failure 5 Acute kidney injury No. of patients Acute renal failure Empagliflozin Placebo Acute kidney injury Empagliflozin Placebo Months CI, confidence interval; HR, hazard ratio; Wanner C, et al. Presented at the 52 nd EASD Annual Meeting 216. Munich, Germany; 16 th September 216; OP S

26 24-hr Albuminuria Change IMPROVE: Dapagliflozin consistently reduces albuminuria in type 2 diabetes and micro/macroalbuminuria Albuminuria response second exposure Dapa Wash-out Placebo Wash-out Dapa r=.67 P= Albuminuria response first exposure Petrykiv S. et.al. Submitted

27 Summary of Product Characteristics Dapagliflozin Canagliflozin

28 Glycemic effects of dapagliflozin is blunted in patients with renal impairment Placebo-adjusted change from baseline over time with dapagliflozin in HbA1c in the overall population Excludes data after rescue. Adj., adjusted; BL, baseline; CI, confidence interval. Petrykiv S. et.al. CJASN provisionally accepted

29 UACR, % (95% CI) Albuminuria lowering effect persists in patients with renal impairment egfr 45 <6, n 6 <9, n 9, n BL egfr subgroup (ml/min/1.73 m 2 ) UACR 3 mg/g at baseline Mean UACR Baseline (SD) Week 24 adjusted (%) 95% CI 45 <6 211 (37) , <9 26 ( , (248) , 3.8 Petrykiv S. et.al. CJASN provisionally accepted Study week

30 Clinical implications: Individualize treatment In patient with longstanding diabetes and established atherosclerotic cardiovascular disease empagliflozin or liraglutide should be considered as they have shown to reduce cardiovascular events ADA standard of care guideline; Diabetes Care 217; Supplement 1; S1-S135

31 Conclusions SGLT2 inhibitors form a new class of oral glucose lowering agents These drugs have multiple pleiotropic effects The alleged renoprotective effects are mediated by Restoring tubulo-glomerular feedback, Inducing natriuresis/diuresis Lowering renal glucotoxicity Glucose lowering efficacy in patients with CKD is diminished but albuminuria, blood pressure, body weight lowering effects persists Hard outcome outcome trials are needed to definitely proof the renoprotective effects

32

33 C-peptide (mmol/l) Incretin effect insulin (%) The incretin effect is reduced or absent in type 2 diabetes patients * Normal glucose tolerance Type 2 diabetes Oral Isoglycemic intravenous g OGTT A dysfunctional incretin system is part of the pathogenesis of type 2 diabetes Enhancement of incretin action was pursued as an interesting therapeutic solution Nauck MA. Diabetologia 1986;29(1): Nauck MA. Lancet Diabetes Endocrinol 216;4(6): Jørgensen MB. Kidney Week 216. TH-PO445