SGLT2 inhibition in diabetes: extending from glycaemic control to renal and cardiovascular protection Hiddo Lambers Heerspink Department of Clinical Pharmacy and Pharmacology University Medical Center Groningen The Netherlands
Disclosures Research Support Abbvie, AstraZeneca, Boehringer Ingelheim, Janssen Consultancy Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, Mitsubishi Pharma.
Objectives Review results of recent outcome trials with SGLT2 inhibitors Summarize effects of SGLT2 inhibitors in Diabetic Kidney Disease Review mechanisms and effects of SGLT2 inhibitors on renal outcomes Discuss the potential role of SGLT2 inhibitors in non-diabetic kidney disease Summarize the position of SGLT2 inhibitors in context of other glucose lowering agents
The sodium glucose mechanism in the proximal tubule ~6 g/day (24kCal) ~25 mmol/day Heerspink / Cherney Circulation 216 134(1):752-72
Cardiovascular outcomes with SGLT-2 inhibitors Patients with event/analysed SGLT-2 Placebo HR (95% CI) p-value EMPAREG 49/4687 282/2333.86 (.74,.99) <.1 (non-inferiority).4 (superiority) CANVAS 585/5795 426/4347.86 (.75,.97) <.1 (non-inferiority).2 (superiority) DECLARE 756/8582 83/8578.93 (.84, 1.3) <.1 (non-inferiority) P=.17 (superiority).5 1 2 Hazard Ratio (95%CI) Zinman B et.al. NEJM 216; Neal B. et.al. NEJM 217; Wiviott S et.al. NEJM 218
Cumulative probability of event (%) Patients with an event (%) Kidney outcomes in SGLT-2 inhibitor trials EMPA-REG CANVAS DECLARE 8 7 6 5 HR.54 (95% CI.4,.75) Placebo Empagliflozin 2 18 16 14 12 Hazard ratio.6 (95% CI,.47-.77) Placebo Canagliflozin Hazard ratio.76 (95% CI,.67-.87) Placebo Dapagliflozin 4 3 2 1 6 12 18 24 3 36 42 48 Months since randomization 1 8 6 4 2 1 2 3 4 5 6 Years since randomisation egfr (ml/min/1.73m 2 ): 74. 76.5 86.1 UACR (mg/g): 17.7 12.3 13.1 Wanner C et.al. NEJM 216; Neal B. et.al. NEJM 217; Wiviott S et.al. NEJM 218
Summary of Product Characteristics Dapagliflozin Canagliflozin Empagliflozin
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 egfr 45-6 ml/min/1.73m 2 egfr 6-9 ml/min/1.73m 2 egfr >9 ml/min/1.73m 2 Excludes data after rescue. Adj., adjusted; BL, baseline; CI, confidence interval. Petrykiv S, et al. Clin J American Soc Nephrol 217;12:751 759
UACR, % (95% CI) Albuminuria lowering effect of dapagliflozin persists in patients with renal impairment UACR, mg/g (95% CI) No renal impairment or CKD stage 1 3A 1a CKD stage 3B 4 2b 3 2 1 egfr sub-group 1 2 3 1 2 3 4 5 6 BL 4 8 12 16 2 24 9 6 <9 45 <6 4 5 6 7 8 BL 4 8 12 16 2 24 37 5 63 Placebo DAPA 1 mg DAPA 5 mg Study week Study week UACR 3 mg/g at baseline a CKD stage 1 3A defined as egfr 9 <6; b CKD stage 3B 4 defined as egfr 15 <45 CI, confidence interval; CKD, chronic kidney disease; DAPA, dapagliflozin; PBO, placebo; UACR, urine albumin:creatinine ratio 1. Petrykiv S, et al. Clin J American Soc Nephrol 217;12:751 759; 2. Dekkers CCJ, et al. Nephrol Dial Transplant 218 [Epub ahead of print]
Adjusted mean change from baseline in HbA 1c, % (95% CI) Dapagliflozin maintains modest Hba1c lowering efficacy in CKD stage 3 Adjusted mean change from baseline in egfr, ml/min/1.73 m 2 (95% CI) Treatment with dapagliflozin over 24 weeks significantly improved glycemic control, body weight, and systolic blood pressure in patients with T2DM and CKD stage 3A a, with no reduction in egfr 4 HbA 1c Dapagliflozin 1 mg (n=159) Placebo (n=161) 4 3 egfr Dapagliflozin 1 mg (n=16) Placebo (n=161) Follow-up period 2.5 1. 1 2 3.5 4 5 6 1. 4 12 24 Time (weeks) 7 8 4 12 24 27 Time (weeks) a egfr: 45 59 ml/min/1.73 m 2 CKD, chronic kidney disease; CI, confidence interval; egfr, estimated glomerular filtration rate; HbA 1c, glycated hemoglobin; T2DM, Type 2 diabetes mellitus Fioretto P, et al. Diabetes Obes Metab 218 [Epub ahead of print]
Alterations in proximal sodium reabsorption modulate TGF Normal TGF Impaired TGF Restored TGF 3 Appropriate afferent arteriole tone Normal GFR Macula densa Afferent arteriole vasodilation Elevated GFR Decreased Na + delivery to macula densa 4 Afferent arteriole constriction 5 Normalization of GFR Increased Na + delivery to macula densa Na + /glucose reabsorption Increased Na + /glucose reabsorption Na + 2 SGLT2 SGLT2 1 Na + SGLT2 inhibition in proximal tubule Glucosuria Normal physiology Hyperfiltration a in early stages of diabetic nephropathy SGLT2 inhibition reduces hyperfiltration via TGF a Renal hyperfiltration: GFR 135 ml/min/1.73 m 2 GFR, glomerular filtration rate; SGLT2, sodium glucose co-transporter 2; TGF, tubuloglomerular feedback Cherney D, et al. Circulation 214;129:587 597
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 12 18 16 14 12 1 8 6 4 1641 1156 2 18 16 14 12 1 8 6 4 172. 139. 1 8 Baseline 2 2 SGLT2 inhibition RBF T1D-H (Euglycemia) 6 baseline week 12 Cherney D et al. Circulation 214:129;587-99 Heerspink et.al. Diab Obes Metab 213: 15:853-62
Mechanism of action of SGLT2 inhibitors and other antihypertensive agents Rajasekeran et.al. Current Opinon Nephrology Hypertension 217
Acetozolamide (proximal diuretic) decreases RBF and GFR in obese non-diabetic individuals Acetazolamide increases urinary sodium excretion and decreases GFR/ERPF Furosemide does not activate tubulo-glomerular feedback as it blocks sodium transport into the macula densa Zingerman Plos One 214
Adjusted mean egfr (ml/min/1.73 m 2 ) Adjusted mean egfr (ml/min/1.73 m 2 ) CANVAS: Canagliflozin attenuates egfr decline CANVAS Patients, n PBO 8 79 78 77 76 75 CANA 74 73 72 71 PBO 7 69 68 Baseline 18/26 52 78 14 13 156 182 28 234 26 286 312 338 CANA 4276 438 3967 3538 3212 174 13 Weeks since randomization 5711 5355 5212 4867 457 2964 223 1961 239 1795 1895 1695 1653 881 899 785 89 726 694 243 548 CANVAS-R Patients, n PBO 8 79 78 CANA 77 76 75 74 73 72 PBO 71 7 69 68 Baseline 26 52 78 14 3 days CANA 2859 2868 2728 2752 Weeks since randomization 2649 2675 244 2512 2124 226 off-treatment 2485 2518 CANA, canagliflozin; egfr, estimated glomerular filtration rate; PBO, placebo. Perkovic V. et.al. Lancet D&E 218
CREDENCE stopped early for overwhelming efficacy
Intraglomerular Hypertension is a common feature and driver of disease progression in chronic kidney disease Hypertensive nephrosclerosis Arterial stiffening Renal plasma flow Intraglomerular hypertension Glomerular hyperfiltration Diabetic nephropathy Whole kidney RBF FF Vasodilation of afferent arteriole Proximal tubular sodium reabsorption and glomerular hypertension RAAS Obesity-induced CKD Renal plasma flow GFR with resulting FF Caloric restriction has been shown to reverse glomerular hyperfiltration Focal segmental glomerulosclerosis Single-nephron level; plasma flow per nephron Intrarenal vasodilation and glomerular hypertension CKD, chronic kidney disease; FF, filtration fraction; GFR, glomerular filtration rate; RAAS, renin angiotensin aldosterone system; RBF, renal blood flow
Body weight change (%) Canagliflozin lowers body weight and CV risk factors in obese nondiabetic individuals (N=376) Systolic BP change (mmhg) Uric Acid change (umol/l) egfr change f(ml/min/1.73m2). Body Weight Systolic BP Uric Acid egfr 5 1 3 Placebo 5 1 3 Placebo 5 1 3 Placebo 5 1 3 Placebo.. 1. -2. -1. -1. -4.. Not reported -2. -2. -1. -6. -3. -3. -8. -2. Bays et.al. Obesity 214;14:142-149
DAPA-CKD and EMPA-KIDNEY: SGLT2 inhibition in patients with diabetic and non-diabetic CKD Randomization 1:1 Randomization 1:1 DAPA-CKD Population: Patients with CKD stage 2 4 (egfr 25 75 ml/min/1.73m 2 ) UACR 2 mg/g Stable ACE inhibitor / ARB Placebo + SoC Dapagliflozin 1 mg + SoC Primary endpoint: Time to composite of 5% sustained decline in egfr, onset of ESRD, CV, or renal death Anticipated targets 4 patients Event-driven Duration 45 months EMPA-KIDNEY Population: Patients with CKD stage 2 4 (egfr 2 9 ml/min/1.73m 2 ) Placebo + SoC UACR 3 mg/g if egr>45 ml/min Stable ACE inhibitor / ARB Empagliflozin + SoC Primary endpoint: Time to composite of 4% egfr decline, onset of ESRD, CV, or renal death Anticipated targets 5 patients Event-driven Duration 54 months ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CV, cardiovascular; egfr, estimated glomerular filtration rate; ESRD, end-stage renal disease; hhf, hospitalized heart failure; SoC, standard of care; T2DM, Type 2 diabetes mellitus; UACR, urine albumin:creatinine ratio
EASD Guideline
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 Perkovic et.al. Cur Med Res Opin 215:31;2219-31 Increased intraglomerular pressure and hyperfiltration are key steps in the progression of diabetic kidney disease
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 2 1 5 Empagliflozin Placebo 1 Acute renal failure 5 Acute kidney injury No. of patients Acute renal failure Empagliflozin Placebo Acute kidney injury Empagliflozin Placebo 6 1 2 4687 2333 4687 2333 4359 2167 4415 2194 4159 231 4238 278 1 8 3937 1889 437 1944 2 4 Months 3398 1588 355 1653 3 2463 1133 2545 1178 3 6 1897 866 1965 92 4 2 975 43 114 427 4 8 268 18 279 111 CI, confidence interval; HR, hazard ratio; Wanner C, et al. N Engl J Med. 216 Jul 28;375(4):323-34
AKI is less frequently observed during SGLT2 inhibition in two large contemporary cohorts of two major US health systems User (n=372) Mount Sinai cohort Nonuser (n=372) P1 User (n=1,27) Geisinger cohort Nonuser (n=1,27) P2 Mount Sinai (unadjusted) AKI KDIGO -inpatient 14 (3.8) 36 (9.7).2 26 (2.2) 55 (4.6).1 AKI ICD 22 (5.9) 4 (1.8).2 15 (1.2) 36 (3.).3 Peak creatinine in AKI KDIGO events Change in serum creatinine during AKI KDIGO events Need for acute dialysis 1.6 (1.4 1.8) 1.9 (1.6 2.4).2 1.7 (1.4 2.6) 1.6 (1.3 2.4).91.5 (.4.7).9 (.8 1.3).4.6 (.5 1.).6 (.4 1.2).8 1 (.3) 1 (.3) 1. (.) 1 (.1).317 P1 and P2 are P values for primary and secondary analyses, respectively. Mount Sinai (adjusted) Geisinger (unadjusted) Geisinger (adjusted).2.4.6.8 1 1.2 1.4 1.6 Hazard ratio (95% confidence interval) Mount Sinai Geisinger AKI, acute kidney injury; SGLT2, sodium glucose co-transporter 2; US, United States. Nadkarni et al. Diabetes Care 217 4:1479 1485
Summary Recent outcome trials with SGLT2 inhibitors confirmed the CV safety and efficacy of these agents (particular protection for Heart Failure and Kidney Failure protection) Hba1c lowering effects attenuated in Diabetic Kidney Disease but other effects persists CREDENCE trial in Diabetic Kidney Disease prematurely stopped for overwhelming efficacy Benefits of SGLT-2 inhibitors mediated by: Diuresis / Natriuresis Activation Tubulo-Glomerular Feedback Reducing intra-renal hypoxia? Given that effects of SGLT2 inhibitors are unlikely mediated by glycemic improvements and SGLT-2 inhibitors can be safely used without inducing hypoglycmemica current trials examine the efficacy in non-diabetic kidney diseases Guidelines recommend SGLT-2 inhibitors as second line treatment (adjunct to metformin) in indivduals with diabetes and CKD