SGLT2 Inhibitors: Town Hall Benefits vs Concerns: A renal perspective

SGLT2 Inhibitors: Town Hall Benefits vs Concerns: A renal perspective Matthew R. Weir, MD Professor and Chief Division of Nephrology University of Maryland School of Medicine

Disclosure Slide Scientific Advisor: Janssen, Astra, BI, MSD, Akebia, Relypsa, Boston Scientific, Lexicon Grant Funding: NIDDK: R01DK 066013 and U01DK106102, NHLBI: R01HL127422

Concerns: Ketoacidosis Reduction in egfr

Case Presentation: History 54-year-old African American female Type 2 diabetes mellitus x 8 years Hypertension x 12 years Nonsmoker Past history Obesity OA of the knees Current medications Insulin, pioglitazone Atorvastatin 20 mg once daily HCTZ 25 mg QD, metoprolol 25 mg BID

Case Presentation: Physical Exam BP 154/92 mm Hg PR 68 Weight 106 kg BMI 36.6 kg/m 2 Retinopathy, S4, 1+ edema Diminished peripheral pulses Peripheral neuropathy egfr = estimated glomerular filtration rate; FBG = fasting blood glucose; FLP = fasting lipid profile; HbA 1c = glycosylated hemoglobin; UAE = urinary albumin excretion; WNL = within normal limits.

Case Presentation: Lab Findings Scr 1.3 mg/dl, K 5.1 meq/l, A1 c 8.8% Estimated GFR = 56 ml/min/1.73 m 2 TG 220 mg/dl, HDL 33 mg/dl, LDL 98 mg/dl Urine Analysis: 1+ glucose, 3+ protein, no cells, casts, crystals 24 hour urine total protein 1,752 mg alb/cr ratio 1,550 mg/g sodium 287 meq Renal Sono: 11 cm kidneys, mild echogenicity

54-year-old African American Female with Hypertension, Type 2 Diabetes, Macroalbuminuria What is working diagnosis and differential? What additional laboratory data? What are the Treatment Options?

What are optimal treatment considerations? 1. BP below 130/80 mmhg 2. RAS inhibition 3. Tight control of hemoglobin A1C 4. Anti-platelet therapy 5. Full dose statin

Concerns: Ketoacidosis Reduction in egfr

Ketogenic Pathways The 2 principal ketone bodies, acetoacetate and beta-hydroxy butyrate are derived from the metabolism of FFA released from adipocytes and delivered to the liver FFA are activated to their acetyl CoA derivative The primary determinates as to whether acetyl CoA is directed toward a ketogenic or non-ketogenic pathway are the concentrations of insulin and glucagon

Malonyl CoA Increased production with high insulin, and low glucagon Increased malonyl CoA inhibits fatty acyl CoA entry into mitochondria Fatty acids are directed to TG Synthesis Under conditions of low insulin and high glucogon, malonyl CoA levels are reduced, facilitating entry of fatty acyl CoA into the mitochondria to form ketoacids

Starvation Ketosis More efficient renal conservation of ketone bodies through saturable and non-saturable pathways Increased production of ketone bodies suppresses protein catabolism by reducing the need for gluconeogenesis Ultimately, the rate of ketone body synthesis matches the rate of ketone body utilization There is usually a sufficient amount of insulin to prevent excessive mobilization of fatty acids, because ketone bodies stimulate insulin production

Starvation Ketosis Adaptive response Minimize loss of metabolic fuels Spares sodium and potassium losses Minimize loss of ammonium nitrogen Minimizes protein break down No net consumption of bicarbonate

Negative feedback loop on insulin secretion does not occur Greater fatty acid mobilization Unrestrained hepatic ketone body production Production of ketones exceeds utilization Increase in gluconeogenesis Diabetic Ketoacidosis Increased muscle breakdown and release of aminoacids Loss of urinary ketone bodies as sodium or potassium salts represents indirect loss of bicarbonate

SGLT 2 Inhibitor Ketoacidosis Reduction in glucose leads to a reduction in insulin (glucose is the chief stimulus for insulin release) Increase in plasma glucagon via 1) diminished inhibitory effect of insulin on glucagon release and 2) inhibition of the SGLT2 transporter in the pancreatic alpha cells (triggering glucagon release) Glucagon may directly suppress insulin release Degree of insulin deficiency and resistance induced by SGLT 2 inhibitors is much less than in DKA, so that glucose over production and underutilization is quantitively less, and often results in euglycemic ketoacidosis

SGLT2 Inhibitor Ketoacidosis delivery of FFA to the kidney oxidation of FFA leads to ATP consumption of ATP byna+ K+ -ATPase because of sodium cellular entry consumption and production of ATP causes a decrease of other ATP generating pathways This change causes a secondary reduction in other cellular pathways to generate ATP, such as renal ammoniagenesis from the metabolism of glutamine and the uptake and metabolism of filtered ketone bodies

SGLT2 Inhibitor Ketoacidosis The excretion of ketone bodies in the urine as either a Na+ or K+ salt represents a net bicarbonate loss However, if ketone bodies are excreted with NH4 +, there is no net change in the H + or HCO 3 concentration Ketonuria may increase and exceed the NH4 + excretion rate, resulting in the development of metabolic acidosis, especially in the setting of ATP excess and reduced ammoniagenesis

SGLT2 Inhibitor Ketoacidosis Since urinary excretion of ketoacid salts coupled to NH4 + is neutral with regard to acid-base balance it is critical to understand predisposing factors: CKD, diabetes, RAAS blockade, Type IV RTA, etc; since hyperkalemia suppresses renal ammoniagenesis Thus, decreased renal ATP consumption in the proximal tubule by SGLT2 inhibitors may lead to bicarbonate loss (with Na + or K + resulting in ketoacidosis

The role of the kidney in SGLT2-induced ketoacidosis. Palmer B. Journal of Diabetes and Its Complications 30 (2016) 1162-1166.

Renal Handling of Ketones in Response to SGLT2 Inhibition in Patients with T2DM n=66 patients with T2DM, egfr >60ml/min 4 weeks of empaglifozin 25 mg daily Fractional excretion of glucose rose from 38 to 46% (fasting, postmeal) Excretion of beta-hydroxybutyrate, lactate, and sodium increased positively related to glycosuria Similar observations of lesser magnitude were seen in non-diabetic controls (n=25) It appears that SGLT2 inhibitor mediated ketoacidosis is due to increased production, rather than reduced renal clearance, as might be seen in starvation ketosis. Fernannini E, et al. Diabetes Care (In Press)

Ketone Bodies and Renal Function Ketone bodies enhance GFR and RPF which may counter the effect of TGF in reducing GFR via pre-glomerular vasoconstriction Stabilization of urinary Na+ losses may be helpful to limit ketone body excretion as a sodium salt which could worsen acidosis Ferraninni, E. et al. Diabetes Care (In Press)

Relationship between glucose excretion and urinary excretion of β- hydroxybutyrate during chronic treatment with empagliflozin Fernannini E, et al. Diabetes Care (In Press)

Relationship between glucose excretion and urinary excretion of lactate during chronic treatment with empagliflozin Fernannini E, et al. Diabetes Care (In Press)

Relationship between glucose excretion and urinary excretion of sodium during chronic treatment with empagliflozin Fernannini E, et al. Diabetes Care (In Press)

Urinary β hydroxybutyrate (β-hb and lactate excretion rate during fasting and following meal ingestion at baseline, after acute and chronic empagliflozin administration in patients with type 2 diabetes Fernannini E, et al. Diabetes Care (In Press)

Factors Which Could Predispose to Ketoacidosis Reduced egfr Hyperkalemia which reduces renal ammoniagenesis RAAS blockers Type 4 RTA Conditions which increase fatty acid delivery to the kidney NSAIDs

Case Presentation Empagliflozin 10 mg and Lisinopril 20 mg started Labs assessed 3 weeks later: 136 101 Anion Gap 18 HgbA1C 7.6% 5.3 17 Creat 1.6 UACR 892 mg/g, urine ketostix positive BP 136/82 mmhg

What would you do? Case Presentation ANION GAP CREATININE BP UACR

HgbA 1 C 7.1% with intensified insulin, pioglitazone and empalifozin BP 128/78 mmhg with increase in HCTZ 50 mg daily Creat stable at 1.6, and anion gap 12 Potassium 4.2 Case Presentation: 6 months later

Are SGLT2 inhibitors Renal and Cardio protective?

Possible Mechanisms of Benefit Glomerular Hyperfiltration Lower systemic blood pressure Lower glomerular capillary BP Pro-inflammatory Processes Lower BP, glucose, cholesterol Anti-inflammatory therapies? Enhance cellular energy via increased production of ATP

Glomerular Structure Mesangial Cell Capillary Loop Endothelial Cell Efferent Arteriole Afferent Arteriole Juxtaglomerular Apparatus

Renal glucose re-absorption under healthy conditions1,2 Filtered glucose load 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% Virtually all of the filtered glucose is re-absorbed in the proximal In healthy tubules through individuals, SGLT2 and SGLT1 the with renal SGLT2 glomeruli accounting filter for ~ 90% ~180 in the g S1 and S2 of segments glucose per and SGLT1 accounting day for ~ 10% in the S3 segment SGLT, sodium glucose cotransporter. Adapted from: 1. Gerich JE. Diabet Med. 2010;27:136 142; 2. Bakris GL, et al. Kidney Int. 2009;75;1272 1277.

Renal glucose re-absorption in patients with diabetes1,2 Filtered glucose load > 180 g/day SGLT2 ~ 90% SGLT1 ~ 10% SGLT, sodium glucose cotransporter. Adapted from: 1. Gerich JE. Diabet Med. 2010;27:136 142; 2. Bakris GL, et al. Kidney Int. 2009;75;1272 1277.. When blood glucose increases above the renal threshold (~ 11 mmol/l or 190 mg/dl), the capacity of the transporters is exceeded, resulting in urinary glucose excretion

Postulated tubuloglomerular feedback (TGF) mechanisms in normal physiology, early stages of diabetic nephropathy, and after sodium-glucose cotransporter (SGLT) 2 inhibition. David Z.I. Cherney et al. Circulation. 2014;129:587-597

Postulated tubuloglomerular feedback (TGF) mechanisms in normal physiology, early stages of diabetic nephropathy, and after sodium-glucose co-transporter (SGLT) 2 inhibition. David Z.I. Cherney et al. Circulation. 2014;129:587-597

Renal Hemodynamic Studies in T1DM 8 weeks of therapy with empagliflozin n=27 hyperfilterers (GFR >135 ml/min) and n=13 normal GFR Studied during euglycemic (4 6 mmol/l) and hyperglycemic (9 11 mmol/l) clamps at the beginning and end of 8 weeks treatment Cherney DZ et al. Circulation. 2014;129:587-97.

Glomerular filtration rate (GFR) responses to empagliflozin during clamped euglycemia (A) and hyperglycemia (B; mean±sd) *P<0.01 for baseline GFR in type 1 diabetes mellitus subjects without (T1D-N) vs with (T1D-H) renal hyperfiltration P<0.01 for the within-group change in GFR in T1D-H P<0.01 for the between-group effect of empagliflozin on change in GFR Cherney DZ et al. Circulation. 2014;129:587-97.

EMPA-REG Outcome Study 7020 patients with T2DM at high risk for CV events were randomized to receive placebo, empaglifozin 10 gm, or empaglifozin 25 mg once daily Median observation time 3.1 years Primary composite outcome measure: death from CV causes, nonfatal MI, or nonfatal stroke Zinman B, et al. NEJM 2015; 373:2117-2128.

Zinman B et al. N Engl J Med 2015;373:2117-2128. Glycated Hemoglobin Levels

Cardiovascular Outcomes and Death from Any Cause Zinman B et al. N Engl J Med 2015;373:2117-2128.

LEADER Study Patients with type 2 diabetes and high cardiovascular risk were assigned to receive either the glucagon-like peptide 1 analogue liraglutide or placebo. The rate of first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was lower with liraglutide.

Marso SP et al. N Engl J Med 2016;375:311-322 Primary and Exploratory Outcomes

Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.

Considerations about Newer Therapies Besides Safety and Efficacy Complementary with RAAS blockers? Would you see the effect if SBP is 110 mmhg, 120 mmhg, 130 mmhg, or only at higher SBP? Persistency of effect after drug cessation? Is change in albuminuria an adequate surrogate measure, or do we need observable stabilization of estimated GFR? Low salt diet and thiazide diuretics have anti-proteinuric effects.

Multiple theories about renal and CV benefits with SGLT2 Inhibitors Is it more than simply pressure/volume reduction?

Physiologic mechanisms implicated in the cardiovascular and renal protection with SGLT2 inhibition Hiddo J.L. Heerspink et al. Circulation. 2016;134:752-772

Raised circulating FFAs are taken up by the liver and metabolized via β-oxidation. Ele Ferrannini et al. Dia Care 2016;39:1108-1114

However, if there is a reduction of GFR with the SGLT2 inhibitors; is this a good or adverse prognostic sign?

Relationship between 2-and 8-week changes in glomerular filtration rate (GFR) and subsequent renal and cardiovascular outcomes in 9340 patients new to RAS Blockade in ONTARGET/TRANSCEND Clase, et al. Kidney International (2017) 91,683-690.

Association between percent decline in renal function in AASK and MDRD participants from time of randomization until month 3-4 and risk of ESRD Ku, Elaine (In Press)

Which balance is required for CV and Renal Risk Reduction? PROTEINUIRA PRESSURE VOLUME EGFR