SGLT2 Inhibitors: A Dynamic and Evolving Therapeutic Option · SGLT2 inhibitors are not indicated...

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

SGLT2 Inhibitors: A Dynamic and Evolving

Therapeutic Option

Presented as a Live Webinar

Thursday, September 17, 2020 1:00 p.m. – 2:00 p.m. ET

On‐demand Activity

Release Date: November 17, 2020 Expiration Date: May 31, 2021

This webinar is not accredited for continuing education.

FACULTY

Ralph J. Riello III, Pharm.D., BCPS Cardiovascular Critical care Pharmacy Specialist Yale New Haven Hospital New Haven, Connecticut

View faculty bio at https://www.ashpadvantage.com/t2d/sglt2/

Any referenced figures, tables and graphs are copyrighted works of their respective owners; used with permission.

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© 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 2

SGLT2 Inhibitors: A Dynamic and Evolving Therapeutic Option

Ralph J. Riello III, Pharm.D., BCPSCardiovascular Critical Care Pharmacy Specialist

Yale New Haven Hospital New Haven, Connecticut

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

Disclosure of Relevant Financial Relationships

Ralph J. Riello III • Consultant: AstraZeneca Pharmaceuticals, Janssen Pharmaceuticals/Johnson &

Johnson, Portola Pharmaceuticals

• Research grant: AstraZeneca Pharmaceuticals

All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant* to this activity.

*As defined by the ACCME definition of commercial entity.



Learning Objectives

At the conclusion of this activity, participants should be able to

• Describe the impact of sodium‐glucose cotransporter 2(SGLT2) inhibitors on the pathophysiology of cardiorenaldisease

• Discuss the clinical effects of SGLT2 inhibition on glycemia,major adverse cardiovascular events, hospitalization for heartfailure, and renal endpoints in diabetes

• Summarize the evolving landscape of evidence related toSGLT2 inhibition in patients without diabetes

Various Systems Play a Role in Balancing Blood Glucose Levels in Healthy Individuals1‐3

Insulin

Plasma Glucose

βαα

Glucose Production

Increase

Decrease

Glucagon

Glucose uptake

Renal Glucose Production and Reabsorption



Dietary Intake

1. Abdul‐Ghani MA. Am J Manag Care. 2013;19(suppl 3):S43‐S50; 2. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐190; 3. Gerich JE. Diabet Med. 2010;27:136‐142.



Multiple Defects Contribute to the Pathophysiology of Type 2 Diabetes

Glucoseuptake

Glucose production

Lipolysis

Insulinsecretion

Glucagon secretion

Glucose reabsorption

ChronicHyperglycemia

Incretineffect

Neurotransmitter dysfunction

β

αα

DeFronzo RA. Diabetes. 2009;58:773‐795.

Normal Glucose Filtration and Reabsorption in the Kidney

Healthy

Glucose excretion

GlucoseFiltration

GlomerulusSGLT2 SGLT1

Distal Tubule

CollectingDuct

No/MinimalGlucoseExcretion

Loopof Henle

GlucoseReabsorption

Proximal Tubule

Healthy Patient Patient with T2D

T2D = type 2 diabetes.

Bays H. Curr Med Res Opin. 2009;25(3);671‐681. Reprinted with permission.



Glucose Filtration and Reabsorption in Patient With Type 2 Diabetes1,2

Healthy T2DM

Glucose excretion

GlucoseFiltration


Distal Tubule

CollectingDuct

PossibleGlucoseExcretion

Loopof Henle

GlucoseReabsorption

Proximal Tubule

Healthy Patient Patient with T2D

T2D = type 2 diabetes.

1. Bays H. Curr Med Res Opin. 2009;25(3):671‐681. Reprinted with permission. 2. Mather A, Pollock C. Kidney Int. 2011;79(suppl 120):S1‐S6.

The Concept of SGLT2 Inhibition:Preventing the Reabsorption of Sodium and Glucose

• SGLT2 inhibition compromises transporter function and reducesrenal glucose reabsorption to induce glucosuria in adults with T2D

• The effect of pharmacologic inhibition of SGLT2 is not the same asthat of naturally occurring mutations

Glucose

Sodium

SGLT1

SGLT2Inhibition

SGLT = sodium‐glucose cotransporter

1. Santer R. Clin J Am Soc Naphrol. 2010:5(1);133‐141. 2 Santer R. J Am Soc Nephrol. 2003;14(11):2873‐2882. 3. Abdul‐Ghani MA et al. Endocr Pract. 2008;14(6):782‐790. 4. Bays H. Curr Med Res Opin. 2009;25(3):671‐681. 5. Rosenwasser RF et al. Diabetes Metab Synr Obes. 2013;6:453‐467.



SGLT2 inhibitors Reduce Threshold for Glucose Excretion and Maximal Glucose Reabsorption1‐3

T2D = type 2 diabetes

1. Bays H. Curr Med Res Opin. 2005;25(3):671‐81. Reprinted with permission. 2. Cryer PE. In;Fauci AS et al. eds. New York, NY; RR Donnelly and Sons, Inc; 2008:2305‐2310. 3. DeFronzo et al. Diabetes Care. 2013;36:3169‐3176.

Normal Range2

70 1400

100

200

300

400

500

600

0 200 400 600

Rate of glucose filtration/

reab

sorption/excretion (mg/m

in)

Plasma glucose (mg/dL)

Simplified from actual data. For illustrative purposes.

Excreted

Reabsorbed

FilteredHealthyat baseline

T2Dat baseline (n=12)3

T2D + dapa10 mg for 7 days (n=12)3

Healthy T2DM T2DM +SGLT2 inhibitor

Glucose excretion

Glucose Filtration and Reabsorption in Patient on SGLT2 inhibition (‐flozin)

Glucose (70 g ofglucose/daywith dapagliflozin10 mg at12 weeks)

SGLT2 inhibitors are not indicated for weight loss

GlucoseFiltration


Distal Tubule

CollectingDuct

Glucose AssociatedCalories,and Fluid

Loopof Henle

GlucoseReabsorption

Proximal Tubule

Healthy Patient Patient with T2D Patient on SGLT2 Inhibitor

T2D = type 2 diabetesBays H. Curr Med Res Opin. 2009;25(3):671‐681. Reprinted with permission.



SGLT2 Inhibitors Can Help Address Multiple Defects of T2D1‐5

Glucose production

Lipolysis

Glucagon secretion



Incretineffect

Neurotransmitter dysfunction

αα

Defect

Insulin Secretion*

SGLT2 inhibitor

Insulin Secretion

Defect

Insulin Sensitivity*

SGLT2 inhibitor

Glucose Uptake

Defect

Glucose Reabsorption

Urinary Glucose Excretion and

Caloric Loss

SGLT2 inhibitor

β

*Secondary to reduction of glucotoxicity

SGLT2 = sodium‐glucose cotransporter 2.

1. DeFronzo RA. Diabetes. 2009;58:773‐795; 2. Merovci A et al. J Clin Invest. 2014;124(2):509‐514; 3. Merovci A et al. J Clin Endocrinol Metab. 2015;100(5):1927‐1932; 4. DeFronzo RA et al. Nat Rev Nephrol. 2017;13(1):11‐26; 5. List JM et al. Diabetes Care. 2009;32(4):650‐657.

Available SGLT2 Inhibitors in the U.S. Market1‐4

Dapagliflozin1 Canagliflozin2 Empagliflozin3 Ertugliflozin4

First approved 2014 2013 2014 2017

Indication

1. T2D, as an adjunct to diet and exercise to improve glycemic control

2. Reduce the risk of hHF in adults with T2D with established CV disease or multiple CV risk factors

3. Reduce the risk of CV death and hHF in HFrEF (NYHA Class II‐IV) patients


2. Reduce the risk of MACE in adults with T2D and established cardiovascular disease

3. Reduce the risk of ESKD, doubling of serum creatinine, CV death, and hHF in adults T2D and diabetic nephropathy with albuminuria


2. Reduce the risk of CV death in adult patients with T2D and established CVD.


Dosing QD; AM dosing QD; take before 1st meal of day QD; AM dosing QD; AM dosing

eGFR (mL/min/1.73m2)

>30 >30 >45 >60

CV = cardiovascular; eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes1. Farxiga (dapagliflozin) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; Revised 05/2020. 2. Invokana (canagliflozin) [package insert]. Titusville, NJ: Janssen Pharmaceuticals; Revised 08/2020. 3. Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceutical, Inc; Revised 01/2020. 4. Steglatro (ertugliflozin) [package insert]. Whitehouse Station, NJ: Merck Sharp Dohme Corp; Revised 10/2020.



-1.03-0.93

-0.44

-0.89

-0.52

-0.96

-0.78 -0.77

-1.02-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Glucose Control with SGLT2 Inhibitors1‐9

*results for the following dose‐groups: canagliflozin 300 mg, dapagliflozin 10 mg, empagliflozin 25 mg; mean change from baseline

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372‐382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217‐2224. 3. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208‐219. 4. Cefalu WT, et al. Lancet. 2013;382:941‐950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015‐2022. 6. Haring HU, et al. Diabetes Care. 2014;37:1650‐1659. 7. Yale J‐F, et al. Diabetes Obes Metab. 2013;15:463‐473. 8. Wilding JPH, et al. Ann Intern Med. 2012;156:405‐415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815‐1823.

Mean Change in HbA1C from Baseline*

(Not head‐to‐head trials) Baseline

HbA1C (%)

Monotherapy Add‐on to Metformin Add‐on to Insulin +/‐ OADs

Cana1 Dapa2 Empa3 Cana4 Dapa5 Empa6 Cana7 Dapa8 Empa9

8.0 8.0 7.9 7.8 7.7 7.9 8.0 8.6 8.3

Mea

n

Hb

A1C

(%

)

‐3.4

‐4.0

‐1.4

‐3.2 ‐3.2

‐1.6

‐2.5 ‐2.5

‐1.5

‐4.5

‐4

‐3.5

‐3

‐2.5

‐2

‐1.5

‐1

‐0.5

0

Weight Change with SGLT2 Inhibitors1‐9

Mean Change in Body Weight from Baseline*(Not head‐to‐head trials)





86.9 94.2 77.8 86.6 88.4 82.2 90.2 94.5 95.9Baseline weight

W

eig

ht

(kg

)



Effects on Blood Pressure with SGLT2 Inhibitors1‐9

Mean Change in Systolic Blood Pressure (SBP) from Baseline*(Not head‐to‐head trials)

Mea

n

in S

eate

d

SB

P (

mm

Hg

)

‐5.0‐4.6

‐6.4

‐3.6

‐4.3

‐6.7

‐3.7

‐5.2

‐2.9

‐8

‐7

‐6

‐5

‐4

‐3

‐2

‐1

0



Baseline SBP (mm Hg)



128.5 N/A 129.9 130.0 132.8 130.0 136.7 140.6 132.9

Safety Precautions in the Use of SGLT2 Inhibitors1‐4

Warnings and Precautions Most Common AEs

Dapagliflozin1

Volume depletion, ketoacidosis in patients with T2D, urosepsis, pyelonephritis, hypoglycemia, necrotizing fasciitis of the perineum (Fournier’s Gangrene), genital mycotic infections

Female genital mycotic infections, nasopharyngitis, urinary tract infections

Canagliflozin2

Volume depletion, ketoacidosis, urosepsis, pyelonephritis, hypoglycemia, necrotizing fasciitis of the perineum (Fournier’s Gangrene), genital mycotic infections, hypersensitivity reactions, bone fracture

Female genital mycotic infections, urinary tract infections, increased urination

Empagliflozin3

Hypotension, ketoacidosis, acute kidney injury and impairment of renal function, urosepsis, pyelonephritis, necrotizing fasciitis of the perineum (Fournier’s Gangrene), genital mycotic infections, hypersensitivity reactions, increased LDL‐C

Urinary tract infections and female genital mycotic infections

Ertugliflozin4

Hypotension, ketoacidosis, acute kidney injury, urosepsis, pyelonephritis, lower limb amputation, hypoglycemia, necrotizing fasciitis of the perineum (Fournier’s Gangrene), genital mycotic infections

Female genital mycotic infections

AE = adverse event; AKI = acute kidney injury; LDL‐C = low‐density lipoprotein cholesterol; US = United States

1. Farxiga (dapagliflozin) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; Revised 05/2020. 2. Invokana (canagliflozin) [package insert]. Titusville, NJ: Janssen Pharmaceuticals; Revised 08/2020. 3. Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceutical, Inc; Revised 01/2020. 4. Steglatro (ertugliflozin) [package insert]. Whitehouse Station, NJ: Merck Sharp Dohme Corp; Revised 10/2020.



Expanding Therapeutic Areas for Treatment with SGLT2 Inhibitors

*CREDENCE evaluated patients with diabetic kidney disease. CANVAS was performed per 2008 FDA published guidance to evaluate cardiovascular risk in the treatment of type 2 diabetes.ACE = acetylcholine esterase; CKD = chronic kidney disease; CV = cardiovascular; DPP‐4 = dipeptidyl peptidase‐4; eGFR = estimated glomerular filtration rate; ESRD = end‐stage renal disease; GLP‐1 = glucagon‐like peptide‐1; HF = heart failure; hHF = hospitalization for HF; MACE = major adverse cardiovascular events; MI = myocardial infraction; SGLT2 = sodium‐glucose cotransporter 2; ESKD = end stage kidney disease

Cefalu WT, et al. Diabetes Care. 2018;41(1):14‐31.

Cardiovascular Outcomes Trials(to assess CV risk and safety)

Heart Failure Trials

CKD Trials

EMPA‐REGn=7020

3‐P MACE

CANVASProgramn=10,1423‐P MACE

VERTIS CVn=8,2463‐P MACE

DAPA‐HFn=4,744

CV death, hHF, urgent HF visit

CREDENCE*n=4,464

ESRD, doubling of creatinine, renal/CV death

DECLARE‐TIMI 58n=17,2763‐P MACE;

CV death + hHF

EMPEROR‐Reducedn=3,730

CV death or hHF

EMPEROR‐Preservedn=4,126

CV death or hHF

2015 2016 2017 2018 2019 2020 2021 2022

EMPA‐KIDNEYn=6,000

ESKD, renal death, ≥40% sustained decline

in eGFR, or CV death

DELIVERn=6,100

CV death, hHF, urgent HF visit

SOLOIST‐WHFn=4,000

CV death or hHF

DAPA‐CKDn=4,304

≥50% sustained decline in eGFR or ESRD, CV death or renal death

All of the following metabolic effects of SGLT2 inhibitors are correct EXCEPT

a. Decrease HbA1c by 0.8‐1.0%

b. Lower body weight by 2.5‐3.0 kg

c. Decrease LDL‐C by 3‐10 mg/dL

d. Reduce systolic blood pressure by 3‐5 mm Hg



Review of CVOTs with SGLT2 Inhibitors

STUDY EMPA‐REG Outcome1 CANVAS Program (CANVAS & CANVAS‐R)2‐4

DECLARE5‐7 VERTIS CV8

Interventions (randomization)

EMPA/PBO (2:1) CANA 100/300 mg or PBO (1:1) DAPA/PBO (1:1) ERTU 5/15 mg/PBO (1:1)

Patient Enrollment 7,028 10,142 17,160 8,246

Key Inclusion Criteria • Established vascularcomplications

• HbA1C 7.0–10.0%

• Age ≥18 years

• Established vascular complications (age ≥30 years) or ≥2 CV risk factors (age ≥50 years)

• HbA1C 7.0–10.5%

• eGFR >30 mL/min/1.73 m2

• Established CVD or multiple CV riskfactors

• HbA1C 6.5‐12%

• Age ≥40 years

• Established vascular ASCVD

• HbA1C 7.0‐10.5%

• Age > 40 years

Primary Endpoint CV death, non‐fatal MI,non‐fatal stroke

CV death, non‐fatal MI, non‐fatal stroke

Two primary end points

• CV death, MI, or ischemic stroke

• hHF or CV death

CV death, non‐fatal MI, non‐fatal stroke

Secondary Endpoints Include

4P‐MACE; 3P‐MACE + hospitalization for UA, hHF, microvascular composite, micro‐and macroalbuminuria

Death from any cause, CV death, progression of albuminuria, composite end point of CV death or hHF

Renal composite end point: confirmed sustained ≥40% decrease in eGFR to eGFR <60 mL/min/1.73 m2 and/or ESRD and/or renal or CV death

All‐cause mortality

CV death/hHF, CV death, Renal composite (renal death, dialysis/transplant, doubling of serum creatinine)

Median follow‐up 3.1 years 2.4 years 4.2 years 5‐7 years

Target number of events

691 688 1,390 939

Status Completed 2015 Completed 2017 Completed 2018 Completed 2020

Overview of the Study Designs of SGLT2 Inhibitors CVOTs

This chart does not imply comparable or superior efficacy/safety profiles. Each study was placebo‐controlled and no direct comparisons to other SGLT2 inhibitor were included. Please refer to study publications and ClinicalTrials.gov for additional information. SCORED (sotagliflozin) not included due to lack of published study baseline data.

1. Zinman B, et al. N Engl J Med. 2. Neal B, et al. Am Heart J. 2013;166:217‐223. 3. Neal B, et al. N Engl J Med. 2017;377:644‐657. 4. Neal B, et al. Diabetes Obes Metab. 2017;19:387‐393. 5. ClinicalTrials.gov website. Identifier NCT01730534. Accessed August 27, 2018. 6. Raz I, et al. Diabetes Obes Metab. 2018;20:1102‐1110. 7. Wiviott SD, et al. Am Heart J. 2018;200:83‐89. 8. Cannon CP et al. Am Heart J. 2018;206:11‐23.



SGLT2 Inhibitors Cardiovascular Outcomes Trials:Percentage of Patients With and Without CVD

~59%*

~41%

DECLARE4

>99%

EMPA‐REG1

<1%

~34%†

~66%

CANVAS Program2,3

<1%

>99%

VERTIS CV5

In the general T2D population, only 20% of patients have established CVD6

Patients without CVD (with multiple CV risk factors)

Patients with ECVD

* Included age ≥55 for men and ≥60 for women, T2D, and at least 1 additional risk factor: dyslipidemia, HTN, or tobacco use.† Included age ≥50 with T2D and 2 or more additional risk factors: T2D >10 years, HTN, tobacco use, high‐density lipoprotein <39 mg/dL, albuminuria.

This chart does not imply comparable or superior efficacy/safety profiles. Each study was placebo controlled, and no direct comparisons to other SGLT2 inhibitors were included. Please refer to study publications and ClinicalTrials.gov for additional information. SCORED (sotagliflozin) is not included due to lack of published study baseline data.

CVD = cardiovascular disease; ECVD = established cardiovascular disease; HDL = high‐density lipoprotein; HTN = hypertension; SGLT2 = sodium‐glucose cotransporter 2; T2D = type 2 diabetes

1. Zinman B, et al. N Engl J Med. 2015;373(22):2117‐2128. 2. Neal B, et al. N Engl J Med. 2017;377(7):644‐657. 3. Neal B, et al. Diabetes Obes Metab. 2017;19(3):387‐393. 4. Wiviott SD, et al. N Engl J Med. 2018;380(4):347‐357.

5. Cannon CP et al. Am Heart J. 2018;206:11‐23. 6. Iglay K, et al. Curr Med Res Opin. 2016;32(7):1243‐1252.

A View Across the CVOTs…..

MACEHR (95% CI)

CV DeathHR (95% CI)

hHFHR (95% CI)

EMPA‐REG OUTCOME10.86

(0.74‐0.99)0.62

(0.49‐0.77)0.65

(0.50‐0.85)

CANVAS PROGRAM2 0.86 (0.75‐0.97)

0.87 (0.72‐1.06)

0.67 (0.52‐0.87)

DECLARE‐TIMI 5830.93

(0.84‐1.03)0.98

(0.82‐1.17)0.73

(0.61‐0.88)

VERTIS CV4 0.97 (0.85‐1.11)

0.92 (0.77‐1.11)

0.70 (0.54‐0.90)

1. Zinman B, et al. N Engl J Med. 2015; 2. Neal B, et al. N Engl J Med. 2017; 3. Wiviott SD, et al. N Engl J Med. 2019; 4. Cosentino F, et al. ESC. 2020.



hHF Outcomes in SGLT2 Inhibitors CV Outcomes TrialsPatients with event (%

)

Month

7

3

4

5

6

1

2

00 126 18 24 30 36 42 48

8

6

7

5

4

2

1

3

0

0 26 52 78 234 312 338104 130 156 182 208 260 286

Hazard ratio, 0.65(95% CI, 0.50–0.85)

EMPA‐REG Outcome1

Hazard ratio, 0.67(95% CI, 0.52–0.87)

Placebo

Empagliflozin

Placebo

Canagliflozin

Patients with event (%

)

Week


)

0 6 12 18 24 30 36 42 48 54 60

4

2

1

0

3 Dapagliflozin

PlaceboHazard ratio, 0.73(95% CI, 0.61–0.88)

6 12 24 36 48 600

0

Placebo

Ertugliflozin

HR, 0.70 (95% CI, 0.54, 0.90)

CANVAS Program2

Day Month

DECLARE‐TIMI 583 VERTIS CV4


)

CI = confidence interval; CV = cardiovascular; hHF = hospitalization for heart failure; HR =hazard ratio; SGLT2 = sodium‐glucose cotransporter 2

1. Zinman B, et al. N Engl J Med. 2015; 2. Neal B, et al. N Engl J Med. 2017; 3. Wiviott SD, et al. N Engl J Med. 2019; 4. Cosentino F, et al. ESC. 2020.

1

2

3

4

5

SGLT2 Inhibitors and HF



T2D and HF Often Intersect

T2D30.3 million in the United States HF

6.5 million

2‐4 million U.S. patients

• 10%‐ 47% of people with HF have T2D• 9%‐22% of people with T2D have HF

‒ 2‐ to 4‐ fold increased risk for HF in T2D

Dunlay SM, et al. Circulation. 2019.

CV Death or Hospitalization Due to HF60

40

20

0

Follow‐up (years)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Diabetes (Low EF)

No Diabetes (Low EF)

Diabetes (Preserved EF)

No Diabetes (Preserved EF)

Cumulative In

cidence, %

CV = cardiovascular; EF = ejection fraction; T2D =type 2 diabetes

MacDonald MR et al. Eur Heart J. 2008;29:1377‐1385.

Patients with T2D were at increased risk of CV events and death, regardless of EF

CV Outcomes in Diabetic and Non‐diabetic Patients



T2D Increases Risk of HF Through Multiple Pathways

Dunlay SM, et al. Circulation. 2019.

Diabetes

Hyperglycemia, insulin resistance, hyperinsulinemia

• Inflammation• Dyslipidemia• Endothelial dysfunction

CAD

Ischemic cardiomyopathy

Cardiomyocyte hypertrophy/LVH

RAAS activation • ∆ Calcium handling

• ∆ Fatty acid utilization

• Formation of AGEs

Automatic dysfunction

Fibrosis

Diabetic cardiomyopathy

Heart failure in diabetes

SGLT2 Inhibitor Trials: A Rethink on Diabetes to Pathways of CV Disease

Sattar N, McGuire D. Circulation. 2018.

Traditional focus

Novel insights

Type 2 Diabetes

Obesity

Lipids Glucose Blood pressure Thrombotic tendency Endothelial dysfunctions

Insulin Renal SGLT2 expression Glomerular hyperfiltration Tubuloglomerular feedback

Other mechanisms?

Accelerated atherogenesis

• Sodium and glucose retention

• Intravascular volume expansion

Volume status/hemodynamic and glomerular stress

MI, CVA, PAD

Heart failure

Kidney disease



Evidence Supports Glycemic and Nonglycemic Effects of SGLT2 Inhibitor

Potential mechanisms by which SGLT2 inhibition reduces risk for heart failure hospitalization are not fully understood and basic research is ongoing

• Decreased preload and afterload6

• Increased cardiac efficiency9,10

• Decreased cardiac remodeling10,11

• Decreased plasma glucose3,4

• Increased β‐cell function3,4

• Decreased blood pressure7

• Decreased plasma volume6,8

• Increased hematocrit6

Approximately reabsorbs 90% filtered glucose

S1

SGLT2

Glucose filtration(approximately 180g/day)

SGLT2 inhibitor

Altered glucose andsodium handling

Glycosuria

Urine: no glucose

Glucose Glucose

1Na+

Lumen Interstitium

GLUT2

SGLT2

• Decreased glucose and sodium reabsorption1,2

• Increased delivery of sodium to the distal tubule1

• Decreased body weight5,6

• Decreased fat mass5,6

• Increased insulin sensitivity7

SGLT2 inhibitors are not indicated for weight loss or hypertension.1. FARXIGA® (dapagliflozin) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; October 2019. 2. Eickhoff MK, et al. J Clin Med. 2019;8(6);E779. 3. Merovci A, et al. J Clin Endocrinol Metab. 2015;100(5):1927‐1932. 4. Kaneto H, et al. J Diabetes. 2017;9(3):219‐225. 5. Bolinder J, et al. J Clin Endocrinol Metab. 2012;97(3):1020‐10311. 6. Heerspink HJL, et al. Kidney Int. 2018;94(1):26‐39. 7. Kalra S, et al. Indian J Endocrinol Metab. 2017;21(1):210‐230. 8. Lambers Heerspink HJL, et al. Diabetes Obes Metab. 2013;15(9):853‐862. 9. Verma S, et al. JACC Basic Transl Sci. 2018; 3(5):575‐587. 10. Tamargo J. Eur Cardiol. 2019;14(1):23‐32. 11. Lee TM, et al. Free Radical Biol Med. 2017;104:298‐310.

Do SGLT2 Inhibitors Offer Benefits in the Treatment of Patients with HFrEF?1‐5

aBased on the Chronic Kidney Disease‐Epidemiology Collaboration Equation. b≥20 years in Japan.

1. McMurray JJV et al. On behalf of the DAPA‐HF Committees and Investigators. Eur J Heart Fail. 2019:21:665‐675. 2. Packer M et al. On behalf of the EMPEROR‐Reduced Trial Committees and Investigators. Eur J Heart Fail.2019;21:1270‐1278. 3. Press release, Boehringer Ingelheim. https://www.boehringer‐ingelheim.com. Accessed August 1, 2020. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03521934. Accessed May 3, 2019. 5. Press release, Lexicon Pharmaceuticals, March 19, 2020. https://www.globenewswire.com. Accessed March 20, 2020

DAPA‐HF1 (Dapagliflozin)

Study size, n 4,744 (actual)

Key inclusion criteria: general

Age ≥18 years eGFRa ≥30 mL/min/1.73 m2

Key inclusion criteria: HF status

NYHA class II‐IV ≥2 mo LVEF ≤40% within last 12 mo Elevated NT‐proBNP Optimized/stable HF therapy ≥4 wk

Key inclusion criteria: glycemic status

With or without T2D

Key exclusion criteria T1D MI, UA, stroke, TIA, or CV procedure/surgery within 12 wk

Acute decompensated HF SBP <95 mm Hg or symptomatic hypotension Recent treatment/intolerance to SGLT2 inhibitor

Primary endpoint Time to first occurrence of any component of the composite of a worsening HF event (hHF or urgent HF visit) or CV death

Completion Date July 17, 2019 (actual) – positive TLR, ESC 2019

EMPEROR‐Reduced2 (Empagliflozin) SOLOIST‐WHF3 (Sotagliflozin)

3,730 (actual) 4,000 (planned)

Age ≥18 yearsb

eGFRa ≥20 mL/min/1.73 m2

Age ≥18 years and ≤85 years eGFR ≥30 mL/min/1.73 m2

NYHA class II‐IV LVEF ≤40% Elevated NT‐proBNP Therapy for HF, stable for ≥1 wk

HF diagnosis >3 mo (LVEF not specifiedc) Worsening HF: hHF or urgent HF visit Elevated NT‐proBNP Prior loop diuretic for HF >30 d Patients with LVEF <40% should be on beta‐blocker or RAAS inhibitor

With or without T1D or T2D T2D

MI, CABG, other major CV surgery, stroke, or TIA within 90 d

Acute decompensated HF SBP ≥180 or <100 mm Hg or symptomatic hypotension

CV procedure/surgery within 1 mo ACS or stroke within 3 mo End‐stage HF

Time to first occurrence of any component of the composite of CV death or hHF

Time to first occurrence of CV death or hHF in patients with LVEF <50%

Time to first occurrence of CV death or hHF in all patients

July 2020 (actual) – positive TLR, ESC 2020 January 2021 (TBD, AHA 2020) – closed early



aCV and renal development program; bWorsening HF includes hHF or urgent HF visit; cNominal p‐value.1. AstraZeneca Pharmaceuticals LP press release. Published August 20, 2019

DAPA ACT HF17 DELIVER18 DAPA-MI19 DETERMINE20,21

More data to come in various types of HF trials…….

First and Largest SGLT2 Inhibitor HFrEF Trial to Successfully Improve Outcomes and Symptoms2,5

N=4744

DAPA-HF Overview5

55%No T2D

45%T2D

1:1

Do

ub

le-b

lin

d

Inclusion Criteria: ≥18 years with or without T2D, LVEF ≤40%, NYHA class II-IV, elevated NT-proBNP,

eGFR ≥30 mL/min/1.73 m2, stable SoC HFrEF treatment

DAPA 10 mgn=2373

Placebon=2371

Significant Reduction in Compositeof CV Death or Worsening HF5,b

26% RRRHR 0.74 (0.65-0.85)

p<0.001

NNT=21

CV Death6

18% RRRp=0.029

hHF6

30% RRRp=0.00003[Includes urgent HF visits]

DAPA-HF Safety5,7

DAPA was well-tolerated in patients with and without T2D Adverse events rarely led to discontinuation of treatment

No events of major hypoglycemia or DKA in patients without T2D

Risk of both first and recurrent hHF events13

HF symptom improvement more common and deteriorationless common14

Significantly reduced riskof CV death or worsening

HFb as early as15

Dapagliflozin is the only SGLT2 inhibitor approved for HFrEF16

Day 28

Consistent Benefit Across a Broad and Representative Population

T2D/No T2D7

Background HF therapy8

Diuretic use and dose9

Baseline LVEF10

NT‐proBNP11

eGFR12

Reduction in all‐cause mortality(p=0.022c)6

aChronic dialysis or renal transplantation or a profound, sustained reduction in the eGFR.

CV = cardiovascular; DKA = diabetic ketoacidosis; eGFR = estimated glomerular filtration rate; EMPA = empagliflozin; HF = heart failure; hHF = hospitalization for heart failure; HR = hazard ratio; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; NNT = number needed to treat; NT‐proBNP = N‐terminal pro‐brain natriuretic peptide; NYHA = New York Heart Association; RRR = relative risk reduction; SGLT2 = sodium‐glucose cotransporter 2; SoC = standard of care; T2D = type 2 diabetes.

1. Packer M et al. N Engl J Med. 2020;383(15):1413‐1424. 2. Study NCT03057977. ClinicalTrials.gov website.

Second SGLT2 Inhibitor HFrEF Trial to Successfully Improve Outcomes and Symptoms – Class Effect?1,2

N=3,730

EMPEROR-REDUCED Overview

50.2%No T2D

49.8%T2D

1:1

Do

ub

le-b

lin

d

Inclusion Criteria: ≥18 years of age, with or without diabetes who had chronic HFrEF with LVEF ≤40%

(NYHA class II–IV) for ≥3 months, Elevated NT-proBNP, Stable SoC HFrEF treatment

EMPAn=1,863

Placebon=1,867

Significant Reduction in Compositeof CV Death or First hHF

25% RRRHR 0.75 (0.65–0.86)

P<0.001

NNT=19

CV Death8% RRR

First hHF31% RRR

EMPEROR-Reduced SafetyEMPA is well-tolerated in patients with and without T2D

No events of major hypoglycemia or DKA in patients without T2D

Risk of both first and recurrent hHF eventsHR = 0.70 (0.58–0.85)

HF symptom improvement more common and deteriorationless common

Significantly reduced riskof composite renal endpointa

HR 0.50 (0.32–0.77)

Consistent Benefit Across a Broad and Representative Population

T2D/No T2D

Background HF therapy

eGFR

NT‐proBNP

Reduction in all-cause mortalityHR 0.92 (0.77–1.10)



Meta‐Analysis of DAPA‐HF and EMPEROR‐Reduced

Adapted from Zannad F, et al. Lancet. 2020.

HR (95% CI)

SGLT2 inhibitor

Number with event/number of patients (%)

Placebo

EMPEROR‐Reduced 0.92 (0.77–1.10)266/1867 (14.2%)

DAPA‐HF 276/2373 (11.6%) 329/2371 (13.9%)0.87 (0.77–0.98)

Test for overall treatment effect p=0.018Test for heterogeneity of effect p=0.39

All‐cause mortality

HR (95% CI)

SGLT2 inhibitor

Number with event/number of patients (%)

Placebo

EMPEROR‐Reduced

DAPA‐HF

Test for overall treatment effect p=0.027Test for heterogeneity of effect p=0.40

Cardiovascular death

0.92 (0.75–1.12)187/1863 (10.0%) 202/1867 (10.8%)

0.82 (0.69–0.98)273/2371 (11.5%)

0.86 (0.76–0.98)

Total

Total

0.25 0.50 0.75 1.00 1.25

0.25 0.50 0.75 1.00 1.25

249/1863 (13.4%)

227/2373 (9.6%)

0.83 (0.71–0.97)

Positive HFrEF Trials 2001 and beyond:SGLT2 inhibitors are now a pillar in HFrEF treatment

*Angiotensin receptor blocker (ARB); **Implantable cardloverter defibrillator/cardiac resynchronization therapy (lCD/CRT).

McMurray JJ. Eur J Heart. 2015; ClinicalTrials.gove.

COMET

CHARM‐Alt

CHARM‐Add

SENIORS AC‐CHF1

HF‐ACTION2

SHIFT

EMPHASIS‐HF

PARADIGM‐HF

DAPA‐HF

EMPEROR

Val‐HeFT A‐HeFT HEAAL

REMATCH COMPANION

SCD‐HeFT

CARE‐HF

MADIT‐CRT

Heart Mate II

RAFT

STICH

1. Rate vs. rhythm control in atrial fibrillation (AF)

2. Exercise prescription

Head‐to‐head comparison

Dose‐response studySGC stimulator

H‐ISDN

MRA

Beta‐blocker

Surgery

ARNI

SGLT2 inhibitor

ARB*

lvabradine

lCD/CRT**

LEGEND:

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2019 2020

VICTORIA



Which of the following SGLT2 inhibitors has been shown to improve overall mortality in HFrEF patients independent of diabetes?

a. Canagliflozin

b. Dapagliflozin

c. Empagliflozin

d. Sotagliflozin

SGLT2 Inhibitors and CKD



Long‐Term Progression of Kidney Disease in Patients with T2D1,2

*The UKPDS enrolled patients with newly diagnosed T2D; †Defined as a urinary albumin concentration 50–299 mg/L; ‡Defined as a urinary albumin concentration ≥ 300 mg/L §Defined as urinary albumin concentration ≥ 50 mg/L.

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes

1. Adler A et al. Kidney Int. 2003;63(1):225–32; 2. Retnakaran R et al. Diabetes. 2006;55(6):1832–9.

A substantial proportion of patients with T2D will develop albuminuria and renal impairment

United Kingdom Prospective Diabetes Study (UKPDS)1

5102 patients with T2D*

15 years after diagnosis2

Developed albuminuria§

Developed eGFR < 60 mL/min/1.73 m2

(CKD stage 3–5)

Albuminuria

Normoalbuminuria Microalbuminuria† Macroalbuminuria‡

Progressed from normo‐ to micro‐ albuminuria per year 2%

2.8%Progressed from micro‐to macro‐ albuminuria

per year

28%

38%

Reduce Glomerular Pressure1

↑Afferent vasoconstric on↓Glomerular hyperfiltra on

Neurohormonal Improvement↓Intrarenal RAAS ac vity3

↓SNS ac vity4

Potential Effects by which SGLT2 Inhibition Improves Renal Outcomes

Preserved Renal Function2

Protection Against Diabetic

Nephropathy1,2

↓Tubular/Glomerular Injury1,2

↓Albuminuria

↓Blood Pressure1

Stabilization of eGFR2

↓Renal Ischemic Injury1

↑Hb/hematocrit2

Inflammation/Fibrosis Reductions1,2

↓Inflammatory markers↓Fibro c markers

Decreased Renal Workload and Hypoxia1,2

↓Solute transport↓Oxygen demand

SGLT2 INHIBITION

O2

CLINICAL EFFECTS

eGFR =estimated glomerular filtration rate; Hb =hemoglobin; RAAS = renin angiotensin aldosterone system; SGLT2 = sodium‐glucose cotransporter 2; SNS = sympathetic nervous system 1. Heerspink HJL, et al. Kidney Int. 2018;94(1):26‐39. 2. Tamargo J. Eur Cardiol. 2019;14(1):23‐32. 3. Shin SJ, et al. PLoS One. 2016;11:e0165703. 4. Sano M. J Cardiol. 2018;71(5):471‐476.



Meta‐Analyses of T2D Treatments in the U.S.: Kidney Outcomes by ASCVD Status

Treatment Placebo

No./total No.

Rate/1000patient‐years

No./total No.

Rate/1000patient‐years

Hazard ratio(95% CI)

Favorstreatment

Favorsplacebo

Weight, %

Patients with ASCVD

EMPA‐REG OUTCOME* 81/4645 6.3 71/2323 11.5 0.54 (0.40‐0.75) 16.67

CANVAS program NA/3756 6.4 NA/2900 10.5 0.59 (0.44‐0.79) 19.23

DECLARE‐TIMI 58 65/3474 4.7 118/3500 8.6 0.55 (0.41‐0.75) 18.06

CREDENCE 69/1113 24.1 102/1107 36.5 0.64 (0.47‐0.87) 17.37

VERTIS CV 175/5499 9.3 108/2747 11.5 0.81 (0.64‐1.03) 28.66

Fixed‐effects model (Q = 6.09; df = 4; P = .19; I2 = 34.4%) 0.64 (0.56‐0.72)

Patients without ASCVD

CANVAS program NA/2039 4.1 NA/1447 6.6 0.63 (0.39‐1.02) 15.72

DECLARE‐TIMI 58 62/5108 3.0 120/5078 5.9 0.51 (0.37‐0.69) 37.41

CREDENCE 84/1089 29.9 122/1092 44.3 0.68 (0.51‐0.89) 46.87

Fixed‐effects model (Q = 1.86; df = 2; P = .40; I2 = 0.0%) 0.60 (0.50‐0.73)

210.2

HR (95% CI)

ASCVD = atherosclerotic cardiovascular disease; CANVAS = Canagliflozin Cardiovascular Assessment Study; CREDENCE = Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; DECLARE‐TIMI 58 = Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA‐REG OUTCOME = Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Patients; NA = not available; VERTIS CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Participants With Vascular Disease.

Adapted from McGuire DK, et al. JAMA Cardilogy. 2020; doi:10.1001/jamacardio.2020.4511

Key Renal Outcome Trials: Do SGLT2 Inhibitors Offer Benefit in Patients with CKD?

ACEi = Angiotensin‐converting‐enzyme inhibitors; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; CV = cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; ESKD = end stage kidney disease; hHF = hospitalization for heart failure; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium‐glucose cotransporter 2; T2D = type 2 diabetes; UA = urinary albumin; UACR = urine albumin to creatinine ratio.

1. Perkovic V et al. N Engl J Med. 2019;380:2295‐2306. 2. Study NCT02540993. ClinicalTrials.gov website. 3. Bakris GL et al. Am J Nephrol. 2019;50:333‐344. 4. Heerspink H et al. N Engl J Med. 2020; 383:1436‐1446. 5. Study NCT03594110. ClinicalTrials.gov website.

SGLT2 Inhibitors MRA

CREDENCE1

N = 4401DAPA‐CKD4

N = 4304EMPA‐KIDNEY5

N ~ 6000FIDELIO‐DKD2,3

N = 5734

StatusCompleted

October 2018

Stopped early due to overwhelming efficacy

in March 2020 (presented at ESC 2020)

OngoingEst. Completion Date

June 2022

CompletedApril 2020

InterventionCanagliflozin vs Placebo

≥4 weeks stable on ACEi or ARBDapagliflozin vs Placebo

≥4 weeks stable on ACEi or ARBEmpagliflozin vs Placebo

On ACEi or ARBFinerenone vs Placebo≥4 weeks on ACEi or ARB

Patient Population

• T2D• eGFR ≥30 to <90 mL/min/1.73 m2

• UACR >300 to ≤5000 mg/g

• T2D and non‐DM• eGFR ≥25 to ≤75 mL/min/1.73 m2

• UACR ≥200 to ≤5000 mg/g

• T2D and non‐DM• eGFR ≥20 to <45 mL/min/1.73 m2

or ≥45 to <90 mL/min/1.73m2 and UACR ≥200 mg/g

• T2D• eGFR ≥25 to <60 mL/min/1.73 m2 and UACR ≥ 30 to <300 mg/g and presence of diabetic retinopathy or eGFR ≥25 to <75 mL/min/1.73m2 and UACR ≥300 mg/g

Primary Endpoint

Composite• Doubling of serum creatinine• ESKD• Renal or CV death

Composite• ≥50% sustained eGFR decline• ESKD• Renal or CV death

Composite• Kidney failure• ≥40% sustained eGFR decline• Renal death

Composite• Kidney failure• ≥40% sustained eGFR decline• Renal death

Secondary Endpoints

• CV death or hHF• CV death, MI, or stroke• hHF• Renal composite• CV death• All‐cause death• Composite of CV death, MI, stroke, hHF or hospitalization for UA

• Renal composite• CV death or hHF• All‐cause death

• CV death or hHF• All‐cause hospitalizations• All‐cause death• Kidney disease progression• CV death• CV death or ESKD

• Stroke or hHF • All‐cause death• All‐cause hospitalizations• ≥57% sustained eGFR decline, kidney failure or renal death

• UACR change from baseline



aEnd-stage kidney disease, doubling of serum creatinine level, or renal death. 1. Perkovic V, et al. N Engl J Med. 2019 Jun 13;380(24):2295-2306. Epub 2019 Apr 14. 2. Study NCT02065791. ClinicalTrials.gov website.

Baseline Characteristics

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy1,2

Significant reduction in composite of ESKD, doubling of serum Cr, renal or CV death

SafetyFractures:

HR 0.98 (0.70-1.37)

Amputation: HR 1.11 (0.79-1.56)

CREDENCE Overview

33% Female

100% Type 2 diabetes

Mean eGFR 56mL/min/1.73 m2

Median UACR

927 mg/g

Mean age 63 yearsCanagliflozin

100 mg once daily

Placebo once dailyN=4,401

randomized

Median follow-up: 2.62 years

Patients:• ≥18 years of age • T2D with HbA1c ≥ 6.5%

and ≤12% with eGFR 30 to 90 mL/min/1.73 m2

• UACR 300 to 5000 mg/g• Stable maximum tolerated

dose of ACEi or ARB for ≥4 weeks

Key Exclusion Criteria: History of DKA or T1D, history of hereditary glucose-galactose malabsorption or primary renal glucosuria, treatment with immunosuppressive therapy, liver disease, NYHA Class IV HF, K+ > 5.5 mmol/L

34% RRRIn renal specific outcomea

HR 0.66 (0.53-0.81; P<0.001

31% RRRIn CV or hHF failure

HR 0.69 (0.57-0.83); P<0.001

17% RRRin all-cause mortalityHR 0.83 (0.68-1.02)

Canagliflozin 100 mgn=2202

Placebon=2199

HR (CI)

CREDENCE

30% RRR

4.3% ARRNNT=23

Serious AE due to trial drug 62 (2.8%) 42 (1.9%)1.45

(0.98‐2.14)

Any SAE 737 (34%) 806 (3.7%)0.87

(0.79‐0.97)

Any AE 1784 (81%) 1860 (85%)0.87

(0.82‐0.93)

Diabetic ketoacidosis 11 (0.5%) 1 (<0.1%)10.80

(1.39‐83.65)

Acute Kidney Injury 86 (3.9%) 98 (4.5%)0.85

(0.64‐1.13)

Hyperkalemia 151 (6.9%) 181 (8.2%)0.80

(0.65‐1.00)

Baseline Characteristics1,2

Significant reduction in composite of sustained

≥50% eGFR decline, ESKD, renal or CV death1

Safety1,a

Dapagliflozin was well tolerated, in keeping with

its established safety profile

Very few events of major hypoglycemia or DKA

aSafety outcomes reported in participants on and off treatment; bSurgical or spontaneous/non‐surgical amputation, excluding amputation due to trauma; cBased on pre‐defined list of preferred terms; dAE with the following criteria confirmed by the investigator: i) symptoms of severe impairment in consciousness or behavior, ii) need of external assistance, iii) intervention to treat hypoglycemia, iv) prompt recovery of acute symptoms following the intervention.1. Heerspink HJL et al. Online ahead of print. N Engl J Med. 2020; 2. Wheeler DC, et al. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020. 3. AstraZeneca Pharmaceuticals LP press release; 4. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 ‐ September 1, 2020.

DAPA-CKD Overview1

36% RRR in patients with T2D HR 0.64 (0.52, 0.79)

33% Female

68% Type 2 diabetes

Mean eGFR 43mL/min/1.73 m2

Median UACR

949 mg/g

Mean age 62 yearsDapagliflozin

10 mg once daily

Placebo once dailyN=4,304

randomized


Patients:• ≥18 years of age • eGFR 25 to 75

mL/min/1.73 m2

• UACR 200 to 5000 mg/g• Stable maximum tolerated

dose of ACEi or ARB for ≥4 weeks

Key Exclusion Criteria: T1D, polycystic kidney disease, lupus nephritis, ANCA-associated vasculitis, immunosuppressive therapy ≤6 months prior to enrollment

44% RRRin composite outcome of sustained

≥50% eGFR decline, ESKD or renal death4.7% ARR; HR 0.56 (0.45, 0.68); P=0.0000000184

29% RRRin CV death or hHF

1.8% ARR;HR 0.71 (0.55, 0.92); P=0.00894

31% RRRin all-cause mortality

2.1% ARR;HR 0.69 (0.53, 0.88); P=0.00354

39% RRR

Dapagliflozin 10 mgn=2149

Placebon=2149

p-value

Discontinuation of study drug 274 (12.7%) 309 (14.4%) ‐

Discontinuation due to AE 118 (5.5%) 123 (5.7%) 0.79

Any SAE 633 (29.5%) 729 (33.9%) 0.002

Amputationb 35 (1.6%) 39 (1.8%) 0.73

Diabetic ketoacidosis 0 (0.0%) 2 (<0.1%) 0.50

Fracturec 85 (4.0%) 69 (3.2%) 0.22

Renal related adverse eventc 155 (7.2%) 188 (8.7%) 0.07

Major hypoglycemiad 14 (0.7%) 28 (1.3%) 0.04

Volume depletionc 127 (5.9%) 90 (4.2%) 0.01

SAE of volume depletion4 22 (1.0%) 18 (0.8%) ‐

50% RRR in patients without T2D HR 0.50 (0.35, 0.72)

p-value interaction=0.244

5.3% ARRNNT=19

The first trial with a SGLT2 inhibitor to demonstrate an improvement in cardiorenal outcomes and reduce mortality in patients with CKD with or without T2D1‐5

2152 2001 1955 1898 1841 1701 1288 831 309DAPA 10 mg2152 1993 1936 1858 1791 1664 1232 774 270Placebo

Placebo312 events

4

8

12

16

20

24

0

0 4 8 12 16 20 24 28 32Months from Randomization

Cu

mu

lat i

ve

Inc

iden

ce%

N at Risk

DAPA9.2%

Placebo14.5%

HR (95% CI)0.61 (0.51-0.72)

p-value4

0.000000028

DAPA 10 mg 197 events



EMPA‐KIDNEY: The Study of Heart and Kidney Protection with Empagliflozin


Placebo

Empagliflozin 10 mg daily

1:1

Do

ub

le-b

lind

6000 patients• ≥18 years of age• Evidence of CKD at risk of progression

defined by CKD-EPI eGFR ≥20 to <45 mL/min/1.73 m² OR CKD-EPI eGFR ≥45 to <90 mL/min/1.73 m² with UACR ≥200 mg/g

• Clinically appropriate doses of ACEi/ARB unless not tolerant to treatment

Secondary Endpoints• Time to first hHF or CV death • Time to occurrences of all-cause hospitalizations (first and recurrent

combined) • Time to death from any cause • Time to first occurrence of kidney disease progression • Time to CV death • Time to CV or ESKD

Primary Endpoint• Composite: Time to first occurrence

of kidney disease progressiona or CV death

*Defined as ESKD, a sustained decline in eGFR to <10 mL/min/1.73 m², renal death, or a sustained decline of ≥40% in eGFR from randomization.Study NCT03594110. ClinicalTrials.gov website

All of the following statements regarding the impact of SGLT2 inhibitors on renal function are true EXCEPT

a. Consistently reduce composite worsening nephropathy risk in diabetes by ≥24%

b. Initially decrease eGFR, but delay overall progression of diabetic nephropathy

c. Contraindicated if eGFR <30 mL/min/1.73 m2 for safety concerns

d. Improve cardiorenal outcomes in patients with and without type 2 diabetes



SGLT2 Inhibitors: A Look Ahead

Phase 3 Mortality/Morbidity Trials with SGLT2 Inhibitors in HFpEF

1. ClinicalTrials.gov. Identifier: NCT03057951; 2. ClinicalTrials.gov. Identifier: NCT03619213

Both trials include patients with and without T2D

Hypothesis Empagliflozin will be superior to placebo, added to background therapy, in patients with symptomatic chronic HFpEF (patients with and without diabetes)

Population 5987 patients; symptomatic HF; EF >40%; NT pro BNP >300 pg/mL (>900 pg/mL for patients with AF); structural heart disease or HF hospitalization in prior 12 months.

Primary Endpoint CV death or HF hospitalization

EMPEROR‐Preserved1 DELIVER2

Hypothesis Dapagliflozin will be superior to placebo, added tobackground therapy, in patients with symptomatic chronic HFpEF (patients with and without diabetes)

Population 6100 patients; symptomatic HF: outpatient or inpatient/ recently discharged; EF >40%; structural heart disease; NT‐proBNP ≥300 pg/L; eGFR ≥30 mL/min/1.73 m2; SBP ≥95 mmHg

Primary Endpoint CV death or worsening HF event



SGTL2 Inhibitor Being Formally Evaluated Among Patients After Myocardial Infarction (MI)

DAPA‐MI Dapagliflozin effects in patients without diabetes with Myocardial Infarction

• Dapagliflozin vs. placebo

– Risk reduction for hHF and CV‐related death post‐MI

• Acute MI without T2D

• N ~6,400; 100 sites in Sweden and UK

• Two national CV disease quality registries

• Global, multicenter, double‐blind, registry‐based RCT

EMPACT‐MIEmpagliflozin for the prevention of chronic heart failure and mortality after an acute Myocardial Infarction

• Empagliflozin vs. placebo

• Acute MI

• N ~3,300; >16 countries

ClinicalTrials.gov

Summary

↓CV outcomes

↓HF hospitaliza onStabilization of eGFR

↓Albuminuria

IMPROVED CLINICAL OUTCOMES3,5

CIRCULATION1,2

↓Plasma volume

↓Arterial s ffness

↓Systolic blood pressure

↑Hematocrit

HEART2

↓Glucose/sodium reabsorp on1

↓Intraglomerular pressure2

↓Intrarenal RAAS ac vity4

↓Hyperfiltra on2

↓Inflamma on/hypoxia3

↓Cardiac preload/a erload

↓Cardiac wall stress

↑Cardiac efficiency/output

KIDNEY

CARDIORENAL PROTECTION2,3

↑Cardiac func on

↑Renal func on

Glycosuria2

Diuresis3

Natriuresis2,3

SGLT2 INHIBITION

1. Sattar N et al. Diabetologia. 2016;59(7):1333‐1339. 2. Verma S et al. JAMA Cardiol. 2017;2(9):939‐940. 3. Scheen RJ. Circ Res. 2018;122:1439‐1459. 4. Shin SJ et al. PLoS One. 2016;11:e0165703. 5. Tamargo J. Eur Cardiol. 2019;14(1):23‐32.

SGLT2 Inhibitors Are a Dynamic and Evolving Therapeutic Option for Cardiorenal Protection


SGLT2 Inhibitors: A Dynamic and Evolving Therapeutic Option · SGLT2 inhibitors are not indicated...

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