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Disclaimer

1

2

Jarett Berry, MDPreventive Cardiologist

Clinical Heart and Vascular CenterUT Southwestern Medical Center

Special Thanks!

Presented by

Supported by an independent educational grant from AstraZeneca

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Diabetes Is a Major Global Threat

2017

2045

451MILLION

693MILLION

8.4% of global population

9.9% of global population

Deaths Due to Diabetes (18–99 years) in 2017

Growing Global Prevalence of Diabetes

Diabetes cost ~$850 billion (USD) in global healthcare spending in 2017

~5 million deaths

$

USD, United States dollar. Cho NH, et al. Diabetes Res Clin Pract. 2018.

T2D Doubles the Risk for Macrovascular Outcomes Meta-analysis of 102 Prospective Studies

Number

of Cases

26,505

11,556

14,741

3,799

1,183

4,973

3,826

HR (95% CI)

2.00 (1.83–2.19)

2.31 (2.05–2.60)

1.82 (1.64–2.03)

2.27 (1.95–2.65)

1.56 (1.19–2.05)

1.84 (1.59–2.13)

1.73 (1.51–1.98)

1 2 4

Coronary heart disease

Coronary death

Nonfatal MI

Stroke subtypes

Ischemic stroke

Hemorrhagic stroke

Unclassified stroke

Other vascular deaths

CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Emerging Risk Factors Collaboration, et al. Lancet. 2010.

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8

n=271,174 T2D Patients vs >1 Million Matched Controls

Core Risk Factor Control

✓ Elevated HbA1c

✓ Elevated LDL-c

✓Albuminuria

✓ Smoking

✓ Elevated blood pressure

Acute MI

Mortality

HF

No Excess Risk among Patients with 5 RF Control

Residual Risk despite 5 RF Control

Swedish National Diabetes Registry

HbA1c, glycated hemoglobin; LDL-c, low density lipoprotein-cholesterol; RF, risk factor. Rawshani A, et al. N Engl J Med. 2018.

The Resurgence of Complications among Younger and Middle-aged Adults with T2D

Acute MI Stroke Lower-extremity amputation Hyperglycemia End-stage kidney disease

1995 2000 2005 2010 2015

Year

0

20

40

100

300

500

Even

ts p

er 1

0,00

0 w

ith

d

iab

etes

per

yea

r

Aged 18–44 years

1995 2000 2005 2010 2015

Year

0

40

80

120

160

200

Aged 45–64 years

1995 2000 2005 2010 2015

Year

0

40

80

200

300

400

Aged ≥65 years

120

U.S. Centers for Disease Control and Prevention, 1995–2015

Gregg EW, et al. JAMA. 2019.

9

10

Glynn P, et al. J Am Coll Cardiol. 2019.

Rise in HF-related Mortality Observed in the United States

HF

T2D

ASCVD

CKD

T2D, HF, ASCVD, and CKD Are Interrelated

76.4%of patients with

CVD and T2D have CKD4

35%–45% of patients with

HF have T2D1~35%

of patients with T2D will develop CKD2

14% of the U.S.

population has diabetes3

32% of patients with CAD have T2D5

1Packer M. Diabetes Care. 2018; 2Wanner C, et al. N Engl J Med. 2016; 3Mendola ND, et al. NCHS Data Brief. 2019;

4Wang T, et al. Diabetes Metab Syndr. 2019; 5Einarson TR, et al. Cardiovasc Diabetol. 2018.

ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CKD, chronic kidney disease; CVD, cardiovascular disease.

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12

Vaduganathan M, et al. JACC Heart Fail. 2020.

HF Prevention Is a Key Therapeutic Goal

T2D + HFrEF face especially high short-term risks of mortality or HF hospitalization.

DM, diabetes mellitus; HFrEF, heart failure with reduced ejection fraction.

Vaduganathan M, et al. J Am Coll Cardiol. 2019.

Clinically Meaningful Difference~5 points KCCQ-OS

HF Prevention Is a Key Therapeutic Goal

T2D + HFrEF Face Adverse QOL

KCCQ-OS, Kansas City Cardiomyopathy Questionnaire-overall summary; QOL, quality of life.

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Sumarsono A, et al. JAMA Intern Med. 2019.

Shifting Landscape of T2D Therapeutics

New Therapeutic Options with Accelerating Uptake

A Decade Later

Suggested 3-point MACE ± Hosp for ACS/Revascularization; non-inferiority vs superiority; trials should include high-risk patients (established CVD or multiple CVD risk factors)

2008 FDA Guidance and the Focus on Atherosclerotic CV Events

Guidance for IndustrySponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all phase 2 and phase 3 trials. These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other endpoints.

FDA Guidance Document. 2008. Available at: https://www.fda.gov/media/71297/download.

ACS, acute coronary syndrome; FDA, Food and Drug Administration; MACE, major adverse cardiovascular event.

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>20 CV Outcomes Trials Encompassing >150,000 Patients

0

5

10

15

20

25

30

35

40

0

20

40

60

80

100

120

140

160

180

200

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Cu

mu

lative # o

f CV

OTs

Cu

mu

lati

ve #

of

Pat

ien

ts E

nro

lled

Acr

oss

C

VO

Ts (

tho

usa

nd

s)

Cumulative # of patients enrolled in CVOTs

Vaduganathan M, et al. Am J Cardiol. 2019.

Cumulative # of CVOTs

Expanding Cardiovascular Safety Programs in T2D

Adapted from Vijayakumar S, et al. Circulation. 2018.DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPAR-γ, peroxisome proliferator-activated receptor gamma.

α-glucosidase inhibitors

Dopamine agonists

DPP-4 inhibitors

Glinides

GLP-1 receptor agonists

Insulin

PPARγ modulators

SGLT2 inhibitors

Spectrum of CV Risk of Target Populations

2020

2018

2016

2014

2012

2010

2008

2006

2004

2002

No Specific CV Risk

Enrichment

Established CV Disease or At High

CV Risk

Recent Acute Coronary Syndrome

Established Heart Failure

Year

of

Tria

l Pu

blic

atio

n

CyclosetSafety TrialRECORD

ELIXA

EXAMINE

PROactive

EXSCELDEVOTE

ACEDECLARE-TIMI 58

CANVASLEADER

SUSTAIN 6EMPA-REG OUTCOME

TECOS

SAVOR-TIMI 53

ORIGIN

NAVIGATOR

DAPA-HF

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Turnbull FM, et al. Diabetologia. 2009.

Intensive Glycemic Control Inconsistent, Neutral Effect on HF

Number of events (yearly rate, %)ΔHbA1c (%) HR (95% CI)

More intensive Less intensive

Admission to hospital/fatal HF

ACCORD 152 (0.90) 124 (0.75) -1.01 1.18 (0.93, 1.49)

ADVANCE 220 (0.83) 231 (0.88) -0.72 0.95 (0.79, 1.14)

UKPDS 8 (0.06) 6 (0.11) -0.66 0.55 (0.19, 1.60)

VADT 79 (1.80) 85 (1.94) -1.16 0.92 (0.68, 1.25)

Overall 459 446 -0.88 1.00 (0.86, 1.16)

0.5 1.0 2.0

Favours more intensive control Favours less intensive control

Drug-specific HF Risks with DPP-4i

StudyStudy drug

n/N (%)Placebon/N (%)

HR(95% CI)

P-value

SAVOR-TIMI 53(saxagliptin)

289/8280(3.5%)

228/8212(2.8%)

1.27(1.07, 1.51)

0.009

EXAMINE(alogliptin)

106/2701(3.9%)

89/2679(3.3%)

1.19(0.89, 1.58)

0.238

TECOS(sitagliptin)

228/7332(3.1%)

229/7339(3.1%)

1.00(0.83, 1.20)

0.983

CARMELINA(linagliptin)

209/3494(6.0%)

226/3485(6.5%)

0.90(0.74, 1.08)

0.264

0 1 2

Schernthaner G, et al. Diabetes Care. 2016; McGuire DK, et al. Circulation. 2019.

Hospitalization for Heart Failure (hHF)

Favors treatment Favors placebo

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U.S. Food and Drug Administration

Saxagliptin and AlogliptinFDA guidance: May increase the risk of heart failure, particularly in patients who already have heart or kidney disease (4/5/2016).

Sitagliptin and Linagliptin

Consider the risks and benefits prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and renal impairment (8/10/2017).

FDA.gov; FDA Prescribing Information.FDA, Food and Drug Administration.

Neutral Effects of GLP-1RA on HF Risk

Trial (agent)

Hospitalization for Heart Failure

P-valueHR

(95% CI)Treatment Incidence (%)

Placebo Incidence (%)

ELIXA (lixisenatide)

122 (4.0) 127 (4.2) 0.75 0.96 (0.75–1.23)

LEADER (liraglutide)

218 (4.7) 248 (5.3) 0.14 0.87 (0.73–1.05)

SUSTAIN-6 (semaglutide)

59 (3.6) 54 (3.3) 0.57 1.11 (0.77–1.61)

EXSCEL (exenatide)

219 (3.0) 231 (3.1) NR 0.94 (0.78–1.13)

Pfeffer M, et al. N Engl J Med. 2015; Marso S, et al. N Engl J Med. 2016; Marso S, et al. N Engl J Med. 2016; Holman RR, et al. N Engl J Med. 2017.RA, receptor agonist.

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The “–flozins”Four FDA-approved SGLT2is

Canagliflozin

March 2013

Dapagliflozin

January 2014

Empagliflozin

August 2014

Ertugliflozin

December 2017

FDA Prescribing Information.

Vaduganathan M, Butler J. Nat Med. 2019.

From Apple Trees to HF The Discovery and Study of SGLT2i

1835 2008 2013 2014 2015 2016 2017 2018

T2D with or at high risk for ASCVD

French scientists isolate phlorizin

in apple tree bark

Regulatory guidance to

industry requiring CVOTs

FDA approval of first SGLT2

inhibitor for diabetes

EMPA-REG OUTCOME

(empagliflozin)

CANVAS (canagliflozin)

DECLARETIMI 58

(dapagliflozin)

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SGLT2 Inhibitors Block SGLT2 and Reduce Glucose and Na+ Reabsorption

Remaining glucose is

reabsorbed by SGLT1 (10%)

Proximal tubule

Glucosefiltration

Reduced glucose and sodium reabsorption SGLT2

SGLT2

Glucose

SGLT2i

Increased urinary excretion of

excess glucoseSodium

Decreased intracellular

sodium concentration Based on this MOA,

the following occur:• Diuresis• Natriuresis• HbA1c reduction• Weight loss• SBP reduction

Butler J, et al. Euro J Heart Fail. 2017;Marsenic O. Am J Kidney Dis. 2009; Mudaliar S, et al. Diabetes Care. 2016. ATPase, adenosine triphosphatase; SBP, systolic blood pressure.

Spectrum of Efficacy of SGLT2i

Verma S, et al. Lancet. 2019.

Primary prevention populationSGLT2i prevent heart failure

and renal disease but may not reduce major adverse

cardiovascular events

Secondary prevention populationSGLT2i prevent heart failure and

renal disease, and reduce atherosclerotic events (major

adverse cardiovascular events)

Diabetes and multiple risk factors

Renal protection

Hospitalization for heart

failureDiabetes

and established

cardiovascular disease

Cardiorenal efficiency of SGLT2i

Major adverse cardiovascular

events

Protection against ESRD, hHF, and Major Adverse CV Events

ESRD, end-stage renal disease; HHF, hospitalized heart failure.

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SGLT2i Afford Marked Benefits in Preventing HF Events

EMPA-REG OUTCOME

Empagliflozin1

• 9.4 vs 14.5 events/1000 PY

• HR 0.65 (0.50–0.85)

CANVAS/CANVAS-R

Canagliflozin2

• 5.5 vs 8.7 events/1000 PY

• HR 0.67 (0.52–0.87)

DECLARE-TIMI 58

Dapagliflozin3

• 6.2 vs 8.5 events/1000 PY

• HR 0.73 (0.61–0.88)

35% 33% 27%

1Zinman B, et al. N Engl J Med. 2015;2Neal B, et al. N Engl J Med. 2017; 3Wiviott SD, et al. N Engl J Med. 2019. PY, patient years.

SGLT2iSubstantial ↓ in hHF Regardless of ASCVD or HF Status

Zelniker TA, et al. Lancet. 2019.

PatientsEvents

Events per 1000 patient-years Weight

(%)HR HR (95% CI)

Treatment (n) Placebo (n) Treatment Placebo

Patients with atherosclerotic cardiovascular disease

EMPA-REG OUTCOME 4687 2333 463 19.7 30.1 30.9 0.66 (0.55–0.79)

CANVAS Program 3756 2900 524 21.0 27.4 32.8 0.77 (0.65–0.92)

DECLARE-TIMI 58 3474 3500 597 19.9 23.9 36.4 0.83 (0.71–0.98)

Fixed effects model for atherosclerotic cardiovascular disease (P<0.0001) 0.76 (0.69–0.84)

Patients with multiple risk factors

CANVAS Program 2039 1447 128 8.9 9.8 30.2 0.83 (0.58–1.19)

DECLARE-TIMI 58 5108 5078 316 7.0 8.4 69.8 0.84 (0.67–1.04)

Fixed effects model for multiple risk factors (P<0.0634) 0.84 (0.68–1.01)

0.35 0.50 1.00 2.50

Favors treatment Favors placebo

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SGLT2 inhibitors GLP-1RAs DPP-4 inhibitors

3P-MACE 14%1,2 13%–26%7–9 NS

CV death 38%1 22%7 NS

hHF 27%–35%1–3 NS NS

Hard kidney outcomes* 34%–47%3–6 NS NS

Albuminuria 27%–38%2,4 23%–36%8,10,11 14%12

CV, HF, and Kidney Outcomes across Recent CVOTs in Patients with T2D

1Zinman B, et al. N Engl J Med. 2015; 2Neal B, et al. N Engl J Med. 2017; 3Wiviott S, et al. N Engl J Med. 2019; 4Wanner C, et al. N Engl J Med. 2016; 5Perkovic V, et al. Lancet Diabetes Endocrinol. 2018;

6Perkovic V, et al. N Engl J Med. 2019; 7Marso SP, et al. N Engl J Med. 2016; 8Marso SP, et al. N Engl J Med. 2016; 9Hernandez AF, et al. Lancet. 2018; 10Mann JFE, et al. N Engl J Med. 2017; 11Gerstein HC, et al. Lancet. 2019; 12Rosenstock J, et al. JAMA. 2019.

SGLT2 InhibitionA HF Drug?

EstablishedSGLT2 inhibitors are

beneficial for preventionof hHF in patients

with T2D

Ongoing*SGLT2 inhibitors are

beneficial for treatmentof HF in patients

without T2D

HF

?

*May 5, 2020 – FDA approves dapagliflozin for reducing risk of CV death and hHF in patients with HFrEF (w/ or w/o T2D)

FDA Prescribing Information.

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30

Vaduganathan M, Butler J. Nat Med. 2019.

From Apple Trees to HF The Discovery and Study of SGLT2i

1835 2008 2013 2014 2015 2016 2017 2018 2019

T2D with or at high risk for ASCVD

HF with or without diabetes

French scientists isolate phlorizin

in apple tree bark

Regulatory guidance to

industry requiring CVOTs

FDA approval of first SGLT2

inhibitor for diabetes

EMPA-REG OUTCOME

(empagliflozin)

CANVAS (canagliflozin)

DAPA-HF(dapagliflozin)

DECLARETIMI 58

(dapagliflozin)

McMurray JJV, et al. N Engl J Med. 2019.

Inclusion criteria: patients with symptomatic HF; LVEF ≤40% NT-proBNP ≥600 pg/mL (if hospitalized for HF within last 12 months

≥400 pg/mL; if atrial fibrillation/flutter ≥900 pg/mL

4,744patients

Placebo(n=2,371)

Dapagliflozin10 mg daily(n=2,373)

Objective: To evaluate dapagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) compared with placebo among patients with heart failure and a reduced ejection fraction (HFrEF).

VS

DAPA-HF TrialDapagliflozin in Patients with Heart Failure

and Reduced Ejection Fraction

Randomized, parallel group, placebo-controlled trial

2019

LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide.

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DAPA-HFBaseline Treatment

Treatment (%) Dapagliflozin (n=2373) Placebo (n=2371)

Diuretic 93.4 93.5

ACE-inhibitor/ARB/ARNI 95.0 93.7

ACE inhibitor 56.1 56.1

ARB 28.4 26.7

Sacubitril/valsartan 10.5 10.9

Beta-blocker 96.0 96.2

MRA 71.5 70.6

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist. McMurray JJV, et al. N Engl J Med. 2019.

DAPA-HF: Primary Composite OutcomeWorsening HF or CV Death


NNT=21

NNT, number needed to treat.

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DAPA-HF: Components of Primary Outcome


P<0.0001

P=0.0294


DAPA-HF: Diabetes/No-Diabetes SubgroupPrimary Endpoint

Dapagliflozin(n=2373)

Placebo(n=2371)

HR(95% CI)

All patients 386/2373 502/2371 0.74 (0.65, 0.85)

Type 2 diabetes at baseline*

Yes 215/1075 271/1064 0.75 (0.63, 0.90)

No 171/1298 231/1307 0.73 (0.60, 0.88)

*Defined as history of type 2 diabetes or HbA1c ≥6.5% at both enrollment and randomization visits.

0.80.5 1.0 1.25

Dapagliflozin Better Placebo Better

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DAPA-HF: ARNI/No-ARNI post hoc SubgroupPrimary Endpoint

Dapagliflozin(n=2373)

Placebo(n=2371)

HR(95% CI)

All patients 386/2373 502/2371 0.74 (0.65, 0.85)

Angiotensin Receptor Neprilysin Inhibitor (ARNI)

Yes 41/250 56/258 0.75 (0.50, 1.13)

No 345/2123 446/2113 0.74 (0.65, 0.86)

0.80.5 1.0 1.25Dapagliflozin Better Placebo Better

DAPA-HFKansas City Cardiomyopathy Questionnaire (KCCQ)


Total Symptom ScoreProportion with ≥5 point change from baseline to 8 months*

Treatment Dapagliflozin Placebo Odds ratio (95% CI)

≥5 point improvement 58.3% 50.9%1.15 (1.08, 1.23)

P<0.001

≥5 point deterioration 25.3% 32.9%0.84 (0.78, 0.90)

P<0.001

*Taking account of death

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DAPA-HFAll-cause Death



DAPA-HFSafety/Adverse Events

Patients exposed to at least one dose of study drug

Dapagliflozin (n=2368)

Placebo (n=2368)

P-value

Adverse events (AE) of interest (%)

Volume depletion 7.5 6.8 0.40

Renal AE 6.5 7.2 0.36

Fracture 2.1 2.1 1.00

Amputation 0.5 0.5 1.00

Major hypoglycaemia 0.2 0.2 —

Diabetic ketoacidosis 0.1 0.0 —

AE leading to treatment discontinuation (%) 4.7 4.9 0.79

Any serious AE (including death) (%) 38 42 <0.01

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DAPA-HF vs Other Trials in HFrEF

TrialBackground

TherapyCV Death/ HF Hospital

HF Hospital CV DeathAll-Cause

Death

SHIFT (n=6,558) placebo vs ivabradine

ACE/ARB 90%BB 90%%MRA 61%

0.82(0.75–0.90)

0.74(0.66–0.83)

0.91(0.80–1.03)

0.9(0.80–1.02)

EMPHASIS-HF(n=2,737) placebo vs eplerenone

ACE/ARB 94%BB 87%

MRA N/A

0.63(0.54–0.74)

0.61(0.50–0.75)

0.76(0.61–0.94)

0.76(0.62–0.93)

PARADIGM-HF(n=8,399)enalapril vs sacubitril/valsartan (control vs neprilysin inhibition)

ACE/ARB 100%BB 93%

MRA 54%

0.80(0.73–0.87)

0.79(0.71–0.89)

0.80(0.71–0.89)

0.84(0.76–0.93)

DAPA-HF(n=4,744) placebo vs dapagliflozin

ACE/ARBa 95%BB 96%

MRA 72%

0.75(0.65–0.85)

0.70(0.59–0.83)

0.82(0.69–0.98)

0.83(0.71–0.97)

aIncluding sacubitril/valsartan.

BB, beta-blocker.

Bohm M, et al. Eur J Heart Fail. 2018; Zannad F, et al. N Engl J Med. 2011; McMurray JJV, et al. N Engl J Med. 2014; McMurray JJV, et al. N Engl J Med. 2019.

SGLT2is

Improved ventricular loading

• ↓preload (natriuresis, osmotic diuresis)

• ↓afterload (↓BP, improved vascular function)

Improved cardiac metabolism and

bioenergetics

Myocardial Na+/H+

exchange inhibition

↓Necrosis and cardiac fibrosis

Alterations in:

• Adipokines

• Cytokine production

• Epicardial adipose tissue mass

Potential Mechanisms Underlying the CV Benefits of SGLT2is

Verma S, McMurray JJV. Diabetologia. 2018.

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DAPA-HF(completed)

• N=4744 ± T2D

• LVEF ≤40%

• eGFR ≥30 mL/min/1.73 m2

• CV death or hHF or urgent HF visit

EMPEROR-Reduced(ongoing)

• N=3,730 ± T2D

• LVEF ≤40%


• CV death or hHF

Inclusion Criteria and Primary Endpoints Major Trials of SGLT2 Inhibitors in HF

EMPEROR-Preserved(ongoing)

• N=5,750 ± T2D

• LVEF >40%


• CV death or hHF

SOLOIST-WHF (ongoing)

• N=4,000 (T2D only)

• Worsening HF, any LVEF


• CV death or hHF

DELIVER (ongoing)

• N=4,700 ± T2D

• LVEF >40%


• CV death or hHF or urgent HF visit

ClinicalTrials.gov.

SGLT2i and GLP-1RAApproved CV Indications

Empagliflozin

• ↓ CV death in T2D with CVD

Canagliflozin

• ↓ MACE in T2D with CVD

• ↓ ESKD, 2x SCr, CV death, hHF in T2D, and diabetic neuropathy with albuminuria

Dapagliflozin

• ↓ hHF in T2D with CVD or multiple CV risk factors

• ↓ CV death and hHF in HFrEF, with or without T2D

SGLT2is

Liraglutide


Semaglutide (once-weekly)


GLP-1RAs

FDA Prescribing Information. SCr, serum creatinine.

Dulaglutide

• ↓ MACE in T2D with CVD or multiple CV risk factors

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Statin (any) 87.8%

High-intensity statin 45.4%

Ezetimibe 9.7%

Fish oil 19.8%

Fibrate 11.8%

PCSK9 inhibitor 8.6%

Antiplatelet or anticoagulant 87.3%

ACE inhibitor or ARB 72.0%

Metformin 54.6%

Insulin 35.9%

Sulfonylurea 21.5%

DPP-4i 12.5%

SGLT2i 9.0%

GLP-1RA 7.9%

Thiazolidinediones 4.6%

Optimal medical therapy 6.9%

Therapeutic Gaps among Patients with Diabetes and Atherosclerotic CVD

80% 100%0% 60%20% 40%

CV Medications

Lipid-lowering Medications

Glucose-lowering Medications

Arnold SV, et al. Circulation. 2019.

• It is now recommended that SGLT2 inhibitors and GLP-1 receptor agonists be considered for patients when ASCVD, HF, or CKD predominate independent of A1C

• For patients with T2D and active CVD, if already on dual therapy or multiple glucose-lowering therapies but not an SGLT2 inhibitor or a GLP-1 receptor agonist, consider switching to one of these agents for the proven CV benefit

• Further, even if patients with comorbid T2D and CVD are already at goal A1C, introduce an SGLT2 inhibitor or a GLP-1 receptor agonist for the CV benefit independent of A1C

2020 ADA Standards in DiabetesSGLT2 Inhibitor Updates

American Diabetes Association. Diabetes Care. 2020.

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Prescriber Guide to Initiate SGLT2i in DM

American Diabetes Association. Diabetes Care. 2020; Honigberg MC, et al. Circ Heart Fail. 2020; Vardeny O, Vaduganathan M. JACC Heart Fail. 2018; FDA Prescribing Information.

T2D + High CV Risk

Irrespective of HbA1C per new ADA Standards

HFrEF with or without T2D (dapagliflozin)

CV efficacy does not vary by Dose

eGFR thresholds vary by specific drug within class

Diuretic dose reduction?

Alter other T2D therapies?

Medication counseling

Candidates for Initiation

Selection of Drug and Dose

Pre-initiationSafety Screen

Long-term Continuation

Prescriptionof SGLT2i

Stepwise Approach to Prescription of SGLT2 Inhibitors by Cardiologists

Patient Case

Mary is a 57-year-old office manager. It has been 3 months since her last office visit. During that time, she presented to the ED with substernal chest discomfort and non-STEMI.

She underwent stenting of her RCA and was noted to have a 70% lesion of her LAD artery. She completed cardiac rehab and is feeling well, but she notes some intermittent ankle edema.

A transthoracic echocardiogram showed an EF of 45% with some inferior wall hypokinesis. She denies dyspnea, but states she is still fatigued and not yet back to baseline.

ED, emergency department; EF, ejection fraction; LAD, left anterior descending; RCA, right coronary artery, STEMI, ST-elevation myocardial infarction.

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Patient Case (…continued)

Current medication regimen• ASA 81 mg daily

• Ticagrelor 90 mg twice daily

• Rosuvastatin 40 mg daily

• Lisinopril 40 mg daily

• Carvedilol 12.5 mg twice daily

• Amlodipine 5 mg daily

• Spironolactone 25 mg daily

• Metformin 500 mg twice daily

• Saxagliptin 2.5mg once daily

• Glargine U-100 32 units every night at bedtime

ASA, aspirin.

• BMI = 30.5 kg/m2

• BP = 136/84 mmHg

• Pulse = 72 bpm

Laboratory studies

• eGFR = 47 mL/min/1.73 m2

• LDL = 58 mg/dL

• HDL = 42 mg/dL

• TGs = 210 mg/dL

Patient Case (…continued)

• NT-proBNP = 1200 pg/mL

• LVEF = 45%

• HbA1c = 7.0%

• FBS = 110–130 mg/dL

• No hypoglycemia

BMI, body mass index; FBS, fasting blood sugar; TG, triglyceride.

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50

A. Increase the DPP-4i dose

B. Switch from DPP-4i to a GLP-1RA

C. Switch from DPP-4i to a SGLT2i

D. Increase the insulin dose

What would be your preferred approach to addressing Mary’s T2D treatment regimen?

GLP-1RA is the better choice1,2

• eGFR <30 mL/min/1.73 m2

• Lower limb ulcers present?

• Frequent genital mycotic infections or UTI

• More A1C reduction needed

• Patient preference

SGLT2i is the better choice1,2

• HF or CKD predominates

• Active gallbladder disease or pancreatitis

• Personal or FH of medullary thyroid cancer

• Patient preference

What Factors Should We Consider in Choosing between a GLP-1RA and an SGLT2i?

Either class of agent potentially could be used by many patients1

1American Diabetes Association. Diabetes Care. 2020; 2FDA Prescribing Information.FH, family history; UTI, urinary tract infection.

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52

Scirica BM, et al. Circulation. 2014.

DPP-4i↑ Risk of HF with Saxagliptin in SAVOR-TIMI 53

Greatest Risk for Hospitalization for HF

• Previous HF

• Elevated NT-proBNP

• eGFR ≤60mL/min

A. Moderate-to-high absolute risks observed in clinical trials

B. Risk identified with all therapies in the SGLT2 inhibitor therapeutic class

C. Uncertain risk; identified in 1 SGLT2 inhibitor clinical trial, but not confirmed in others

You are considering an SGLT2 inhibitor for Mary. What is true about the potential risks related to amputations?

53

54

AmputationsPotential Signal with Canagliflozin in the CANVAS Program

Zelniker TA, et al. Lancet. 2019; FDA Prescribing Information.

Canagliflozin Black Box Warning: “In patients with T2D who have established CVD or are at risk for CVD, canagliflozin has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the lower leg.”

Amputations EventsTreatment events per

1,000 patient yearsPlacebo events per 1,000 patient years

HR(95% CI)

EMPA-REG OUTCOME 131 6.5 6.51.01

(0.70, 1.44)

CANVAS Program 187 6.3 3.41.97

(1.41, 2.75)

DECLARE-TIMI 58 236 3.6 3.31.09

(0.84, 1.40)

FE Model (P-value = 0.0096)(Heterogeneity: Q = 9.56, df = 2, p = 0.01; I2 = 79.08)

1.26(1.06, 1.51)

0.50 1.00 3.00Hazard Ratio

AmputationsCREDENCE Trial Did Not Identify Excess Signal

with Proper Foot Care and Follow-up

Perkovic V, et al. N Engl J Med. 2019.

Study design and participants Intervention

Conclusion

Outcomes

In patients with type 2 diabetes and kidney disease, canagliflozin reduces the risk of kidney failure and cardiovascular events.

4401 patients with T2DM and UACR >300 mg/g

Stable on maximum dose tolerated ACEi or ARB for

4 weeks

62 years

eGFR 57

UACR 927 mg/gCanagliflozin Placebo

CREDENCE: Canagliflozin and renal outcomes in T2D and nephropathy

Primary outcome(doubling of serum creatinine,

ESKD, death due to cardiovascular or kidney disease)

End-stage kidney disease

HR 0.70(95% CI, 0.59–0.82)

NNT 21

HR 0.68(95% CI, 0.54–0.86)

NNT 42

No increased risk of:

HR 1.10(95% CI, 0.79–1.56)

HR 0.98(95% CI, 0.70–1.37)

Amputations Fractures

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56

SGLT2i SafetyCVOT Experience

A recent meta-analysis of 112 RCTs of SGLT2is found no difference in bone fracture or DKA; amputation risk was neutral compared with active controls7

1Neal B, et al. N Engl J Med. 2017; 2Perkovic V, et al. N Engl J Med. 2019; 3Wiviott SD, et al. N Engl J Med. 2019;

4Zinman B, et al. N Engl J Med. 2015; 5Inzucchi SE, et al. Diabetes Care. 2018;6Matthews DR, et al. Diabetologia. 2019; 7Donnan JR, et al. BMJ Open. 2019.

Bone fracture1–4 Lower extremity

amputation1,3–6 DKA2–4PotentialConcern

Fournier’s

gangrene*1–4

1.5%–5.3%

SGLT2is

1.2%–5.1%

placebo

1.4%–3.2%

SGLT2is

1.1%–2.9%

placebo

0.1%–0.5%

SGLT2is

0.03%–0.1%

placebo

Rates in CVOTs

1 Case

DECLARE

dapagliflozin

5 Cases

DECLARE

placebo

*SGLT2 class precaution, not just dapagliflozin

DKA, diabetic ketoacidosis.

A. Renal function is expected to transiently decline shortly after initiation, but SGLT2 inhibitors afford long-term kidney protection

B. SGLT2 inhibitors do not affect renal function

C. SGLT2 inhibitors increase long-term risks of acute kidney injury

When starting an SGLT2 inhibitor, what are the potential risks related to renal function?

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58

SGLT2is and Renal FunctionEarly Reductions, Long-term Benefits

Heerspink H, et al. Lancet DE. 2020.

Current Renal ParametersSGLT2is

200–300 mg

okayCanagliflozin 100 mg okay*Canagliflozin contraindicated

60453015Dialysis eGFRa

Dapagliflozin contraindicated Dapagliflozin 5–10 mg okayNot

recommended*

Discontinue empagliflozin if consistently in this range Empagliflozin 10–25 mg okay

Do not use ertugliflozinErtugliflozin

5–15 mg okayErtugliflozin not recommended

FDA Prescribing Information.aeGFR in mL/min/1.73 m2

*30-45 mL/min okay in HFrEF

*30-45 mL/min okay if albuminuria > 300 mg/day

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Neuen BL, et al. Lancet Diabetes Endocrinol. 2019.

SGLT2is Improve Renal Outcomes in T2D

Events PatientsHR

(95% CI)

Dialysis, transplantation, or death due to kidney disease

252 38,723 0.67 (0.52–0.86)

ESKD 335 38,723 0.65 (0.53–0.81)

Substantial loss of kidney function, ESKD, or death due to kidney disease

967 38,671 0.58 (0.51–0.66)

Substantial loss of kidney function, ESKD, or death due cardiovascular to kidney disease

2323 38,676 0.71 (0.63–0.82)

Acute kidney injury 943 38,684 0.75 (0.66–0.85)

0.5 1.0 1.5

Favors SGLT2 inhibitor Favors placebo

As a PCP, cardiologist, or other clinician (PharmD, RN, NP, PA), should you refer the patient for evaluation and follow-up with an endocrinologist?

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62

High-risk T2D PatientsWhich Clinician Do They See Most Often?

Gunawan F, et al. J Endocrin Soc. 2019.

All T2D

T2D+CVD

T2D+HF

3:1

5:1

8:1

Yale New Haven (78,878 T2D patients)Ratio of Cardiologist-to-Endocrinologist Patient Encounters

Newly Diagnosed Cases of Diabetes per Specialist, 2016

CardiologistsN=22,848

EndocrinologistsN=7,793

NephrologistsN=7,504

0 500 0 500 0 500

Average caseload per cardiologist

Best: 30Worst: 154

Average caseload per endocrinologist

Best: 37Worst: 667

Average caseload per nephrologist

Best: 46Worst: 2,000

Patel RB, et al. JAMA Cardiol. 2019.

63

64

10

87

67 68

2 0

88

53

77

59 57

614

86

28

77

58 58

0 0

85

0

20

40

60

80

100

Glycemic control Blood pressurecontrol

ACEi/ARB withCAD

Nephropathyscreening

Eye exam Foot exam Tobaccoscreening and

counseling

Cardiology (n=93) Endocrinology (n=20) Primary care (n=146)

Achievement of Quality Metrics in Patients with T2D, by Medical Specialty

<0.001 <0.001 <0.001 <0.001 0.935 0.001 0.073P

Me

dia

n A

dh

ere

nc

e %

Arnold SV, et al. J Am Heart Assoc. 2017.

Endorses NIH Team Care

approach developed for T2D

Interprofessional Team-based Care for Patients with T2D and HF—AHA/HFSA, 2019

HF and DM

Community Resources

• Social worker

• Community health workers

Other Clinicians

• Pharmacist

• RN/APRN

• Physician assistant

• Dietician

• Physical therapist

Specialists(When Needed)

• Palliative care

• Nephrology

• Hospitals

Primary T2D and HF Clinicians

• Primary care

• Cardiology

• Endocrinology

AHA, American Heart Association; HFSA, Heart Failure Society of America; NIH, National Institutes of Health.

Dunlay SM, et al; Circulation. 2019; Dunbar SB, et al. Nurs Outlook. 2014;

Dunbar SB, et al. J Card Fail. 2015.

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