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Disclaimer
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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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16
>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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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
McMurray JJV, et al. N Engl J Med. 2019.
NNT=21
NNT, number needed to treat.
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DAPA-HF: Components of Primary Outcome
McMurray JJV, et al. N Engl J Med. 2019.
P<0.0001
P=0.0294
McMurray JJV, et al. N Engl J Med. 2019.
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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McMurray JJV, et al. N Engl J Med. 2019.
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)
McMurray JJV, et al. N Engl J Med. 2019.
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
McMurray JJV, et al. N Engl J Med. 2019.
McMurray JJV, et al. N Engl J Med. 2019.
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%
• eGFR ≥20 mL/min/1.73 m2
• 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%
• eGFR ≥20 mL/min/1.73 m2
• CV death or hHF
SOLOIST-WHF (ongoing)
• N=4,000 (T2D only)
• Worsening HF, any LVEF
• eGFR ≥30 mL/min/1.73 m2
• CV death or hHF
DELIVER (ongoing)
• N=4,700 ± T2D
• LVEF >40%
• eGFR ≥25 mL/min/1.73 m2
• 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
• ↓ MACE in T2D with CVD
Semaglutide (once-weekly)
• ↓ MACE in T2D with CVD
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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46
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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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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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?
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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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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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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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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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American Diabetes Association. Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020;43(Suppl 1).
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