Diabetes and Heart Failuresdbiomarkerssymposium.com/presentations2019/Fonarow_1.pdf · 2019. 2....
Transcript of Diabetes and Heart Failuresdbiomarkerssymposium.com/presentations2019/Fonarow_1.pdf · 2019. 2....
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Cardiologists and HbA1c: Novel Diabetes Drugs and the
Cardiologist as Diabetician
Gregg C. Fonarow, MD, FACC, FAHA, FHFSAElliot Corday Professor of Cardiovascular MedicineUCLA Division of CardiologyDirector, Ahmanson–UCLA Cardiomyopathy CenterCo-Chief, UCLA Division of Cardiology
Biomarkers 2019
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Diabetes and Cardiovascular Disease
• Atherosclerotic and HF complications responsible for – 80% of mortality among patients with diabetes– 75% of all hospitalizations for diabetic
complications
• 50% of patients with type 2 diabetes have preexisting CAD. (This number may be less now that more younger people are diagnosed with diabetes.)
• 1/3 of patients presenting with myocardial infarction have undiagnosed diabetes mellitus
• 45% of patients hospitalized with HF have DMLewis GF. Can J Cardiol. 1995;11(suppl C):24C-28CNorhammar A, et.al. Lancet 2002;359;2140-2144
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The Emerging Risk Factors Collaboration N Engl J Med 2011;364:829-41
50-year-old with diabetes died, on average, 6 years earlier than those without diabetes (58% attributable to vascular, 9%, cancer, 30% other causes )
Reduction in life expectancy from long-term cigarette smoking ~10 years
Diabetes and Survival
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Framingham Heart Study 30-Year Follow-up of CVD Events in Patients With Diabetes
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Diabetes and Heart Failure
• The two diseases entities are highly co-prevalent
• Diabetes contributes to disease progression in HF and is associated with substantially worse prognosis, even when conventional HF therapies are applied
• The relationship between HbA1c and outcome in patients with diabetes and heart failure is complex
• The choice of pharmacologic glycemic management can markedly impact heart failure outcomes – Certain therapies are neutral or associated with harm– Certain therapies markedly improve outcomes
• Pharmacologic glycemic management is a critical component of HF management
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Kannel WB et al. JAMA. 1979;241:2035–2038. Nichols GA. Diabetologia. 2000;43(suppl A2):7. Chue CU et al. Circulation. 1998;98(suppl 1):721.
Diabetes and Incident Heart Failure in the US• Framingham study (risk of HF in diabetics)
– 2x diabetic males– 5x diabetic females– 4x young diabetic males– 8x young diabetic females
• US HMO prevalence study– With diabetes, incident HF developed at a rate
of 3.3% per year
• Each 1% elevation in HbA1c leads to a 15% increase in frequency of HF
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Prevalence of Diabetes in Patients with Heart Failure
Clinical Trial Diabetics
SOLVD 25.8%
MERIT 24.5%
Val HEFT 25.4%
EMPHASIS-HF 31.4%
PARADIGM-HF 34.7%
OPTIME (hospitalized) 44.2%
VMAC (hospitalized) 47.0%
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Poor Glycemic Control in DM is Independently Associated with Increased HF Risk
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2
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6
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Heart Failure Rates in Diabetes Glucose Control Trials
Risk of HF events with glucose-lowering drugs or strategies versus standard care
Lancet Diabetes Endocrinol 2015 March 17, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00044-3
PPAR Agonists
DPP-4 Inhibitors
Intensive Control
Insulin
Weight loss
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Effect of Glycemic Control in Type 2 DM on Cardiovascular Outcomes
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Diabetics and Heart Failure: Poor Prognosis
Bertoni et al. Diabetes Care 27:699–703, 2004
HR 10.6,95% CI 10.4–10.9
N = 151,738 Medicare beneficiaries with diabetes, age ≥ 65 years
Gustafsson et al. JACC 2003; 43: 771-777.
N = 5491 patients hospitalized with HF and followed for a median of 7.1 years
Multivariate analysis RR DM = 1.5
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Major CV Outcome Trials in Type 2 Diabetes
2015 20172016 2018 201920132012 2014
CAROLINAN = 6041MACE4
ELIXA*(n = 6000)
805 MACE4
: SGLT2i
: DPP4i
: GLP1
*lixisenatide (Sanofi, post-ACS).†liraglutide (Novo Nordisk).
‡semaglutide (Novo Nordisk). §exenatide (Amylin).
¶once-weekly DPP4i (Merck).#dulaglutide (Eli Lilly).
TECOS(n = 14,723)
1400 MACE4
CANVAS(n = 4339)
MACE3
DECLARE-TIMI 58
(n = 27,000)MACE3
SAVOR-TIMI 53
(n = 16,492)1222 MACE3
SUSTAIN-6‡(n = 3260)
MACE3
EXAMINE(n = 5380)621 MACE3
LEADER†(n = 9341)611 MACE3
CANVAS-R(n = 5700)Alb.uria
CREDENCE(n = 3627)
Cardiorenal
EXSCEL§(n = 14000)
MACE3
REWIND#(n = 9622)
MACE3
Ertugliflozin CVOT
(n = 3900)MACE3
CARMELINA N = 8300MACE4
Omarigliptin¶(n = 4000)
Q42017? MACE4
EMPA-REG OUTCOMEN = 7034MACE3
FREEDOM§(n = 4000)? MACE4
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Glycemic Management Medications: Possible Mechansims Impacting CVD and HF
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SAVOR TIMI 53-Hospitalization for Heart Failure: DPP-4
Time to the 1st occurrence of any hospitalization for heart failure; 517 events
Scirica BM, et al. Circulation 2014; 130:1579-88.
Saxagliptin Placebo3.5%
2.8%
0.6%
1.1%
HR 1.80P=0.001
1.3%
1.9%
HR 1.46P=0.002
HR 1.27P=0.007
0%
1%
2%
3%
4%
0 180 360 540 720
Hos
pita
lizat
ion
forH
eart
Failu
re( %
)
Days from Randomization
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Hospitalization for HF with Alogliptin: Observations from EXAMINE
Zannad F. et al. Lancet 2015: 385 : 2067-2076
HR: 1.19 1.00 1.7695% CI: 0.90-1.58 0.71-1.42 1.07-2.90P-value: p=0.22 p=0.99 p=0.026
Pinteraction=0.068
Chart1
OverallOverall
Prior HFPrior HF
No Prior HFNo Prior HF
Alogliptin
Placebo
%
3.9
3.3
8.2
8.5
2.2
1.3
Sheet1
AlogliptinPlacebo
Overall3.93.3
Prior HF8.28.5
No Prior HF2.21.3
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CV Effects of Lixisenatide:
ELIXA Trial Results
Pfeffer, M. A., et al. N Engl J Med 2015 373: 2247-2257 Marso SP et al. N Engl J Med. 2016;375:311-22.
LEADER: Hospitalization for
heart failure
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Outcome # of events HR 95%CIsemaglutide vs placebo
CV Death/MI/Stroke 108 vs 146 0.74 0.58-0.95HF hospitalization 59 vs 54 1.11 0.77-1.61
N=3297 T2DM w/ CVD/CV riskSemaglutide 0.5 or 1.0mg vs. placebo once weekly
104 Weeks
Marso SP, et al. NEJM 2016; DOI: 10.1056/NEJMoa1607141
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Liraglutide in Systolic Heart Failure:The FIGHT Trial
N=300: liraglutide (n = 154) vs. placebo (n = 146)
Margulies KB et al. JAMA. 2016;316:500-508.
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SGLT2 Inhibitors
• Virtually all glucose filtered by the kidney is reclaimed in the proximal tubule.1 Sodium glucose cotransporter 2 (SGLT2) is responsible for 90% of this reabsorption.
• Selective inhibitors of SGLT2 have been developed .2
• By reducing renal glucose reabsorption, SGLT2 inhibitors increases urinary glucose excretion.3
• In patients with type 2 DM, SGLT2 inhibitors leads to:4
– Significant reductions in HbA1c– Weight loss– Reductions in BP without increases in heart rate
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1. Abdul-Ghani et al. Curr Diab Rep. 2012;12:230-8.2. Grempler et al. Diabetes Obes Metab.2012 ;14:83-90.3. Heise T et al. Diabetes Obes Metab 2013;15:613-21.4. Liakos A et al. Diabetes Obes Metab 2014;16:984-93.
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Filtered glucose load 180 g/day
SGLT1
SGLT2
~ 10%
~ 90%
Gerich JE. Diabet Med. 2010;27:136–142.
Renal Glucose Re-absorption in Healthy Individuals
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Gerich JE. Diabet Med. 2010;27:136–142.
Renal Glucose Re-absorption in Patients with Hyperglycaemia
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SGLT1
SGLT2
~ 10%
~ 90%
When blood glucose increases above the
renal threshold (~ 10 mmol/l or 180
mg/dL), the capacity of the transporters is exceeded, resulting in urinary glucose
excretion
Filtered glucose load > 180 g/day
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*Loss of ~ 80 g of glucose/day (~ 240 cal/day).Gerich JE. Diabet Med. 2010;27:136–142.
Urinary Glucose Excretion via SGLT2 Inhibition
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SGLT2SGLT2inhibitor
SGLT1
SGLT2 inhibitors reduce glucose re-absorption
in the proximal tubule, leading to
urinary glucose excretion* and
osmotic diuresis
Filtered glucose load > 180 g/day
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GLUT2 AMG Uptake
NGT T2DM NGT T2DM
AMG=methyl-α-D-[U14C]-glucopyranoside; CPM=counts per minute.Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
SGLT2
NGT T2DM0
2
6
8
0
500
1000
1500
2000
Nor
mal
ized
Glu
cose
Tr
ansp
orte
r Lev
els
CPM
Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes
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Mechanism of Action of SGLT2 Inhibitors
Inhibition of SGLT2 Reversal of glucotoxicityInsulin sensitivity in muscle
• ↑ GLUT4 translocation• ↑ Insulin signaling
• Other
Insulin sensitivity in liver• ↓ Glucose- 6-phosphatase
Gluconeogenesis• Decreased Cori cycle• ↓ PEP carboxykinase
β-Cell function
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EMPA-REG OUTCOMETrial design: SGLT2 Inhibitor
• Key inclusion criteria:– Adults with type 2 diabetes and established CVD– BMI ≤45 kg/m2; HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD)
– 10.2% of patients enrolled with pre-existing heart failure
Randomized and treated
(n=7020)
Empagliflozin 10 mg(n=2345)
Empagliflozin 25 mg (n=2342)
Placebo (n=2333)
Screening(n=11531)
Zinman B et al. N Engl J Med 2015 [Epub ahead of print].
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EMPA-REG OUTCOME Trial
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EMPA-REG OUTCOME Study
Empagliflozin is a highly selective inhibitor of Sodium-Glucose Cotransporter-2
Zinman B et al. N Engl J Med 2015 [Epub ahead of print].
7020 adults with type 2 diabetes and established CVD
BMI ≤45 kg/m2; HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD)
HF Hospitalization or CV Death HF Hospitalization or HF Death
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Heart Failure Hospitalization or CV death
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Cumulative incidence function. CV, cardiovascular; HR, hazard ratio; CI, confidence interval.
European Heart Journal doi:10.1093/eurheartj/ehv728
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European Heart Journal doi:10.1093/eurheartj/ehv728
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Patients with
heart failure hospitalization
or CV death
(%)
Heart Failure Hospitalization or CV Death in Patients with vs without HF at Baseline
7.1
20.1
4.5
16.2
0
5
10
15
20
25
Patients without heart failure at baseline
Patients with heart failure at baseline
HR 0.72(95% CI 0.50, 1.04)
HR 0.63(95% CI 0.51, 0.78)
Zinman B et al. N Engl J Med 2015 [Epub ahead of print].
Chart1
Patients without heart failure at baselinePatients without heart failure at baseline
Patients with heart failure at baselinePatients with heart failure at baseline
Placebo
Empagliflozin
7.1
4.5
20.1
16.2
Sheet1
PlaceboEmpagliflozin
Patients without heart failure at baseline7.14.5
Patients with heart failure at baseline20.116.2
To resize chart data range, drag lower right corner of range.
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SGLT2 Inhibitors
Empagliflozin1 Dapagliflozin2 Canagliflozin3
Launch year 2014(EU/US) 2012 (EU) 2014 (US) 2013 (EU/US)
MoA Molecular class
C-glycoside C-glycoside C-glycoside
Metabolism Dual renal and hepatic50:50
Mainly hepatic97:3
Mainly hepatic, no details reported
Dosing Administration Oral Oral Oral
Regimen Once daily Once daily Once daily
Doses 10 mg and 25 mg 5 mg and 10 mg 100 mg and 300 mg
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Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS
DOI: 10.1056/NEJMoa1611925
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CANVAS ProgramHospitalization for Heart Failure
Neal B et al. N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925.
Number of participantsPlacebo 4347 4198 3011 1274 1236 1180 829Canagliflozin 5795 5653 4437 2643 2572 2498 1782
HR 0.67 (95% CI 0.52, 0.87)ARR=1.6% at 5 y;
NNT3y=105; NNT5y=63
Placebo
Canagliflozin
33% RRR
NNT = 63
Chart1
0
1
2
3
4
5
6
Series 1
Years since randomization
Participants with an event (%)
4.3
2.5
3.5
4.5
Sheet1
Series 1Series 2Series 3
04.32.42
12.54.42
23.51.83
34.52.85
4
5
6
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Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS
DOI: 10.1056/NEJMoa1611925
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Component Analyses of MACE Events: Dapagliflozin
Http://www.Fda.Gov/DOWNLOADS/ADVISORYCOMMITTEES/COMMITTEESMEETINGMATERIALS/DRUGS/ENDOCRINOLOGICANDMETABOLICDRUGSADVISORYCOMMITTEE/UCM262994.Pdf
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Potential Mechanisms Involved in the Reduction of Cardiovascular Events
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The Metabolodiuretic Promise of SGLT2 Inhibition
JAMA Cardiol. 2017;2(9):939-940
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How Does Empagliflozin Reduce Cardiovascular Mortality? Mediation Analysis of the EMPA-REG OUTCOME Trial
Diabetes Care 2018;41:356–363
In this exploratory investigation into potential mediators of the reduction in risk of CV death with empagliflozin versus placebo, found that changes in hematocrit and hemoglobin, markers of the effects of the drug on volume, appeared to be important mediators of the reduction in mortality risk in univariable and multivariable models. Obesity, blood pressure, lipids, and renal function made negligible contribution
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CV Outcome Trials with SGLT2 Inhibitors
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EMPEROR-Preserved1
EMPEROR-Reduced2 Dapa-HF
3
Sample size 4126 2850* 4500
Key inclusion criteria
• Patients with chronic HF†
• Elevated NT-proBNP• eGFR ≥20 ml/min/1.73 m2
• Symptomatic HFrEF†
• Elevated NT-proBNP• eGFR ≥30 ml/min/1.73
m2
HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) HFrEF (LVEF ≤40%)
Primaryendpoint
• Time to first event of adjudicated CV death or adjudicated HHF
• Time to first occurrence of CV death, HHF or urgent HF visit
Key secondary endpoints
• Individual components of primary endpoint• All-cause mortality
• All-cause hospitalisation• Time to first occurrence of sustained
reduction of eGFR • Change from baseline in KCCQ
• Total number of HHF or CV death
• All-cause mortality• Composite of ≥50%
sustained eGFR decline ESRD or renal death
• Change from baseline in KCCQ
Start dateExpectedcompletiondate
March 2017June 2020
March 2017June 2020
February 2017December 2019
Upcoming Trials of SGLT2 Inhibitors in HF
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SGLT2 Inhibitors, GLP 1 Agonists, and DPP 4 Inhibitors and Outcomes in Patients With Type 2 Diabetes: Meta-Analysis
JAMA. 2018;319(15):1580-1591. doi:10.1001/jama.2018.3024
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Comparison of Mortality Reduction in HF Trials with EMPA-REG Trial in Patients with Diabetes
European Journal of Heart Failure (2017) 19, 43–53
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2016 ESC Guidelines for the Diagnosis and Treatment of Acute & Chronic HF
European Heart Journal (2016) 37, 2129–2200
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• Until 2015, no known diabetes therapy demonstrated in RTCs to improve CV outcomes in general or for HF
• Most diabetes medications were neutral in ASCVD and worsened outcomes in HF or at best were neutral
• EMPA-REG Outcome and CANVAS trial data – SGLT2 inhibitors are a new option to reduce CV events, CV death
and HF in patients with diabetes with and without HF– Compelling data
• Pharmacological diabetes management is an essential component of ASCVD and HF therapy
• It is critical for cardiologists and HF specialists to play an active role in this management as choice of therapy is key determinate of outcomes, including survival
Conclusions
Cardiologists and HbA1c: �Novel Diabetes Drugs and the Cardiologist as DiabeticianDiabetes and Cardiovascular DiseaseSlide Number 3Framingham Heart Study 30-Year Follow-up of CVD Events in Patients With Diabetes Diabetes and Heart FailureDiabetes and Incident Heart Failure in the USPrevalence of Diabetes in Patients with Heart FailurePoor Glycemic Control in DM is Independently Associated with Increased HF RiskHeart Failure Rates in Diabetes Glucose Control TrialsSlide Number 10Diabetics and Heart Failure: Poor PrognosisMajor CV Outcome Trials in Type 2 DiabetesGlycemic Management Medications: Possible Mechansims Impacting CVD and HFSAVOR TIMI 53-Hospitalization for Heart Failure: DPP-4Hospitalization for HF with Alogliptin: �Observations from EXAMINECV Effects of Lixisenatide:�ELIXA Trial ResultsSlide Number 17Liraglutide in Systolic Heart Failure:�The FIGHT TrialSGLT2 InhibitorsRenal Glucose Re-absorption in Healthy IndividualsRenal Glucose Re-absorption in Patients with HyperglycaemiaUrinary Glucose Excretion via SGLT2 InhibitionIncreased Glucose Transporter Proteins and Activity in Type 2 DiabetesMechanism of Action of �SGLT2 InhibitorsEMPA-REG OUTCOME�Trial design: SGLT2 InhibitorSlide Number 26EMPA-REG OUTCOME StudyHeart Failure Hospitalization or CV death Slide Number 29Slide Number 30Heart Failure Hospitalization or CV Death �in Patients with vs without HF at BaselineSGLT2 InhibitorsCanagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVASCANVAS Program�Hospitalization for Heart FailureCanagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVASComponent Analyses of MACE Events: DapagliflozinPotential Mechanisms Involved in the Reduction of Cardiovascular EventsSlide Number 38How Does Empagliflozin Reduce Cardiovascular Mortality? Mediation Analysis of the EMPA-REG OUTCOME TrialCV Outcome Trials with SGLT2 InhibitorsUpcoming Trials of SGLT2 Inhibitors in HFSGLT2 Inhibitors, GLP 1 Agonists, and DPP 4 Inhibitors and Outcomes in Patients With Type 2 Diabetes: �Meta-AnalysisComparison of Mortality Reduction in HF Trials with EMPA-REG Trial in Patients with Diabetes2016 ESC Guidelines for the Diagnosis and Treatment of Acute & Chronic HFConclusions