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

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

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

Framingham Heart Study 30-Year Follow-up of CVD Events in Patients With Diabetes

P

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

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

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%

Poor Glycemic Control in DM is Independently Associated with Increased HF Risk

0

2

4

6

8

10

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

Effect of Glycemic Control in Type 2 DM on Cardiovascular Outcomes

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

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

Glycemic Management Medications: Possible Mechansims Impacting CVD and HF

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

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

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

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

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.

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

19

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.

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

Gerich JE. Diabet Med. 2010;27:136–142.

Renal Glucose Re-absorption in Patients with Hyperglycaemia

21

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

*Loss of ~ 80 g of glucose/day (~ 240 cal/day).Gerich JE. Diabet Med. 2010;27:136–142.

Urinary Glucose Excretion via SGLT2 Inhibition

22

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

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

P

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

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].

EMPA-REG OUTCOME Trial

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

Heart Failure Hospitalization or CV death

28

Cumulative incidence function. CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

European Heart Journal doi:10.1093/eurheartj/ehv728

European Heart Journal doi:10.1093/eurheartj/ehv728

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.

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

32

Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS

DOI: 10.1056/NEJMoa1611925

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

Canagliflozin and Cardiovascular Events in Type 2 Diabetes: CANVAS

DOI: 10.1056/NEJMoa1611925

Component Analyses of MACE Events: Dapagliflozin

Http://www.Fda.Gov/DOWNLOADS/ADVISORYCOMMITTEES/COMMITTEESMEETINGMATERIALS/DRUGS/ENDOCRINOLOGICANDMETABOLICDRUGSADVISORYCOMMITTEE/UCM262994.Pdf

Potential Mechanisms Involved in the Reduction of Cardiovascular Events

The Metabolodiuretic Promise of SGLT2 Inhibition

JAMA Cardiol. 2017;2(9):939-940

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

CV Outcome Trials with SGLT2 Inhibitors

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

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

Comparison of Mortality Reduction in HF Trials with EMPA-REG Trial in Patients with Diabetes

European Journal of Heart Failure (2017) 19, 43–53

2016 ESC Guidelines for the Diagnosis and Treatment of Acute & Chronic HF

European Heart Journal (2016) 37, 2129–2200

• 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