diabetes: a cardiovascular disease: implications for...

Diabetes: A Cardiovascular Disease: Implications for Therapy with SGLT Inhibitors

Gregg C. Fonarow, MD, FACC, FAHA, FHFSAElliot Corday Professor of Cardiovascular MedicineUCLA Division of CardiologyDirector, Ahmanson–UCLA Cardiomyopathy CenterCo-Chief, UCLA Division of Cardiology

UCSD Hawaii CME 2019 Symposium

Diabetes and Cardiovascular Disease

• Atherosclerotic complications responsible for – 80% of mortality among patients with diabetes– 75% of cases due to coronary artery disease

(CAD)– Results in >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

Lewis 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

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%

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

aComposite of CV death, nonfatal myocardial infarction, and nonfatal stroke for SAVOR-TIMI 53, EXAMINE, and CARMELINA, with the addition of hospitalization for unstable angina in TECOS; bParenthetical value is the upper boundary of one-sided repeated CI at an alpha level of 0.01; cMACE reported HR, 95% CI, and P-value were for the secondary composite of CV death, nonfatal myocardial infarction, and nonfatal stroke.1. Scirica B, et al. N Engl J Med. 2013;369:1317–1326; 2. White W, et al. N Engl J Med. 2013;369:1327−1335; 3. Zannad P, et al. Lancet. 2015;385:2067–2076; 4. Green JB, et al. N Engl J Med. 2015;373:232–242; 5. Rosenstock J et al. JAMA. 2019;321:69-79.

Favors DPP-4 inhibitor

EXAMINE2,3

TECOS4,c

CARMELINA5

HR (95% CI) HR (95% CI)

SAVOR-TIMI 531

HR (95% CI)

0.96 (≤1.16)b

0.99 (0.89, 1.10)

1.02 (0.89, 1.17)

1.00 (0.89, 1.12)

P value

0.32

0.84

0.74

0.99

HR (95% CI)

1.19 (0.90, 1.58)

1.00 (0.83, 1.20)

0.90 (0.74, 1.08)

1.27 (1.07, 1.51)

P value

0.007

0.22

0.98

0.26

0.5 1.0 2.0 0.5 1.0 2.0

hHFMACEa

Favors DPP-4 inhibitorFavors placebo Favors placebo

DPP-4 Inhibitors are Neutral on MACE and HF Outcomes: No Improvement Compared to Placebo

Chart1

10.960.991.02

0.890.960.890.89

1.121.161.11.17

SAVOR-TIMI 53

EXAMINE

TECOS

CARMELINA

4

3

2

1

4

3

2

1

4

3

2

1

Sheet1

StudyDescriptionxy

SAVOR-TIMI 53ES1.004

CI lower0.894

CI upper1.124

EXAMINEES0.963

CI lower0.963

CI upper1.163

TECOSES0.992

CI lower0.892

CI upper1.102

CARMELINAES1.021

CI lower0.891

CI upper1.171

Sheet1

SAVOR-TIMI 53

EXAMINE

TECOS

CARMELINA

Chart1

1.271.1910.9

1.070.890.830.74

1.511.591.21.08

SAVOR-TIMI 53

EXAMINE

TECOS

CARMELINA

4

3

2

1

4

3

2

1

4

3

2

1

Sheet1

StudyDescriptionxy

SAVOR-TIMI 53ES1.274

CI lower1.074

CI upper1.514

EXAMINEES1.193

CI lower0.893

CI upper1.593

TECOSES1.002

CI lower0.832

CI upper1.202

CARMELINAES0.901

CI lower0.741

CI upper1.081

Sheet1

SAVOR-TIMI 53

EXAMINE

TECOS

CARMELINA

Hospitalization for HF – GLP1 RA

ELIXA LEADER

SUSTAIN-6 EXSCEL

Pfeffer M et al. N Engl J Med. 2015;373:2247-57; Marso S et al. N Engl J Med. 2016;375:311-22; Marso S et al. N Engl J Med. 2016;375: 1834-44; N Engl J Med. 2017;377:1228-39.

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

14

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

16

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

17

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

Potential CV and Renal Function Preservation Mechanisms of SGLT2i that May Benefit HF

Mechanism1−4 Possible cardio−renal effects5,6 Outcomes7,8SGLT2 inhibition1,2

Effect Consequence

Diuresis Reduced filling pressures, pre/afterload reduction

Natriuresis Reduced filling pressures, pre/afterload reduction

Blood pressure lowering Reduced myocardial work, reduced filling pressures, pre/afterload reduction

Weight loss Improved CV risk profile, lower blood pressure

Reduction in/prevention of albuminuria, slowing of kidney function decline

Reduction in kidney risk profile, possibly lower incident CV events, including less HF

Effects on myocardial and kidney metabolism: shift to more efficient ketone-based metabolism

Improved metabolic efficiency, less myocardial work-load

Blockade of kidney and myocardial sodium-hydrogen co-transporter

Tissue protection: reduction in kidney and myocardial injury

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


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

23

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)


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

27

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

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

17,160 patients with type II diabetes, including 10,186 without ASCVD randomized to dapagliflozin 10 mg daily vs placebo, who were followed for a median of 4.2 years.

NEJM 2018 DOI: 10.1056/NEJMoa1812389

Hospitalization for HF in Patients with T2DM Treated with SGL2i

EMPA-REG OUTCOMEEmpagliflozin1

• 9.4 vs 14.5 events/1000 p-y• HR 0.65 (0.50-0.85)

CANVAS/CANVAS-RCanagliflozin2

• 5.5 vs 8.7 events/1000 p-y• HR 0.67 (0.52-0.87)

DECLARE-TIMI 58Dapagliflozin3

• 6.2 vs 8.5 events/1000 p-y• HR 0.73 (0.61-0.88)

* P < .05; p-y, patient-years; NR, not reported. Not currently indicated by the US FDA for reducing hospitalization in patients with HF.1. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128; 2. Neal B, et al. N Engl J Med. 2017;377(7):644-657; 3. Wiviott SD, N Engl J Med. 2019;380(4):347-357.

35%* 33%* 27%*

Meta-Analysis: SGLT2 Inhibitors and Heart Failure Hospitalizations

Lancet. 2019 Jan 5;393(10166):31-39

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy: CREDENCE

The canagliflozingroup also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization forheart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P

DAPA-HF Trial in HFrEF with or with Type 2 Diabetes

DOI: 10.1056/NEJMoa1911303

McMurray J. ESC Presentation Sept 1, 2019, Paris, France DOI: 10.1056/NEJMoa1911303

DOI: 10.1056/NEJMoa1911303

DAPA-HF Primary Composite Outcome

DOI: 10.1056/NEJMoa1911303

McMurray J. ESC Presentation Sept 1, 2019, Paris, France

DOI: 10.1056/NEJMoa1911303

Diabetes Status and Effect of SGLT2i in HFrEF

DOI: 10.1056/NEJMoa1911303

Add DAPA HF slides


DOI: 10.1056/NEJMoa1911303


DOI: 10.1056/NEJMoa1911303

Safety of SGLT2i in HFrEF

DOI: 10.1056/NEJMoa1911303

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

Dapa-HF• N = 4744 ± T2DM

• LVEF ≤ 40%• eGFR ≥ 30 mL/min/1.73 m2

• CV death or HHF or urgent HF visit

EMPEROR-Reduced• N = 2850 ± T2DM

• 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•N = 6000 ± T2DM

•LVEF > 40%•eGFR ≥ 20 mL/min/1.73 m2

•CV death or HHF

SOLOIST-WHF•N = 4000 (T2DM only)

•Worsening HF, any LVEF•eGFR ≥ 30 mL/min/1.73 m2

•CV death or HHF

DELIVER•N = 4700 ± T2DM

•LVEF > 40%•eGFR ≥ 25 mL/min/1.73 m2

•CV death or HHF or urgent HF visit

https://clinicaltrials.gov. Accessed February 8, 2019.

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

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

European Heart Journal (2016) 37, 2129–2200

Cumulative Impact of Evidence-BasedHeart Failure with Reduced EF Medical Therapies on

All Cause Mortality (Quadruple Rx)

Cumulative risk reduction in mortality if all evidence-based medical therapies are used: Relative risk reduction 72.9%, Absolute risk reduction: 25.5%, NNT = 3.9

Relative Risk 2 Year MortalityNone - - 35.0%ARNI (vs imputed placebo) 28% 25.2%Beta Blocker 35% 16.4%Aldosterone Ant 30% 11.5%SGLT2 inhibitor 17% 9.5%

Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030 and Lancet 2008;372:1195-1196.

• 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, CANVAS, DECLARE 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

• DAPA-HF establishes SGLT2i therapy as part of standard of care GDMT for HFrEF patients

• 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

Diabetes: A Cardiovascular Disease: Implications for Therapy with SGLT InhibitorsDiabetes and Cardiovascular DiseaseSlide Number 3Diabetes and Heart FailureDiabetes and Incident Heart Failure in the USPrevalence of Diabetes in Patients with Heart FailureHeart Failure Rates in Diabetes Glucose Control TrialsSlide Number 8Diabetics and Heart Failure: Poor PrognosisMajor CV Outcome Trials in Type 2 Diabetes Slide Number 12Liraglutide 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 DiabetesPotential CV and Renal Function Preservation Mechanisms of SGLT2i that May Benefit HFEMPA-REG OUTCOME�Trial design: SGLT2 InhibitorSlide Number 21EMPA-REG OUTCOME StudyHeart Failure Hospitalization or CV death Slide Number 24Slide Number 25Heart 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: CANVASDapagliflozin and Cardiovascular Outcomes in Type 2 DiabetesHospitalization for HF in Patients with �T2DM Treated with SGL2i Meta-Analysis: SGLT2 Inhibitors and Heart Failure HospitalizationsSlide Number 34DAPA-HF Trial in HFrEF with or with Type 2 DiabetesSlide Number 36Slide Number 37DAPA-HF Primary Composite OutcomeSlide Number 39Diabetes Status and Effect of SGLT2i in HFrEFAdd DAPA HF slidesSlide Number 42Slide Number 43Potential Mechanisms Involved in the Reduction of Cardiovascular EventsSlide Number 45How Does Empagliflozin Reduce Cardiovascular Mortality? Mediation Analysis of the EMPA-REG OUTCOME TrialInclusion Criteria and Primary Endpoints �Major Trials of SGLT2 Inhibitors in HFSGLT2 Inhibitors, GLP 1 Agonists, and DPP 4 Inhibitors and Outcomes in Patients With Type 2 Diabetes: �Meta-Analysis2016 ESC Guidelines for the Diagnosis and Treatment of Acute & Chronic HFSlide Number 50Slide Number 51Conclusions

diabetes: a cardiovascular disease: implications for...

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