Diabetes and Heart Failure: Truth and Consequences · 2019-10-30 · cardiovascular (CV) risk, including heart failure •Describe the results of cardiovascular outcomes trials of

Diabetes and Heart Failure: Truth and Consequences

Jeffrey Unger, MD

Disclosures: None

10/28/2019

1


Jeff Unger, MD, FAAFP, FACE

Diplomat, American Board of Family Practice

Fellow, American Association of Clinical Endocrinologists

Assistant Clinical Professor of Family Medicine, UC

Riverside School of Medicine

Director, Metabolic Studies; Catalina Research Institute

Director, Unger Concierge Primary Care Medical Group

Rancho Cucamonga, CA

Statement of Sponsorship and Support

This CME Symposium is sponsored by

and supported by an education grant from

AstraZeneca Pharmaceuticals LP.

Statement of Sponsorship and Support

In collaboration with

Join PCMG for opportunities for free CME and more

opportunities to learn about metabolic issues!

10/28/2019

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CME Information

This Live activity, Diabetes and Heart

Failure: Truth and Consequences, from

06/01/2019 - 05/01/2020, has been reviewed

and is acceptable for up to 1.00 Prescribed

credit(s) by the American Academy of Family

Physicians. Physicians should claim only

the credit commensurate with the extent of

their participation in the activity.

Faculty Disclosure Statement

Primary Care Education Consortium adheres to the conflict of interest policy

of the ACCME and the AMA. It is the policy of PCEC to ensure balance,

independence, objectivity, and scientific rigor in all of its educational

activities. All individuals in a position to control the content in our programs

are expected to disclose any relationships they may have with commercial

companies whose products or services may be mentioned so that

participants may evaluate the objectivity of the presentations. In addition,

any discussion of off-label, experimental, or investigational use of drugs or

devices will be disclosed by the faculty. Only those participants who have no

conflict of interest or who agree to an identified resolution process prior to

their participation were involved in the CME activity.

Disclosures Jeff Unger, MD, has disclosed that he is on the advisory board for Abbott Diabetes, Novo Nordisk Diabetes; as well as on the speakers bureau for Abbott and Novo Nordisk. Additionally, he owns stock in Novo Nordisk.

Stephen Brunton, MD, has disclosed that he is on the advisory board for Abbott Diabetes, Salix, Astra Zeneca, Boehringer Ingelheim, Jansen, Lilly, Novo Nordisk, Teva, and Esperion; as well as on the speakers bureau for Astra Zeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk.

Gregory Scott, PharmD, RPh, Editorial Support, disclosed no relevant financial relationship or interest with a proprietary entity producing, marketing, reselling or distributing health care goods or services.

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Learning Objectives

After participating in this presentation, the

learner will be able to:

• Assess patients with type 2 diabetes mellitus for

cardiovascular (CV) risk, including heart failure

• Describe the results of cardiovascular outcomes trials

of glucose-lowering medications for type 2 diabetes

mellitus, focusing on heart failure

• Select glucose-lowering medication shown to be

beneficial in patients with type 2 diabetes mellitus at

risk of heart failure

Diabetes Mellitus as a Cardiovascular Risk Factor

0

5

10

15

20

25

30

35

40

45

Coronary HeartDisease

AtherothromboticBrain Infarction

IntermittentClaudication

Congestive HeartFailure

CardiovascularDeath

CardiovascularDisease

Annual age-a

dju

ste

d e

vent

rate

per

1000

Framingham Heart Study

Women without Diabetes Women with Diabetes

Men without Diabetes Men with Diabetes

Kannel WB, McGee DL. JAMA. 1979;241:2035-2038.

Linear Relationship Between Glycemic Control and HF

RR, relative risk

For

every

1%

increase

in A1c

15%

increase

in RR of

HF

Erqou S, et al. Eur J Heart Fail. 2013;15:185-193.

10 studies involving 178,929 patients with

diabetes and 14,176 incident cases of HF

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Patients with T2DM are at greater Risk of developing HF and being hospitalized due to HF

Patients with T2DM are

2.5x more likely to develop HF than people without T2DM1,2

Risk of hospitalization from HF is

33% higher in patients with T2DM3

Even with optimal glycemic management,

patients with T2DM have a high risk of

morbidity and mortality4

1. Nichols GA, et al. Diabetes Care. 2004;27(8):1879-1884.

2. Komanduri S, et al. J Community Hosp Intern Med Perspect. 2017;7(1):15-20.

3. Cavender MA, et al. Circulation. 2015;132:923-931.

4. Vijaykumar S, et al. Exp Rev Cardiovasc Ther. 2018;16(2):123-131.

UKPDS: 1% HbA1c Decrease and Reduced Risk of Complications

UKPDS, United Kingdom Prospective Diabetes Study

Stratton IM, et al. BMJ. 2000;321:405-412.

43%

37% 19% 16% 14% 12%

Lower-extremity

amputation or

fatal peripheral

vascular disease (P<0.0001)

Microvascular

disease (P<0.0001)

Cataract

extraction (P<0.0001)

Heart failure (P<0.05)

Myocardial

infarction (P<0.0001)

Stroke (P<0.05)

Cardiovascular complications

Initial Presentation of Cardiovascular Disease in T2DM

2.98

1.72

1.64

1.62

1.58

1.56

1.54

1.53

1.45

1.43

0 0.5 1 1.5 2 2.5 3 3.5

Peripheral Arterial Disease

Ischemic Stroke

Stroke Not Further Specified

Stable Angina

Coronary Disease Not Further Specified

Heart Failure

Non-fatal Myocardial Infarction

Unstable Angina

Transient Ischemic Attack

Unheralded Coronary Death

Adjusted Hazard Ratio*

Shah AD, et al. Lancet Diabetes Endocrinol. 2015;3;105-113.

*Adjusted for age, sex, body mass index, deprivation, HDL cholesterol, total cholesterol, systolic blood

pressure, smoking status, and statin and antihypertensive medications

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Worse Prognosis in Patients with HF and T2DM*

*Excluding patients admitted for acute HF caused by acute coronary syndrome without evidence of systolic

or diastolic dysfunction

van den Berge JC, et al. Diabetes Care. 2018;41(1):143-149.

American Diabetes Association. Short and long-term prognosis of patients with acute heart failure with and without diabetes: Changes over the last three

decades, American Diabetes Association, 2018. Copyright and all rights reserved. Material from this publication has been used with the permission of

American Diabetes Association.

Total Population 30-Day Event-Free Survivors

Exercise Capacity is diminished in patients with HFpEF and T2DM

328

297

0

100

200

300

400

Mete

rs

Exercise Capacity (6-minute walk test)

P<0.001

Lindman BR, et al. J Am Coll Cardiol. 2014;64(6):541-549.

HFpEF without Diabetes HFpEF with Diabetes

HFpEF, heart failure with preserved ejection fraction, ie, ejection fraction ≥50%

Patients with T2DM and HFpEF have worse outcomes

MacDonald MR, et al. Eur Heart J. 2008;29:1377-1385.

MacDonald MR, et al for the CHARM Investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure. Eur

Heart J. 2008;29(11):1377-1385 by permission of the European Society of Cardiology.

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How Heart Failure Is Diagnosed

Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-e239.

• History & Physical examination

• Risk scoring- Seattle Heart Failure Model, ADHERE

Clinical Evaluation

• CBC, lytes, urinalysis, BUN, SCr, glucose, fasting lipids, LFTs, TSH

• Biomarkers- BNP, NT-proBNP

• Chest X-ray

• 12-lead ECG

• 2-dimensional echocardiogram with Doppler

• Angiogram

Testing

All of the Major Risk Factors for HF are Associated with Diabetes

Chronic Kidney

Disease

Coronary Heart

Disease

Anemia

Dyslipidemia

Advanced

Age

Sleep Apnea

Hypertension

Obesity

Thomas MC. Curr Cardiol Rev. 2016;12:249-255.

H e a r t F a i l u r e D i a b e t e s M e l l i t u s

Type 2 Diabetes Mellitus

Mechanick JI, et al. Endocr Pract. 2018;24(11):995-1011.

Insulin Resistance

Prediabetes

Type 2 Diabetes Mellitus

Vascular Complications

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Treating Patients with T2DM is more than Glucose Control

There’s also

• Antiplatelet therapy ● Cholesterol ● Exercise

• Blood pressure ● Dietary

And let’s not

forget

• Smoking ● Regular examination of:

• Weight -Eyes, mouth/teeth, feet/skin, kidneys

Plus

• Diabetes distress

• Quality of life

And now

• Choose glucose-lowering medication shown to reduce cardiovascular risk (when possible)

Case Scenario: Fred

• 62 yo man diagnosed with T2DM 10 y ago (A1c 8.6%)

• 3-y history of mixed dyslipidemia

• Complains of occasional SOB, fatigue

• Currently • A1c 7.5% • BMI 30.6 kg/m2 • BP 160/95 mmHg • LDL-C 125 mg/dL • Triglycerides 364 mg/dL • Non-HDL-C 156 mg/dL

• Medications • Metformin 1 g BID • Losartan 100 mg QD • Simvastatin 40 mg QD • ASA 81 mg QD

Case Scenario: Fred (cont)

• Diagnostic evaluation reveals Fred has

heart failure with preserved ejection fraction

• Ejection fraction 60%

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FDA Diabetes Mellitus Guidance - 2008

US Food and Drug Administration.

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf.

Accessed May 10, 2017.

The goal of cardiovascular safety

trials is to demonstrate that the CV

safety of the new glucose-lowering

therapy is SIMILAR TO PLACEBO.

Nomenclature

• Primary vs secondary prevention

• Primary end point:

• Composite of: CV death, non-fatal MI, and

non-fatal stroke

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Diabetes Medication CV Outcomes/Safety Trials

DPP-4i GLP-1RA SGLT-2i

Alogliptin EXAMINE Albiglutide* HARMONY

Canagliflozin

CANVAS

Linagliptin

CARMELINA Dulaglutide REWIND CANVAS-R

CAROLINA Exenatide

QW EXSCEL CREDENCE

Saxagliptin SAVOR-

TIMI53 Liraglutide LEADER Dapagliflozin

DECLARE-

TIMI 58

Sitagliptin TECOS

Lixisenatide ELIXA Empagliflozin EMPA-REG

OUTCOME

Semaglutide SUSTAIN 6 Ertugliflozin VERTIS CV

NOTE: All trials are randomized, double-blind, parallel, placebo-controlled, multi-center

*Will no longer be available as of December 2019.

Case Scenario: Fred






Results of CV Outcomes Trials

CV Safety CV Benefit

Dipeptidyl peptidase-4 inhibitors

Alogliptin

Linagliptin

Saxagliptin

Sitagliptin

Glucagon-like peptide-1 receptor agonists

Albiglutide*

Dulaglutide

Exenatide BID Not required

Exenatide QW

Liraglutide

Lixisenatide

Semaglutide

Sodium glucose cotransporter-2 inhibitors

Canagliflozin

Dapagliflozin

Empagliflozin

Ertugliflozin

CV safety • Non-inferiority

• No increase in CV risk

compared to placebo as

part of standard therapy

CV benefit • If non-inferiority is

demonstrated, can look for

superiority

• Superiority- CV risk

significantly reduced

compared to placebo as

part of standard therapy

*Will no longer be available as of December 2019.

10/28/2019

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Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: SGLT-2 Inhibitors

Canagliflozin (1◦ & 2◦ Prevention)

Endpoint

Rate/100 patient -years

Hazard Ratio (95% CI)

Canagliflozin Placebo

CV death, nonfatal MI, nonfatal strokea 2.69 3.15 0.86 (0.75-0.97)

HF hospitalization 0.55 0.87 0.67 (0.52-0.87)

CV death or HF hospitalization 1.63 2.08 0.78 (0.67-0.91)

Progression of albuminuria 8.94 12.87 0.73 (0.67-0.79)

40% reduction eGFR, renal dialysis or transplantation, renal death

0.55 0.90 0.60 (0.47-0.77)

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; MI, myocardial

infarction aPrimary endpoint

Neal B, et al. N Engl J Med. 2017;377(7):644-657..

Independent of prior stroke at baseline

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: SGLT-2 Inhibitors (cont)

Dapagliflozin (1◦ & 2◦ Prevention)

Endpoint



Dapagliflozin Placebo


CV death or HF hospitalizationa 1.22 1.47 0.83 (0.73-0.95)


≥40% decrease in eGFR to <60 mL/min/1.73 m2, ESRD, or death from renal or CV cause

1.08 1.41 0.76 (0.67-0.87)

CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease;

HF, heart failure; MI, myocardial infarction aPrimary endpoint

Wiviott SD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812389.

Consistent across multiple groups,

including history of ASCVD or heart failure

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: SGLT-2 Inhibitors (cont)

Empagliflozin (2◦ Prevention)

Endpoint

Rate/100 patient-years


Empagliflozin Placebo


All-cause deathb 1.94 2.86 0.68 (0.57-0.82)

CV death 1.24 2.02 0.62 (0.49-0.77)


HF hospitalization or CV death (excluding fatal stroke)

1.97 3.01 0.66 (0.55-0.79)

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; MI, myocardial

infarction aPrimary endpoint bNNT=39 over 3 years

Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.

Independent of prior MI and/or stroke at baseline

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Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: GLP-1 Receptor Agonists

Dulaglutide (1◦ & 2◦ Prevention)

Endpoint


Hazard Ratio

(95% CI)

P

Liraglutide Placebo

CV death, nonfatal MI, nonfatal strokea,b

2.35 2.66 0.88 (0.79-0.99) 0.026

Nonfatal stroke 0.52 0.69 0.76 (0.61-0.95) 0.017

New macroalbuminuria, sustained decline in eGFR ≥30% or chronic renal replacement therapy

3.47 4.07 0.85 (0.77-0.93) 0.0004

aPrimary endpoint

Gerstein HC, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31149-3.

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: GLP-1 Receptor Agonists

Liraglutide (1◦ & 2◦ Prevention)

Endpoint



Liraglutide Placebo

CV death, nonfatal MI, nonfatal strokea,b 3.4 3.9 0.87 (0.78-0.97)

CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for UA or HF

5.3 6.0 0.88 (0.81-0.96)

All-cause deathc 2.1 2.5 0.85 (0.74-0.97)

CV death 1.2 1.6 0.78 (0.66-0.93)

Microvascular event 2.0 2.3 0.84 (0.73-0.97)

Nephropathy 1.5 1.9 0.78 (0.67-0.92)

aPrimary endpoint bNNT=66 over 3 years cNNT=98 over 3 years

Marso SP, et al. N Engl J Med. 2016;375(4):311-322.

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: GLP-1 Receptor Agonists (cont)

Semaglutide (1◦ & 2◦ Prevention)

Endpoint



Semaglutide Placebo

CV death, nonfatal MI, nonfatal strokea,b 3.24 4.44 0.74 (0.58-0.95)

CV death, nonfatal MI, nonfatal stroke, revascularization, hospitalization for UA or HF

6.17 8.36 0.74 (0.62-0.89)

All-cause death, nonfatal MI, nonfatal stroke

3.66 4.81 0.77 (0.61-0.97)

Nonfatal stroke 0.80 1.31 0.61 (0.38-0.99)

Revascularization 2.50 3.85 0.65 (0.50-0.86)

New or worsening nephropathy 1.86 3.06 0.64 (0.46-0.88)

Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.

aPrimary endpoint bNNT=45 over 2 years

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Effect of Selected Glucose-Lowering Medications on Heart Failure Hospitalization


Hazard Ratio

(95% CI) Active Placebo

SGLT-2 Inhibitor

Canagliflozin 0.55 0.87 0.67 (0.52-0.87)

Dapagliflozin 0.62 0.85 0.73 (0.61-0.88)

Empagliflozin 0.94 1.45 0.65 (0.50-0.85)

GLP-1 Receptor Agonist

Dulaglutidea 0.83 0.89 0.93 (0.77-1.12)

Liraglutide 1.2 1.4 0.87 (0.73-1.05)

Semaglutide 1.76 1.61 1.11 (0.77-1.61)

aHF hospitalization or urgent visit

Summary & Implications for Primary Care • Reducing cardiovascular risk is the key treatment

objective for patients with diabetes

• Available evidence shows that medications from 3

classes do not pose an increased risk of major

adverse cardiovascular events

• Available evidence shows that the following

medications reduce the risk of key cardiovascular

outcomes

• SGLT-2 inhibitors: canagliflozin, dapagliflozin,

empagliflozin

• GLP-1 RAs: albiglutide, dulaglutide, liraglutide,

semaglutide

New Paradigm in Diabetes Treatment

American

Diabetes

Association.

Diabetes Care.

2019;42(Suppl

1):S90-S102.

American

Diabetes

Association.

Standards of

medical care in

diabetes-2019,

American

Diabetes

Association,

2019.

Copyright and

all rights

reserved.

Material from

this publication

has been used

with the

permission of

American

Diabetes

Association.

10/28/2019

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Patients with T2DM and Established ASCVD or CKD

American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S90-S102.

American Diabetes Association. Standards of medical care in diabetes-2019,

American Diabetes Association, 2019. Copyright and all rights reserved.

Material from this publication has been used with the permission of American

Diabetes Association.

Case Scenario: Fred






For patients with type 2 diabetes mellitus and established coronary heart disease, which one of the following treatment goals should be optimized?

1. A1c

2. blood lipids

3. blood pressure

4. cardiovascular risk reduction

10/28/2019

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Diabetes and Heart Failure: Truth and Consequences · 2019-10-30 · cardiovascular (CV) risk, including heart failure •Describe the results of cardiovascular outcomes trials of