diabetes and heart failure: truth and consequences · 2020-05-27 · •assess patients with type 2...

Diabetes and Heart Failure: Truth and Consequences

Michael Cobble, MD, FNLA Director

Canyon Medical Center Sandy, Utah

Adjunct Faculty University of Utah

Salt Lake City, Utah

Statement of Sponsorship and Support

This CME Symposium is sponsored by

and supported by an education grant from

AstraZeneca Pharmaceuticals LP.

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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

Michael Cobble, MD, has disclosed that he is on the speakers bureau for Amarin, Amgen, AstraZeneca and Regeneron for the clinical conditions of Lipids, CAD and Diabetes.

Stephen Brunton, MD, has disclosed that he is on the advisory board for Abbott Diabetes, AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi and Xeris Pharmaceuticals; as well as on the speakers bureau for AstraZeneca, Bayer, 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.

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

Cardiovascular Death CardiovascularDisease

An

nu

al a

ge-a

dju

sted

eve

nt

rate

per

10

00

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

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

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

Met

ers

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.

How Heart Failure Is Diagnosed

• 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

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

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

Insulin Resistance

Prediabetes

Type 2 Diabetes Mellitus

Vascular Complications

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

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%

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

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 *No longer available as of December 2019.

Case Scenario: Fred


dyslipidemia




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

*No longer available as of December 2019.

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

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

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

Updated Prescribing Information to Reflect CV Outcomes Trials

MACE FDA Labeling Regarding CV Risk

GLP-1 Receptor Agonists

Albiglutide* –

Dulaglutide –

Exenatide

once-weekly

Liraglutide …to reduce the risk of major adverse CV events (CV death, non-fatal myocardial infarction, or non-fatal

stroke) in adults with T2DM and established CV disease

Lixisenatide

Semaglutide –

SGLT-2 Inhibitors

Canagliflozin

…to reduce the risk of major adverse CV events in adults with T2DM and established CV disease

…to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, CV death, and

hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria ˃

300 mg/d

Dapagliflozin …to reduce the risk of hospitalization for heart failure in adults with T2DM and established CV disease or

multiple CV risk factors

Empagliflozin …to reduce the risk of CV death in adults with T2DM and established CV disease

Ertugliflozin

*No longer available as of December 2019

Tanzeum [package insert]. Research Triangle, NC: GlaxoSmithKline; December 2017. Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Co.; January 2019. Bydureon [package insert]. Wilmington, DE: Astrazeneca Pharmaceuticals LP; February 2019. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; September 2019. Adlyxin [package insert]. Bridgewater, NJ: Sanofi-aventis U.S., LLC; January 2019. Ozempic [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; April 2019. Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; October 2019. Farxiga [package insert]. Wilmington, DE: Astrazeneca Pharmaceuticals LP; October 2019. Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2019. Steglatro [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; October 2018.

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.

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


dyslipidemia




Diabetes and Heart Failure: Truth and Consequences

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diabetes and heart failure: truth and consequences · 2020-05-27 · •assess patients with type 2...

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