Transcript
Page 1: Diabetes and Heart Failure: Truth and Consequences · 2020-02-28 · Diabetes and Heart Failure: Truth and Consequences Learning Objectives Assess patients with type 2 diabetes mellitus

Diabetes and Heart Failure: Truth and Consequences

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Paul P. Doghramji, MD, FAAFP

Family Practice Physician

Collegeville Family Practice & Pottstown Medical Specialists, Inc.

Medical Director of Health Services, Ursinus College – Collegeville, PA

Attending Family Practice Physician, Pottstown Memorial Medical Center – Pottstown, PA

Diabetes and Heart Failure: Truth and Consequences

Learning Objectives

▪ 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

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Coronary HeartDisease

AtherothromboticBrain Infarction

IntermittentClaudication

Congestive HeartFailure

CardiovascularDeath

CardiovascularDisease

An

nu

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ag

e-a

dju

ste

d e

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nt

rate

pe

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Framingham Heart Study

Women without Diabetes Women with Diabetes

Men without Diabetes Men with Diabetes

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

Diabetes Mellitus as a Cardiovascular Risk Factor

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

2.5x more likelyto develop HF than people without T2DM1,2

Risk of hospitalization from HF is

33% higherin 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.

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

UKPDS = United Kingdom Prospective Diabetes StudyStratton 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

UKPDS: 1% HbA1c Decrease and Reduced Risk of Complications

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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

*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

Worse Prognosis in Patients with HF and T2DM*

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Heart Failure with Preserved Ejection Fraction (HFpEF)

▪ Also referred to as “diastolic heart failure”

▪ Characterized by signs and symptoms of heart failure

and LVEF > 50%

▪ Heart failure associated with intermediate reductions

in LVEF (40% to 49%) is also commonly grouped into

this category

Pathophysiology of HFpEF

▪ Abnormalities of active ventricular relaxation and passive

ventricular compliance, resulting in ventricular stiffness and

higher diastolic pressures

▪ These pressures are transmitted through atrial and pulmonary

venous systems, reducing lung compliance

▪ A combination of decreased lung compliance and cardiac

output leads to symptoms

▪ Physiologic stressors, such as a hypertensive crisis, can

overcome compensatory mechanisms and result in

pulmonary edemaBorlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670–679.

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Epidemiology

▪ ~5 million persons in the United States have been diagnosed

with heart failure, with an incidence of more than 650,000 new

diagnoses per year

▪ Almost one-half of patients with heart failure have preserved

ejection fraction

▪ Risk factors: older age, female sex, obesity, hypertension,

tobacco use, diabetes mellitus, coronary artery disease (CAD),

valvular heart disease, and atrial fibrillation

Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the

Framingham Heart Study of the National Heart, Lung, and Blood Institute. Circulation. 2009;119(24):3070–3077.

Chronic Kidney

Disease

Coronary Heart

Disease

AnemiaDyslipidemia

Advanced

Age

Sleep ApneaHypertension

Obesity

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

Heart Failure Diabetes Mellitus

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

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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.

Signs and Symptoms of HFpEF

▪ Fatigue

▪ Weakness

▪ Dyspnea

▪ Orthopnea

▪ Paroxysmal nocturnal dyspnea

▪ Jugular venous distention on exam

▪ S3 heart sound

▪ Displaced apical impulse

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Framingham Criteria for Diagnosis of Heart Failure

Major criteria

▪ Acute pulmonary edema

▪ Cardiomegaly

▪ Hepatojugular reflux

▪ Neck vein distention

▪ Paroxysmal nocturnal

dyspnea/orthopnea

NOTE: Heart failure is present in patients with at least two major criteria or one major and two minor criteria (positive

likelihood ratio = 10; negative likelihood ratio = 0.4)

Minor criteria ▪ Ankle edema

▪ Dyspnea on exertion

▪ Hepatomegaly

▪ Nocturnal cough

▪ Pleural effusion

▪ Tachycardia (pulse > 120)

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285(26):1441–1446.

Diagnostic Tests

▪ Brain natriuretic peptide (BNP)

▪ IN ER: <100 pg per mL (100 ng per L) rules out acute heart failure

▪ In primary care setting: <35 rules out heart failure in low risk patients

▪ N-terminal pro-BNP (NT pro-BNP)

▪ IN ER: <300 pg per mL (300 ng per L) can reliably rule out acute heart failure

▪ In primary care setting: <125 rules out heart failure in low risk patients

▪ EKG: reduced likelihood of heart failure when normal

▪ CXR: moderately helpful when abnormal, not so much when normal

Mant J, Doust J, Roalfe A, et al. Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different

diagnostic strategies in primary care. Health Technol Assess. 2009;13(32):1–207.

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Diagnostic Tests (cont’d)

▪ Trans-thoracic echocardiogram (TTE)

▪ Preferred test to confirm HFpEF

▪ The combined finding of normal left ventricular systolic

function and diastolic dysfunction confirms HFpEF

▪ Transesophageal echocardiography is not recommended

for routine evaluation of HFpEF

Chinnaiyan KM, Alexander D, Maddens M, McCullough PA. Curriculum in cardiology: integrated diagnosis and management of diastolic heart failure. Am Heart J.

2007;153(2):189–200.

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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%

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.

Patients with T2DM and HFpEFhave worse outcomes

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STAGE RECOMMENDATION

A: Heart failure risk factorsGuideline-directed treatment of hypertension and

hyperlipidemia

B: Diastolic dysfunction without symptoms

Treat hypertension with thiazide diuretics, ACE

inhibitors, or nondihydropyridine calcium channel

blockers

C: Symptomatic heart failure with preserved

ejection fraction and hypertension

Treat volume overload with diuretics; consider use of

beta blockers, ACE inhibitors

D: Symptomatic heart failure with preserved

ejection fraction without hypertensionTreat volume overload with diuretics

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology

Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147–e239.

AHA/ACC Recommendations for Treatment

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

Type 2 Diabetes Mellitus

Insulin Resistance

Prediabetes

Type 2 Diabetes Mellitus

Vascular Complications

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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)

Treating Patients with T2DM is more than Glucose Control

▪ 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

Exam findings:

▪ JVD

▪ S3

▪ Ankle edema

Case Study: David

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▪ BNP =75, NTBNP = 150

▪ EKG normal

▪ CXR normal

▪ TEE: reveals David has heart failure with preserved

ejection fraction

▪ Ejection fraction 60%

Case Study: David (cont)

US Food and Drug Administration.

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

Accessed February 10, 2020.

FDA Diabetes Mellitus Guidance - 2008

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The goal of cardiovascular safety trials is to demonstrate that the CV safety of the new glucose-lowering therapy is

SIMILAR TO PLACEBO.

▪ Primary vs secondary prevention

▪ Primary end point:

▪ Composite of CV death, non-fatal MI, and

non-fatal stroke

Nomenclature

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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 DapagliflozinDECLARE-TIMI

58

Sitagliptin TECOS

Lixisenatide ELIXA EmpagliflozinEMPA-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.

Results of CV Outcomes Trials

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

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*Will no longer be available as of December 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 death0.55 0.90 0.60 (0.47-0.77)

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

Independent of prior stroke at baseline

CV = cardiovascular; eGFR = estimated glomerular filtration rate;

HF = heart failure; MI = myocardial infarctionaPrimary endpoint

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

Dapagliflozin(1◦ & 2◦ Prevention)

Endpoint

Rate/100 patient -

years

Hazard

Ratio

(95% CI)Dapagliflozin Placebo

CV death, nonfatal MI, nonfatal strokea 2.26 2.42 0.93 (0.84-1.03)

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

HF hospitalization 0.62 0.85 0.73 (0.61-0.88)

≥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)

Consistent across multiple groups,

including history of ASCVD or heart failure

ESRD = end-stage renal diseaseaPrimary endpoint

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

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

Empagliflozin(2◦ Prevention)

Endpoint

Rate/100 patient -

years

Hazard

Ratio

(95% CI)Empagliflozin Placebo

CV death, nonfatal MI, nonfatal strokea 3.74 4.39 0.86 (0.74-0.99)

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 0.94 1.45 0.65 (0.50-0.85)

HF hospitalization or CV death

(excluding fatal stroke)1.97 3.01 0.66 (0.55-0.79)

Independent of prior MI and/or stroke at baselineaPrimary endpoint bNNT=39 over 3 years

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

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: GLP-1 Receptor Agonists

Dulaglutide(1◦ & 2◦ Prevention)

Endpoint

Rate/100 patient -

years

Hazard

Ratio

(95% CI)

P

Dulaglutide Placebo

CV death, nonfatal MI, nonfatal

strokea 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.

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

Liraglutide(1◦ & 2◦ Prevention)

Endpoint

Rate/100 patient -

years

Hazard

Ratio

(95% CI)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

Rate/100 patient -

years

Hazard

Ratio

(95% CI)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

stroke3.66 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)

aPrimary endpoint bNNT=45 over 2 years

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

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Effect of Selected Glucose-Lowering Medications on Heart Failure Hospitalization

Rate/100

Patient - years

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

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

Updated Prescribing

Information to Reflect CV Outcomes

Trials

*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.

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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.

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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.

▪ 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 Study: David

Diagnosed with HFpEF

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