diabetes and heart failure: truth and consequences · 2019-10-30 · cardiovascular (cv) risk,...
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Diabetes and Heart Failure: Truth and Consequences
Jeffrey Unger, MD
Disclosures: None
10/28/2019
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Diabetes and Heart Failure: Truth and Consequences
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
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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
• 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
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
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)
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
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)
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
Rate/100 patient -years
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
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 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
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
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
• 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
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
Diabetes and Heart Failure: Truth and Consequences