cardio-renal complications of type 2 diabetes mellitus ... · cardio‐renal complication of type 2...

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Cardio-Renal Complications of Type 2 Diabetes Mellitus: Focus on Heart Failure

Proceedings from a Live Webinar Wednesday, February 26, 2020 1:00 p.m. – 2:00 p.m. ET

On-demand Activity Release Date: March 2, 2020 Expiration Date: August 26, 2020 This webinar is not accredited for continuing education.

FACULTY Ralph J. Riello, III, Pharm.D., BCPS Cardiovascular Critical Care Pharmacist Coronary Intensive Care Unit (CICU) Yale New Haven Hospital Department of Pharmacy Services Heart and Vascular Center New Haven, Connecticut View faculty bio at http://www.ashpadvantage.com/t2dheartfailure

http://www.ashpadvantage.com/t2dheartfailure

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© 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 2

Cardio‐Renal Complications of Type 2 Diabetes Mellitus: Focus on Heart Failure

Ralph J. Riello III, Pharm.D., BCPS

Clinical Pharmacy Specialist, Cardiovascular Critical Care

Yale New Haven Hospital

New Haven, Connecticut

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

• Ralph J. Riello III

– Janssen, Johnson & Johnson, Portola, and

AstraZeneca: consultant

All other planners, presenters, reviewers, ASHP staff, and

others with an opportunity to control content report no

financial relationships relevant to this activity.

Disclosures


Cardio‐Renal Complication of Type 2 Diabetes Mellitus: Focus on Heart Failure

Learning Objectives

• Recognize the causative role of type 2 diabetes mellitus (TD2M) in the development of cardiovascular and renal disease

• Define the prevalence, pathophysiology, and healthcare burden of heart failure (HF) in the United States

• Discuss the risk of HF as an underappreciated complication of T2DM

• Describe the progression of chronic kidney disease (CKD) as a common comorbidity of T2DM

T2DM: Cardio‐Renal Complications



T2DM Epidemiology

Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Accessed February 1, 2020.

Burrows NR, et al. Morbid Mortal Weekly Rep. 2017;66:1165‐70. American Diabetes Association. Diabetes Care. 2019;42(Suppl 1);S103‐S123.

30.3 millionHad BP ≥140/90 mmHg or on antihypertensive medications75%

Die from cardiovascular (CV) disease50%

Of CKD is attributable to diabetes25%

At risk of developing HF50%

T2DM Pathophysiology

Inzucchi SE, Sherwin RS. Cecil Medicine. 2011;267.

++

‐‐

‐‐

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

gutcarbohydratedelivery &absorption

incretineffect

peripheralglucose uptake

TZDsMetformin

DPP‐4 inhibitors

GLP‐1Ragonists

SUs

Insulin

renal glucose excretion

SGLT‐2 inhibitors

HYPERGLYCEMIAHYPERGLYCEMIA



T2DM and CVD Pathophysiology

Kasznicki J et al. Arch Med Sci. 2014;10:546‐56.

Diabetes mellitus

Metabolic Disturbances(Hyperglycemia, Hyperinsulinemia, Insulin Resistance, Dyslipidemia, Obesity)

Oxidative stress, Glycation

Autonomic neuropathy

Inflammation

Cardiac fibrosisCardiac dysfunction

Endothelial dysfunctionAtherosclerotic CVD (ASCVD)

Heart Failure

Activation of Reticular Activating

System (RAS)

Coronary Artery Disease (CAD)

T2DM and HF Pathophysiology

Marwick, TH et al. J Am Coll Cardiol. 2018;71:339‐51.

Perfusion

CAD

Hypertrophy Apoptosis

Δ Glucose UtilizationΔ Fatty Acid UtilizationΔ EC CouplingMitochondrial FunctionDiastolic Dysfunction

Systolic Dysfunction

Diabetic HF

Impaired glucosehandling insulin

resistance

Oxidative Stress

Inflammation Hypertension

Atherosclerosis

Cardiomyocytes

Compliance

AutonomicDysfunction

SystemicMyocardium

Fibrosis

Diabetes



Cardiorenal T2DM Complications

Verma S et al. Lancet. 2018;393:3‐5.

Diabetes affects the

FILTER


PUMP


PLUMBING ASCVD

HEART FAILURE

RENAL DISEASE

HF as a T2DM Complication

Ofstad AP et al. Heart Fail Rev. 2018;23:303‐23.Low Wang C et al. Circulation. 2016;133:2459‐502.Seferović PM et al. Eur Heart J. 2015;36:1718‐27.

Jia G et al. Diabetologia. 2018;61:21‐8.

HEART FAILURE

T2DM causes ischemic HF by increasing CAD and

hypertension risk

T2DM directly induces myocardial structural and

functional changes



HF is more likely than myocardial infarction or stroke to be the first cardiovascular complication of type 2 diabetes?

a. True

b. False

Heart Failure



Epidemiology

Benjamin E et al. Circulation. 2018;137:e67‐e492.

• 6.5 million adults with HF– Increase 46% by 2030

• 960,000 new cases diagnosed annually• 46% five‐year survival rate after diagnosis

– 1 in 9 deaths attributed to HF

• $30.7 billion in healthcare costs per year• #1 hospitalization cause among age >65 y/o

– 25% readmitted within 30 days

• Heart is unable to pump blood at a rate commensurate with tissue demand or only can with high filling pressures

McMurray JJ et al. Eur Heart J. 2012;33:1787‐847. Aziz F et al. J Clin Med Res. 2013;5:327‐34.

Yancy CW et al. Circulation. 2013;62:1495‐539.

Pathophysiology

Impaired left ventricular (LV) filling• During diastole, LV fills with blood• Improper relaxation reduces stroke volume

Impaired blood ejection• During systole, LV ejects blood• Improper ejection reduces cardiac output



• LV ejection fraction (EF) is key HF measurement

Yancy CW et al. Circulation. 2013;62:1495‐539. Bloom MW et al. Nat Rev Dis Primers. 2017;3:1‐19.

Classification

• Portion of blood pumped from heart with each beat– ≥50% is normal

• HF with reduced EF (HFrEF)– ≤40% or systolic HF

• HF with preserved EF (HFpEF) – ≥50% or diastolic HF

• Gold standard assessment of cardiac function

Yancy CW et al. J Am Coll Cardiol. 2013;62:e147‐239.Flores AS et al. J Thorac Dis. 2015;7:2139‐50.

Echocardiography

• Diagnostic ultrasound measurement of LVEF, cardiac volume, mass

• Characterizes structural, flow abnormalities

• Reveals subclinical HF– Predict future CV risk



Biomarker

Nakagawa Y et al. Peptides. 2019; 111:18‐25.Huelsmann M et al. Eur Heart J. 2008;29:2259‐64.Yancy CW et al. Circulation. 2013;128:e240‐e327.

• Counterregulatory, vasoactive hormone– Myocytes release during ventricular wall stress

– Elevated levels indicate HF, rise with severity

• Assay identifies T2DM patients at risk for HF

Kaplan‐Meier Analysis of 631 T2DM Patients Using NT‐proBNP at Cutoff of 125 pg/mL2

1.00

0.95

0.90

0.20

0.15

0.10

0.05

0

0 2 4 6 8 10 12

Months

Death or Unplanned

CV Hospitalization

NT‐proBNP >125 pg/mL (n=358)NT‐proBNP <125 pg/mL (n=273)

P<0.0001

• N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP)

Redfield MM et al. N Engl J Med. 2016;375:1868.Seferović PM et al. Eur Heart J. 2015;36:1718‐27.

Borlaug B. Nat Rev Cardiol. 2014;11:507‐15.Yancy C et al. J Am Coll Cardiol. 2013;62:e147‐e149.

Classification

• Systolic LV dysfunction • Diastolic LV dysfunction

• LV dilation • No LV dilation

• Eccentric LV remodeling • Concentric LV remodeling

• Due to loss of systolic function, typically afteran acute cardiac event

• Due to pro‐inflammatoryCV and non‐CV co‐existing conditions

• Associated with coronary artery disease risk factors (eg, hypertension, diabetes, advanced age, smoking, dyslipidemia)

• Associated with hypertension, obesity, diabetes, metabolic syndrome, lung disease, smoking, and iron deficiency

• Accounts for nearly 50% of all HF cases • Accounts for >50% of all HF cases

HFrEF (Systolic HF) HFpEF (Diastolic HF)



Yancy CW et al. Circulation. 2013;128:e240‐e327. Yancy CW et al. J Am Coll Cardiol. 2017;70:776‐803.

StagingACCF/AHA Stages of HF NYHA Functional Classification

AAt high risk for HF but without structural heart disease or symptoms of HF

None

BStructural heart disease but without signs or symptoms of HF

INo limitation of physical activity. Ordinary physical activity does not cause symptoms* of HF.

CStructural heart disease with prior or current symptoms of HF

INo limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.

IISlight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF.

IIIMarked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF.

IVUnable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

DRefractory HF requiring specialized interventions

IVUnable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

Existing HF

HF Risk

The ACCF/AHA stages progressively worsen such that patients cannot revert to an earlier stage. NYHA functional classes can progress in either direction.

Platz E et al. Eur J Heart Fail. 2015;17:906‐16.Mayo Clinic Cardiology. 2012:858‐63.

Presentation

Trouble SleepingDifficulty breathing at night when recumbent

Swelling in Feet and Ankles

Pulmonary EdemaPleural Effusion

Ascites

+Edema and Fluid Retention Sudden weight gain 2‐3 lbs in 24 hours

Dyspnea

Fatigue and Exercise Intolerance

Dry Cough

Loss of Appetite



Disease Progression

Gheorghiade M et al. Am J Cardiol. 2005;96:11G‐17G.Jencks SF et al. N Engl J Med. 2009;360:1418‐28.De Couto G et al. Nat Rev Cardiol. 2010;7:334‐44.

• Cardiac function progressively declines after acute HF hospitalization

• Exacerbations more frequent after HF diagnosis– >60% readmission rate within 1 year

Acute Event

Myo

cardial Function

Time

Adapted from Gheorghiade M, et al. Am J Cardiol. 2005

Mortality After Acute HF

Loehr L et al. Am J Cardiol. 2008;101:1016‐1022.Chen J et al. JAMA. 2011;306:1669‐1678.

10%

22%

42%

0

20

40

60

Day 30 Year 1 Year 5

Deaths (%

of Patients)

Time after Hospitalization

31% 31% 30%28%

30%

0

10

20

30

40

2000 2002 2004 2006 2008

Risk‐Adjusted 1‐year

Mortality (%

)

Year

Atherosclerosis Risk in Communities (ARIC) Study

US Acute Care Study



HF Hospitalization Rates by EF

Steinberg BA et al. Circulation. 2012;126:65‐75.Andersson C Vasan RS. Heart Fail Clin. 2014;10:377–88.

52% 51% 50% 51% 49% 47%

15% 14% 14% 14% 13% 14%

33% 35% 36% 35% 38% 39%

2005 2006 2007 2008 2009 2010

HFpEF

HFrEF

40‐50%

HF Rehospitalization Risk by Time

Caughey M et al. Am J Cardiol. 2018;122:108‐14.

30 Days

HFpEF

Incidence Rate per 100

Person‐Yea

rs

90 Days 6 Months 1 Year

HFrEF0

40

80

120

160

HFpEFHFrEF HFpEFHFrEF HFpEFHFrEF



Which of the following patient characteristics is associated with an increased risk of heart failure hospitalization?

a. No prior hospitalization for acute decompensated heartfailure

b. Reduced N‐terminal pro‐B‐type natriuretic peptide level

c. Presence of comorbid type 2 diabetes mellitus

d. Absence of comorbid chronic kidney disease

HF as a Complication of T2DM



T2DM and HF Risk

Nichols GA et al. Diabetes Care. 2004;27:1879‐84.Cavender MA et al. Circulation. 2015;132:923‐31.

Zhou L et al. Current Diabetes Reviews. 2009;5:171‐84.Vijaykumar S et al. Exp Rev Cardiovasc Ther. 2018;16:123‐31.

Patients with T2D are

2.5x more likely to develop HF than people

without diabetes

Risk of hospitalization

from heart failure was

33% higherin patients with diabetes

Even with optimal glycemic management, patients with T2D

and HF have a high risk of

morbidity and mortality

The prevalence of HF in US

patients with T2DM is

as high as 22%

HF Risk by T2DM Control

Iribarren C et al. Circulation. 2001;103:2668‐73.

4.5

5.86.3

8.3

9.2

0

1

2

3

4

5

6

7

8

9

10

<7 7 to <8 8 to <9 9 to <10 10

Rates of HF Hospitalization or

Death per 1000 Person‐Years

Hemoglobin A1C (%)

≥



HF Risk by T2DM Control

Matsushita K et al. Diabetes. 2010;59:2020–6.Hemoglobin A1c (%)

Adjusted in

cidence rate of HF

(per 1000 patient years) P

roportio

n of P

opulatio

n (%

)

HF risk increases linearly above an A1c 5.0%

HF Risk by T2DM and Age

Nichols GA et al. Diabetes Care. 2001;24:1614–9.

Prevalence of HF by AgeIncidence of HF by Age

Age at baselinePrevalence rate per 1000 People

400

300

200

100

0<45 45–54 55–64 65–74 75–84 85–94 95+

Diabetes patients

Control patients

80

60

40

20

0<45 45–54 55–64 65–74 75–84 85–94 95+

Age at baseline

Incidence rate per 1000 People

Diabetes patients

Control patients



HF and T2DM Share Risk Factors

Thomas MC. Curr Cardiol Rev. 2016;12:249‐55.

Hypertension

Advanced AgeDyslipidemia

Chronic Kidney Disease

CoronaryHeart Disease

Obesity

RISKFACTORSFOR HF

ALL are associated with diabetes

Risk of T2DM Complications

Bergenstal RM et al. Am J Med. 2010;123:374.e9‐374.e18.Foley RN et al. J Am Soc Nephrol. 2005;16:489‐95.Haffner SM et al. N Engl J Med. 1998;339:229‐34.

Noel RA et al. Diabetes Care. 2009;32:834‐8.Trautner C et al. Diabetes Care. 1997;20:1147‐53.

Events per 1000 Patient‐years0 20 40 60 80 100

CHF

MI (prior MI)

PVD

Stroke (prior MI)

MI (no prior MI)

Death

Stroke (no prior MI)

Pancreatitis

End Stage Renal Disease

Blindness



Risk of T2DM Complications

Shah AD et al. Lancet Diabetes Endocrinol. 2015;3:105‐13.

16%

14%

12%10%

4%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

PAD Heart Failure Nonfatal MI Stroke CV death

Initial C

V event presentations (of

6,137 events in

T2DM cohort,%

)

16%

27%

25%

32%

Diastolic LVDn=61

LV Dysfunction Precedes HF in T2DM

Shah AD et al. Lancet Diabetes Endocrinol. 2015;3:105‐13.

Systolic LVDn=106

Normal LVFunctionn=124

Systolic andDiastolic LVD

n=95

● 68% of T2DM patients had LV dysfunction (LVD) 5 years after diagnosis

● LVD was without evidence of inducible ischemia by stress testing at baseline



Undiagnosed HF is Common in T2DM

Boonman‐de Winter LJ et al. Diabetologia. 2012;55:2154–62.

●High risk subsets−BMI ≥30 kg/m2

−Hypertension−Age >65 y/o−Female−Fatigue−Dyspnea

No HF72%

HFrEF5%

HFpEF23%

T2DM Patients Previously Undiagnosed with HF (n=581)

T2DM Worsens HF Hospitalization Risk

Cavender MA et al. Circulation. 2015;132:923‐31.

5.9%

9.4%

0%

2%

4%

6%

8%

10%

Incidence of HF

Hospitalization (%)

DiabetesNo Diabetes

Risk of HF hospitalization was 33% higher in T2DM patients



Comorbid T2DM and HF Worsens Survival

Bertoni AG et al. Diabetes Care. 2004;27:699‐03.

0

0.25

0.50

0.75

1.00

Years

Proportion Surviving

0 1 2 43 5

Diabetes with incident HF(n=46,720)

Diabetes without HF(n=69,083)

P<0.001

HF significantly decreased survival in T2DM patients

T2DM Worsens Overall CV Risk

MacDonald MR et al. Eur Heart J. 2008;29:1377‐85.

CV Death or Hospitalization Due to HF60

40

20

0

Follow‐Up (Years)0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Diabetes (HFrEF)

No Diabetes (HFrEF)Diabetes (HFpEF)

No Diabetes (HFpEF)

Cumulative In

cidence, % T2DM increased CV morbidity

and mortality, irrespective of EF



Relative to patients without type 2 diabetes mellitus, which complication occurs most commonly?

a. End stage renal disease

b. Myocardial infarction

c. Heart failure

d. Stroke

CKD as a Complication of T2DM



CKD is a Common T2DM Complication

Afkarian M et al JAMA. 2016;316:602‐10.

●~26% of T2DM patients have diabetic nephropathy −Persistent albuminuria, reduced glomerular filtration rate (GFR), or both

High CKD Prevalence Among T2DM

Murphy D et al. Ann Intern Med. 2016;165:473‐81.

4.15.3

14.3

19.1

0

5

10

15

20

25

1988‐1994 2011‐2012

Prevalence of CKD (%)

Without DiabetesDiabetes

Prevalence of CKD is 3 times higher in T2DM



CKD Progression in T2DM

Williams ME. Med Clin North Am. 2013;97:75‐89.

Preclinical Incipient diabeticnephropathy

Overt diabeticnephropathy

End‐stagerenal disease

Proteinuria

Mesangial nodules (Kimmelsteil‐Wilson lesions)Tubulointerstitial fibrosis

Mesangial expansion,glomerular basementmembrane thickening,arteriolar hyalinosis

Microalbuminuria,hypertension

Proteinuria, nephrotic syndrome, GFRGFR

Renalhypertrophy

GFR

Functional

Structural

Years0

50

100

150

GFR

(mL/min/1.73 m

2)

Urin

ary protein excre

tion

(mg/24 hours)

5000

1000

200

20

5 10 15 20 25

Cardio‐Renal T2DM Connection

Connelly K et al. Cell Metab. 2018;28:813‐15.

Diabetes

Na+ RetentionHypervolemiaRAAS activationNeurohumoral

ActivationInflammationIschemia

Altered Energetics

Consider cardio‐renal systems together



CKD Increases HF Risk

Nayor M et al. Eur J Heart Fail. 2017;19:615‐23.

Cumulative in

cidence of HF CKD HFrEF

CKD HFpEFNo CKD HFrEFNo CKD HFpEF

0 2 4 6 8 10 12

8%

6%

4%

2%

0%

Years7281764479948318859688458983

No. at Risk

511596648711783854906CKDNo CKD

Higher incidence rates of HF among CKD patients

CKD Progression Worsens CV Risk

Go AS et al. N Engl J Med. 2004;351:1296‐305.

Reduced GFR increases risk of major adverse CV events

2.113.65

11.29

21.8

36.6

0

5

10

15

20

25

30

35

40

≥60 45‐59 30‐44 15‐29 <15

Estimated GFR (ml/min/1.73m2)

Age‐Standardized Rate of CV Events

(per 100 person/yr)



Which of following statements describing diabetic nephropathy is true?

a. Prevalence of CKD is equivalent with and without diabetes

b. Risk of HF decreases with progressive renal dysfunction

c. Proteinuria and GFR increase with the progression to ESRD

d. Decreased GFR correlates with risk for adverse CV events

Summary



Summary

• T2DM is associated with multiple cardio‐renal comorbidities, worse outcomes, and increased healthcare costs

• Both HF and T2DM prevalence are increasing• Diabetes increases risk for HF, CVD, and CKD• Earlier identification and management of T2DM patients at risk for HF is critical

Potential Action Items

• Evaluate type 2 diabetes mellitus (T2DM) patients for risk of cardiovascular and renal complications

• Collaborate with a multidisciplinary team of endocrinology, cardiology, and nephrology specialists early in the diabetes care continuum

• Help develop a T2DM management algorithm prioritizing antihyperglycemic agents with demonstrated cardiorenal benefits

• Optimize individual T2DM treatment plans to reduce heart failure hospitalization rates among at risk patients

• Champion discussion of diabetes as a risk equivalent for heart failure among pharmacy, nursing, and medical colleagues



Selected Resources

• Dunlay SM, Givertz MM, Aguilar D et al. Type 2 diabetes mellitus and heart failure: a scientific statement from the American Heart Association and the Heart Failure Society of America: this statement does not represent an update of 2017 ACC/AHA/HFSA heart failure guideline update. Circulation. 2019; 140:e294‐e324.

• Cherney DZI, Repetto E, Wheeler DC et al. Impact of cardio‐renal‐metabolic comorbidities on cardiovascular outcomes and mortality in type 2 diabetes mellitus. Am J Nephrol. 2020;51(1):74‐82.

• Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus: impact of glucose‐lowering agents, heart failure therapies, and novel therapeutic strategies. Circulation Research. 2019;124:121‐41.

Thank you for joining us

• On‐demand activity coming March 2020

• Related topics in this series coming soon www.ashpadvantage.com/t2dheartfailure/

www.ashpadvantage.com/t2dheartfailure

This activity is not eligible for CE Credit


cardio-renal complications of type 2 diabetes mellitus ... · cardio‐renal complication of type 2...

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