Heart Failure: The Frequent, Forgotten and often Fatal Complication of Type 2 Diabetes

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1 Heart Failure: The Frequent, Forgotten and often Fatal Complication of Type 2 Diabetes DAVID S. H. BELL CHAIRMAN BELL, DSH. DIABETES CARE(2003)26:

2 The Rest of the Story? Two CVD Disorders 1) Disorders of perfusion due to atherosclerosis 2) Disorders of cardiac structure and function due to LVH and LV dysfunction

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5 Prevalence Rate per 1000 Incidence Rate per 1000 Congestive Heart Failure Is More Common in Patients With Type 2 Diabetes No Diabetes Diabetes < < Age at Baseline Nichols, GA, et al. Diabetes Care. 2001; 24:

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8 CHEMO-RELATED CARDIOTOXICITY 83 PATIENTS (54 BREAST, 20 LYMPHOMA, 9 GASTRIC) PRESENCE OF REDUCED E# AND GLOBAL LONGITUDINAL STRAIN IN DIABETIC SUBJECTS Gomez, AC. Euro Echo-Imaging(2016) Leipzig Germany Dec 7-10.

9 PROGNOSIS OF DIABETES AND HEART FAILURE HR ALL CAUSE MORTALITY CV MORTALITY HOSPITALIZATION DEATH OR HOSPITALIZATION CI Dauriz, M. Diabetes Care(2017)40:

10 DIABETES STATUS AND OUTCOMES IN HEART FAILURE Kristensen, SL. Circ Heart Fail(2016)9(1)e0025

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12 Cardiotoxic Triad Diabetic cardiomyopathy Hypertension Myocardial ischemia Macrovascular Microvascular No lactate increase during atrial pacing Endothelial dysfunction leading to vasconstriction, reperfusion injury, and myocardial fibrosis Endothelial dysfunction leading to vessel permeability and myocardial fibrosis Genda A et al. Clin Cardiol. 1986;9: Ahmed SS et al. Am Heart J. 1975;89: Factor SM et al. The Diabetic Heart. 1991;89:101.

13 LV Hypertrophy and Diabetes Framingham Study: Women with diabetes had a ventricular mass 22% greater than their nondiabetic peers 1 Tayside Study: LV hypertrophy present in 32% of normotensive patients with type 2 diabetes independent of CAD, ACEIs, or HTN 2 Echocardiographic study of 371 subjects with type 2 diabetes showed that 71% had LV hypertropy 3 Relative risk of death in African Americans with*,4 : LV hypertrophy: 2.4 LV systolic dysfunction (EF 45%): 2.0 Coronary artery disease: 1.6 *Based on cohort study from a hospital registry with a mean follow-up of 5 years. 26.1% of those studied had diabetes. 1. Galderisi M. Am J Cardiol. 1991;68: Struthers AD. Lancet. 2002;359: Dawson A et al. Diabetologia. 2005;48: Liao Y. JAMA. 1995;273:

14 Diabetic Cardiomyopathy 1) Diastolic Dysfunction 30% by Echo 52% - 60% using pulse waved doppler examinations during second stage of valsalva maneuver Frequency proportional to A 1C Degree proportional to level of microalbuminuria Redfield MM JAMA (2003) 289: Poirier P Diabetes Care (2001) 24:5-10 Devereux JB Circulation (2000) 101: Liu JE J Am Coll Cardiol (2003) 42:2022-8

15 MECHANISMS FOR DIABETIC CARDIOMYOPATHY (2) 4) BIOCHEMICAL - Ca AND K CHANNELS - Na/Ca EXCHANGERS - Ca BINDING PROTEINS - MITOCHONDRIAL Ca UNIPORTER 5) UPREGULATION OF RAS 6) OXIDATIVE STRESS 7) GLYCATION OF PROTEINS 8) ACTIVATION OF PKC

16 MECHANISMS FOR DIABETIC CARDIOMYOPATHY (1) 1) ENDOTHELIAL DYSFUNCTION 2) AUTONOMIC NEUROPATHY - IMPAIRED VASODILATION TO SYMPATHETIC RESPONSE - IMPAIRED CONTRACTILITY 3) METABOLIC - GLUCOSE LACTATE METABOLISM - ENHANCED FFA METABOLISM LIPID ACCUMULATION LIPOTOXICITY APOPTOSIS

17 CERAMIDE MYOCARDIAL APOPTOSIS IR INSULIN LVH GLUCOSE MICROVASCULAR GLYCOSOCATION FIBROSIS PROPOSED ETIOLOGY OF DIABETIC CARDIOMYOPATHY

18 Background on Remodelling Acute infarction (hours) Infarct expansion (hours to days) Global remodelling (days to months) Improvement of LV remodelling has been associated with improvement in mortality and morbidity outcomes in CHF

19 Myocardial Remodeling Sustained Increase in Cardiac Volume Hyperinsulinemia Hyperglycemia Connelly CM, et al. Circulation. 1991;84: Ohya Y, et al. Hypertension. 1996;27:

20 Cardiac Remodeling Gothic Arch Dysfunction Roman Arch Fibrosis Normal Left Ventricle Reversal of Remodeling Remodeled / Dilated Left Ventricle Reduced Wall Compliance Increased Wall Stress Increased Filling Pressure Coghlan HC, Coghlan L. Semin Thorac Cardiovasc Surg. 2001;13: Decreased Contractile Performance

21 Progression of Cardiovascular Disease Coronary artery disease Arrhythmia Hypertension Left ventricular injury Pathologic remodeling LV dysfunction Death Diabetic Cardiomyopathy Diabetes (Metabolic Syndrome) (Hypertrophy, Myocyte Loss, Fibrosis) Neurohormonal activation Pump failure

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27 Ventricular Function and Autonomic Imbalance Ventricular function. Abnormal left ventricular responses to exercise in patients with CAN. Depressed left ventricular systolic function in the absence of ischemic heart disease in approximately one-third of patients with autonomic neuropathy. Reduced mean ejection fractions at rest and with maximal exercise Abnormal diastolic function has been found in patients with more severe CAN. This finding was correlated with a reduction in catecholamine levels and postural hypotension, indicating sympathetic involvement with cardiac diastolic dysfunction. Kahn JK, Zola B, Juni J, Vinik A: Decreased exercise heart rate and blood pressure response in diabetic subjects with cardiac autonomic neuropathy. Diabetes Care 9:389-94, Kahn JK, Sisson JC, Vinik AI: Prediction of sudden cardiac death in diabetic autonomic neuropathy. J Nucl Med 29: , Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologia 34:182-85, Kahn JK, Zola B, Juni JE, Vinik AI: Radionuclide assessment of left ventricular diastolic filling in diabetes mellitus with and without cardiac autonomic neuropathy. J Am Coll Cardiol 7: , 1986.

28 TRACE: Effect of Trandolapril on CHF Progression after Acute MI Diabetics Non-Diabetics Placebo Placebo 0.2 Trandolapril Trandolapril Relative risk, 0.38 p < Years Relative risk, 0.81 p = Years TRACE JACC 1999; 34; 83-89

29 Mortality Risk Reduction (%) Meta-Analysis of COREG Placebo-Controlled Outcomes Trials (HF or Post-MI LVD): Mortality All Patients Patients Without DM Patients With DM P.0001 P.0001 P=.029 Treatment by Diabetes Interaction P=NS Meta-analysis of trials include: US Carvedilol Trials, ANZ Heart Failure study, CAPRICORN, and COPERNICUS. All patients with LVD in these trials were included in the meta-analysis. Bell DSH et al. Curr Med Res Opin. 2006;22:

30 NEPRILYSIN IN NATURE DEGRADES PEPTIDE (ANGIOTENSIN BRADYKININ) INHIBITION NO BP EFFECT DUE TO ACTIVATION OF RENIN/ANGIOTENSIN/ALDOSTERONE LOWERED BP COMBINED WITH VALSARTAN DECREASED HOSPITAL ADMISSION FOR HF DECREASED CV AND TOTAL MORTALITY Paradigm HF Trial (NEJM).

31 TREATMENT EFFECTS OF SACUBITRIL/VALSARTAN VERSUS ACE INHIBITOR RR 95% CI HF HOSP/CV DEATH CV DEATH HF HOSP MORTALITY (ALL CAUSE) CLINICAL SCORE Kristensen, SL. Circ Heart Fail(2016)9(1)e

32 VITAMIN D AND HOSPITALIZATION FOR HEART FAILURE ITALIAN ADULTS > 35 WITHOUT HF (n=19092) LESS THAN 10 VERSUS OVER 30 ng/ml HR 1.61 ( ) Constanzo, S. Nutrition Metabolism and Cardiovasc Dis(2017).

33 TESTOSTERONE AND HEART FAILURE 25% WITH HF LOW T PROPORTIONAL TO HF SEVERITY LOW T ASSOCIATED WITH CARDIAC CACHEXIA (HIGH MORTALITY) IV T INCREASES EF AND DECREASES PERIPHERAL RESISTANCE, INFLAMATORY MEDIATORS AND REDUCES LV FIBROSIS LONG-ACTING T IMPROVES EXERCISE CAPACITY WITHOUT IMPROVED EF Elagizi, A. Mayo Clinic Proceedings(2018)93(1)

34 HEART FAILURE normal EJECTION FRACTION (HFnEF) 40%-60% ADMISSIONS WITH HF DIABETES 45% OTHER FACTORS AGE, FEMALE HYPERTENSION, OBESITY, AF, CAD Mentz, RJ. J Am Coll Cardiol(2014)64(21)

35 Diastolic Dysfunction Documented in young diabetic patients, most of whom have type 1 DM 30% incidence on standard echocardiography With more rigorous Doppler methods, early diastolic dysfunction can be diagnosed Diastolic dysfunction seen in 52% of diabetic patients in Olmstead County, Minnesota Diastolic dysfunction seen in 60% of diabetic patients in Quebec, Canada Discharge diagnosis of idiopathic cardiomyopathy more common in the diabetic patient Schannwell CM et al. Cardiology. 2002;98: Di Bonito P et al. Diabet Med. 1996;13: Redfield MM et al. JAMA. 2003;289: Poirier P et al. Diabetes Care. 2001;24:5-10. Bertoni AG et al. Diabetes Care. 2003;26:

36 CARDIAC REMODELING AND DM DM MYOCARDIAL REMODELING IR INFLAMATION DYSFUNCTION AGE/LIPOTOXICITY FREE RADICAL APOPTOSIS CARDIOMYOCYTE HYPERTROPHY FIBROSIS HFpEF HFrEF Paulus, WJ. JACC Heart Failure(2018)6(1)

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38 HPnEF 1) LARGE CLINICAL TRIALS HAVE NOT SHOWN LIMITED EVIDENCE OF CLINICAL BENEFIT 2) AGGRESSIVE MANAGEMENT OF CONTRIBUTING FACTORS HTN, AF, MYOCARDIAL ISCHEMIA AND SLEEP APNEA BENEFICIAL 3) DIURETICS TO IMPROVE DYSPNEA 4) AVOID UNBENEFICIAL THERAPIES 5) SALT AND WATER RESTRICTON, EXERCISE Basaraba JE, Barry AR. Pharmacotherapy(2015)35(4)

39 LOWERING LEFT ATRIAL PRESSURE IN HFnEF (1) 1) THERAPEUTIC OPTIONS LIMITED 2) INCREASED LEFT ATRIAL PRESSURE ESPECIALLY DURING EXERCISE IS A KEY CONTRIBUTOR TO SYMPTOMS 3) 8 mm PERMANENT SHUNT IN ATRIAL SEPTUM TO LOWER LEFT ATRIAL PRESSURE 4) AT 30 DAYS LV FILLING PRESSURE REDUCED FROM 19.7 TO 14.2 mmhg (p=0.005) 5) NYHA CLASS IMPROVED IN 63.6% OF SUBJECTS 6) NO PULMONARY HYPERTENSION Søndergaard, L. Eur J Heart Fail(2014)16(7)

40 From: Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failurean analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme Eur Heart J. 2008;29(11): doi: /eurheartj/ehn153 Eur Heart J Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org

41 CHINESE PROVERB A MEDIOCRE PHYSICIAN TREATS END-STAGE DISEASE A GOOD PHYSICIAN TREATS DISEASE A GREAT PHYSICIAN PREVENTS DISEASE

42 DIAGNOSIS AND Rx OF DIABETIC HF SIGNS AND SYMPTOMS BNP/PRO-BNP ECHO <40% >40% Rx UNDERLYING PATHOLOGY (HTN+HF) REVASCULARISATION EXERCISE SLEEP ANEA B-BLOCKERS ALDOSTEONE BLOCKADE VALSARTAN/SACUBITRIL (ENTRESTO)

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46 Cell Exocytosis of insulin Ca 2+ GLUT 2 Glucose Protein Phosphorylation? Ca 2+ influx Voltage gated Ca 2+ channel Glucose-6- phosphate Glucokinase Glucose metabolism K + Cell depolarization ATP-sensitive K + channel

47 METFORMIN AND HEART FAILURE (1) 35% REDUCTION IN MORTALITY cf 45% RAS BLOCKERS, 24% BETA- BLOCKERS IN RETROSPECTIVE CASE CONTROL STUDY OF UKGPRD DIABETIC PATIENTS WITH LOW EJECTION FRACTION, HEART FAILURE METFORMIN IMPROVED ONE YEAR SURVIVAL BY 63% VA DATABASE 32% DECREASE IN HF ADMISSIONS WITH METFORMIN VERSUS SU McDonald, MR. Diabetes Care(2010)33(6) Shah, DD. J Card Fail(2010)16(3) Roumie, CL. J Am Heart Assoc(2017)16(4)e

48 METFORMIN AND HEART FAILURE (2) MAJOR CARDIOPROTECTIVE EFFECT ON METFORMIN LIKELY DUE TO IT S EFFECT ON HF EFFECT THROUGH 5-AMP ACTIVATED PROTEIN KINASE (5AMPK) FUEL GAUGE EFFECT INCREASING GENERATION OF AND DECREASING UNNECESSARY UTILIZATION OF ATP INCREASING MYOCARDIAL GLUCOSE UPTAKE, ACCELERATING GLYCOLYSIS AND LIMITING CELLULAR APOPTOSIS Bell, DS. Endocr Pract(2017)23(3)374. Hardie, DG. Eur J Biochem(1997)246(2)

49 METFORMIN AND HEART FAILURE (3) PRESERVE MYOCARDIAL MASS AND FUNCTION THUS DECREASING MORTALITY AND HF ADMISSIONS MEDICARE BILLING RECORDS HF HOSPITAL DISCHARGES ON METFORMIN VERSUS SU OR INSULIN: 13% DECREASE IN MORTALITY AND 8% IN READMISSION Masoudi, FA. Circulation(2005)111(5)

50 INCREASED PREVALENCE OF CANCER WITH DIABETES LIVER PANCREAS* ENDOMETRIUM COLON AND RECTUM BREAST BLADDER *NEW-ONSET OR WORSENING DIABETES MAY BE FIRST SIGN OF PANCREATIC CANCER

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54 PIOGLITAZONE AND DIASTOLIC DYSFUNCTION IN T2DM 12 SUBJECTS WITH T2DM STUDIED WITH EUGLYCEMIC CLAMP, MYOCARDIAL PET SCAN AND E/A FLOW RATIO WITH MRI BEFORE AND 12 MONTHS AFTER PIOGLITAZONE INSULIN SENSITIVITY IMPROVED IN THE MYOCARDIUM MYOCARDIAL, SYSTOLIC AND DIASTOLIC DYSFUNCTION STRONGLY CORRELATED WITH MYOCARDIAL INSULIN SENSITIVITY Clarke, GD. Diabetes Care(2017)Aug 28.

55 PIOGLITAZONE AND HF DIASTOLIC DYSFUNCTION E/A RATIO PEAK LV FILLING RATE SYSTOLIC DYSFUNCTION E #61 66% STROKE VOLUME L/MIN Clarke, GD. Diabetes Care(2017)40:

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58 HF HOSPITALIZATIONS WITH DPP4-INHIBITORS STUDY DRUG ODDS RATIO CI EXAMINE ALAGLIPTIN 1.19 ( ) SAVOR-TIMI SAXAGLIPTIN 1.27 ( ) META-ANALYSIS 1.24 ( ) DAPAGLIFLOZIN 0.36 ( ) PIOGLITAZONE 1.32 ( ) Lago, RM. Lancet(2007)378:1129.

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61 EMPA-REG STUDY COMPLICATION n=2333 PLACEBO n=4687 EMPAGLIFLOZIN HEART FAILURE 4.1% 2.7% NON-FATAL MI 5.2% 4.5% NON-FATAL STROKE 2.6% 3.2% CV DEATH 5.9% 3.7% TOTAL MORTALITY 8.3% 5.7% MACE 12.1% 10.5% HR p Zinman, B. NEJM(2015)373(22)

62 CANVAS STUDY COMPLICATION PLACEBO 1000 YEARS CANAGLIFLOZIN 1000 YEARS HEART FAILURE * NON-FATAL MI NON-FATAL STROKE CV DEATH TOTAL MORTALITY MACE * HR CI Neal, B. N Eng J Med(2017)377(7)

63 CANAGLIFLOZIN AND AMPUTATIONS (2) AT THERAPEUTIC LEVELS CANAGLIFLOZIN BUT NOT DAPAGLIFLOZIN OR EMPAGLIFLOZIN INHIBITED MITOCHONDRIAL COMPLEX-1 ACTIVITY IN THE RESPIRATORY CHAIN DECREASED INTRACELLULAR ATP LEVELS INHIBITED O2 UPTAKE Hawley, SA. Diabetes(2016)65(9)

64 CVD REAL STUDY 6 COUNTRIES T2DM 87% NO CVD SGLT2 VERSUS OTHER DIABETIC DRUGS DECREASE IN HF HOSPITALIZATION, ALL CAUSE MORTALITY NO GEOGRAPHIC DIFFERENCES (CANA-USA DAPP-REST OF WORLD) SGLT2 BENEFITS LIKELY A CLASS EFFECT Kosiborod, M. ACC 3/19/17 Washington DC.

65 CVD REAL DAPAGLIFLOZIN v DPP-4 COMPLICATION HR CI HEART FAILURE NON FATAL MI NON FATAL STROKE CV DEATH MORTALITY MACE Persson, F. Diabetes Obes Metab(2017)Aug 3, e-published.

66 Empagliflozin Modulates Several Factors Related to CV Risk 66 Other BP Arterial stiffness Albuminuria Sympathetic nervous system activity Glucose Insulin Uric acid Weight Visceral adiposity LDL-C HDL-C Triglycerides Oxidative stress

67 SHIFT IN FUEL ENERGETICS WITH SGLT2-INHIBITORS MOVE AWAY FROM INEFFICIENT FREE FATTY ACID AND GLUCOSE OXIDATION ENERGY EFFICIENT KETONE LEVELS INCREASED IMPROVED MYOCARDIAL AND RENAL WORKLOAD IMPROVED MYOCARDIA/RENAL EFFICIENCY Mudaliar, S. Diabetes Care(2016)39(7)

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73 CANAGLIFLOZIN AND AMPUTATIONS CASE CONTROL STUDY T2DM (n=12,140) VERSUS OTHER ANTI-HYPERTENSIVES THIAZIDE DIURETICS AMPUTATIONS INCREASED HR 7.04 (1.10, 45.3) VERSUS ACEI HR 6.11 (1.32, 28.7) FREQUENCY OF AMPUTATION INCREASED WITH DURATION OF THIAZIDE USE Erkens, JA. Pharmacoepidemol Drug Saf(2004)13(3)

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75 THE END???