1. Maria Rosa Costanzo, M.D., F.A.C.C., F.A.H.A. Medical Director, Midwest Heart Specialists-Advocate Medical Group Heart Failure and Pulmonary Arterial Hypertension Programs Medical Director, Edward Hospital Center for Advanced Heart Failure Naperville, Illinois, U.S.A.

3. “We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment.”

5. Prevalence of DM in General Population with and without HF Study/DateNo. of Subjects Mean Age (yrs) HF Prevalence Prevalence of DM with HF Prevalence of DM without HF Rotterdam /01 5255693.4%17.5%10.3% Italy/97 1339749.5%29.6%13.2% Rekjavik/ 05 19381-3.8%11.6%3.4% Olmstead /06 65577All with HF 13%-25%-

6. Prevalence of DM in Populations with and without LVSD Study/DateNo. of PtsMean Age (yrs) Definition of LVSD by EF LVSD Pr1evalence Prevalence of symptomatic LVSD LVSD + DMNo LVSD, DM ECHOES/01 396061< 40 %1.8%1%30%3.8% Copenhagen/ 03 76466≤ 40%4.767%7.2%5.9% Poole/99 81776Visual Ass. 7.5%21%10%6% Glasgow/’97 164050≤ 35%7.7%23%12.4%2.5% Vasteras/01 40175LWMI < 1.7% 6.8%54%22%7% Olmsted/03 188863≤ 50%6.5%-17%6.8% Copenhagen/ 05 18869< 45%100% 25.5%-

7. Prevalence of DM in Patients with HF in Clinical Trials Clinical TrialPrevalence % SOLVD 25.8 MERIT-HF 24.5 ELITE II 24.0 Val-HeFT 25.4 COPERNICUS 25.7 OPTIME (hospitalized) 44.2 VMAC (hospitalized) 47.0

8. DM and Mortality in HF: Clinical Trials Populations TrialTreatmentNO. of Pts.Mortality Risk of DM (HR) SOLVD/91Enalapril6797Overall 1.29 HF due to CAD 1.37 HF, no CAD 0.98 BEST/01Bucindolol2708HF due to CAD 1.333 HF, no CAD 0.98 DIG/97Digoxin6422HF due to CAD 1.43 HF, no CAD, not stated DIAMOND-HFDofetilide5491Women 1.7 Men 1.4 CHARM/03Candesartan7599Insulin 1.80 No Insulin 1.50

9. DM and Mortality in HF: Non Clinical Trials Populations Location/DateNo. of PatientsMortality Risk of DM (HR) Rotterdam/015540 3.19 Framingham/939405 Women 1.70 Men 0.99 Scotland/0066547 Women 1.5 Men 1.55 USA/99170,239 Black 1.11 White 1.22 USA/05495 1.71 USA/05554 No insulin 0.95 Insulin 4.30 France/041246 HF due to CAD 1.54 HF, no CAD 0.65 Olmstead/06665 Overall 1.48 HF due to CAD 1.11 HF, no CAD 1.79 Italy/032843 1.44

11. Risk Factors For Congestive Heart Failure Wilson PW. Am J Cardiol 1997;80:3-8 0 2 4 6 8 10 HypertensionMyocardialInfarction Angina Pectoris Diabetes Mellitus Left Ventricular HypertrophyValvular Heart Disease Relative Risk of CHF WomenMen

13. Prediction of Heart Failure in Women with CAD (Bibbins-Domingo K, et al. Circulation 2004;1424-1430) Diabetes 3.1 Atrial Fib 2.9 CrCL 40-60 1.2 <40 2.3 SBP 120-139 1.6 140-159 2.1 <159 2.1 Smoking Past 1.2 Current 1.9 BMI 25-36 1.2 >36 1.9 LBBB 1.6 LVH 1.5 CABG 1.3 Adjusted HR for HF

15. Iribarren C et al. Circulation 2001; 103: 2668 All: p = 0.0001 Men: p = 0.0001 Women: p = 0.009

16. Association between Elevated Blood Glucose and Outcome in Acute HF in a Multinational Cohort of 6,212 Subjects 30-Day Mortality Rates According to Admission Blood Glucose Risk of Death Associated with Elevated BG as a Function of the Presence or Absence of DM on Admisssion Mebaaza A et al. JACC 2013; 61:820-9

17. Association of HgbA1c with Risk of HF in 10 Studies with Maximally adjusted Covariates Association of HgbA1c with Risk of HF in Patients Subgroups Erqou S. et al. Eur J Heart Fail 2013; 15: 185-193

18. Shekelle PG et al. JACC 2003; 41:1529-38

20. Conclusions HF and DM commonly coexist Each condition increases the likelihood of developing the other When HF and DM coexist in the same patient the risk of morbidity and mortality increases markedly Screening strategies are needed to identify DM patients at high risk of HD and those with asymptomatic LVSD A strong effort must be made to place patients with coexisting HF and DM on optimal HF therapy Strategies for managing DM in patients with HF must be tested in prospective controlled clinical trials Patients with both DM and HF require the care of a multidisciplinary team aware of the unique issues characterizing the two conditions.