This document summarizes a journal club presentation on the effects of post-prandial versus fasting glycemia on cardiovascular outcomes in patients with type 2 diabetes. The HEART2D trial found no difference in cardiovascular outcomes between intensive prandial glucose control and basal insulin strategies. Both strategies achieved similar A1C levels but did not reach the target of 7%. The prandial strategy was associated with lower rates of nocturnal hypoglycemia and cardiac failure.

1. Department of Family Medicine Perpetual Succour Hospital JOURNAL CLUB SERIES Vivian C. Barrera,MD 1 st year resident

2. Answerable question….. Which strategy is better…..?

7. ↑ 0xidative stress inflammation Endothelial Dysfunction Decreased fibrinolysis Plaque instability Cardiac events

8. DECODE: IGT Increases Mortality Risk Collaborative Analysis of Diagnostic Criteria in Europe N = 25,364 aged > 30 years Cumulative Mortality Hazard (%) DECODE Study Group. Lancet 1999;354:617-21. Follow-up (years) Diagnosed diabetes (n = 1275) Undiagnosed diabetes (n = 3071) Impaired glucose tolerance (n = 2766)* Normal glucose tolerance (n = 18,252)* *2-hour oral glucose tolerance test (OGTT) IGT = impaired glucose tolerance 0 2 4 6 8 10

9. STOP-NIDDM Trial: Acarbose Prevents Type 2 Diabetes Mellitus and Cardiovascular Events in Subjects With Impaired Glucose Tolerance Study Population Favors Acarbose Favors Placebo Hazard Ratio Chiasson JL, et al. JAMA. 2003;290;486–494. Copyright © 2003 American Medical Association. All rights reserved. CI = confidence interval 0.03 0.51 0.63 0.18 0.13 0.02 P Value 0.51 (0.28–0.95) 0.56 (0.10–3.07) 0.55 (0.05–6.11) 0.61 (0.29–1.26) 0.45 (0.16–1.28) 0.09 (0.01–0.72) Hazard Ratio (95% CI) 32 4 2 2 20 12 12 Placebo n=888 15 2 0 1 11 5 1 Acarbose n=662 Congestive heart failure Cerebrovascular stroke Cardiovascular death Revascularization procedures Angina Myocardial infarction Any cardiovascular event 0 0.5 1.0 1.5

10. Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Malmberg K, et al. BMJ. 1997;314:1512-1515. 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Mortality Mortality Total Cohort No Insulin – Low Risk Years in Study Years in Study Control Insulin-glucose Infusion Insulin-glucose Infusion Control p = .0111 p = .004 n=133 n=139 n=314 n=306 0 1 2 3 4 5 0 1 2 3 4 5

14. Determination of Sample Size and Statistical Methods To achieved 80% power, 490 patients must have experienced one of the primary outcomes to detect a difference between groups assuming the following difference of 2.5mmol/l between groups in postprandial glucose

15. 1355 patients were planned for random assignment with 678 patients in each group All comparisons were performed using 2 tailed tests with a nominal significance level 0.05

16. PRANDIAL STRATEGY 3x daily Insulin Lispro BASAL STRATEGY target AIC 7.0 % If >8.0 % Add NPH at bedtime NPH insulin BID or Lantus OD FBG <6.7mmol/L or < 121mg/dl Human insulin 30/70 BID Self monitor PPBG <7.5mmol / <135mg/dl Follow-up 7 years

17. Results 1227 enrolled in the study , 1,115 randomly assigned Prandial n 557 ( 338) Basal n 558 ( 346) Prandial 51 deaths, 38 discontinued Bsal 51 deaths, 44 discontinued

18. Table 1Baseline characteristics of the intent to treat study population by treatment group 0.829 50.97 ± 10.08 50.54 ± 10.05 LVEF (%) 0.428 434 ± 34 435 ± 33 QTc interval (ms) 0.171 163 ± 610 115 ± 430 Urinary albumin-to-creatinine ratio (mg/g) 0.556 2.71 ± 1.02 2.68 ± 1.02 LDL cholesterol (mmol/l) 0.607 0.96 ± 0.23 0.96 ± 0.25 HDL cholesterol (mmol/l) 0.871 4.45 ± 1.25 4.45 ± 1.25 Total cholesterol (mmol/l) 0.074 1.77 ± 0.95 1.89 ± 1.15 Triglycerides (mmol/l) 0.089 8.27 ± 1.52 8.42 ± 1.40 A1C (%) 0.807 160 (28.8) 160 (28.8) Intravenous insulin infusion (recent AMI) 0.970 98 (17.6) 97 (17.4) Thrombolysis (recent AMI) 0.858 101 (18.1) 99 (17.8) Prior myocardial infarction 0.542 76.87 ± 9.56 76.60 ± 9.06 Diastolic blood pressure (mmHg) 0.346 127.76 ± 17.75 126.88 ± 16.63 Systolic blood pressure (mmHg) 0.832 447 (80.3) 449 (80.8) Overweight (BMI ≥25 kg/m 2 ) 0.380 29.2 ± 5.0 29.0 ± 4.6 BMI (kg/m 2 ) 0.513 81.86 ± 15.86 81.12 ± 15.17 Weight (kg) 0.143 12.3 ± 15.4 13.7 ± 16.5 Past tobacco use (years) 0.316 81 (14.5) 93 (16.7) Current tobacco use 0.518 9.0 ± 7.3 9.3 ± 7.2 Duration of diabetes (years) >0.999 Country 11 (2.0) 11 (2.0) Other 6 (1.1) 1 (0.2) African descent 58 (10.4) 61 (11.0) Western Asian 483 (86.6) 484 (86.9) Caucasian 0.302 Origin 0.277 220 (39.4) 202 (36.3) Aged ≥65 0.724 60.9 ± 9.8 61.1 ± 9.7 Mean Age (years) 350 (62.7) 356 (63.9) Male 208 (37.3) 201 (36.1) Female 0.680 Sex 558 557 n P value BASAL PRANDIAL Variable

19. Table 1—Diabetes therapy at baseline (p=0·740 between groups ) 7 (1.3%) 4 (0.7%) Other 4 (0.7%) 2 (0.4%) Any combination of oral agents and MDI 27 (4.9%) 38 (6.9%) Multiple daily insulin injection (MDI) [≥3 inj/day] 40 (7.3%) 41 (7.5%) Combination oral + basal/premixed insulin 124 (22.5%) 121 (22.0%) Basal/premixed insulin (once- or twice-daily) 13 (2.4%) 10 (1.8%) Other combination of oral agents 11 (2.0%) 16 (2.9%) Metformin and sulfonylurea, + any other oral 86 (15.6%) 83 (15.1%) Metformin and sulfonylureas 3 (0.5%) 6 (1.1%) Fast-acting insulin secretagogues 1 (0.2%) 3 (0.5%) Alpha-glucosidase inhibitors 147 (26.7%) 138 (25.1%) Sulfonylureas 33 ( 6 . 0%) 41 ( 7 . 5%) Biguanides 54 ( 9 . 8%) 46 ( 8 . 4%) Diet and exercise BASAL (n=550) PRANDIAL (n=549) Variable (n, %)

21. Table 2—Summary and analysis of individual outcomes for time to first adjudicated event 0.471 0.89 (0.66, 1.22) 86 (15.4%) 75 (13.5%) Coronary angiography planned after randomization 0.800 1.13 (0.44, 2.93) 8 (1.4%) 9 (1.6%) Amputation for PVD 0.863 0.93 (0.41, 2.11) 12 (2.2%) 11 (2.0%) Revascularization for PVD 0.662 0.90 (0.56, 1.44) 37 (6.6%) 33 (5.9%) Congestive heart failure 0.647 1.09 (0.75, 1.58) 54 (9.7%) 58 (10.4%) Hospitalized acute coronary syndromes 0.525 0.91 (0.68, 1.22) 94 (16.8%) 84 (15.1%) Coronary revascularization planned after randomization 0.948 1.01 (0.71, 1.43) 63 (11.3%) 63 (11.3%) Any myocardial infarction 0.419 0.50 (0.09, 2.75) 4 (0.7%) 2 (0.4%) Silent myocardial infarction 0.716 1.07 (0.73, 1.58) 50 (9.0%) 53 (9.5%) Nonfatal clinical myocardial infarction 0.983 1.01 (0.45, 2.25) 12 (2.2%) 12 (2.2%) Fatal myocardial infarction 0.581 1.20 (0.63, 2.29) 17 (3.0%) 20 (3.6%) Any stroke 0.573 1.21 (0.62, 2.35) 16 (2.9%) 19 (3.4%) Nonfatal stroke 0.654 1.50 (0.25, 8.99) 2 (0.4%) 3 (0.5%) Fatal stroke 0.816 1.05 (0.69, 1.60) 42 (7.5%) 44 (7.9%) Cardiovascular death 0.982 1.00 (0.68, 1.48) 51 (9.1%) 51 (9.2%) All-cause death p-value Estimated Hazard Ratio (95% CI) BASAL (n=558) PRANDIAL (n=557) Individual Outcomes*

22. FIGURE 2— Glycemic measures. A : Mean ± SD A1C at each visit by treatment strategy (PRANDIAL versus BASAL). B : Seven-point mean self-monitored blood glucose profiles at baseline (dotted line) and throughout the study (postrandomization, solid line) by treatment strategy (PRANDIAL versus BASAL 28% 31%

23. PRIMARY & SECONDARY CARDIOVASCULAR ENDPOINTS prandial basal P value (0.952) 424.1 423.8 QT INT (0.257) 52.39 54.3 LVEF (0.817) 52.39 71.4 HEART RATE (0.978) 77.5 77.4 DIASTOLIC (0.782) 132.4 131.8 SYSTOLIC (0.719) 2.70 2.26 LDL (0.523) 1.11 1.14 HDL (0.997) 4.65 4.65 TCHOL (0.894) 2.18 2.21 TGL (0.233) 7.3 7.7 Premeal BG (p0.005) 7.0 8.1 FBG

24. prandial basal P value 0.038 0 5 sepsis >.999 2.3 2.2 Congestive HF .030 0.7 2.3 Cardiac failure .007 61.5 65.7 Nocturnal hypoglycemia 0.071 9.5 12.9 Severe hypoglycemia 0.367 55.2 55. Incidence of hypoglycemia 0.05 21 28 Regimen intensification, frequency <0.00 0.52 .60 Received greater insulin dose <.001 3.1 4.8 Gain more weight 0.046 78.9 83.7 Beta- blocker 0.478 95.9 95.0 Cardivascular drugs

26. PROactive Trial: Significant Reduction in Secondary Outcome Events, % 0 6 18 24 36 12 30 Time from randomization (months) *Excluding silent myocardial infarction (MI) All-cause mortality, nonfatal MI*, stroke Dormandy JA et al. Lancet 2005;366:1279–1289. Pioglitazone 301 events Placebo 358 events 16% RRR HR 0.84 (0.72–0.98) P = 0.027

28. ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Primary objective: To determine the effect of blood pressure treatment (ACE-inhibitor + diuretic vs. placebo) and glycemic intervention (intensive vs. standard) on microvascular and macrovascular complications in patients with type 2 diabetes mellitus (2  2 factorial design) Patient population: Type 2 diabetes (hypertensive + nonhypertensive) (N = 11,140) Primary endpoint: Macrovascular : composite of nonfatal stroke, nonfatal myocardial infarction, cardiovascular death Microvascular : composite of new or worsening nephropathy or retinopathy Secondary endpoints: Cerebrovascular disease, cardiovascular disease, peripheral vascular disease, microalbuminuria, visual deterioration, neuropathy, heart failure, cognitive function and dementia, all-cause mortality Treatment duration: 4.5 years ADVANCE Management Committee. Diabetologia. 2001;44:1118–1120. Placebo Perindopril + Indapamide Standard ¶ Placebo Perindopril + Indapamide Intensive* (HbA 1c ≤6.5%) Blood Pressure Intervention *Gliclazide plus oral agents/insulin to achieve hemoglobin A 1c (HbA 1c ) target ¶ Based on standard guidelines Glycemic Control

30. thank you Lee min ho