Hypoglycemia as a risk factor for cardiovascular disease and mortality

Transcription

1 Hypoglycemia as a risk factor for cardiovascular disease and mortality Dong-Jun Kim, M.D.,PhD. Department of Internal Medicine, Inje University College of Medicine

2 Hypoglycemia: the most important complication of diabetes treatment Ideal HbA1c: normal value without any side effect of treatment Diabetic Complications vs. Complications of Diabetes Treatment

3 Self-reported hypoglycemia in diabetes Type 1 diabetes: mild - 30/patients/year severe 3.2/patients/year Type 2 diabetes: mild 2-10/patients/year severe /patients/year Dibetes Metab Res Rev 2004;20: Diabetologia 2007;50: Daibetes Metab Res Rev 2008;24:87-92

4 Mechanisms by which hypoglycemia may affect CV events Diabetes Care 2010;33:

5 Effects of experimental hypoglycemia on QT interval

6 Clinical studies about the association of hypoglycemia with mortality 1. Glucose lowering intervention in diabetes 2. Studies of AMI or ICU patients 3. Studies of general wards or ambulatory patients

7 In diabetic patients, Intensive Treatment cardiovascular or all-cause mortality 1. different intensity 2. different regimen

8 DCCT (Diabetes Control and Complications Trial) Severe hyoglycemia: Intensive Tx. group 27% conventional group 10% Inverse relationship of achieved HbA1c with risk of severe hypoglycemia Glucose lowering treatment: 42% (9-63) risk reduction of CV disease after 17 years F/U In type 1 diabetes: glucose-lowering Tx. - increase the risk of hypoglycemia - do not increase long-term CV risk N Eng J Med 1993;329:97786 Diabetes 1997;46:271-86

9 ACCORD, ADVANCE, and VADT Diabetes Care 2011;34(suppl2):s132-s137

10 ACCORD, ADVANCE, and VADT Diabetes Care 2011;34(suppl2):s132-s137

11 Annualized Mortality Rates in ACCORD study Severe hypoglycemia vs. no severe hypoglycemia Circulation 2011;13:342-8 BMJ 2009;339:b4909

12 HbA1c and hypoglycemia in ACCORD trial BMJ 2010;340:b5444

13 HbA1c and hypoglycemia in ACCORD trial BMJ 2010;340:b5444

14 Risk factor for hypoglycemia ACCORD VADT Duration of diabetes Insulin Tx. at baseline Low BMI Previous CVD High ACR BMJ 2010;340:b5444

15 Severe hypoglycemia and vascular outcome, death in ADVANCE (5 year F/U) N Eng J Med 2010;363:1410-8

16 Severe hypoglycemia and adverse clinical outcome in ADVANCE (5 year F/U) N Eng J Med 2010;363:1410-8

17 Meta-analysis of RCTs in type 2 diabetes 13 RCTs - UGDP 1975, 1976,1982; Kumamoto; Veteran Affairs; UKPDS; PROactive; Darie et al; ACCORD; ADVANCE; VADT, HOME Risk ratio of intensive Tx. vs. conventional Tx. All cause mortality RR (95% CI) P RR (95% CI) P 1.04 ( ) 0.47 Non-fatal MI 0.85 ( ) <0.001 CV death 1.11 ( ) 0.29 All stroke 0.96 ( ) 0.55 All MI 0.90 ( ) 0.02 Non-fatal stroke 1.00 ( ) 0.95 BMJ 2011;343:d4169

18 Risk of hypoglycemia in intensive treatment group BMJ 2011;343:d4169

19 Trials comparing different glucose-lowering regimens in type 2 diabetes Circulation 2011;13:342-8

20 Intensive glucose lowering treatment in RCTs Intensive treatment: increase risk of hypoglycemia Hypoglycemia: predictor for mortality, CV events, and other adverse clinical outcome Most interventions: favorable or neutral effects on mortality or CV outcome except for ACCORD Presence of hypoglycemia-prone population Benefit of normoglycemia vs. harmful effect of hypoglycemia

21 In critically ill patients, Intensive Treatment cardiovascular or all-cause mortality

22 Glucose and In-hospital Mortality in AMI 16,871 AMI patients -70 vs vs mg/dl Circulation; 2008:117:

23 Benefits and Risks of Tight Glucose Control in Critically Ill Adults: A Meta-analysis Primary outcome measure Hospital mortality Death occurring during the hospital stay or within 30 days following admission Secondary outcome measure Septicemia New need for dialysis hypoglycemia JAMA ; 2008:300:933-44

24 Meta-analysis of intensive insulin Tx. for mortality (29 trials) JAMA ; 2008:300:933-44

25 NICE-SUGAR study (The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) Randomized, prospective un-blinded Primary end-point: death Secondary end-points: survival time within the first 90 days cause-specific death duration of mechanical ventilation RRT stays in the ICU and hospital Tertiary outcomes: death within 28 days of randomization incidence of new organ failure positive blood culture RBC transfusion volume of transfusion New Eng J Med 2009;360:

26 NICE-SUGAR study (The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) 6,104 ICU patients, 42 hospitals, 90 days mortality Intensive group: mg/dl Conventional group: < 180 mg/dl HR 1.14 ( ) 24.9% 27.5% New Eng J Med 2009;360:

27 NICE-SUGAR study (The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) No difference between surgical vs. medical ICU patients. Severe hypoglycemia(<40mg/dl): 6.8% in the intensive control 0.5% in the conventional group No difference of median length of ICU, hospital stay, days of mechanical ventilation, RRT, positive blood cultures, RBC transfusions. New Eng J Med 2009;360:

28 NICE-SUGAR study (The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) Limitations: More patients in the IIT group received corticosteroids which could affect the variable were studying. 10% of the IIT discontinued prematurely. No significant difference in secondary or tertiary outcomes, despite the difference in the primary outcome, death. Inclusion criteria, i.e. length of stay is a subjective parameter. The study was not blinded to the treating personnel. New Eng J Med 2009;360:

29 DIGAMI 2 (Diabetes, Glucose, and Acute Myocardial Infraction 2) 1,253 diabetes with acute MI Group 1: 24 hr insulin-glucose infusion s.c. insulin Group 2: 24 hr insulin-glucose infusion standard glucose control Group 3: routine control (local practice) F/U: 6 mo-3 yrs In case of severe hyoglycemia, during the 2-year F/U unadjusted RR of all cause mortality: 1.99 ( ), p = unadjusted RR of CV mortality: 2.06 ( ), p = after adjusting for age, sex, smoking, previous infarction, heart failure, renal function, diabetes duration, coronary interventions, pharmacological treatment and glucose at hospital admission RR of all cause mortality: 1.09 ( , p = RR of CV mortality: 1.20 ( ), p = Heart 2009;95:721-7

30 Admission hypoglycemia vs. post-admission hypoglycemia for death Circulation 2009;120:

31 Admission hypoglycemia vs. post-admission hypoglycemia for death Circulation 2009;120:

32 Spontaneous vs. Iatrogenic hypoglycemia for in-hospital mortality in AMI patients Retrospective 7,820 AMI patients at 40 hospitals JAMA; 2009:301:

33 Meta-analysis of intensive insulin Tx. for mortality (26 trials) CMAJ ; 2009:180:821-7

34 In critically ill patients, Intensive treatment: increase risk of hypoglycemia Hypoglycemia: increase mortality J-shaped relationship between glucose and mortality Admission vs. post-admission glucose Spontaneous vs. iatrogenic hypoglycemia Medical ICU vs. surgical ICU Decrease risk of infection Hypoglycemia itself vs. comorbid condition prone to hypoglycemia

35 In non-critically ill patients, Intensive Treatment cardiovascular or all-cause mortality

36 UK GP database study Aged 50 years or older, type 2 diabetes Cohort 1-27,965 patients: mono Tx. combination Tx. Of OHA (4.5 year F/U) Cohort 2-20,005 patients: initiation of insulin (5.2 year F/U) HR for all-cause mortality * Cohort 1 * Cohort 2 * * * * * 6.4% 7.5% 10.6% 6.4% 7.5% 10.6% HR 1.30 (1, ) 1.93 ( ) 1.79 ( ) 1.80 ( ) After adjusting for age, sex, smoking, cholesterol, BMI, and general comorbidity Lancet; 2010:375:481-89

37 UK GP database study HR for progression to 1 st large-vessel disease events by HbA1c decile Lancet; 2010:375:481-89

38 Hypoglycemia and Mortality in General Ward Patients Retrospective 31,970 patients Am J Med 2011;124:

39 Meta-analysis of intensive glycemic control for mortality (19 studies) Non-critically ill patients RR for infection 0.41 ( ) J Clin Endocrinol Metab 2012;97:49-58

40 In non-critically ill patients, J-shaped relationship between glucose and mortality Spontaneous vs. drug-induced hypoglycemia Decrease risk of infection

41 In the interpretation of these reports, 1. Under-estimation of hypoglycemia (ex. Hypoglycemia unawareness) 2. Different definition of criteria 3. Different methods of detection or recording 4. Different treatment for hypoglycemia 5. Potential cardio-protective drugs or therapies

42 Summary 1. Considering plausible mechanisms, hypoglycemia could be one of major causes for mortality in diabetes. 2. Intensive treatment: increase risk of hypoglycemia 3. Presence of hypoglycemia-prone population 4. J-shaped relationship between glucose and mortality 5. Hypoglycemia itself vs. comorbid condition prone to hypoglycemia 6. Different relationship by clinical situation or clinical characteristics

43 Hypoglycemia The most important complication of anti-diabetes treatment Risk factor for CV or all-cause mortality Only surrogate marker for poor prognosis more vulnerable to hypoglycemia more vulnerable to CV disease or mortality both hypoglycemia and serious health outcome; ( hepatic disease, renal disease, cognitive impairment, cancer, some medication, weight loss d/t chronic disease ) Risk factor, especially in specific group & Surrogate marker in general

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