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Hypoglycemia in Diabetes: the limiting factor to optimal control June 7, 2012

Hypoglycemia in Diabetes: the limiting factor to optimal control June 7, 2012. Kenneth Cusi, MD, FACP, FACE Professor of Medicine Chief, Division of Endocrinology, Diabetes & Metabolism University of Florida, Gainesville. Hypoglycemia: benefits and risks (DCCT). 16. 100. Retinopathy

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Hypoglycemia in Diabetes: the limiting factor to optimal control June 7, 2012

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  1. Hypoglycemia in Diabetes:the limiting factor to optimal controlJune 7, 2012 Kenneth Cusi, MD, FACP, FACE Professor of Medicine Chief, Division of Endocrinology, Diabetes & Metabolism University of Florida, Gainesville

  2. Hypoglycemia: benefits and risks (DCCT) 16 100 Retinopathy (per 100 patient-years) Intensive group 14 Retinopathy 80 12 10 60 Severe hypoglycemia (per 100 patient-years) 8 Conventional group 40 6 4 20 2 0 0 5 6 7 8 9 10 11 12 13 14 HbA1c (%) DCCT, Diabetes Control and Complications Trial DCCT Research Group. N Engl J Med 1993;329:977–86

  3. The Physician’s Dilemma 100 12 80 10 60 8 Rate of severe hypoglycaemia (per 100 patient-years) Rate of progression of retinopathy (per 100 patient-years) 6 40 4 20 2 0 0 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 HbA1c (%) Retinopathy risk Hypoglycaemia rate Adapted from DCCT Research Group N Engl J Med 1993;329:977–86

  4. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Added cost to diabetes treatment • Effect on morbidity and mortality • Role in compliance with treatment 2. How can we prevent hypoglycemia? • Who is at greater risk? When? • Individualizing insulin therapy • Choosing the right insulin to avoid hypoglycemia

  5. Definition of Hypoglycemia • Low plasma glucose causing neuroglycopenia • Clinical definition of hypoglycaemia: • Mild: self-treated • Severe: requiring help for recovery • Biochemical definition of a low plasma glucose: • 3.0 mmol/L (<54.1 mg/dL) (EMA)1 • 3.9 mmol/L (≤70 mg/dL) (ADA)2 • 4.0 mmol/L (<72 mg/dL) for clinical use in patients treated with insulin or an insulin secretagogue (CDA)3 ADA, American Diabetes Association; CDA, Canadian Diabetes Association; EMA, European Medicines Agency 1. EMA. CPMP/EWP/1080/00. 2006; 2. ADA. Diabetes Care 2005;28:1245–9; 3. Yale et al. Canadian J Diabetes 26:22–35

  6. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Its is common and adds cost to diabetes treatment

  7. Medications Most Commonly Associated with Emergency Admissions in Patients >65 Years of Age Opioids Data given are number and percentage of annual national estimates of hospitalisations. Data from the NEISS-CADES project. ER visits n=265,802/Total cases n=12,666 Budnitz et al. N Engl J Med 2011;365:21

  8. Hypoglycemia Accounts for Most Endocrine-related Emergency Hospital Admissions Budnitz et al. N Engl J Med 2011;365:21

  9. Severe Hypoglycemia in T2DM is as Common as in T1DM with Increasing Duration of Insulin Therapy Severe hypoglycemia Mild hypoglycemia Proportion reporting at least one hypoglycaemic episode SU <2 yr >5 yr <5 yr >15 yr SU <2 yr >5 yr <5 yr >15 yr T2D T1D T2D T1D SU, sulfonylurea; T1D, type 1 diabetes; T2D, type 2 diabetes UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–7

  10. Socioeconomic Consequences of Non-Severe Symptomatic Hypoglycemia in Type 2 Diabetes Direct impact of reduced productivity Indirect impact through increased treatment cost (France, Germany, UK, USA) • Productivity loss: up to $90 per event • Following a daytime event: • 18% lose an average of 10 h of work time • 24% miss a meeting/deadline • Following a nocturnal hypoglycaemic event: • 23% arrive late/miss work • 32% miss a meeting/deadline • 15 h of work are lost • 5.6 extra blood glucose tests within 7 days after event • Risk of suboptimal insulin dose (25% of patients reduce dose) • 25% contact a healthcare provider after an episode • Out-of-pocket costs due to extra/special groceries, extra testing supplies and transport: ~$25 per month Brod et al. Value Health 2011;14:665–71

  11. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Its is common and adds cost to diabetes treatment • Increases morbidity and mortality

  12. ADVANCE1 ACCORD2 VADT3 Per 100-patients per year Per 100-patients per year Per 100-patients per year 15 15 15 12.0 12 12 12 9 9 9 Severe hypoglycaemic events Severe hypoglycaemic events Severe hypoglycaemic events 6 6 6 4.0 3.0 3 3 3 1.0 0.7 0.4 0 0 0 Standard Intensive Standard Intensive Standard Intensive p<0.001 p<0.01 p<0.001 Intensive glucose lowering contributes to an increased risk of hypoglycemia by 2- to 3-fold, particularly in advanced type 2 diabetes Intensive Insulin Therapy is Associated withIncreased Incidence of Severe Hypoglycemia • ADVANCE. N Engl J Med 2008;358:2560–72; 2. ACCORD. N Engl J Med 2008;358:2545–59; 3. VADT. N Engl J Med 2009;360:129–39

  13. ADVANCE: Severe Hypoglycemia is Associated with Increased Risk of Adverse Outcomes Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

  14. ADVANCE: Severe Hypoglycemia is Associated with Increased Risk of Adverse Outcomes Severe hypoglycaemia (n=231) No severe hypoglycaemia (n=10,909) Events Hazard ratio (95% CI) No. patients with events (%) Major macrovascular events 33 (15.9) 1114 (10.2) 3.53 (2.41–5.17) Major microvascular events 24 (11.5) 1107 (10.1) 2.19 (1.40–3.45) “Severe hypoglycemia (SH) was strongly associated with increased risk of a range of adverse clinical outcomes… (it either) contributes to adverse outcomes or is a marker of vulnerability to such events” Death from any cause 45 (19.5) 986 (9.0) 3.27 (2.29–4.65) Cardiovascular disease 22 (9.5) 520 (4.8) 3.79 (2.36–6.08) Non-cardiovascular disease 23 (10.0) 466 (4.3) 2.80 (1.64–4.79) Respiratory system events 18 (8.5) 656 (6.0) 2.46 (1.43–4.23) Digestive system events 20 (9.6) 867 (7.9) 2.20 (1.31–3.72) Diseases of the skin 6 (2.7) 146 (1.3) 4.73 (1.96–11.40) Cancer 5 (2.2) 149 (1.4) 2.11 (0.65–6.82) 1.0 10.0 0.1 Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

  15. ADVANCE: Severe Hypoglycemia is Associated with Increased Risk of Adverse Outcomes Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

  16. ADVANCE:Hazard Ratios (HR) of Cardiovascular Disease, Microvascular Events and Death Among Patients that Experienced Severe Hypoglycemia vs. Those Who Did Not Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

  17. VADT:Severe Hypoglycemia is a Major Predictor of Cardiovascular Death VADT: N Engl J Med 2009;360:129–39.

  18. ACCORD: Severe Hypoglycemia is Associated with Increased Risk of Death Launer et al for the ACCORD Study Group. Diabetes Care 2012 ;35:787-793

  19. Association of Hypoglycemia with Acute Cardiovascular Events in T2DM • Retrospective, observational study (n=860,845) assessing association between hypoglycaemia and acute CV events • 3.1% patients had a hypoglycemic event during evaluation period (1 year) • Patients who experienced hypoglycemia had a 79% higher odds of an acute CV event than patients without hypoglycaemia Johnston et al. Diabetes Care 2011;34:1164–70

  20. Severe Hypoglycemia Increases the Risk of CVD and Microvascular Complications in the Elderly Outcome HR P value CVD 2.0 <0.001 PVD 2.6 <0.001 Stroke 2.3 <0.001 CHF 1.8 0.001 Microvascular 1.8 <0.001 Zhao et al. Diabetes Care 2012 ;35:1126-1132

  21. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Its is common and adds cost to diabetes treatment • Increases morbidity and mortality • Decreases compliance with treatment and has long-term effects

  22. Impact of Severe Hypoglycaemic* Eventon Patient’s Behavior *Severe hypoglycaemia defined as any event requiring external assistance and with a PG <2.8 mmol/L Leiter L et al. Can J Diabetes 2005;29:186–92

  23. Fear of Hypoglycemia is Related to Preceding History of Hypoglycemia p<0.0001* 20 19.0 16 12 Mean HFS-II worry score 10.2 8 4 0 No history of hypoglycaemia(n=264) History of hypoglycaemia(n=136) *Based on the t-test. HFS-II, Hypoglycaemia Fear Survey-II. Vexiau et al. Diabetes Obes Metab 2008;10(suppl 1):16–24

  24. Neurological Consequences of Hypoglycemia • Long-term: • Cerebrovascular events – hemiparesis • Focal neurological deficits • Ataxia; choreoathetosis • Epilepsy (rare) • Vegetative state (rare) • Cognitive impairment with behavioural and psychosocial problems Short-term: • Cognitive dysfunction • Behavioural abnormalities • Confusional state • Coma • Seizures • TIAs; transient hemiplegia • Focal neurological deficits (rare) TIA, transient ischaemic attack Frier. Diabetes and the Brain; Eds Biessels & Luchsinger 2010:131–57

  25. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Its is common and adds cost to diabetes treatment • Increases morbidity and mortality • Decreases compliance with treatment 2. How can we prevent hypoglycemia? • Keep in mind times of greatest risk • Individualize insulin therapy • Take advantage of insulin preparations associated with less hypoglycemia

  26. Causes and risk factors for hypoglycaemia • General causes of hypoglycaemia1,2 • Inadequate, delayed or missed meal • Exercise • Too much insulin or oral anti-diabetes medications • Drug/alcohol consumption • Increased insulin sensitivity • Reduced insulin clearance • Risk factors for severe hypoglycaemia3,4 • Age/duration of insulin treatment • Strict glycaemic control • Impaired awareness of hypoglycaemia • Sleep • History of previous severe hypoglycaemia • Renal failure 1.Briscoe and Davis. Clin Diabetes 2006;24(3):115–21; 2. Workgroup on Hypoglycemia, American Diabetes Association. Diabetes Care 2005;28(5):1245–9; 3. Frier. Diabetes Metab Res Rev 2008;24(2):87–92; 4. Cryer. Diabetes 2008;57(12):3169–76

  27. Risk of Severe Hypoglycemia Increases with Baseline Poor Cognitive Function: Importance of early recognition when starting insulin Launer et al for the ACCORD Study Group. Diabetes Care 2012 ;35:787-793

  28. Hypoglycemia is FrequentlyUnrecognized by Patients • Many episodes are asymptomatic; CGMS data show that unrecognised hypoglycaemia is common in people with insulin-treated diabetes • In one study, 63% of patients with type 1 diabetes and 47% of patients with type 2 diabetes had unrecognised hypoglycaemia as measured by CGMS (n=70)1 • In another study, 83% of hypoglycaemic episodes detected by CGMS were not detected by patients with type 2 diabetes (n=31)2 74% of all events occurredat night 54% of hypoglycaemic episodes were nocturnal, none of which were detected CGMS, continuous glucose monitoring system 1. Chico et al.Diabetes Care 2003;26(4):1153–7; 2. Weber et al. Exp Clin Endocrinol Diabetes 2007;115(8):491–4

  29. Risk of Hypoglycemia during Sleep • No symptoms detectable during sleep • Catecholamine responses are diminished1 • May not impair cognitive function the next day2,3 • Subjective well-being affected with greater fatigue during exercise3 • May induce impaired awareness of hypoglycaemia the next day4 1. Jones et al. New Engl. J Med 1998;338:1657-62; 2. Bendtson et al. Diabetologia1992;35:898-903; 3. King et al. Diabetes Care 1998;21:341-5; 4. Veneman et al. Diabetes 1993;42:1233-7.

  30. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Its is common and adds cost to diabetes treatment • Increases morbidity and mortality • Decreases compliance with treatment 2. How can we prevent hypoglycemia? • Keep in mind times of greatest risk • Individualize insulin therapy

  31. Beware of Patients with Hypoglycemia Unawareness • Hypoglycemia unawareness affects • 20–25% of adults T1DM • 10%1 insulin-treated T2DM • Risk of severe hypoglycaemia is 3 to 6 fold greater2 • Broad spectrum of severity Severe hypoglycaemia without warning3 % events 100 50 0 0–9 >40 10–19 20–29 30–39 Diabetes duration (years) 1. Gold et al. Diabetes Care 1994;17:697-703 2. Geddes et al. Diabetic Med 2008;25: 501–4 3. Pramming et al. Diabetic Med 1991;8:217–22

  32. Hypoglycemia in the Management of Diabetes • The impact of hypoglycemia: • Its is common and adds cost to diabetes treatment • Increases morbidity and mortality • Decreases compliance with treatment 2. How can we prevent hypoglycemia? • Keep in mind times of greatest risk • Individualize insulin therapy • Take advantage of insulin preparations associated with less hypoglycemia

  33. Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A1C Levels Before and After Treatment Intensification in T2DM Riddle et al. Diabetes Care 34:2508–2514, 2011

  34. Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A1C Levels Before and After Treatment Intensification in T2DM Riddle et al. Diabetes Care 34:2508–2514, 2011

  35. Role of Insulin Analogues in the Prevention of Hypoglycemia 60 Insulin A 50 40 Hypoglycaemic events per patient-year 30 20 Insulin B 10 7 6 10 8 11 9 HbA1c (%) Adapted from DCCT Research Group N Engl J Med 1993;329:977–86

  36. HbA1c and Hypoglycemia in Patients with Type 2 Diabetes Confirmed hypoglycaemia (events/patient-year) Insulin detemir 14 NPH insulin 12 10 8 Hypoglycaemic events per patient-year 6 4 2 0 6.0 9.0 7.0 5.0 8.0 HbA1c (%) Hermansen et al. Diabetes Care 2006;29:1269–74

  37. Hypoglycemia in the Management of Diabetes • Prevention of hypoglycemia is essential to success: • Hypoglycemia • Increases morbidity and mortality • Adds significant cost • Decreases patient compliance and overall success • How to prevent hypoglycemia? • Be aware of times of greatest risk (i.e., nocturnal hypoglycemia) • Individualize insulin therapy • Take advantage of insulin preparations associated with less hypoglycemia

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