Hypoglycemia in Diabetes the limiting factor to optimal

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 80 14 12 10 60 8 Conventional group 40 6 4 20 Retinopathy (per 100 patient-years) Severe hypoglycemia (per 100 patient-years) Intensive group 2 0 5 6 7 8 9 10 11 12 13 0 14 Hb. A 1 c (%) DCCT, Diabetes Control and Complications Trial DCCT Research Group. N Engl J Med 1993; 329: 977– 86

100 12 80 10 60 8 6 40 4 20 2 0 0 5. 5 6. 0 6. 5 7. 0 7. 5 8. 0 8. 5 9. 0 9. 5 10. 0 10. 5 Rate of progression of retinopathy (per 100 patient-years) Rate of severe hypoglycaemia (per 100 patient-years) The Physician’s Dilemma Hb. A 1 c (%) Retinopathy risk Hypoglycaemia rate Adapted from DCCT Research Group N Engl J Med 1993; 329: 977– 86

Hypoglycemia in the Management of Diabetes 1. 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

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/d. L) (EMA)1 – 3. 9 mmol/L (≤ 70 mg/d. L) (ADA)2 – 4. 0 mmol/L (<72 mg/d. L) 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

Hypoglycemia in the Management of Diabetes 1. The impact of hypoglycemia: – Its is common and adds cost to diabetes treatment

35, 000 35% 30, 000 30% 25, 000 25% 20, 000 20% 15, 000 15% 10, 000 10% 0 0% AD O O pi oi ds An tib io An tic tin s D eo ig pl An ox as in tia Re tic dr ni a nen ge an er nt gi gi s ot c ag en Se en si da n ts in tiv hi es bi o to r rs hy pn An ot tic ic on s vu ls an ts D iu re tic s a ge n ts s lin l a nt ip la te le t In su fa ar W O ra s 5% rin 5, 000 Percentage of admissions Number of hospital admissions Medications Most Commonly Associated with Emergency Admissions in Patients >65 Years of Age 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

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

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

Socioeconomic Consequences of Non-Severe Symptomatic Hypoglycemia in Type 2 Diabetes (France, Germany, UK, USA) Direct impact of reduced productivity 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 Indirect impact through increased treatment cost • 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

Hypoglycemia in the Management of Diabetes 1. The impact of hypoglycemia: – Its is common and adds cost to diabetes treatment – Increases morbidity and mortality

Intensive Insulin Therapy is Associated with Increased Incidence of Severe Hypoglycemia ADVANCE 1 ACCORD 2 Per 100 -patients per year 15 15 12 12 12 9 6 3 0 0. 4 0. 7 Standard Intensive p<0. 001 9 6 3. 0 3 0 1. 0 Severe hypoglycaemic events 15 Severe hypoglycaemic events Per 100 -patients per year VADT 3 12. 0 9 6 4. 0 3 0 Standard Intensive p<0. 001 Standard Intensive p<0. 01 Intensive glucose lowering contributes to an increased risk of hypoglycemia by 2 - to 3 -fold, particularly in advanced type 2 diabetes 1. 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

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

ADVANCE: Severe Hypoglycemia is Associated with Increased Risk of Adverse Outcomes Severe hypoglycaemia (n=231) Events No severe hypoglycaemia (n=10, 909) 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) 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) 6 (2. 7) 146 (1. 3) 4. 73 (1. 96– 11. 40) 5 (2. 2) 149 (1. 4) 2. 11 (0. 65– 6. 82) “Severe hypoglycemia (SH) was strongly associated with Death from any cause 45 (19. 5) 986 (9. 0) 3. 27 (2. 29– 4. 65) increased risk of a range of adverse clinical outcomes… Cardiovascular disease (it either) contributes to adverse outcomes or is a marker 22 (9. 5) 520 (4. 8) 3. 79 (2. 36– 6. 08) Non-cardiovascular disease 23 (10. 0)of vulnerability to such events” 466 (4. 3) 2. 80 (1. 64– 4. 79) Diseases of the skin Cancer 0. 1 1. 0 10. 0 Zoungas at al. N Engl J Med 2010; 363: 1410– 8, for the ADVANCE Collaborative Group

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

ADVANCE: Hazard Ratios (HR) of Cardiovascular Disease, Microvascular Events and Death Among Patients that Experienced Severe Hypoglycemia vs. Those Who Did Not Clinical Outcome HR p-value Macrovascular events 4. 0 <0. 001 Microvascular events 2. 4 <0. 001 Death from any cause 4. 9 <0. 001 Death from CV cause 4. 9 <0. 001 Death from non-CV cause 4. 8 <0. 001 Zoungas at al. N Engl J Med 2010; 363: 1410– 8, for the ADVANCE Collaborative Group

VADT: Severe Hypoglycemia is a Major Predictor of Cardiovascular Death Predictor HR p-value Hypoglycaemia 4. 0 0. 01 Hb. A 1 c 1. 2 0. 02 HDL 0. 7 0. 02 Age 2. 1 <0. 01 Previous event 3. 1 <0. 01 VADT: N Engl J Med 2009; 360: 129– 39.

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

Association of Hypoglycemia with Acute Cardiovascular Events in T 2 DM • 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

Severe Hypoglycemia Increases the Risk of CVD and Microvascular Complications in the Elderly Outcome CVD PVD Stroke CHF Microvascular HR 2. 0 2. 6 2. 3 1. 8 P value <0. 001 0. 001 <0. 001 Zhao et al. Diabetes Care 2012 ; 35: 1126 -1132

Hypoglycemia in the Management of Diabetes 1. 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

Impact of Severe Hypoglycaemic* Event on Patient’s Behavior Response to major hypoglycaemic event (%) Stayed at home next day Feared future hypoglycaemic events Changed insulin dose Type 1 diabetes 20. 0 63. 6 78. 2 Type 2 diabetes 26. 3 84. 2 57. 9 *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

Mean HFS-II worry score Fear of Hypoglycemia is Related to Preceding History of Hypoglycemia p<0. 0001* 20 19. 0 16 12 8 10. 2 4 0 No history of hypoglycaemia (n=264) *Based on the t-test. HFS-II, Hypoglycaemia Fear Survey-II. History of hypoglycaemia (n=136) Vexiau et al. Diabetes Obes Metab 2008; 10(suppl 1): 16– 24

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

Hypoglycemia in the Management of Diabetes 1. 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

Causes and risk factors for hypoglycaemia • General causes of hypoglycaemia 1, 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 hypoglycaemia 3, 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

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

Hypoglycemia is Frequently Unrecognized by Patients • Many episodes are asymptomatic; CGMS data show that unrecognised hypoglycaemia is common in people with insulintreated 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 74% of all events occurred at night • In another study, 83% of hypoglycaemic episodes detected by CGMS were not detected by patients with type 2 diabetes (n=31)2 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

Risk of Hypoglycemia during Sleep • No symptoms detectable during sleep • Catecholamine responses are diminished 1 • May not impair cognitive function the next day 2, 3 • Subjective well-being affected with greater fatigue during exercise 3 • May induce impaired awareness of hypoglycaemia the next day 4 1. Jones et al. New Engl. J Med 1998; 338: 1657 -62; 2. Bendtson et al. Diabetologia 1992; 35: 898 -903; 3. King et al. Diabetes Care 1998; 21: 341 -5; 4. Veneman et al. Diabetes 1993; 42: 1233 -7.

Hypoglycemia in the Management of Diabetes 1. 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

Beware of Patients with Hypoglycemia Unawareness • Hypoglycemia unawareness affects • 10%1 insulin-treated T 2 DM • Risk of severe hypoglycaemia is 3 to 6 fold greater 2 100 % events • 20– 25% of adults T 1 DM Severe hypoglycaemia without warning 3 50 0 0– 9 10– 19 20– 29 30– 39 >40 Diabetes duration (years) • Broad spectrum of severity 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

Hypoglycemia in the Management of Diabetes 1. 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

Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A 1 C Levels Before and After Treatment Intensification in T 2 DM Riddle et al. Diabetes Care 34: 2508– 2514, 2011

Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A 1 C Levels Before and After Treatment Intensification in T 2 DM Riddle et al. Diabetes Care 34: 2508– 2514, 2011

Hypoglycaemic events per patient-year Role of Insulin Analogues in the Prevention of Hypoglycemia 60 Insulin A 50 40 30 20 Insulin B 10 6 7 8 9 10 11 Hb. A 1 c (%) Adapted from DCCT Research Group N Engl J Med 1993; 329: 977– 86

Hb. A 1 c and Hypoglycemia in Patients with Type 2 Diabetes Confirmed hypoglycaemia (events/patient-year) Insulin detemir Hypoglycaemic events per patient-year 14 NPH insulin 12 10 8 6 4 2 0 5. 0 6. 0 7. 0 8. 0 9. 0 Hb. A 1 c (%) Hermansen et al. Diabetes Care 2006; 29: 1269– 74

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