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Hypoglycemia in Diabetes: the limiting factor to optimal control June 7, 2012 Kenneth Cusi, MD, FACP, FACE Professor of Medicine Chief, Division of Endocrinology,

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Presentation on theme: "Hypoglycemia in Diabetes: the limiting factor to optimal control June 7, 2012 Kenneth Cusi, MD, FACP, FACE Professor of Medicine Chief, Division of Endocrinology,"— Presentation transcript:

1 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

2 Hypoglycemia: benefits and risks (DCCT) DCCT Research Group. N Engl J Med 1993;329:977– Severe hypoglycemia (per 100 patient-years) HbA 1c (%) Retinopathy (per 100 patient-years) Conventional group Intensive group Retinopathy DCCT, Diabetes Control and Complications Trial

3 The Physicians Dilemma Adapted from DCCT Research Group N Engl J Med 1993;329:977–86 Rate of progression of retinopathy (per 100 patient-years) Rate of severe hypoglycaemia (per 100 patient-years) HbA 1c (%) Retinopathy riskHypoglycaemia rate

4 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

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 1. EMA. CPMP/EWP/1080/ ; 2. ADA. Diabetes Care 2005;28:1245–9; 3. Yale et al. Canadian J Diabetes 26:22–35 ADA, American Diabetes Association; CDA, Canadian Diabetes Association; EMA, European Medicines Agency

6 Hypoglycemia in the Management of Diabetes 1.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 Budnitz et al. N Engl J Med 2011;365:21 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 Opioids

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 SU, sulfonylurea; T1D, type 1 diabetes; T2D, type 2 diabetes UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–7 SU<2 yr>5 yr<5 yr>15 yr T1DT2D Severe hypoglycemia Proportion reporting at least one hypoglycaemic episode SU<2 yr>5 yr<5 yr>15 yr T1D T2D Mild hypoglycemia

10 Socioeconomic Consequences of Non-Severe Symptomatic Hypoglycemia in Type 2 Diabetes (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 Direct impact of reduced productivity Indirect impact through increased treatment cost Brod et al. Value Health 2011;14:665–71

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

12 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 StandardIntensive p<0.001 p<0.01 p<0.001 Per 100-patients per year VADT 3 ACCORD 2 ADVANCE 1 Per 100-patients per year Per 100-patients per year Severe hypoglycaemic events StandardIntensiveStandardIntensive 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 with Increased Incidence of Severe Hypoglycemia

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 Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group Severe hypoglycaemia (n=231) No severe hypoglycaemia (n=10,909) 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) Death from any cause 986 (9.0)45 (19.5)3.27 (2.29–4.65) Cardiovascular disease 520 (4.8)22 (9.5)3.79 (2.36–6.08) Non-cardiovascular disease 466 (4.3)23 (10.0)2.80 (1.64–4.79) Respiratory system events 656 (6.0)18 (8.5)2.46 (1.43–4.23) Digestive system events 867 (7.9)20 (9.6)2.20 (1.31–3.72) Diseases of the skin 146 (1.3)6 (2.7)4.73 (1.96–11.40) Cancer 149 (1.4)5 (2.2)2.11 (0.65–6.82) Hazard ratio (95% CI)Events 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

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 Clinical OutcomeHRp-value Macrovascular events4.0<0.001 Microvascular events2.4<0.001 Death from any cause4.9<0.001 Death from CV cause4.9<0.001 Death from non-CV cause4.8<0.001 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: N Engl J Med 2009;360:129–39. PredictorHRp-value Hypoglycaemia HbA 1c HDL Age2.1<0.01 Previous event3.1<0.01 VADT: Severe Hypoglycemia is a Major Predictor of Cardiovascular Death

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

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 Zhao et al. Diabetes Care 2012 ;35: OutcomeHRP value CVD2.0<0.001 PVD2.6<0.001 Stroke2.3<0.001 CHF Microvascular1.8<0.001

21 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

22 Impact of Severe Hypoglycaemic* Event on Patients Behavior Response to major hypoglycaemic event (%) Type 1 diabetes Type 2 diabetes Stayed at home next day Feared future hypoglycaemic events Changed insulin dose Leiter L et al. Can J Diabetes 2005;29:186–92 *Severe hypoglycaemia defined as any event requiring external assistance and with a PG <2.8 mmol/L

23 Fear of Hypoglycemia is Related to Preceding History of Hypoglycemia History of hypoglycaemia (n=136) No history of hypoglycaemia (n=264) Mean HFS-II worry score p< * *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 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

25 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

26 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

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:

28 Hypoglycemia is Frequently Unrecognized 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 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 74% of all events occurred at night 54% of hypoglycaemic episodes were nocturnal, none of which were detected

29 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: ; 2. Bendtson et al. Diabetologia1992;35: ; 3. King et al. Diabetes Care 1998;21:341-5; 4. Veneman et al. Diabetes 1993;42:

30 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

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 greater 2 Broad spectrum of severity 1. Gold et al. Diabetes Care 1994;17: Geddes et al. Diabetic Med 2008;25: 501–4 3. Pramming et al. Diabetic Med 1991;8:217–22 Severe hypoglycaemia without warning Diabetes duration (years) 0–9 10–1920–2930–39 > % events

32 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

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 Hypoglycaemic events per patient-year Insulin A Insulin B HbA 1c (%) Adapted from DCCT Research Group N Engl J Med 1993;329:977–86

36 Confirmed hypoglycaemia (events/patient-year) HbA 1c and Hypoglycemia in Patients with Type 2 Diabetes Hermansen et al. Diabetes Care 2006;29:1269–74 Insulin detemir NPH insulin Hypoglycaemic events per patient-year HbA 1c (%)

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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