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) 100 16 (per 100 patient-years) Retinopathy Intensive group 14 Retinopathy 80 12 10 60 Severe hypoglycemia (per 100 patient-years) 8 40 Conventional group 6 The Diabetes Control and Complications Trial (DCCT) showed an inverse relationship between HbA1c and risk of hypoglycaemic events. 4 20 2 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 2

The Physician’s Dilemma 80 60 40 20 100 12 10 8 6 4 2 Rate of severe hypoglycaemia (per 100 patient-years) Rate of progression of retinopathy (per 100 patient-years) As previously noted, the risk of hypoglycaemia and fear of it impacts on the level of glycaemic control that physicians and patients can aim for, and hence affects a patients prognosis. The DCCT research group (ref on slide) showed an inverse relationship between glycated haemoglobin (HbA1c) and risk of hypoglycaemia. 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 3

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

Definition of 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 Although the criteria for defining hypoglycaemia may vary somewhat, association guidelines provide some guidance for standardisation American Diabetes Association (ADA) Canadian Diabetes Association (CDA) European Association for the Study of Diabetes (EASD) European Medicines Agency (EMA) 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 The impact of hypoglycemia: Its is common and adds cost to diabetes treatment

Budnitz et al. N Engl J Med 2011;365:21 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

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

Proportion reporting at least one hypoglycaemic episode 25/03/2017 12:0725/03/2017 12:07 Severe Hypoglycemia in T2DM is as Common as in T1DM with Increasing Duration of Insulin Therapy SU <2 yr >5 yr <5 yr >15 yr T1D T2D Severe hypoglycemia Proportion reporting at least one hypoglycaemic episode SU <2 yr >5 yr <5 yr >15 yr T1D T2D Mild hypoglycemia The UK Hypoglycaemia Study was an observational study over 9–12 months in six UK secondary care diabetes centres. Altogether, 383 patients were involved. Patients were divided into the following three treatment groups for type 2 diabetes (T2D): Sulphonylureas Insulin for <2 years Insulin for >5 years and into two treatment groups for type 1 diabetes (T1D), namely <5 years’ disease duration and >15 years’ disease duration. Self-reported (mild and major) episodes were recorded. Highlighted area links hypo episodes in T1D and T2D – adressing the myth that hypos are less common/ severe in T2D than T1D SU, sulfonylurea; T1D, type 1 diabetes; T2D, 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 Indirect impact through increased treatment cost 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 Abstract: Brod et al. Value Health 2011;14:665–71 Objectives: Hypoglycaemia is a common complication of treatment with certain diabetes drugs. Non-severe hypoglycemic events (NSHEs) occur more frequently than severe events and account for the majority of total events. The objective of this multi-country study was to identify how NSHEs in a working population affect productivity, costs, and self-management behaviors. Methods: A 20-minute survey assessing the impact of NSHEs was administered via the Internet to individuals (over 18 years of age) with self-reported diabetes in the US, UK, Germany, and France. The analysis sample consisted of all respondents who reported an NSHE in the past month. Topics included: reasons for, duration of, and impact of NSHE(s) on productivity and diabetes self-management. Results: A total of 1404 respondents were included in this analysis. Lost productivity was estimated to range from £9.90 to £60.69 per NSHE, representing 8.3 to 15.9 hours of lost work time per month. Among individuals reporting an NSHE at work (n=972), 18.3% missed work for an average of 9.9 hours (SD 8.4). Among respondents experiencing an NSHE outside working hours (including nocturnal), 22.7% arrived late for work or missed a full day. Productivity loss was highest for NSHEs occurring during sleep, with an average of 14.7 (SD 11.6) working hours lost. In the week following the NSHE, respondents required an average of 5.6 extra blood glucose test strips. Among respondents using insulin, 25% decreased their insulin dose following the NSHE. Conclusions: NSHEs are associated with substantial economic consequences for employers and patients. Greater attention to treatments that reduce NSHEs could have a major, positive impact on lost work productivity and overall diabetes management. Brod et al. Value Health 2011;14:665–71 10

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

Severe hypoglycaemic events Intensive Insulin Therapy is Associated with Increased Incidence of Severe Hypoglycemia Standard Intensive p<0.001 p<0.01 Per 100-patients per year 0.4 0.7 4.0 12.0 3 6 9 12 15 VADT3 ACCORD2 ADVANCE1 1.0 Severe hypoglycaemic events 3.0 Intensive glucose lowering contributes to an increased risk of hypoglycemia by 2- to 3-fold, particularly in advanced type 2 diabetes 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 12

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

No severe hypoglycaemia No. patients with events (%) ADVANCE: Severe Hypoglycemia is Associated with Increased Risk of Adverse Outcomes Severe hypoglycaemia (n=231) No severe hypoglycaemia (n=10,909) Events No. patients with events (%) Hazard ratio (95% CI) 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) 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 Death from any cause 4.9 Death from CV cause Death from non-CV cause 4.8 Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group 16

VADT: Severe Hypoglycemia is a Major Predictor of Cardiovascular Death HR p-value Hypoglycaemia 4.0 0.01 HbA1c 1.2 0.02 HDL 0.7 Age 2.1 <0.01 Previous event 3.1 VADT: N Engl J Med 2009;360:129–39. 17

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 T2DM 19 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 The final study cohort comprised 860,845 patients with type 2 diabetes. Patients with hypo events in the evaluation period were significantly older than patients without such events (average age of 64.0 years vs. 60.6 years; p<0.001). Johnston et al. Diabetes Care 2011;34:1164–70

Zhao et al. Diabetes Care 2012 ;35:1126-1132 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

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

Impact of Severe Hypoglycaemic* Event on Patient’s Behavior Response to major hypoglycaemic event (%) Type 1 diabetes Type 2 diabetes Stayed at home next day 20.0 26.3 Feared future hypoglycaemic events 63.6 84.2 Changed insulin dose 78.2 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 Novo Nordisk NovoMix <presenter name> <reference>

Fear of Hypoglycemia is Related to Preceding History of Hypoglycemia 4 8 12 16 20 History of hypoglycaemia (n=136) No history of hypoglycaemia (n=264) Mean HFS-II worry score 19.0 10.2 p<0.0001* Patient Fear of Hypoglycaemia Increases With History of Hypoglycaemia Veixau study: Patients with T2DM (N=400) being treated with metformin and SU for ≥6 months were recruited from 98 primary care centers in France. Patients reported history of macrovascular events (angina pectoris, congestive heart failure, myocardial infarction, stroke, transient ischemic attacks, and arteriopathy) and microvascular events (blindness, renal failure, renal insufficiency, lower extremity ulcer, diabetic foot, and macular degeneration). Patients were asked to read and fill out the Worry subscale of the Hypoglycaemia Fear Survey-II (HFS-II) with 18 items each preceded by the statement “Because my blood sugar could go low, I worried about . . .” A 5-point Likert scale was used to quantify patient results. Patients who reported hypoglycaemia were more likely to worry about hypoglycaemic episodes than patients who did not report episodes of hypoglycaemia. Reference Vexiau P, Mavros P, Krishnarajah G, Lyu R, Yin D. Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France. Diabetes Obes Metab. 2008;10(suppl 1):16-24. *Based on the t-test. HFS-II, Hypoglycaemia Fear Survey-II. Vexiau et al. Diabetes Obes Metab 2008;10(suppl 1):16–24

Neurological Consequences of Hypoglycemia 25/03/2017 12:0725/03/2017 12:07 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 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 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 Risk factors for hypoglycaemia Key message: Multiple risk factors can lead to hypoglycaemia in patients with diabetes. Review as stated References 1. Briscoe VJ, Davis SN. Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management. Clin Diabetes 2006;24(3):115–121. 2. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005;28(5):1245–9. 3. Frier BM. How hypoglycaemia can affect the life of a person with diabetes. Diabetes Metab Res Rev 2008;24(2):87–92. 4. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57(12):3169–76. 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

Importance of early recognition when starting insulin 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 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 occurred at night Hypoglycemic episodes often go unrecognised by patients Key message: CGMS data have demonstrated that unrecognised hypoglycaemic episodes are common and often occur at night. Chico study: This study evaluated the usefulness of a continuous glucose monitoring system (CGMS) for identifying unrecognised hypoglycaemia in patients with T1DM and T2DM. A total of 70 patients were monitored using CGMS, and the frequency of asymptomatic hypoglycaemia detected by the CGMS (glucose values <3.3 mmol/L) was calculated. Unrecognised hypoglycaemia was identified in 63% of patients with T1DM and 47% of patients with T2DM, as measured by CGMS (n=70) — 74% of all events occurred at night.1 Weber study: CGMS was used for ≥3 days to identify hypoglycaemia in patients with T2DM (n=31). Similar to the Chico study, there were a substantial number of hypoglycaemic episodes that went unrecognised by patients. Hypoglycaemic events were categorised as ≤2.79 mmol/L and borderline events as 2.8–3.9 mmol/L — duration and time of day were also recorded. A total of 83% of hypoglycaemic episodes were recognised by CGMS and unnoticed by patients. Of the total classified hypoglycaemic and borderline events, 54% were nocturnal, and all of these went unnoticed by patients.2 References Chico A, Vidal-Ríos P, Subirà M, Novials A. The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes Care 2003;26(4):1153–7. Weber KK, Lohmann T, Busch K, Donati-Hirsch I, Riel R. High frequency of unrecognized hypoglycaemias in patients with type 2 diabetes is discovered by continuous glucose monitoring. Exp Clin Endocrinol Diabetes 2007;115(8):491–4. 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 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 Key message: Sleep decreases the epinephrine response to hypoglycaemic events in patients with T1D and the warning signs of hypoglycaemia are reduced. Jones study: Epinephrine response was measured in adolescents with T1D (n=8) and age-matched controls (n=6) in daytime and nighttime in response to insulin-induced hypoglycaemia. In each study, the plasma glucose concentration was stabilised for 60 min at approximately 100 mg/dL and then reduced to 50 mg/dL for 40 min at various time points. 0 on the x-axis represents the beginning of the hypoglycaemic period. In both healthy participants and patients with T1D, epinephrine response was blunted while they were asleep, and maintained while they were awake in daytime. When patients with T1D were awake at night, epinephrine response was maintained.1 Banarer study: With a similar control case-matched study design to the Jones study, healthy adult participants were compared to adult patients with T1D. Epinephrine response was significantly decreased (p=0.001) during induced hypoglycaemic events in sleeping patients with T1D compared to healthy adult participants. Furthermore, patients with T1D exhibited markedly reduced awakening from sleep during these hypoglycaemic events.2 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.

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

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 100 Diabetes duration (years) 0–9 10–19 20–29 30–39 >40 50 % events 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 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

25/03/2017 12:07 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

25/03/2017 12:07 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

Role of Insulin Analogues in the Prevention of Hypoglycemia 25/03/2017 12:07 Role of Insulin Analogues in the Prevention of Hypoglycemia 60 Insulin A 50 40 Hypoglycaemic events per patient-year 30 20 This curve represents the relationship between HbA1c and hypoglycaemia for a hypothetical insulin. [CLICK] However, there may exist a second preparation, insulin B, with a slightly different curve. [CLICK] If we look at a particular HbA1c value, it is clear that insulin B has a lower associated rate than insulin A. Insulin B 10 6 7 8 9 10 11 HbA1c (%) Adapted from DCCT Research Group N Engl J Med 1993;329:977–86

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 5.0 6.0 7.0 8.0 9.0 HbA1c (%) Hermansen et al. Diabetes Care 2006;29:1269–74 36

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