Post on 26-Mar-2015
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)
DCCT Research Group. N Engl J Med 1993;329:977–86
1413121110987650
20
40
60
80
100
Sev
ere
hypo
glyc
emia
(p
er 1
00 p
atie
nt-y
ears
)
HbA1c (%)
0
2
4
6
8
10
12
14
16
Retinopathy
(per 100 patient-years)
Conventional group
Intensive groupRetinopathy
DCCT, Diabetes Control and Complications Trial
The Physician’s Dilemma
Adapted from DCCT Research Group N Engl J Med 1993;329:977–86
Rate of progression of retinopathy
(per 100 patient-years)
12
10
8
6
4
2
05.0 6.0 7.0 8.0 9.0 10.09.5 10.58.57.56.55.5
80
60
40
20
0
100
Rat
e of
sev
ere
hypo
glyc
aem
ia(p
er 1
00 p
atie
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ears
)
HbA1c (%)
Retinopathy risk Hypoglycaemia rate
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/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/1080/00. 2006; 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
Hypoglycemia in the Management of Diabetes
1. The impact of hypoglycemia:
– Its is common and adds cost to diabetes treatment
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
Opioi
ds
Hypoglycemia Accounts for Most Endocrine-related Emergency Hospital Admissions
Budnitz et al. N Engl J Med 2011;365:21
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
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
SU <2 yr >5 yr <5 yr >15 yr
T1DT2D
Severe hypoglycemia
Pro
port
ion
repo
rtin
g at
leas
t one
hy
pogl
ycae
mic
epi
sode
0.0
0.2
0.4
0.6
0.8
1.0
SU <2 yr >5 yr <5 yr >15 yr
T1DT2D
Mild hypoglycemia
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
Hypoglycemia in the Management of Diabetes
1. The impact of hypoglycemia:
– Its is common and adds cost to diabetes treatment
– Increases morbidity and mortality
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
Standard Intensive
p<0.001 p<0.01p<0.001
Per 100-patients per year
0.4 0.7
4.0
12.0
3
6
9
12
15
VADT3ACCORD2ADVANCE1
Per 100-patients per year
1.0
0
Per 100-patients per year
Se
vere
hyp
og
lyca
em
ic e
ven
ts
Se
vere
hyp
og
lyca
em
ic e
ven
ts
Se
vere
hyp
og
lyca
em
ic e
ven
ts
3
6
9
12
15
0
3
6
9
12
15
0
3.0
Standard Intensive Standard Intensive
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
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
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)
0.1 1.0 10.0
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”
“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”
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
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
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
VADT: N Engl J Med 2009;360:129–39.
Predictor HR p-value
Hypoglycaemia 4.0 0.01
HbA1c 1.2 0.02
HDL 0.7 0.02
Age 2.1 <0.01
Previous event 3.1 <0.01
VADT: Severe Hypoglycemia is a Major Predictor of
Cardiovascular Death
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
• 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
Zhao et al. Diabetes Care 2012 ;35:1126-1132
Outcome HR P valueCVD 2.0 <0.001PVD 2.6 <0.001Stroke 2.3 <0.001CHF 1.8 0.001Microvascular 1.8 <0.001
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* Eventon 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
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
Fear of Hypoglycemia is Related to Preceding History of Hypoglycemia
0
4
8
12
16
20
History of hypoglycaemia
(n=136)
No history of hypoglycaemia
(n=264)
Me
an
HF
S-I
I wor
ry s
core
19.0
10.2
p<0.0001*
*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
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
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 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
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 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
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
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.
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
• 20–25% of adults T1DM
• 10%1 insulin-treated T2DM
• Risk of severe
hypoglycaemia is 3 to 6
fold greater2
• 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
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
Severe hypoglycaemia without warning3
100
Diabetes duration (years)
0–9 10–19 20–29 30–39 >40
50
0
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 A1C Levels Before and After Treatment Intensification in T2DM
Riddle et al. Diabetes Care 34:2508–2514, 2011
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
1110987610
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Hypogly
caem
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ven
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pati
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Insulin A
Insulin B
HbA1c (%)
Adapted from DCCT Research Group N Engl J Med 1993;329:977–86
Confirmed hypoglycaemia (events/patient-year)
HbA1c and Hypoglycemia in Patients with Type 2 Diabetes
Hermansen et al. Diabetes Care 2006;29:1269–74Hermansen et al. Diabetes Care 2006;29:1269–74
Insulin detemir
NPH insulin
0
5.0
12
8
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6.0 7.0 8.0 9.0
Hyp
ogly
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tient
-yea
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HbA1c (%)
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14
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