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
Intensive group
80
14
12
10
60
8
Conventional
group
40
6
4
Retinopathy
(per 100 patient-years)
Severe hypoglycemia
(per 100 patient-years)
Retinopathy
20
2
0
5
6
7
8
9
10
11
12
13
0
14
HbA1c (%)
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
5.0
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
HbA1c (%)
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/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
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%
5,000
5%
0
0%
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
Percentage of admissions
Number of hospital admissions
Medications Most Commonly Associated with
Emergency Admissions in Patients >65 Years of Age
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 T2DM is as Common as in
T1DM with Increasing Duration of Insulin Therapy
Severe hypoglycemia
Proportion reporting at least one
hypoglycaemic episode
0.8
Mild hypoglycemia
1.0
0.7
0.8
0.6
0.5
0.6
0.4
0.4
0.3
0.2
0.2
0.1
0.0
SU
<2 yr
>5 yr
<5 yr
T2D
>15 yr
T1D
0.0
SU
<2 yr
T2D
>5 yr
<5 yr
>15 yr
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
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
ADVANCE1
ACCORD2
Per 100-patients per year
VADT3
Per 100-patients per year
15
Per 100-patients per year
15
15
12
12
9
6
3
0.4
0.7
Standard
Intensive
9
6
3.0
3
1.0
p<0.001
9
6
4.0
3
0
0
0
Severe hypoglycaemic events
Severe hypoglycaemic events
Severe hypoglycaemic events
12.0
12
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)22contributes
(9.5)
(4.8)
3.79 (2.36–6.08)
to520adverse
outcomes or is a marker
Non-cardiovascular disease
23 (10.0)of vulnerability
466 (4.3) to such events”
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
HbA1c
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 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
Outcome
CVD
PVD
Stroke
CHF
Microvascular
HR
2.0
2.6
2.3
1.8
1.8
P value
<0.001
<0.001
<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
Fear of Hypoglycemia is Related to
Preceding History of Hypoglycemia
Mean HFS-II worry score
p<0.0001*
20
19.0
16
12
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
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 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 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 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
• 10%1 insulin-treated T2DM
• Risk of severe
hypoglycaemia is 3 to 6
fold greater2
100
% events
• 20–25% of adults T1DM
Severe hypoglycaemia
without warning3
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 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
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
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
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
HbA1c (%)
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