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Company Confidential © 2012 Eli Lilly and Company
Hypoglycaemia
Speaker name and affiliation
Prescribing information is available on the last slide.
© 2013 Eli Lilly and Company
UKDBT01514 October 2013
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Table of contents
2
Epidemiology of hypoglycaemia
Risk factors, causes, symptoms and consequences of hypoglycaemia
A barrier to glycaemic control
Lessons learnt from clinical trials
Summary
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Epidemiology of hypoglycaemia in UK
3
SU, sulphonylurea1. UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–7
0.0
0.2
0.4
0.6
0.8
1.0
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
SU <2 yr >5 yr <5 yr >15 yr
T1DT2D
Severe hypoglycaemia Mild hypoglycaemia
Pro
por
tion
repo
rtin
g a
t le
ast
one
hy
pogl
ycae
mic
epi
sode
Requiring help for recovery Self-treated
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Severe hypoglycaemia in type 1 DM
4
American Journal of Medicine Diabetes Control and Complications Trial 1991;90: 450-59
occurs frequently during sleep often go unrecognised by patients
36% of severe episodes that oc-curred while awake had no warn-ing signs
216 participants with T1DM reported 714 episodes of severe hypoglycaemia, the majority of which occurred during sleep. Severe hypoglycaemia was defined as blood glucose <2.8 mmol/L requiring third-party assistance.
55% of severe hypoglycaemic episodes occur during sleep
Risk factors, causes, symptoms and consequences of hypoglycaemia
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Causes and risk factors for hypoglycaemia
6
Common causes of hypoglycaemia1,2
– Delayed or missed meal– Consuming a smaller meal than planned– Increased level of physical activity– Insulin, Sulphonylureas, prandial regulators– Renal decline/impairment– Autonomic neuropathy
Common risk factors for severe hypoglycaemia3,4
– Type of Diabetes – Age/duration of diabetes treatment– Strict glycaemic control– Impaired hypoglycaemia awareness– History of severe hypoglycaemia
1. Briscoe and Davis. Clin Diabetes 2006;24(3):115–121; 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
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Common symptoms of hypoglycaemia
7
1. McAulay. Diabetic Medicine 2001;18:690–705
Autonomic Neuroglycopenic General malaise
Sweating Confusion Headache
Palpitations Drowsiness Nausea
Shaking Odd behaviour
Hunger Speech difficulty
Incoordination
Edinburgh Hypoglycaemia Scale in which the 11 most commonly reported symptoms were incorporated
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Neurological consequences of hypoglycaemia
8
1. de Galan et al. Neth J Med 2006;64:269–79; 2. DCCT. N Eng J Med 2007;356;1842–52
Hypoglycaemia deprives the brain of glucose, promoting an autonomic response (e.g., sweating, trembling, anxiety) and neuroglycopenic-induced behavioural changes and cognitive impairment
Normal counter-regulatory responses to hypoglycaemia can be impaired following repeated hypoglycaemia1
Chronic cognitive impairment is rare2
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Pathophysiological cardiovascular consequences of hypoglycaemia
9
CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor
Desouza et al. Diabetes Care 2010;33:1389–94
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Major hypoglycaemia significantly increases the risk for adverse outcomes in patients with T2DM
10
CI, confidence interval
Zoungas et al. N Engl J Med 2010;363(15):1410–18
Clinical outcome and interval after hypoglycaemia
No. of events
Hazard ratio adjusted for treatment assignment
(95% CI)
p-value Hazard ratio adjusted for multiple covariates
(95% CI)
p-value
Macrovascular events 1147 4.05 (2.86–5.74) <0.001 3.45 (2.34–5.08) <0.001
Microvascular events 1131 2.39 (1.60–3.59) <0.001 2.07 (1.32–3.26) <0.001
Death from any cause 1031 4.86 (3.60–6.57) <0.001 3.30 (2.31–4.72) <0.001
Death from cardiovascular cause
542 4.87 (3.17–7.49) <0.001 3.78 (2.34–6.11) <0.001
Death from non-cardiovascular cause
489 4.82 (3.16–7.35) <0.001 2.86 (1.67–4.90) <0.001
Hazard ratios for incident vascular outcomes and death among patients who had major hypoglycaemia as compared with those who did not
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Normal counterregulation
11
SNS - Sympathetic nervous system, GH – Growth Hormone
insulin
glucagon
GH
cortisol
4.7
3.83.7
3.2
cognition2.8
coma2.2
adrenaline SNS
autonomicsymptoms
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
12
CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor
Desouza et al. Diabetes Care 2010;33:1389–94
4
3
2
1
Adrenaline release
Coma /hypoglycaemic seizure
Confusion / loss of concentration
Sweating tremor
Start of brain dysfunction
Hypo Aware
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
13
4
3
2
1
Adrenaline release
Coma /hypoglycaemic seizure
Confusion / loss of concentration
Sweating tremor
Start of brain dysfunction
Hypo Aware Hypo Unaware
Start of brain dysfunction
Adrenaline release Sweating tremor
Confusion / loss of concentration
Coma /hypoglycaemic seizure
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Vicious cycle of repeated hypoglycaemia
14
Repeated episodes of hypoglycaemia
Defective counter-regulation
Impaired awareness of hypoglycaemia
Increased vulnerability to further hypoglycaemia
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Effect of one episode of antecedent hypoglycaemia
15
2 h at ~3 mM
Pre PrePost Post
1000
500
0
40
35
30
25
20
15
10
0
5
Adr
enal
ine
(pg/
ml) S
ymptom
score
***
*
Responses measured 1 day apart
*p<0.05,***p<0.001
Heller and Cryer. Diabetes 1991;40(2):223–6
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Hypoglycaemia unawareness is associated with a higher rate of severe hypoglycaemia
16
Henderson et al. Diabet Med 2003;20(12):1016–21
0
0.5
1.0
1.5
2.0
2.5
9-fold higher rate of severe hypoglycaemia
0.22
2.15
Normalawareness
(n=144)
Impairedawareness
(n=13)
Major hypoglycemia was defined as an episode requiring external assistance for recovery. Subjective changes in hypoglycemia symptom intensity were recorded by the participants based on a hypoglycemia awareness scale of 1 to 7, where 1 = always aware and 7 = never aware, and a score of 4 or more correlates with impaired awareness
*Based on data from a retrospective survey of 215 patients with T2DM treated with ≥2 injections of insulin daily for ≥1 year
A barrier to glycaemic control
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Hypoglycaemia Represents a Psychological Barrier to Effective Glycaemic Control
18
1. Nakar S et al. J Diabetes Complications. 2007;21(4):220-226; 2. Frier BM. Diabetes Metab Res Rev. 2008;24(2):87-92; \
3. Alvarez Guisasola F et al. Diabetes Obes Metab. 2008;10(suppl 1):25-32.
Physicians and patients express fear of hypoglycaemia, which may be an impediment to effective diabetes management1
Desire to avoid hypoglycaemia leads some patients to intentionally compromise glycaemic control and maintain a state of hyperglycaemia2
Fear of hypoglycaemia extends to family members who have had to assist an affected relative during a hypoglycaemic event on previous occasions2
Patient reports of hypoglycaemic symptoms are associated with significantly lower treatment satisfaction and barriers to adherence3
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Patients fear severe hypoglycaemia as highly as developing serious chronic complications*
19
Pramming et al. Diabet Med 1991;8(3):217–22
‘Mild’ hypoglycaemia
‘Severe’hypoglycaemia
Thoughts about diabetes
Blindness Kidneycomplications
Not worried
Very worried
Men
Women
*Based on patient (n=411, T1DM) attitudes on hypoglycemia using a visual analogue scale
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Consequences of Hypoglycaemia
20
NHS Diabetes 2011:Recognition, treatment and prevention of hypoglycaemia in the communit
Quality of life (52% of people surveyed believed hypos affected their quality of life)
Time off work (1in 10 people had to take at least one day off work as a result of hypoglycaemia)
Elderly more prone to falls and fractures
Driving and RTA’s (hypoglycaemia is implicated in 30 serious RTA’s each month)
Weight Gain, additional calories consumed to treat hypos
Medication adherence, Reluctance to take medication because of fear of hypos
y
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Consequences of hypoglycaemia for driving in the UK
21
DVLA guidance. Available at: www.dft.gov.uk/dvla/medical/ataglance.aspx
Patients who manage their diabetes with insulin must inform the DVLA of their treatment and also if the following apply:
You suffer more than one episode of disabling hypoglycaemia (low blood sugar) within 12 months, or if you or your carer feels you are at high risk of developing disabling hypoglycaemia
You develop impaired awareness of hypoglycaemia (difficulty in recognising the warning symptoms of low blood sugar)
You suffer disabling hypoglycaemia while driving
Lessons learnt from clinical trials
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Reports of Hypoglycemia Are Likely Underestimated in Clinical Trials
23
1. Bonds DE et al. Am J Cardiol. 2007;99(12A):80i-89i; 2. Cryer PE. Hypoglycemia in Diabetes: Pathophysiology, Prevalence, and Prevention. Alexandria, VA: American Diabetes Association; 2009; 3. Zammitt NN, Frier BM. Diabetes Care. 2005;28(12):2948-2961.
Definitions vary in clinical trials1
Inconsistent event reporting and data collection2,3
– Difference between clinical trial participants and real life patients Prospective clinical trials often exclude high-risk patients3
– Self-reporting vs self-reporting + glucose measurements2
Asymptomatic or unrecognized episodes can be missed– Greater psychological impact and recall of severe hypoglycemic episodes3
– Interindividual variations in symptom thresholds3
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Severe Hypoglycemia Is Defined Differently Across Trials in Patients With T2DM
24
1. Bonds DE et al. Am J Cardiol. 2007;99(12A):80i-89i; 2. Patel A et al; ADVANCE Collaborative Group [ADVANCE]. N Engl J Med. 2008;358(24):2560-2572.
Trial Definition of Severe Hypoglycemia
UKPDS Requiring help from another person1
DIGAMI Not defined1
VA CSDM Requiring help from another person and a prompt recovery with therapy or a confirmed low glucose level (not defined)1
ACCORD Requiring medical attention in which there was eithera documented capillary glucose level <50 mg/dL orin which prompt recovery was achieved with oral carbohydrate, intravenous glucose, or glucagon1
ADVANCE Transient dysfunction of the CNS and inability to self-treat2
ACCORD=Action to Control Cardiovascular Risk in Diabetes trial; The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial; DCCT=Diabetes Control and Complications Trial; DIGAMI=Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction trial; UKPDS=United Kingdom Prospective Diabetes Study; VA CSDM=Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus.
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Event rates for severe hypoglycaemia in insulin-treated diabetes
25
Cryer PE. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention. Table 1.1, page 9. American Diabetes Association, Alexandria, Virginia, 2009
Severe hypoglycaemia: requiring the assistance of another person
Expressed as episodes per 100 patient-year
Studies covering at least 6 months, involving at least 48 patients, and reporting severe hypoglycaemia event rates are included. This table is derived from Cryer PE. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention.
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
As beta-cell function declines, treatment intensification increases hypoglycaemia risk
26
Adapted from: Lebovitz. Diab Rev 1999;7:139–53; UK Hypoglycaemia Study Group Diabetologia 2007;50:1140–7
SU <2 yr >5 yr <5 yr >15 yr
Type 1Type 2
Mild hypoglycaemia
Pro
por
tion
repo
rtin
g ≥
1 hy
pogl
ycae
mic
epi
sode
Bet
a-ce
ll fu
nctio
n (%
)
100
14
Years from diagnosis
Diagnosis50
75
25
00 1062–2–6–10–12
0.0
0.2
0.4
0.6
0.8
1.0
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Higher rate of severe hypoglycaemia with intensive glycaemic control*
27
1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–53; 2. Patel et al; ADVANCE Collaborative Group [ADVANCE]. N Engl J Med 2008;358:2560–72; 3. Gerstein et al; Action to Control Cardiovascular Risk in Diabetes Study Group [ACCORD]. N Engl J Med 2008;358:2545–59; 4. Duckworth et al. N Engl J Med 2009;360:129–39
p<0.001vs. conventional
HR 1.86 (1.42–2.40)p<0.001
p<0.001 p=0.001
UKPDS1 ADVANCE2 ACCORD3 VADT4
Ann
ualis
ed r
ate
of s
ever
e hy
pogl
ycae
mia
† (
%)
7.9% 7.2% 7.3% 6.5% 7.5% 6.4% 8.4% 6.9%7.1%HbA1c=
0.7
1.41.8
0.40.7
1.0
3.0
0.5
2.0
0.0
1.0
2.0
3.0
4.0
5.0
Conv Gly Ins Std Int Std Int Std Int
*Intensive glycaemic control was defined differently in these trials †Hypoglycaemia requiring any assistance in glucose-lowering trials Conv, conventional therapy; Gly, glibenclamide; HbA1c, glycated haemoglobin; HR, hazard ratio; Ins, insulin; Int, intensive therapy; Std, standard therapy
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
The clinician’s dilemma: prognosis vs. tolerability
28
Adapted from: DCCT Research Group. N Engl J Med 1993;329:977–86
Rate
of prog
ression o
f retinopath
y (per 10
0 patient-ye
ars)
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 o
f se
vere
hyp
ogly
caem
ia(p
er 1
00
pat
ient
-ye
ars)
HbA1c (%)Retinopathy risk Hypoglycaemia rate
120
Managing hypoglycaemia
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
What is a Hypo?
30
Healthcare professional - Blood GLucose falls below a certain level (e.g 3.9mmol/l) Patient perspective:
– Sweating / shaking– Loss of concentration, tasks taking too long– Being force-fed lucozade or something sweet– Being injected with glucagon
“Sometimes I feel fine when my BG is 1.8”
“Once I had a hypo when I was walking along, people thought I was drunk ... Nobody asked if I needed help”
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Assessing for Hypoglycaemia
31
HCP in clinic / phone:
“How is your diabetes?” Patient, “fine, no problems”
HCP “Any hypos?” Patient “No, occasional minor one, otherwise OK”
HCP “Sounds good, see you in 6 months”
HCP A
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Assessing for Hypoglycaemia
32
HCP B asks .....
What do you understand by the term hypoglycaemia
What symptoms of hypoglycaemia do you get /or how would you recognise you were hypo?
At what blood glucose level do you know you are hypo?
Who recognises hypos first themselves or others?
Are they always able to treat hypos themselves, have they ever needed help to treat a hypo
Can they always identify why they've had a hypo
Checks diary ( ask if they always record hypos)
Checks meter How do they treat hypos and how long it takes
to recover
If you suspect hypos also worth asking...
Any morning headaches ? Sleep pattern to see if disturbed ? Any unexplained profuse
sweating?
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Hypoglycaemia treatment
33
Mild Hypoglycaemia Treatment aims to deliver 15 –
20g glucose 100mls lucozade 150mls of non diet fizzy drink 200mls fruit juice 5 – 6 dextrose tablets 4 large jelly babies 7 large jelly beans After 5 – 10minutes if pt not feeling any
better/ and or blood glucose level still less than 4mmol/s repeat treatment
Follow up initial treatment with unrefined carbohydrate, if not due to eat a meal.
Severe hypoglycaemia Person cannot self treat Can swallow offer treatment as per
mild hypoglycaemia Cannot swallow, nil by mouth Glucagon injection /or ambulance
Aim to identify cause of all hypos to prevent reoccurrence
Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company
Conclusions
34
Hypoglycaemia is .... A common side effect of diabetes treatments, predominantly insulin, also
sulphonylureas, post prandial regulators The main factor preventing good metabolic control Impactful on the individuals quality of life
Managing hypoglycaemia should include A thorough assessment to ensure hypoglycaemia is not undetected by the
individual and/or HCP, Education to ensure recognition of symptoms, appropriate treatment and
prevention strategies Teaching patients effectively to self manage their diabetes to reduce the risk
of severe episodes
THANKS FOR YOUR ATTENTION
Questions ?
UKDBT01514 October 2013