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Management of severe /
refractory hypoglycaemia
Dr Pratik Choudhary
Senior Lecturer and Consultant in Diabetes
King’s College London
Disclosures
• Speaker fees / travel support / advisory boards for Sanofi,
Lilly, Novo Nordisk, Astra Zeneca, MSD, Janssen
/Medtronic / Roche / Animas / Abbott
Page 2
Incidence of severe hypoglycaemia
Pedersen Bjergaard et al Diabetes Metab Res Rev 2004; 20: 479–486. Choudhary, Diabetologia 2006
The balancing act
DCCT Research Group. N Engl J Med
1993;329:977–86
Se
ve
re h
yp
og
lyc
ae
mia
pe
r 1
00
pa
tie
nt-
ye
ars
HbA1c (%)
14 13 12 11 10 9 8 7 6 5 0
20
40
60
80
100
0
2
4
6
8
10
12
14
16 R
etin
op
ath
y p
er 1
00 p
atie
nt-
ye
ars
Hypoglycemia
Retinopathy
Factors for increased SH:
- Duration of T1D
- Age
- Financial status
- Impaired awareness
Weinstock et al; JCEM 2013, 98(8):3411–3419 Choudhary et al; Diabetic Medicine, 2010
What causes problematic / refractory
hypoglycemia
Acute hypoglycaemia
Mismatch of food and
insulin
Exercise
Alcohol
Recurrent / refractory
Impaired awareness
Duration of diabetes
C-peptide -ve
Co-morbidities
Renal impairment
Hepatic impairment
Cognitive impairment
Page 7
So – how do we restore
awareness?
Hypoglycaemia awareness can
be restored
Cranston , Lancet 1994 Cranston; Lancet 1994
Get the right data..
Ask the right questions
Can you detect when symptoms are less than 3 mmol/l [ 64mg/dl]
• 30% of those with T1D > 15 yrs have IAH
• Those with GS > 4 have a 2-6 fold higher risk of SH
• Up to 20% of T2DM with insulin > 5 yrs have IAH
Choudhary – Diabetic Medicine 2011
Do you know when your Hypos are commencing
Always 1 2 3 4 5 6 7 Never
0
5
10
15
20
25
30
35
40
5 yrs 25 yrs
Nephropathy Impaired awareness
Complications of T1DM
DCCT-EDIC study group December 22, 2011- NEJM
Common errors of insulin usage
predisposing to hypoglycemia
Timing of meal insulin doses
Failure to reduce insulin dose in response to exercise
or alcohol
Over-correction of high blood glucose values
Failure to snack between meals (for certain insulin
regimens)
“Stacking” – build-up of small, too-frequent doses
Choudhary P and Amiel K. Postgrad Med J 2011;87:298-306.
• 18 RCT’s
• 25 before and after studies
• 27 – educational
• 11 – technological
• 5 - pharmacological
• At least 1 month FU
Yeoh et al, Diabetes Care 2015; 38;1592
Educational strategies
S M A R T M E T E R S
Food insulin + correction insulin – Insulin on board
CHO + BG – Target BG - Insulin on board
I:C ISF
Complex / emotional responses to high BG
HypoAna: severe hypoglycaemia
0
10
20
30
40
50
60
70
80
90
100
Intention-to-treat
p=0.012
39%
Patients
(%
)
Human insulin Analogue insulin
n=141
*For baseline covariates (age, C-peptide status, hypoglycaemia awareness) and concurrent HbA1c
Severe hypoglycaemia requring third-party assistance and assessed according to Whipple’s triad (symptoms, recovery, plasma glucose ≤3.9 mmol/L) Pedersen-Bjergaard et al. Lancet Diabetes Endocrinol 2014;2:553–61
Prevalence
–10
–20
–30
–40
–50
–60
Intention-to-treat n=141
Rela
tive r
ate
reduction (
%)
0
29% p=0.010
Relative rate reduction insulin analogues vs. human insulin
55%
Need to treat
for 1 year with
analogue insulin to
avoid 1 episode of
severe hypoglycaemia
Insulin Pump therapy
NOTE: Weights are from random effects analysis
Overall (I-squared = 84.2%, p = 0.000)
Rudolph & Hirsch (2002)
Rodrigues (2005)
Hunger-Dathe (2003)
Bode (good control) (1996)
McMahon (2004)
Bruttomesso (2002)
Weinzimer (2004)
Siegel-Czarkowski (2004)
Plotnick (2003)
Maniatis (2001)
Study ID
Kadermann (1999)
Cohen (2003)
Weintrob (2003)
Rizvi (2001)
Linkeschova (2002)
Litton (2002)
Alemzadeh (2004)
Hoogma (2006)
Bode (poor control) (1996)
Sciaffini (2005)
Lepore (2005)
Mack-Fogg (2005)
4.19 (2.86, 6.13)
3.81 (2.49, 5.84)
35.41 (21.94, 57.15)
3.62 (2.23, 5.85)
10.50 (4.24, 26.01)
2.89 (1.67, 4.98)
3.44 (1.62, 7.33)
2.11 (1.50, 2.96)
7.07 (0.87, 57.46)
2.18 (1.05, 4.52)
1.29 (0.31, 5.42)
Rate Ratio (95% CI)
6.47 (3.09, 13.55)
4.69 (0.52, 41.98)
3.00 (0.62, 14.44)
8.00 (1.84, 34.79)
13.92 (6.95, 27.86)
5.75 (0.72, 45.97)
2.51 (0.67, 9.47)
2.50 (1.53, 4.08)
5.55 (3.57, 8.61)
1.25 (0.34, 4.65)
3.50 (2.04, 6.01)
2.09 (1.12, 3.92)
100.00
5.87
5.75
5.75
4.66
5.60
5.07
6.03
2.17
5.13
3.34
Weight
5.11
2.04
3.04
%
3.26
5.23
2.19
3.58
5.73
5.84
3.61
5.61
5.40
4.19 (2.86, 6.13)
3.81 (2.49, 5.84)
35.41 (21.94, 57.15)
3.62 (2.23, 5.85)
10.50 (4.24, 26.01)
2.89 (1.67, 4.98)
3.44 (1.62, 7.33)
2.11 (1.50, 2.96)
7.07 (0.87, 57.46)
2.18 (1.05, 4.52)
1.29 (0.31, 5.42)
Rate Ratio (95% CI)
6.47 (3.09, 13.55)
4.69 (0.52, 41.98)
3.00 (0.62, 14.44)
8.00 (1.84, 34.79)
13.92 (6.95, 27.86)
5.75 (0.72, 45.97)
2.51 (0.67, 9.47)
2.50 (1.53, 4.08)
5.55 (3.57, 8.61)
1.25 (0.34, 4.65)
3.50 (2.04, 6.01)
2.09 (1.12, 3.92)
100.00
5.87
5.75
5.75
4.66
5.60
5.07
6.03
2.17
5.13
3.34
Weight
5.11
2.04
3.04
%
3.26
5.23
2.19
3.58
5.73
5.84
3.61
5.61
5.40
Favours MDI Favours CSII
1.2 .5 1 2 5 10 25
Rate ratio 4.19 [95% CI 2.86 to 6.13]) Pickup and Sutton, Diabet Med. 2008 ;25:765-74.
ln(RR) = -1.02 (se 0.44) + 0.57 (se 0.010) x ln(Rate on MDI per 100py)
12
510
30
RR
(ln
scale
)
10 100 1000 3000Rate on MDI/100py (ln scale)
Hypoglycaemia rate on MDI (episodes/100 pt-yr)
Hyp
ogly
caem
ia r
ate r
atio
Continuous Glucose Monitoring
Liebl et al; JDST 2013
0
2
4
6
8
10
Baseline 6 months
SH• 96 pts with HU
• 2x2 intervention
• MDI vs CSII
• SMBG vs CGM
• Monthly visits
• Overall SH rates dropped from
8.9 to 0.8 events / pt / yr
• Awareness improved
• No diff between
• MDI vs CSII or SMBG vs CGM
Effect of Low glucose suspend
P Choudhary, Diabetes Care, 2013 Bergenstal et al, NEJM 2013
Newer technologies
22
Studies underway with both
Predictive low glucose suspend Medtronic 640G
Choudhary P. et al., Diabetes Technology Therapeutics, 2016
Hypo aware Hypo unaware
0
25
50
75
100
HA IAH
% adherent
Effect of unawareness on
adherence?
Smith et al., Diabetes Care. 2009 ;32:1196-8.
0,
25,
50,
75,
100,
Rogers et al; Diabetic Medicine 2011
% of unaware patients, n = 17
High Low
Concerns
Normalise HU
Overestimate hyper-glycaemia
**
Interpretation…
Internal
motivation to
avoid future
episodes
NO internal
motivation to
avoid hypoglycaemia
HA, hypoglycaemia awareness; IAH, impaired
hypoglycaemia Awareness
Unpublished data
0
1
2
3
4
Baseline 1 year
Psychological approach to
hypoglycaemia
Page 26
0
2
4
6
8
10
12
14
16
Baseline 1 Year
Moderate Hypo Severe Hypo
Can Closed loop solve the
problem?
Integrated approach to resistant
hypoglycaemia
• Brush up Carb counting skills
• Rectify basal to bolus ratio
• Ideally 50:50 [ adults]
• Pre-meal bolus [ 10-15 mins ]
• Soften Corrections
• less aggressive correction factor [ 130-40 / TDD ]
• Address Lipohypertrophy / site problems
• Variability in insulin absorption
• DON’T need to deteriorate control
• Focus on avoiding hypos – not creating hypers
• Management of exercise / alcohol
Summary – Practical Tips
Page 30
Thank you!!
Page 31