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