Company Confidential © 2012 Eli Lilly and Company Hypoglycaemia Speaker name and affiliation Prescribing information is available on the last slide. ©

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


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


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


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


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


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


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


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


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


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


13

4

3

2

1

Adrenaline release



Sweating tremor


Hypo Aware Hypo Unaware


Adrenaline release Sweating tremor




Vicious cycle of repeated hypoglycaemia

14

Repeated episodes of hypoglycaemia

Defective counter-regulation

Impaired awareness of hypoglycaemia

Increased vulnerability to further hypoglycaemia


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


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


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


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


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


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


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


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.


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.


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


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


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


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”


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


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?


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


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

Company Confidential © 2012 Eli Lilly and Company Hypoglycaemia Speaker name and affiliation Prescribing information is available on the last slide. ©

Documents

eli lilly

companycompany confidential

epidemiology of hypoglycaemia

diabetes t1d

diabetes t2d

observational study

treatment groups

major episodes