Prof. Kamlesh  KhuntiUniversity of Leicester

Epidemiology of Hypoglycaemia

© Leicester Diabetes Centre at University Hospitals of Leicester NHS Trust, 2015. Not to be reproduced in whole or in part without the permission of the copyright owner.

Disclosures

Consultant: AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Novo Nordisk and Sanofi, Roche. 

Research Support: AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis, Novo Nordisk, Roche and Sanofi, Janssen

Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Novo Nordisk and Sanofi

Overview

• Epidemiology of hypoglycaemia• Causes and consequences of

hypoglycaemia• Cardiovascular impact of hypoglycaemia

The challenge when improving HbA1c

HbA1c, glycosylated haemoglobin

Hypoglycaemic events are categorisedby severity and time of occurrence

1. Brod et al. Value In Health 2011;14:665–71; 2. Dailey & Strange. Am J Manag Care 2008;14:25–30; 3. Cryeret al. Diabetes Care 2003;26:1902–12; 4. Allen & Frier. Endocr Pract 2003;9:540–3

SevereRequires the assistance of

another person1; may require hospitalisation or ambulance service2; in rare cases severe events may result in coma or

death2

Non-severeDoes not require assistance of another individual1; symptoms may include pounding heart,

sweating, weakness, trembling, confusion3

NocturnalOccurs at night, usually during sleep; can result in headache, poor sleep, convulsions; severe nocturnal events can result in

“death-in-bed” syndrome4

National Trends in US Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare

Beneficiaries, 1999 to 2011

Rates of Estimated Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries With Diabetes Mellitus, 1999 to 2010The circles and diamonds indicate observed values; the lines represent the smoothed trend over time.

Figure Legend:

Lipska KJ et al. JAMA Intern Med, 2015;174(7)

Medications most commonly associated with emergency hospitalisation

0%

5%

10%

15%

20%

25%

30%

35%

0

5.000

10.000

15.000

20.000

25.000

30.000

35.000

Per

cen

tag

e o

f es

tim

ated

n

um

ber

of

hos

pit

alis

atio

ns

Esti

mat

ed n

um

ber

of

hos

pit

alis

atio

ns

Data given are number and percentage of annual national estimates of hospitalisations. ER visits, n=265,802; total cases, n=12,666ER, emergency room; OAD, oral antidiabetic drugBudnitz et al. N Engl J Med 2011;365:2002–12

*Indicates significant difference; †Compared to the treated with SU group SU, sulphonylureaUK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–1147

n=103 n=85

n=75 n=46

n=54p=0.14 †

p=0.002*†

0.0

Treated with SU

<2 years >5 years

T2DM T1DM

<5 years >15 years

of insulin treatment*

Prop

ortio

n re

port

ing

at le

ast

one

seve

re h

ypog

lyca

emic

epis

ode

0.2

0.4

0.6

0.8

1.0

Risk increases with T2DM progression

Proportion of people experiencing mild/moderate hypoglycaemia in the real world studies

46 studies involving 532,542 participants

Eldridge CA et al. PLOS One DOI:10.1371/journal.pone.0126427

Insulin 52 % Sulphonylurea 33 %

Proportion of people experiencing severe hypoglycaemia in the real world studies

40 studies involving 528,310 participants

Eldridge CA et al. PLOS One DOI:10.1371/journal.pone.0126427

Insulin 21% Sulphonylurea 5% Non-Sulphonylurea therapies 5%

Hypoglycaemic episodes often go unrecognised by patients

• Many patients are asymptomatic and CGMS data show that unrecognised hypoglycaemiais common in patients with diabetes– In one study, 63% of patients with T1DM and 47% of patients

with T2DM had unrecognised hypoglycaemia as measured by CGMS (n=70)1

CGMS, continuous glucose monitoring system1. Chico et al. Diabetes Care 2003;26(4):1153–7;

74% of all events occurred at night

0

5

10

15

20

25

30

No symptoms Mild Moderate Severe/very severe

Mea

n H

FS-I

I w

orry

sco

re

Patient fear of hypoglycaemia increases with increased severity of hypoglycaemia

Total patient sample, n=1984HFS, Hypoglycaemia Fear SurveyMarrett et al. Diabetes 2008;57(Suppl. 1):P586. Poster presented at the ADA 2008 conference.

6.2

20.1

All comparisons significant (p=0.05)

12.3

27.5

Severity of hypoglycaemia

Decreasing Q

oL

UK (n=75)Canada (n=78)

QoL decreases with increasing frequency of hypoglycaemic events

*HRQoL measured using the time trade-off utilityHRQoL, health-related quality of life; QoL, quality of lifeLevy et al. Health Qual Life Outcomes 2008;6:73

Health utility reported to decrease with increased frequency of non-severe hypoglycaemic episodes

0.97

Frequency of non-severe hypoglycaemic events

0.880.94

0.850.90

0.770.83

0.66

0,0

0,2

0,4

0,6

0,8

1,0

None Rare (quarterly) Intermittent(monthly)

Frequent(weekly)

HR

QoL

*

Hypoglycaemia and potential impact from a cost perspective

Community Care

TreatmentsMonitoring

Repeat visitsCo-morbidities

Specialist Care Emergency care

TreatmentsMedical staff

Bed use

Paramedic staffA&E

Admissions

Accidents

Road trafficWork accidents

Litigation

Personal

PsychologicalFear & behaviour

change

Ambulance callouts for severe hypoglycaemia

• Retrospective analysis of routinely collected data: East Midlands Ambulance, UK

• Incidence of 2.76 per 100 patient years; 74% of individuals insulin-treated

• 28% of events occurred nocturnally• 32% transported to hospital• Predictors of transportation: lower post treatment blood glucose, non

insulin-treated and day-time episodes • Median treatment costs

– £ 92 for those not transported– £176 for those transported

Khunti K et al. Prim Care Diabetes 2012

Hypoglycaemia rates were higher than expected;in particular, severe events

HAT, Hypoglycaemia Assessment Tool; T1D, type 1 diabetes; T2D, type 2 diabetes

Khunti et al. Diabetologia 2014;57(Suppl. 1):S201

T2D, retrospective (n=19,563)T2D, prospective (n=19,563)

16,5

0,9

19,3

2,5

0

5

10

15

20

25

Any hypoglycaemia Severe hypoglycaemia

Hyp

ogly

caem

ia ra

te,

even

ts p

er p

atie

nt-y

ear

• Non-interventional, global, 6-month retrospective and 1-month prospective study of patient self-reported hypoglycaemic events

Patients reduced insulin dose and/or increased blood glucose monitoring following a hypoglycaemic event

60,9

11,7

36,7

69,7

12,7

47,4

0 10 20 30 40 50 60 70

Increased blood glucose monitoring

Skipped insulin injections

Reduced insulin dose

% of patients

Proportion of patients responding ‘Yes’T1D, type 1 diabetes; T2D, type 2 diabetesPedersen-Bjergaard et al. Presented at the International Diabetes Federation-Western Pacific Region Congress scientific meeting, 2014, Singapore, PO-116

T1D

T2D

Patient responses to hypoglycaemia during prospective period (HAT study)

Pathophysiological CV consequences of hypoglycaemia

CRP, C-reactive protein; CV, cardiovascular; IL-6, interleukin-6; VEGF, vascular endothelial growth factorAdapted from Desouza et al. Diabetes Care 2010;33:1389–94; Frier et al. Diabetes Care 2011;34(Suppl. 2):S132–7

VEGF IL-6 CRP

Neutrophilactivation

Plateletactivation

Factor VII

Blood coagulationabnormalities

Sympathoadrenal response Adrenaline

Inflammation

Endothelialdysfunction

Vasodilatation

Heart rate variability

Rhythm abnormalities Haemodynamic changes

Heart workload Contractility Oxygen consumption

HYPOGLYCAEMIA

Hypoglycaemic events: CGM

20 daytime episodes in 11 patients, 14 nocturnal episodes in 10 patientsHypoglycaemic nadir = episode time 0; negative time values = from the beginning of the hypoglycaemic episode to nadir; positive values = from the nadir to recovery from hypoglycaemia. Data are mean ± SDIG, interstitial glucose; SD, standard deviationChow E et al. Diabetes 2014;63:1738–1747

-50 -40 -30 -20 -10 0 10 20 30

Episode time (min)

Glu

cose

(mm

ol/L

)

5

4

3

2

1

0

Mean IG at nadir2.8 ± 0.5 mmol/L

Episode time (min)G

luco

se (m

mol

/L)

5

4

3

2

1

0-100 -50 0 50

Mean IG at nadir1.9 ± 0.7 mmol/L

Daytime episodes Nocturnal episodes

Incidence rate of arrhythmias during hypoglycaemia vs euglycaemia

CI, confidence interval; IRR, incident rate ratio; N/A, not available; VPB, ventricular premature beatChow E et al. Diabetes 2014;63:1738–1747

Day Night

IRR 95% CIp-

value

IRR 95% CI p-value

Bradycardia N/A N/A N/A 8.42 1.40; 51.0 0.02

Atrial ectopic 1.35 0.92; 1.98 0.13 3.98 1.10; 14.40 0.04

VPB 1.31 1.10; 1.57 <0.01 3.06 2.11; 4.44 <0.01

Complex VPB 1.13 0.78; 1.65 0.52 0.79 0.22; 2.86 0.72

Higher rate of severe hypoglycaemia with intensive glycaemic control*

1. UKPDS Group. Lancet 1998;352:837–53; 2. Patel et al.; ADVANCE Collaborative Group. N Engl J Med2008;358:2560–72; 3. Gerstein et al. ACCORD Group. N Engl J Med 2008;358:2545–59; 4. Duckworth et al. N Engl J Med 2009;360:129–39

*Intensive glycaemic control was defined differently in these trials; †Hypoglycaemia requiring any assistance in glucose-lowering trials; ‡With documented blood glucose <50 mg/dL (2.8 mmol/L)Conv, conventional therapy; Gli, glibenclamide; HbA1c, glycosylated haemoglobin; HR, hazard ratio; Ins, insulin; Int, intensive therapy; Std, standard therapy; UKPDS, UK Prospective Diabetes Study

Rat

e of

sev

ere

hypo

glyc

aem

ic e

vent

s†(p

er 1

00 p

atie

nt-

year

s)

0.0

1.0

2.0

3.0

4.0

5.0

Conv7.9%

0.7

Gli7.2%

1.4

Ins7.1%

1.8

HbA1c =Std

7.3%

0.4

Int6.5%

0.7

Std7.5%

1.0

Int6.4%

3.1

Std8.4%

0.5

Int6.9%

2.0

UKPDS1

p<0.001vs standard treatment

ADVANCE2

HR 1.86 (1.42; 2.40)p<0.001

ACCORD3

p<0.001VADT4

p=0.001‡

Non-CVD deaths

Adjusted model 2.80 (1.64–4.79)

Influence of severe hypoglycaemia on events in ADVANCE

Major macrovascular events

Major microvascular events

All-cause deaths

CVD deaths

Adjusted model

Adjusted model

Adjusted model

Adjusted model

Events

Number (%) of patients with event

23 (10.0%)

33 (15.9%)

24 (11.5%)

45 (19.5%)

22 (9.5%)

Sv. hypo: Yes(n=231)

466 (4.3%)

1114 (10.2%)

1107 (10.1%)

986 (9.0%)

520 (4.8%)

Sv. hypo: No(n=10909) Hazard ratio (95% CI)

3.53 (2.41–5.17)

2.19 (1.40–3.45)

3.27 (2.29–4.65)

3.79 (2.36–6.08)

1.00.1 10.0

Hazard ratio

'Severe hypoglycaemia (SH) was strongly associated with increased risk of a range of adverse clinical outcomes. It is possible that SH

contributes to adverse outcomes but hypoglycaemia is just as likely to be a marker of vulnerability to such events'

Zoungas S et al. N Engl J Med 2010;363:1410–1418

Adverse outcomes among patients with type 2 diabetes experiencing severe hypoglycaemia

Total patient sample, n=11,140; patients with severe hypoglycaemia, n=231Zoungas. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

Num

ber o

f adv

erse

out

com

es

0

5

10

15

20

25

0–12

Time from severe hypoglycaemia to event (months)

Macrovascular event

Microvascular event

Death from any cause

Cardiovascular death

Non-cardiovascular death

13–24 25–36 37–48

Incidence of CVD and mortality in patients experiencing hypoglycaemia

• CV, cardiovascular; CVD, cardiovascular disease; T1D, type 1 diabetes; T2D, type 2 diabetes• Khunti et al. Diabetes Care 2015;38:316–22

0

10

20

30

40

50

60

70

80

90

100

CV events All-cause mortality

Inci

denc

e ra

te(p

er 1

,000

per

son-

year

s)

T1D

0

10

20

30

40

50

60

70

80

90

100

CV events All-cause mortalityIn

cide

nce

rate

(per

1,0

00 p

erso

n-ye

ars)

T2DCVD historyNo CVD history

Time from hypoglycaemia to first CV event or death

CV, cardiovascular; T1D, type 1 diabetes; T2D, type 2 diabetesKhunti et al. Diabetes Care 2015;38:316–22

T1D T2D

Patients with hypoglycaemia and ≥1 CV event, n 38 97

Time from first hypoglycaemic episode to first CV event, years

1.5 (0.5; 3.5) 1.5 (0.5; 3.0)

Patients with hypoglycaemia and death, n 169 493

Time from first hypoglycaemic episode to death, years 1.1 (0.3; 2.3) 0.8 (0.3; 2.3)

Summary

• Hypoglycaemic events are frequent in the real-world setting.• Hypoglycaemia is associated with adverse events including

cardiovascular events and increased mortality.• It is important to act immediately when your patient

experiences hypoglycaemia.• The financial impact of hypoglycaemia, particularly severe

events, is hard to establish as both direct and indirect (e.g. reduced productivity) costs need to be taken into account.

• Risks and benefits of intensive glycaemic control vary for different subgroups

AIM FOR INDIVIDUALISED TARGETS

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