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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