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Hypoglycaemia in Older People
Suzy Hope5th February 2016
Overview• Hypos: setting the scene • Recognition of hypos in older patients• HbA1c targets• Endogenous insulin levels• Clinical implications
Dorothy• 78, lives alone• Type 2 diabetes for 19 years• Been on insulin for 10 years• “I’m told my diabetes is very good” • Denies getting hypos• On closer questioning… keeps biscuits by bed for
“when I feel a bit wobbly in the night”• Other PMH: hypertension, osteoporosis• Recent investigations for unsteadiness on her feet
What are hypos?Hypoglycaemia = low blood
glucose• Whipple’s triad:
– Low blood glucose – Symptoms– Resolution of symptoms with treatment
• Hypo definitions
Why do hypos matter?• Fear and quality of life• Impact on driving• Can cause falls, accidents• Risk of hospitalisation• Longer hospital stays & poorer outcomes• Cognitive impairment & dementia• Affects compliance & thus other treatment goals
Lundkvist et al 2005 Eur J Health Econ 6: 197-202Jermendy et al 2008 Health Qual Life Outcomes 6: 88
Solli et al 2010 Health Qual Life Outcomes 8: 18Signorovitch et al 2013 Diabetes Obes Metab 15: 335-41
Mayne D et al 2010 Age Ageing 39: 522-5 Johnston et al 2012 Diabetes Obes Metab 14: 634-43
Turchin et al 2009 Diabetes Care 32: 1153-7
Cognition and hypos• Bidirectional relationship• Cognitive impairment predisposes to hypos• Episodes of severe hypos associated with graded
increase in risk of dementia (after adjustment for age, comorbidities, HbA1c etc) eg:– 1 hypo – 1.26x risk for dementia– 2 hypos – 1.8x– 3 hypos – 1.94x
Whitmer et al 2009 JAMA 301:1565-1572Lin et al 2013 J Intern Med 273: 102-110Aung et al 2012 Diabet Med 29: 328-336
Bruce et al 2009 Diabetologia 52: 1808-1815Yaffe et al 2013 JAMA Intern Med 173(14): 1300-1306
Who is at risk?• Diabetes = problem with glucose homeostasis • Insulin keeps glucose levels in the normal range
• Type 1 diabetes – absolute insulin deficiency– need insulin treatment to survive
• Type 2 diabetes – insulin resistance and insulin deficiency – evolves over time and treatment intensifies
Simple glucose physiology
Hypoglycaemia
1) Insulin secretion falls
Hypoglycaemia
1) Insulin secretion falls
2) Glucagon released
Summary: hypoglycaemia
• Physiological response to increase glucose:– 1) Insulin secretion falls– 2) Glucagon levels increase– 3) Adrenaline levels increase
• Symptomatic response to increase glucose– Behaviour change - eat!
Summary: hypoglycaemia in
insulin-deficient diabetes• Physiological response to increase glucose:
– Endogenous insulin secretion can’t fall – Exogenous insulin “in the system”– Glucagon response diminished– Adrenaline response diminished
• Symptomatic response less marked– Reduced opportunity for behavioural change
Who is at risk of hypos?• Major risk factors
– Type 1 diabetes– Treatment with insulin– Treatment with sulphonylurea tablets– Previous hypoglycaemia
• Other risk factors*– Missing meals– Exercise– Tight glycaemic control*especially when on the above treatments
Symptoms of hypoglycaemia are non-specific in the elderly
Autonomic:PalpitationsSweatingAnxiety
Neuroglycopenic:Fatigue Irritability Confusion DizzinessDrowsiness Coma
Particularly in older people:UnsteadinessLight-headedness
All these are also common in elderly people without diabetesSymptoms can be different on
different occasions!Deary et al 1993 Diabetologia 36: 771-777
Jaap et al 1998 Diabet. Med. 15: 398-401Zammitt et al 2011 Diabetes Technol Ther 13: 571-8
Dorothy keeps biscuits by bed for “when I feel a bit wobbly in the night”
Is Dorothy having hypos?
Pilot data suggested symptoms of hypoglycaemia are not always recognised by
the medical team or patient • 106 patients in primary care
– insulin or sulphonylurea treatment– HbA1c <7.5% (58.5mmol/mol)
• Retrospective review of consultations over 1 year• % patients with >1 “hypo clue” symptom documented
Can non-specific symptoms associated with hypos be
important clues for recognising hypoglycaemia in this group?
Methods
• Axminster Medical Practice • Inclusion criteria:
– Patients over the age of 65– All those on insulin– All those on sulphonylureas– All those just on metformin – 50 patients who were not diabetic
• Data collected retrospectively for a one year period: documented hypos, and potential “hypo clues”
• “Hypo clue” consultation: – a consultation with >1 “hypo clue” symptom, where no obvious explanation
or diagnosis was recorded
Hypoglycaemia events reported to primary care are much more frequent in insulin-
treated patients
0
0.2
0.4
0.6
0.8
1
1.2
Hypo
glyc
aem
ia e
piso
des /
per
son
/ yea
r
p<0.0001 for a difference across groups
“Hypo clue” consultations are common in all treatment groups – and in patients without
diabetes
0
0.4
0.8
1.2
1.6
Episo
des /
per
son
/ yea
r p=0.16
“Hypo clue” consultations are more frequent in
insulin-treated patients who have had a recognised episode of hypoglycaemia
≥1 hypo 20/27
No hypo 21/52
≥1 hypo 2/4
No hypo 39/81
≥1 hypo 1/2
No hypo 58/119
≥1 hypo 0/0
No hypo 18/50
Insulin n=79 Sulphonylurea n=85 Metformin only n=121
Non-diabetic n=50
0
10
20
30
40
50
60
70
80
90
100
Prop
ortio
n of
pati
ents
with
≥ 1
“h
ypo
clue
” co
nsul
tatio
n
p=0.004
p=NS p=NS
Are any particular symptoms more often seen in “hypo clue”
consultations in those patients with documented hypos?
Most commonly presenting symptoms overall in those who had also presented with >1
hypo, compared to those with no documented hypos
Bold columns p<0.05 for a difference
Fall
Nausea
Lethargy/ti
redness
Depression
Unsteadiness
Apprehension
Shive
ring/sh
aking
Lightheadedness/
dizziness
Headache
Unexplained w
aking
0
5
10
15
20
25
30
35
>=1 hypoNo hypos
Prop
ortio
n of
pati
ents
con
sulti
ng w
ith sy
mpt
om (%
)
In insulin-treated patients, falls, unsteadiness and nausea were most
notable• 33% with a documented hypo consulted on another
occasion over the year with a fall, compared to 8% of those without a documented hypo (p=0.008)
• 22% with a documented hypo consulted on another occasion with unexplained nausea, compared to 2% without (p=0.006)
• 19% with a documented hypo consulted on another occasion with unsteadiness, compared to 4% without (p=0.04)
So….1) Hypos reported to primary care are much more
common in those who are treated with insulin2) Overall “hypo clue” consultation rate is high across
the treatment groups, and in patients without diabetes
3) But in patients who have had a recognised hypo, “hypo clue” consultations are 1.5x as common
4) Unexplained falls, unsteadiness and nausea seem more common in those with recognised hypos: could these represent unrecognised hypoglycaemia?
What could this mean for Dorothy?
• Being on insulin, she is at increased risk of hypos
• Consultations with “hypo clue” symptoms may be indicative of possible hypoglycaemia, with unsteadiness one of the alarm bells
• “Hypo clue” symptoms should not necessarily just be put down to hypos – other diagnoses should be considered too!
Does “very good” mean her HbA1c is low? Is Dorothy actually being “over-treated”?
I’m told my diabetes is very good!
HbA1c• WHO 2011 guidelines:
– diagnosis of diabetes in asymptomatic patients• >2 readings of 48mmol/mol• repeated two weeks apart from each other
• “3 months’ average glucose” - HbA1c value typically comes – 50% from the previous month’s red blood cells (RBCs)– 32% from the month before– 18% from the month before that
2011: http://www.who.int/diabetes/publications/report-hba1c_2011
Factors affecting HbA1c• Increases with age • Will be higher if low RBC turnover ie
disproportionate numbers of old RBCs • iron deficiency anemia• vitamin B12 deficiency anemia• folate deficiency anemia• chronic renal failure• alcoholism• asplenia
• Will be lower if high RBC turnover ie more young RBCs
• haemolysis• haemorrhage• blood transfusions• treatment for iron, vitamin B12, or folate
deficiency
Kilpatrick et al 1996 QJM 89(4):307-12Gallagher et al 2009 J. Diabetes 1:9-17
r=0.49
HbA1c treatment targets• Increased appreciation of perceived risks in older
patients with too stringent HbA1c targets
• Little evidence but discussions and consensus statements
• Adjustment of QOF guidelines over time
• National/international guidelines now qualify HbA1c targets for older adults according to comorbidities – eg IDF, AGS/ADA, ADA/EASD guidelines and consensus reports
2013: http://www.idf.org/guidelines-older-people-type-2-diabetes.pdf2012: http://www.americangeriatrics.org/files/documents/ADA_Consensus_Report.pdf
2012: ADA/EASD Consensus report. Diabetes Care 35(6): 1364-1379
IDF glycaemic targets for older adults
Category HbA1c (%) HbA1c (mmol/mol)Functionally independent 7-7.5% 53-59
Functionally dependent 7-8% 53-64
- frail Up to 8.5% may be appropriate Up to 70
- dementia Up to 8.5% may be appropriate Up to 70
End of life care Avoid symptomatic hypoglycaemia
2013: http://www.idf.org/guidelines-older-people-type-2-diabetes
All-cause mortality by HbA1c deciles
A: Metformin + sulphonylureas B: Insulin therapies
Adjusted hazard ratiosHbA1c deciles with 1289 – 3513 people per group
Vertical bars 95% confidence intervals
Currie et al 2010 Lancet 375: 481-89
Could Dorothy be having hypos?
HbA1c = 69mmol/mol (8.5%)
Are hypos or “hypo clue” symptom consultations more frequent in patients
with lower HbA1c?
Proportion of insulin or sulphonylurea-treated patients (per HbA1c group)
who had at least one “hypo clue” visit
<6% n=5
6-6.5% n=9
6.5-7% n=32
7-7.5% n=34
0
20
40
60
80
100
% p
atien
ts w
ith a
t lea
st o
ne
“hyp
o cl
ue” c
onsu
ltatio
n
Proportion of insulin or sulphonylurea-treated patients with >1 “hypo clue” consultation is similar across HbA1c
groups
<6%
n=5
6-6.5%
n=9
6.5-7% n=32
7-7.5% n=34
7.5-8% n=32
8-8.5% n=17
8.5-9% n=12
9-9.5%
n=7
>9.5% n=16
0102030405060708090
100
HbA1c
Prop
ortio
n of
pati
ents
with
at l
east
one
“h
ypo
clue
” co
nsul
tatio
n
p=0.42
Dorothy• On insulin• Unsteadiness, and sometimes “wobbly” at night• HbA1c 8.5%
• Could she be having hypos? • What else could be happening?
Glucose variability
Siegelaar et al 2010DeVries 2013
HbA1c represents the mean glucoseBut these graphs represent the same means
Potential for more hypos
Self-monitoring can miss
fluctuations
Detecting glucose variabilityContinuous glucose monitoring can reveal extra details - Glucose reading taken every 5 minutes- Can wear up to 7 days - Summary graphs and statistics obtained
Glucose variability higher in T1D than T2DDue to insulin deficiency and impaired counter-regulationBasal bolus regimens attempt to minimise variability
Medtronic – iPro2 Professional continuous glucose monitor
Glucose variability increases with increasing treatment intensity in T2D
• Calculated from individual 72-h continuous glucose monitoring tracings• Between-treatment group differences statistically significant, p < 0.001• Intensification of treatment in T2D is due to progressive insulin deficiency• Heterogeneity within even insulin-treated population of T2D
White columns:
patients with T2D treated with - diet (DIET)- metformin (MET)- a-glucosidase inhibitor (AGI) - sulphonylurea (SU)- thiazolidinedione (TZD)- conventional insulin therapy (INSct)- intensified insulin therapy (INSict)
Hatched column:
patients with T1D
Kohnert et al 2013 Diabetes Tech & Therapeutics 15(6): 448-454
Could measuring insulin levels help stratify hypoglycaemia
risk?
C-peptide• C-peptide = measure of
endogenous insulin levels
• Recent validation of more practical methods– blood C-peptide – fasting or random– Urinary c-peptide creatinine ratio (UCPCR)
• Absolute insulin deficiency in T1D (DCCT):– C-peptide <200pmol/L
McDonald et al 2009 Clinical Chemistry 55(11): 2035–2039Besser et al 2011 Diabetes Care 34: 607–609
Jones et al 2011 Diabetic Medicine 28(9): 1034-1038Bowman et al 2012 Diabetic Medicine 29: 90–93
McDonald et al 2012 PLoS ONE 7(7): e42084
Progressive insulin deficiency in T2D can result in absolute insulin
deficiency• 3% insulin-treated patients with a clinical diagnosis
of T2D had absolute insulin deficiency (AID)– UCPCR screening– Confirmation in MMTT
• Anecdotally patients with AID found glycaemic control difficult – both high and low
• Treatment regimes may suggest clinicians finding it difficult too - eg only 27% those with absolute insulin deficiency were on a basal bolus regime
Hope et al 2013 Diabetic Medicine 30(11): 1342–1348
Are these people with T2D and absolute insulin deficiency at the same
risk of complications as those with T1D?
Can c-peptide be used as a biomarker to predict glucose variability and
hypoglycaemia risk?
Random non-fasting C-peptide (rCP): Correlation between rCP and 90 minute blood
stimulated C-peptide (sCP) in the mixed meal tolerance text for 50 patients
Spearman’s rho correlation coefficient=0.93, p<0.0001
Hope et al, submitted
Do people with T2D but severe insulin deficiency have increased glucose
variability? • Two matched groups of insulin-treated participants
with clinical diagnosis of T2D (diagnosed >35yrs, took at least 2yrs to start insulin)– Severe insulin deficiency – rCP <200pmol/L– Retained insulin levels – rCP >500pmol/L
• Matched for glycaemia (HbA1c), age, diabetes duration, BMI
• Continuous glucose monitoring (mean 4.1 days)
• Clarke’s hypoglycaemia questionnairerCP = random C-peptide
Characteristics of matched participants
Glucose variability on continuous glucose monitoring is much higher in the low C-peptide
group
23
45
6S
tand
ard
devi
atio
n (m
mol
/L)
C-peptide <200 pmol/L C-peptide >500 pmol/L
p = 0.0004
Midnight Midday Midnight
Proportion of patients with >1 hypoglycaemia episode is much higher in the low C-peptide
group
<=200 >5000
10
20
30
40
50
60
70
80
90
100
3 to 42.2 to 3<=2.2
Random non-fasting C-peptide
Prop
ortio
n w
ith a
t lea
st o
ne e
piso
de
p=0.002
In people with clinically diagnosed T2D:
Low c-peptide measured on routine blood samples is associated with increased glucose
variability and increased risk of hypoglycaemia
Clarke’s hypoglycaemia questionnaire (Q5&6):frequency of episodes <3.5 with or without symptoms,
by C-peptide group
Does this association between random C-peptide and
hypoglycaemia risk hold true on a larger scale?
• All insulin-treated patients in DARE invited to participate
• Answered Clarke’s hypoglycaemia questionnaire • System set up so a random C-peptide could be
measured when a routine HbA1c from consenting patients was sent into the lab
• Results analysed for people where a rCP was obtained within a year of questionnaire completion
Results• 480 participants• Given a Type 1 or 2 diagnosis according to
RCGP diagnosis guidelines
Participant characteristics
Distribution of random C-peptide by C-peptide deciles and diabetes
diagnosis
Approx 48 patients per decile
More self-estimated episodes of blood glucose <3.5mmol/L overall, the lower the C-peptide
decile
Approx 48 patients per decile
… despite HbA1c being similar across the deciles
Median estimated number of episodes <3.5mmol/L was higher the lower the C-
peptide decile, regardless of clinical diagnosis
More episodes reported, both with and without symptoms,
in those with C-peptide <200pmol/L
In summary:1) Need to recognise severe insulin deficiency - which cannot always be clinically obvious
2) Need to be given right treatment (review!)
3) Need to have education to go with it – coping with a more complex insulin regimen, self-monitoring, effect of diet and exercise, driving…
4) Learning (complex) new concepts more challenging in older age
Those with long-standing T1D already have strategies to cope with all the above… need to think about those with “type 2” diabetes
carefully too!
Knowing C-peptide level can be helpful
C-peptide 45pmol/L
C-peptide 1200pmol/L
Conclusion• People with T2D but low endogenous insulin levels
are at significantly higher risk of hypos than those with more substantial residual endogenous insulin
• Simple C-peptide measurement in people with insulin-treated diabetes may help with risk stratification, education and management regimens for older patients, carers and healthcare professionals
AcknowledgementsStudy participants
Exeter NIHR Clinical Research team especially Professor Andrew Hattersley, Drs Bev Shields, Angus Jones and Bea Knight, and Anita
Hill and Tina Libretto
Dr Phil Taylor and Axminster Medical Practice team, and Professor Willie Hamilton (Exeter)
Drs Pratik Choudhary (King’s) and Kai Tan Horng (Plymouth)
Northcott Devon Medical Foundation for funding the continuous glucose monitoring study
RCGP diabetes classification guidelines
Method• 601 adults recruited, with
– insulin-treated diabetes – diabetes duration >5y
• Home urine sample collected for C-peptide measurement (UCPCR test)
• Performance of clinical diagnostic criteria assessed and other criteria explored using ROC curves
“Gold-standard” Type 1 defined asUCPCR<0.2nmol/mmol (absolute insulin deficiency)
ANDcontinuous insulin treatment within 3 years of diagnosis
“Gold-standard” Type 2 all other patients (insulin-treated and duration >5y)
Number of patients classified as having T1D or T2D according to the RCGP guidelines, and proportions
classified correctly or incorrectly compared to the gold standard
Age Diag<35 & TTI<6m
Age Diag>=35 & TTI=0m
Age Diag<35 & TTI>=6m
Age Diag>=35 & TTI>0m
Type 1 Type 2
0
50
100
150
200
250
300
350
400
MisclassifiedCorrectly classified
Num
ber o
f pati
ents
44% 77%
93%
TTI = time to insulin treatment from diagnosis
87%
ROC curve for discriminating between Type 1 and Type 2 diabetes based on the gold standard definition
Red: time to insulin from diagnosis (AUC=0.904); black: age at diagnosis (AUC=0.871); blue: BMI at diagnosis (AUC=0.824); green: BMI at recruitment (AUC=0.715)
Conclusions• RCGP guidelines are clinically useful
• Correctly classified 86% insulin-treated patients >5y from diagnosis
• In those diagnosed >35y and on insulin from diagnosis, 37/66 (56%) were misclassified as T1D
• Time to insulin & diagnosis age performed best in predicting long-term endogenous insulin production, but altering guidelines with optimal cut-offs did not significantly improve guideline accuracy
• BMI was not a clinically significant predictor