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

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100

Prop

ortio

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pati

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with

≥ 1

“h

ypo

clue

” co

nsul

tatio

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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

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15

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35

>=1 hypoNo hypos

Prop

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pati

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con

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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

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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

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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

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45

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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

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3 to 42.2 to 3<=2.2

Random non-fasting C-peptide

Prop

ortio

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piso

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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

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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