simon heller - university of york heller presenter disclosure simon heller advisory board member:...

How low should you go?

Simon Heller

Presenter Disclosure

Simon Heller

Advisory Board Member: Eli Lilly, NovoNordisk, Sanofi Aventis, Takeda

Consultant: Eli Lilly, NovoNordisk, Takeda, Boeringher Ingelheim

Research Support: Medtronic

Speaker’s Bureau: Eli Lilly, NovoNordisk, Sanofi Aventis, Takeda, Astra Zeneca, Johnson & Johnson

Audience poll

1. How often do you assess your patients for hypoglycaemia? a) Every visit

b) Every year

c) Rarely or never

2. How knowledgeable are you about addressing hypoglycaemia risk factors? (scale from 1 to 7, with 7 = most confident)

3. How do you usually deal with patients with problematic hypoglycaemia?

a) discuss hypoglycaemia prevention/management with the patient

b) refer the patient to a diabetes education specialist

c) review the patient’s lifestyle/treatment and implement changes as needed

Non-severe vs. severe symptomatic: • Non-severe: Patient has

symptoms but can self-treat and cognitive function is mildly impaired

• Severe: Patient impaired cognitive function sufficient to require external help to recover (Level 3)

EASD/ADA supported reclassification of hypoglycemia

Seaquist ER et al. ADA/Endocrine Society consensus report on hypoglycemia. Diabetes Care 2013;36:1384 International Hypoglycaemia Study Group Diabetes Care/Diabetologia 2017 in press.

Alert value Plasma glucose < 3.9 mmol/L (70 mg/dL) and no symptoms

Serious biochemical Plasma glucose < 3.0 mmol/L (55 mg/dL)

Level 1 Level 2

RCT, randomised clinical trial

• Risk of hypoglycaemia in diabetes

• Pathophysiology

• Consequences of hypoglycaemia

• Clinical guidance on hypoglycaemia

Overview


• Pathophysiology



Overview

2010 – STAR-3 Study group7

Frequency* – 0.13/0.13

Proportion affected – 8.6% /7.1%

1993 – DCCT1

0.62 (intensive) versus

0.19 (conventional) episodes*

1990s

2000 – Ter Braak2

Netherlands

Frequency* – 1.5

Proportion affected – 41%

2004 – Pedersen-Bjergaard3

Denmark

Frequency* – 1.3


2005 – Leiter4

Canada

Frequency* – 2.6


2007 – UK Hypoglycaemia Study Group5

Frequency* – 1.1†/3.2††

Proportion affected – 22%†/46%††

2012 – Kristensen6

Denmark

Frequency* – 1.2


2000s 2010s

HbA1c in each trial: 1. ~7% (intensive) and ~9% (conventional) over 10 years follow-up; 2. Mean = 7.8 ± 1.2%; 3. Mean = 8.6 ± 1.3%; 4. Most recent HbA1c =

7.4%; 5. Mean 7.3 ± 1.02% and 7.3 ± 1.16%†; 7.8 ± 0.73% and 7.6 ± 0.85%†† at baseline and year 1, respectively; 6. Mean = 8.0 ± 1.0% and 7.9 ± 1.0% for patients treated with long-acting insulin analogue and human insulin, respectively. Median follow-up across all studies was between 9–12 months *Per patient/year; † diabetes duration <5 years †† diabetes duration >15 years 1. The DCCT Research Group NEJM 1993; 2. Ter Braak et al. Diabetes Care 2000; 3. Pedersen-Bjergaard et al. Diabetes Metab Res Rev 2004; 4. Leiter et al. Can J Diabetes 2005; 5. UK Hypoglycaemia Study Group Diabetologia 2007; 6. Kristensen et al. Diabetes Res Clin Pract 2012; 7. Bergenstal et al. NEJM 2010

Frequency of severe hypoglycaemia in adults with type 1 diabetes

Annual incidence of reported severe hypoglycaemia in a population-based survey in Dundee

Prospective recording over 1 month: Type 1 diabetes n=94; Type 2 diabetes on insulin n=173 Donnelly et al. Diabetic Med 2005;22:749–55

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Insulin-treated Type 2 diabetes

Type 1 diabetes

Severe

epis

odes p

er

patient

per

year

Prevalence of severe hypoglycaemia in types 1 and 2 diabetes

Error bars = 95% confidence intervals. Adapted from: UK Hypoglycaemia Study Group, Diabetologia 2007; 50: 1140-7

An

nu

al p

reva

len

ce o

f

seve

re h

ypo

glyc

em

ia (

%)

(S

ever

e: r

equ

irin

g ex

tern

al a

ssis

tan

ce)

T2DM on SUs

T2DM Insulin <2 yrs

T2DM Insulin >5 yrs

Type 2 DM Sulphonylureas (n = 103) Type 2 DM <2 years insulin (85) Type 2 DM >5 years insulin (75) Type 1 DM <5 years (46) Type 1 DM >15 years (54)

T1DM < 5 yrs

T1DM > 15 yrs

50

40

30

20

10

0


• Pathophysiology



Overview

Common hypoglycemia symptoms

1. Development of symptoms

2. Low blood glucose (< 3.9 mmol/l or 70 mg/dL)

3. Response to treatment with carbohydrate

1. Seaquist ER et al. ADA/Endocrine Society consensus report on hypoglycemia. Diabetes Care 2013;36:1384. 2. McAulay V et al. Diabet Med 2001;18:690. 3. Deary IJ et al. Diabetologia 1993;36:771.

Autonomic Neuroglycopenic Non-specific

• Trembling • Pounding

heart • Sweating • Anxiety • Hunger

• Difficulty concentrating

• Confusion • Weakness • Drowsiness,

dizziness • Vision changes • Difficulty speaking

• Nausea • Headache

5.0

4.0

1.0

3.0

2.0

Blood glucose

mmol/L

4.6 mmol/L 83 mg/dL

Inhibition of endogenous insulin secretion

EEG, electroencephalogram Adapted from Zammit and Frier. Diabetes Care 2005:28:2948–61

Normal physiological responses preventing hypoglycaemia

Protective mechanisms

3.5 mmol/L 63 mg/dL

3.8 mmol/L 68 mg/dL

3.2–3.0 mmol/L 63–54 mg/dL

Symptom onset Autonomic–Neuroglycopenic

Counter-regulatory hormones: Glucagon Adrenaline

5.0

4.0

1.0

3.0

2.0

In most patients, counterregulatory and symptomatic defences usually prevent severe hypoglycaemia


4.6 mmol/L 83 mg/dL

Inhibition of endogenous insulin secretion


3.0 mmol/L 54.0 mg/dL) 2.8 mmol/L

50.4 mg/dL

Neurophysiological dysfunction

• Evoked responses

Widespread EEG changes

3.0–2.4 mmol/L 54.0–43.2 mg/dL

Cognitive dysfunction

• Inability to perform complex tasks

Consequences of hypoglycaemia

Blood glucose

mmol/L

5.0

4.0

1.0

3.0

2.0

Impaired responses and altered thresholds lead to impaired awareness and severe hypoglycaemia

3.0 mmol/L 54.0 mg/dL) 2.8 mmol/L

50.4 mg/dL

Neurophysiological dysfunction

• Evoked responses

Widespread EEG changes

<1.5 mmol/L <27 mg/dL

Severe neuroglycopenia

• Reduced conscious level

• Convulsions

• Coma

3.0–2.4 mmol/L 54.0–43.2 mg/dL

Consequences of hypoglycaemia


Adrenaline 2.5 mmol/L 45 mg/dL

Cognitive dysfunction

• Inability to perform complex tasks

Counter-regulatory hormones: Glucagon Adrenaline


2.8 – 2.5 mmol/L 50 – 45 mg/dL

Symptom onset Autonomic–Neuroglycopenic

3.5 mmol/L 63 mg/dL

Blood glucose

mmol/L

Risk factors for severe hypoglycemia

1. IHSG. Diabetes Care 2015;38:1583. 2. Gerstein HC et al (ORIGIN trial investigators). Diabetes Care 2015;38.:22. 3. Lipska KJ et al. Diabetes Care 2013;36:3535.

T1D T2D (on insulin or SUs)

• History of severe episodes

• HbA1c < 6.5% • Long duration of

diabetes • Renal impairment • Impaired awareness of

hypoglycaemia • Extremes of age

• Advancing age • Cognitive impairment • Depression • Aggressive treatment of glycaemia • Impaired awareness of

hypoglycemia • Duration of MDI insulin therapy • Renal impairment and other

comorbidities

SU = sulphonylurea MDI = multiple daily injections

Impaired Awareness of Hypoglycemia (IAH)

Impaired awareness of hypoglycemia:

• Affects 20-25% with T1D and about 10% with insulin-treated T2D1

• Increases risk of severe hypoglycemia up to 6-fold2-4

• May result from > 2 episodes of hypoglycemia per week5

1. Schopman et al. Diab Res Clin Pract 2010;87:64. 2. Gold et al. Diabetes Care 1994;17:697. 3. Geddes et al. Diabetic Med 2008;25:501. 4. Pramming et al. Diabetic Med 1991;8:217. 5. Riddell M. Emerging complications: hypoglycemia/autonomic neuropathy (slide presentation). American Diabetes Association Clinical Guidelines for the Transition of Care in Young Aduts with Type 1 Diabetes Position Statement Conference. Available at http://docslide.us/documents/emerging-complications-hypoglycemia-autonomic-neuropathy-michael-riddell.html 6. Cryer PE. Elimination of hypoglycemia from the lives of people affected by diabetes. Diabetes 2011;60:24-27.

May be reversed by scrupulous

avoidance of hypoglycemia

6

Quiz question

Which of the following is/are known to increase the risk of hypoglycemia in older people?

a) Polypharmacy

b) Impaired renal function

c) Reduced weight

d) Recent hospitalization

e) Peripheral vascular disease


• Pathophysiology



Overview

Acute consequences of hypoglycaemia

Increased mortality

Physical injuries

Falls, Accidents, Fractures, Dislocations, Road Traffic Accidents

Cardiovascular

Myocardial ischaemia, Cardiac arrhythmias

Brain Coma, Seizures, Cognitive dysfunction, Mood change, Psychological effects

Impact of non-severe hypoglycaemia

1. Fidler C et al. J Med Econ 2011;14:646. 2. Rombopoulos G et al. Hormones (Athens) 2013;12:550. 3. Barendse S et al. Diabet Med 2012; 29: 293.

• Reduced quality of life in both T1D and T2D1,2

• May cause fear of hypoglycaemia

• May cause psychological morbidity3

Hypoglycaemia and treatment adherence

Walz L et al. Pat Pref Adher 2014;8:593.

T2D patients on metformin + sulphonylurea

70

56 46

0

10

20

30

40

50

60

70

80

90

100

No hypoglycemia Mild hypoglycemia Moderate/Worsehypoglycemia

Percen

t o

f ad

heren

t p

ati

en

ts

p=0.01

n=59 n=80 n=266

• Risks of hypoglycaemia in diabetes

• Pathophysiology


• Clinical approaches to hypoglycaemia

Overview

“The lowest A1C that does not cause severe hypoglycemia and preserves awareness of hypoglycemia.” Cryer PE. Diabetes 2014;63:2188

What is a reasonable glycaemic goal?

“The lowest HbA1c that does not cause severe hypoglycemia, preserves awareness of hypoglycemia and results in an acceptable number of documented episodes of symptomatic hypoglycemia” Report of a workgroup of ADA and ES, Diabetes Care 2013; 36:1384

Hypoglycaemia and glucose targets

1. Seaquist ER et al. ADA/Endocrine Society consensus report on hypoglycemia. Diabetes Care 2013;36:1384. 2. Global guideline for type 2 diabetes. International Diabetes Federation 2012.

Type 1 diabetes Type 2 diabetes

• Aim for lowest HbA1c not associated with frequent hypoglycaemia

• It may sometimes be appropriate to relax targets in patients with advanced disease, complications, or limited life expectancy

• In such patients, aim for glucose levels low enough to minimize symptoms of hyperglycaemia

• Aim for lowest HbA1c not associated with frequent hypoglycaemia

• HbA1c < 7.0% (53 mmol/mol) is usually appropriate for recent-onset disease

• It may sometimes be appropriate to relax targets (e.g. severe complications, advanced co-morbidities, cognitive impairment, limited life expectancy, unacceptable hypoglycaemia from stringent control)

Less stringent targets in frail elderly may be appropriate

1. Kirkman MS et al. Diabetes in older adults. Diabetes Care 2012;35:2650. 2. Seaquist ER et al. ADA/Endocrine Society consensus report on hypoglycemia.

Diabetes Care 2013;36:1384.

A1c < 7.5% (58

mmol/mol)

A1c < 8% (64

mmol/mol)

A1c < 8.5% (69

mmol/mol)

Complicated regimens should be simplified

• Few comorbidities

• Good physical function

• Preserved cognitive function

• Multiple chronic illnesses

• Mild cognitive impairment

• Risk of falls and hypoglycaemia

• End-stage chronic illness

• Moderate-to-severe cognitive impairment

• In long-term care

Screening for risk of severe hypoglycemia

Screening should be based on established risk factors:

• Low HbA1c; high pre-treatment HbA1c in T2D

• Long duration of diabetes

• A history of previous hypoglycaemia

• Impaired awareness of hypoglycaemia*

• Recent episodes of severe hypoglycemia

• Daily insulin dosage > 0.85 U/kg/day

• Physically active (e.g., athlete)

* Clinical tip: In IAH, blood glucose monitoring records reveal many low values, without hypoglycaemia symptoms being experienced. Symptoms occurring below 3mmol/l is a RED FLAG

1. IHSG. Diabetes Care 2015;38:1583. 2. Gerstein HC et al (ORIGIN trial investigators). Diabetes Care 2015;38.:22. 3. Canadian Diabetes Association 2013 clinical practice guidelines. Chapter 14: Hypoglycemia. Can J Diabet 2013;A3. 4. ISPAD Guidelines 2014. Pediatric Diabetes 2014: 15 (Suppl 20).

Strategies to prevent hypoglycaemia

Patient education

• Discuss hypoglycaemia risk factors and treatment with patients on insulin or sulfonylureas/glinides

• Educate patients and caregivers on how to recognize and treat hypoglycaemia

• Instruct patients to report hypo episodes to their doctor/educator

IHSG. Diabetes Care 2015;38:1583.

• Consider enrolling patients with frequent hypoglycaemia in a blood glucose awareness training programme


Seaquist ER et al. ADA/Endocrine Society consensus report on hypoglycemia. Diabetes Care 2013;36:1384.

Diet and exercise

• Follow a predictable eating plan, including carbohydrate counting

• Monitor glucose before and after exercise

• Eat pre-exercise snacks if blood glucose levels are low/declining

• Modify physical activity that has led to hypoglycaemia in the past

• Avoid alcohol, or run glucose high


Glucose and medication monitoring

• If on sulphonylureas (for T2D), consider changing to another drug class

• If add-on to basal insulin is needed, consider alternatives to prandial insulin

• If on basal-bolus insulin, check blood glucose before each meal every day

• Ensure medication is dosed correctly

• Consider insulin adjustments:

o Regular/soluble insulin → rapid-acting insulin

o NPH/isophane → insulin analogues

o Adjusting insulin in relation to exercise

1. Diamant M, et al. Diabetes Care 2014;37:2763–2773. 2. Eng C et al. Lancet 2014;384:2228. 3. McIntyre HD et al. Med J Aust 2010; 192:637. 3. The management of Type 2 Diabetes. NICE guidelines 2009, updated 2014. Accessed at www.guidance.nice.org.uk/cg87

http://www.guidance.nice.org.uk/cg87

Treatment of hypoglycaemia

Cryer PE. Management of hypoglycemia during treatment of diabetes mellitus. UpToDate review, last updated May 15, 2014. Canadian Diabetes Association 2013 clinical practice guidelines. Chapter 14: Hypoglycaemia. Can J Diabet 2013;A3.

Recognise symptoms so they can be treated as soon as they occur

1

Confirm the need for treatment if possible (blood glucose <3.9 mmol/L is the alert value)

2

Treat with 15 g fast-acting carbohydrate to relieve symptoms 3

Retest in 15 minutes to ensure blood glucose > 4.0 mmol/L and re-treat (see above) if needed

4

Eat a long-acting carbohydrate to prevent recurrence of symptoms

5

Hypoglycaemia and driving: prevention & treatment

Graveling AJ, Frier BM. Driving and Diabetes. Clin Diabet Endocrinol DOI 10.1186/s40842-015-0007-3.

< 4 mmol/L

< 5 mmol/L

≥ 5 mmol/L

Safe to drive

Have a snack

Don’t drive or stop driving

• Test glucose ≤ 1 hour before driving • Test glucose regularly while driving

(every 2 hours)

• Ingest fast-acting glucose; retest glucose • Wait 45 minutes after glucose has

normalized

• Rates of severe hypoglycaemia don’t appear to have fallen in clinical practice despite therapeutic advances

• There are well identified pathophysiological pathways which explains why patients with diabetes are so vulnerable to hypoglycaemia

• Clinicians (and patients and their families) need to be better informed about hypoglycaemia and its causes

Conclusions

New therapies and technologies, combined with education, training and professional support can

reduce hypoglycaemic risk

Key take-home messages

• Hypoglycaemia is a significant clinical outcome with potentially serious short- and long-term effects

• Hypoglycaemia may occur in T1D or T2D, including in patients not on insulin

• Benefits of intensive glucose control need to be balanced against risks

• Glycaemic targets may be relaxed in some populations at high risk of hypoglycaemia

• Frequent glucose monitoring and medication adjustments may help reduce the risk of hypoglycaemic episodes

• Education about hypoglycaemia prevention strategies may help patients reduce the risk

simon heller - university of york heller presenter disclosure simon heller advisory board member:...

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