hypoglycemia in diabetes: the limiting factor to optimal control june 7, 2012 kenneth cusi, md,...

Hypoglycemia in Diabetes:the limiting factor to optimal control

June 7, 2012

Kenneth Cusi, MD, FACP, FACE

Professor of Medicine

Chief, Division of Endocrinology, Diabetes & Metabolism

University of Florida, Gainesville

Hypoglycemia: benefits and risks (DCCT)

DCCT Research Group. N Engl J Med 1993;329:977–86

1413121110987650

20

40

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HbA1c (%)

0

2

4

6

8

10

12

14

16

Retinopathy

(per 100 patient-years)

Conventional group

Intensive groupRetinopathy

DCCT, Diabetes Control and Complications Trial

The Physician’s Dilemma

Adapted from DCCT Research Group N Engl J Med 1993;329:977–86

Rate of progression of retinopathy

(per 100 patient-years)

12

10

8

6

4

2

05.0 6.0 7.0 8.0 9.0 10.09.5 10.58.57.56.55.5

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Retinopathy risk Hypoglycaemia rate

Hypoglycemia in the Management of Diabetes

1. The impact of hypoglycemia:

– Added cost to diabetes treatment

– Effect on morbidity and mortality

– Role in compliance with treatment

2. How can we prevent hypoglycemia?

– Who is at greater risk? When?

– Individualizing insulin therapy

– Choosing the right insulin to avoid hypoglycemia

Definition of Hypoglycemia• Low plasma glucose causing neuroglycopenia

• Clinical definition of hypoglycaemia:

– Mild: self-treated

– Severe: requiring help for recovery

• Biochemical definition of a low plasma glucose:

– 3.0 mmol/L (<54.1 mg/dL) (EMA)1

– 3.9 mmol/L (≤70 mg/dL) (ADA)2

– 4.0 mmol/L (<72 mg/dL) for clinical use in patients treated with insulin or an insulin secretagogue (CDA)3

1. EMA. CPMP/EWP/1080/00. 2006; 2. ADA. Diabetes Care 2005;28:1245–9; 3. Yale et al. Canadian J Diabetes 26:22–35

ADA, American Diabetes Association; CDA, Canadian Diabetes Association; EMA, European Medicines Agency



– Its is common and adds cost to diabetes treatment

Medications Most Commonly Associated with Emergency Admissions in Patients >65 Years of Age

Budnitz et al. N Engl J Med 2011;365:21

Data given are number and percentage of annual national estimates of hospitalisations. Data from the NEISS-CADES project.ER visits n=265,802/Total cases n=12,666

Opioi

ds

Hypoglycemia Accounts for Most Endocrine-related Emergency Hospital Admissions

Budnitz et al. N Engl J Med 2011;365:21

Severe Hypoglycemia in T2DM is as Common as in T1DM with Increasing Duration of Insulin Therapy

SU, sulfonylurea; T1D, type 1 diabetes; T2D, type 2 diabetes

UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–7

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

SU <2 yr >5 yr <5 yr >15 yr

T1DT2D

Severe hypoglycemia

Pro

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repo

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0.2

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1.0

SU <2 yr >5 yr <5 yr >15 yr

T1DT2D

Mild hypoglycemia

Socioeconomic Consequences of Non-Severe Symptomatic Hypoglycemia in Type 2 Diabetes

(France, Germany, UK, USA)

Productivity loss: up to $90 per event

Following a daytime event:• 18% lose an average of 10 h of work

time• 24% miss a meeting/deadline

Following a nocturnal hypoglycaemic event:

• 23% arrive late/miss work• 32% miss a meeting/deadline• 15 h of work are lost

• 5.6 extra blood glucose tests within 7 days after event

• Risk of suboptimal insulin dose (25% of patients reduce dose)

• 25% contact a healthcare provider after an episode

• Out-of-pocket costs due to extra/special groceries, extra testing supplies and transport: ~$25 per month

Direct impact of reduced productivity

Indirect impact through increased treatment cost

Brod et al. Value Health 2011;14:665–71




– Increases morbidity and mortality

1. ADVANCE. N Engl J Med 2008;358:2560–72; 2. ACCORD. N Engl J Med 2008;358:2545–59; 3. VADT. N Engl J Med 2009;360:129–39

Standard Intensive

p<0.001 p<0.01p<0.001

Per 100-patients per year

0.4 0.7

4.0

12.0

3

6

9

12

15

VADT3ACCORD2ADVANCE1


1.0

0


Se

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hyp

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Standard Intensive Standard Intensive

Intensive glucose lowering contributes to an increased risk of hypoglycemia by 2- to 3-fold, particularly in advanced type 2 diabetes

Intensive Insulin Therapy is Associated with Increased Incidence of Severe Hypoglycemia

ADVANCE: Severe Hypoglycemia is Associated with Increased Risk of Adverse Outcomes

Zoungas at al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group



Severe hypoglycaemia

(n=231)

No severe hypoglycaemia

(n=10,909)

No. patients with events (%)

Major macrovascular events 33 (15.9) 1114 (10.2) 3.53 (2.41–5.17)

Major microvascular events 24 (11.5) 1107 (10.1) 2.19 (1.40–3.45)

Death from any cause 986 (9.0)45 (19.5) 3.27 (2.29–4.65)

Cardiovascular disease 520 (4.8)22 (9.5) 3.79 (2.36–6.08)

Non-cardiovascular disease 466 (4.3)23 (10.0) 2.80 (1.64–4.79)

Respiratory system events 656 (6.0)18 (8.5) 2.46 (1.43–4.23)

Digestive system events 867 (7.9)20 (9.6) 2.20 (1.31–3.72)

Diseases of the skin 146 (1.3)6 (2.7) 4.73 (1.96–11.40)

Cancer 149 (1.4)5 (2.2) 2.11 (0.65–6.82)

0.1 1.0 10.0

Hazard ratio (95% CI)Events

“Severe hypoglycemia (SH) was strongly associated with increased risk of a range of adverse clinical

outcomes… (it either) contributes to adverse outcomes or is a marker of vulnerability to such events”

“Severe hypoglycemia (SH) was strongly associated with increased risk of a range of adverse clinical

outcomes… (it either) contributes to adverse outcomes or is a marker of vulnerability to such events”

Clinical Outcome HR p-value

Macrovascular events 4.0 <0.001

Microvascular events 2.4 <0.001

Death from any cause 4.9 <0.001

Death from CV cause 4.9 <0.001

Death from non-CV cause 4.8 <0.001

ADVANCE: Hazard Ratios (HR) of Cardiovascular Disease, Microvascular

Events and Death Among Patients that Experienced Severe Hypoglycemia vs. Those Who Did Not


VADT: N Engl J Med 2009;360:129–39.

Predictor HR p-value

Hypoglycaemia 4.0 0.01

HbA1c 1.2 0.02

HDL 0.7 0.02

Age 2.1 <0.01

Previous event 3.1 <0.01

VADT: Severe Hypoglycemia is a Major Predictor of

Cardiovascular Death

ACCORD: Severe Hypoglycemia is Associated with Increased Risk of Death

Launer et al for the ACCORD Study Group. Diabetes Care 2012 ;35:787-793

Association of Hypoglycemia with Acute Cardiovascular Events in T2DM

• Retrospective, observational study (n=860,845) assessing association between hypoglycaemia and acute CV events

• 3.1% patients had a hypoglycemic event during evaluation period (1 year)

• Patients who experienced hypoglycemia had a 79% higher odds of an acute CV event than patients without hypoglycaemia

Johnston et al. Diabetes Care 2011;34:1164–70

Severe Hypoglycemia Increases the Risk of CVD and Microvascular Complications in the Elderly

Zhao et al. Diabetes Care 2012 ;35:1126-1132

Outcome HR P valueCVD 2.0 <0.001PVD 2.6 <0.001Stroke 2.3 <0.001CHF 1.8 0.001Microvascular 1.8 <0.001





– Decreases compliance with treatment and has long-term effects

Impact of Severe Hypoglycaemic* Eventon Patient’s Behavior

Response to major hypoglycaemic event (%)

Type 1 diabetes

Type 2 diabetes

Stayed at home next day 20.0 26.3

Feared future hypoglycaemic events 63.6 84.2

Changed insulin dose 78.2 57.9

Leiter L et al. Can J Diabetes 2005;29:186–92

*Severe hypoglycaemia defined as any event requiring external assistance and with a PG <2.8 mmol/L

Fear of Hypoglycemia is Related to Preceding History of Hypoglycemia

0

4

8

12

16

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History of hypoglycaemia

(n=136)

No history of hypoglycaemia

(n=264)

Me

an

HF

S-I

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core

19.0

10.2

p<0.0001*

*Based on the t-test.HFS-II, Hypoglycaemia Fear Survey-II.

Vexiau et al. Diabetes Obes Metab 2008;10(suppl 1):16–24

Neurological Consequences of Hypoglycemia

Short-term:

•Cognitive dysfunction

•Behavioural abnormalities

•Confusional state

•Coma

•Seizures

•TIAs; transient hemiplegia

•Focal neurological deficits (rare)

Long-term:

•Cerebrovascular events – hemiparesis

•Focal neurological deficits

•Ataxia; choreoathetosis

•Epilepsy (rare)

•Vegetative state (rare)

•Cognitive impairment with behavioural and psychosocial problems

TIA, transient ischaemic attack

Frier. Diabetes and the Brain; Eds Biessels & Luchsinger 2010:131–57

TIA, transient ischaemic attack

Frier. Diabetes and the Brain; Eds Biessels & Luchsinger 2010:131–57





– Decreases compliance with treatment


– Keep in mind times of greatest risk

– Individualize insulin therapy

– Take advantage of insulin preparations associated with less hypoglycemia

Causes and risk factors for hypoglycaemia

• General causes of hypoglycaemia1,2

• Inadequate, delayed or missed meal• Exercise• Too much insulin or oral anti-diabetes medications• Drug/alcohol consumption• Increased insulin sensitivity • Reduced insulin clearance

• Risk factors for severe hypoglycaemia3,4

• Age/duration of insulin treatment• Strict glycaemic control• Impaired awareness of hypoglycaemia • Sleep• History of previous severe hypoglycaemia• Renal failure

1.Briscoe and Davis. Clin Diabetes 2006;24(3):115–21; 2. Workgroup on Hypoglycemia, American Diabetes Association. Diabetes Care 2005;28(5):1245–9; 3. Frier. Diabetes Metab Res Rev 2008;24(2):87–92; 4. Cryer. Diabetes 2008;57(12):3169–76

Risk of Severe Hypoglycemia Increases with Baseline Poor Cognitive Function:Importance of early recognition when starting insulin

Launer et al for the ACCORD Study Group. Diabetes Care 2012 ;35:787-793

Hypoglycemia is FrequentlyUnrecognized by Patients

• Many episodes are asymptomatic; CGMS data show that unrecognised hypoglycaemia is common in people with insulin-treated diabetes

• In one study, 63% of patients with type 1 diabetes and 47% of patients with type 2 diabetes had unrecognised hypoglycaemia as measured by CGMS (n=70)1

• In another study, 83% of hypoglycaemic episodes detected by CGMS were not detected by patients with type 2 diabetes (n=31)2

CGMS, continuous glucose monitoring system

1. Chico et al. Diabetes Care 2003;26(4):1153–7; 2. Weber et al. Exp Clin Endocrinol Diabetes 2007;115(8):491–4

74% of all events occurred at night

54% of hypoglycaemic episodes were nocturnal, none of which were detected

Risk of Hypoglycemia during Sleep

• No symptoms detectable during sleep

• Catecholamine responses are diminished1

• May not impair cognitive function the next day2,3

• Subjective well-being affected with greater fatigue during exercise3

• May induce impaired awareness of hypoglycaemia the next day4

1. Jones et al. New Engl. J Med 1998;338:1657-62; 2. Bendtson et al. Diabetologia1992;35:898-903; 3. King et al. Diabetes Care 1998;21:341-5; 4. Veneman et al. Diabetes 1993;42:1233-7.

Beware of Patients with Hypoglycemia Unawareness

• Hypoglycemia

unawareness affects

• 20–25% of adults T1DM

• 10%1 insulin-treated T2DM

• Risk of severe

hypoglycaemia is 3 to 6

fold greater2

• Broad spectrum of severity 1. Gold et al. Diabetes Care 1994;17:697-703

2. Geddes et al. Diabetic Med 2008;25: 501–4

3. Pramming et al. Diabetic Med 1991;8:217–22

1. Gold et al. Diabetes Care 1994;17:697-703

2. Geddes et al. Diabetic Med 2008;25: 501–4

3. Pramming et al. Diabetic Med 1991;8:217–22

Severe hypoglycaemia without warning3

100

Diabetes duration (years)

0–9 10–19 20–29 30–39 >40

50

0









– Take advantage of insulin preparations associated with less hypoglycemia

Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A1C Levels Before and After Treatment Intensification in T2DM

Riddle et al. Diabetes Care 34:2508–2514, 2011

Role of Insulin Analogues in the Prevention of Hypoglycemia

1110987610

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Insulin B

HbA1c (%)

Adapted from DCCT Research Group N Engl J Med 1993;329:977–86

Confirmed hypoglycaemia (events/patient-year)

HbA1c and Hypoglycemia in Patients with Type 2 Diabetes

Hermansen et al. Diabetes Care 2006;29:1269–74Hermansen et al. Diabetes Care 2006;29:1269–74

Insulin detemir

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Prevention of hypoglycemia is essential to success: Hypoglycemia

• Increases morbidity and mortality• Adds significant cost• Decreases patient compliance and overall success

How to prevent hypoglycemia?• Be aware of times of greatest risk (i.e., nocturnal hypoglycemia)• Individualize insulin therapy• Take advantage of insulin preparations associated with less

hypoglycemia

hypoglycemia in diabetes: the limiting factor to optimal control june 7, 2012 kenneth cusi, md,...

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