#diabetesmatters - the burden and impact of hypoglycemia - adams

The Burden and Impact of Hypoglycemia Shannell MacKinnon, NP

Lenley Adams, MD Diabetes MaBers May 12, 2017

Presenter Disclosure

•  Presenter: Shannell MacKinnon, NP •  Rela,onships with commercial interests: None

•  Presenter: Lenley Adams, MD FRCPC FACP •  Rela,onships with commercial interests:

–  Advisory Board: NovoNordisk, Sanofi, Medtronic, Merck –  Speakers Honoraria: AstraZeneca, NovoNordisk, Sanofi, Medtronic,

Merck, Boehringer Ingelheim/Lilly, Janssen, Valeant

Quote

•  “I tend to keep myself higher than I should because I am so fearful of dropping. I have had to call my husband from the gym parking lot to come get me because I was too low to drive. I miss the spontaneity of going for a walk or a jog without extensive planning “

Quote

•  “I remember hiRng the back of the transfer truck, and right away geRng my 9 year old daughter out of the back seat.. and hearing the driver behind me outside his car now-‐ yelling profaniUes at me, calling me a drunk driver.. when the paramedics got there they tested my blood and it was 1.8”

Quote •  “It was a beauUful summer day and I was playing outside

with my 1 and 2 year old, they wanted to play in their pool so I started to fill up the pool. I had their swim shorts just inside our house door so I opened it to grab them. That is when I fell to the cement floor having a seizure from a low blood sugar with my 2 very young children outside. I remember trying to get up to get my kids but falling every Ume. I remember trying to call out to them but not being able to. Somehow a[er someUme I managed to get myself up and get them back in the house I remember once I got them inside the house thinking to myself “they can’t get back out” and locking the door. That’s the last thing I remember.”

ObjecUves

•  Recognize the burden that hypoglycemia has on people with diabetes

•  Describe the impact hypoglycemia has on management of diabetes

•  IdenUfy ways to reduce/ manage hypoglycemia in diabetes

Definition of Hypoglycemia

•  Without diabetes: <2.7 mmol/L •  Glycemic goal 4‒7 mmol/L

•  The guidelines suggest a <4 mmol/L level for the clinical definition of hypoglycemia in patients using a secretagogue or insulin

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-201.

1.  Development of neurogenic or neuroglycopenic symptoms

2.  Low blood glucose (<4 mmol/L if on insulin or secretagogue) 3.  Response to carbohydrate load

Neurogenic (autonomic)

Neuroglycopenic

Trembling Difficulty Concentrating Palpitations Confusion Sweating Weakness Anxiety Drowsiness Hunger Vision Changes Nausea Difficulty Speaking

Dizziness

DefiniUon of Hypoglycemia


•  Mild –  Autonomic symptoms present –  Individual is able to self-treat

•  Moderate –  Autonomic and neuroglycopenic symptoms –  Individual is able to self-treat

•  Severe –  Requires the assistance of another person –  Unconsciousness may occur –  Plasma glucose is typically <2.8 mmol/L

Severity of Hypoglycemia


Hypoglycemia unawareness

•  Occurs when the threshold for the development of autonomic warning symptoms is close to, or lower than, the threshold for the neuroglycopenic symptoms, such that the first sign of hypoglycemia is confusion or loss of consciousness

Kalra et al. Indian Journal of Endocrinology and Metabolism / Sep-‐Oct 2013 / Vol 17 | Issue 5

Causes of Hypoglycemia •  Incorrect insulin administraUon

–  Insulin taken in excess or at the wrong Ume relaUve to food intake and/or physical acUvity; incorrect type of insulin

•  Insufficient exogenous carbohydrate

–  Delayed or missed meals or overnight fast •  Decreased endogenous glucose producUon

–  Excess alcohol consumpUon

•  Increased uUlizaUon of carbohydrate/depleUon of hepaUc glycogen stores –  Exercise or weight loss


Causes of Hypoglycemia •  Increased insulin sensiUvity

–  During the night, exercise, weight loss

•  Delayed gastric emptying –  gastroparesis

•  Decreased insulin/oral hypoglycemic clearance –  progressive renal failure


Burden of Hypoglycemia

•  Evidence from several studies suggests that – severe hypoglycemia occurs in 35-‐42% of T1DM paUents

–  the rate of severe hypoglycemia is between 90-‐130 episodes/100 paUent years

•  A study using conUnuous glucose monitoring (CGM) idenUfied – unrecognized hypoglycemia in 60% of the paUents – 73.7% of those episodes occurring during night


RECURRENT UNRECOGNIZED HYPOGLYCEMIA IN WELL-CONTROLLED PATIENTS WITH T2DM

Glu

cose

con

cen

trat

ion

(m

mol

/L)

12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM Time

Hypoglycemia: ≤2.8 mmol/L

Borderline hypoglycemia:

2.83-3.9 mmol/L

13.9

11.1

8.3

5.6

2.8

0

Q. Do you consider the risk for hypoglycemia in your well-‐controlled paUents?

Even paUents treated with OADs with well-‐controlled glucose levels can experience recurrent unrecognized hypoglycemia daily.

17

Data were collected over 5 consecutive days, as indicated by each of the 5 coloured lines. Example of a 24-hour CGMS glucose profile from one patient with T2DM well controlled (A1C=6.2%) on OADs showing recurrent unrecognized hypoglycemia. CGMS: continuous glucose monitoring system; OADs=oral antidiabetic agents. 1. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491-4.

Risk of Hypoglycemia May Be UnderesUmated by SMBG

18

•  MulUcentre open-‐label study (n = 125)

•  367 paUents with type 2 diabetes who were on mulUple daily insulin injecUons

•  Glucose levels were measured by: •  CGMS or

•  SMBG

Pat

ient

s w

ith h

ypog

lyce

mia

(%)

CGMS SMBG

CGMS = continuous glucose monitoring system; SMBG = self-monitoring of blood glucose Adapted from: Zick R et al. Diabetes Technol Ther 2007; 9(6):483-92.

0

10

20

30

40

50

60

26.4% (n = 97)

56.9% (n = 209)

HYPOGLYCEMIA IS UNDER-‐RECOGNIZED

•  PaUents on insulin report that they don’t think to raise the topic of hypoglycemia, or conUnued snacking to prevent hypoglycemia to their GP1

•  Only 15% of type 2 paUents spoke to their doctor about mild or moderate events at the visit that followed2

•  Majority (58%) of hypoglycemic events occurred while the paUent was sleeping2

22 1. Data on file. Market Research. Novo Nordisk, Nov. 2010; 2. Leiter, et al. Can J Diabetes. 2005;29(3):186-92.

PROPORTION OF PATIENTS EXPERIENCING SEVERE HYPOGLYCEMIA INCREASES AS DURATION OF DIABETES INCREASES 1.0

Type 2 <2 years

Type 1 <5 years

Type 2 >5 years

Type 1 >15 years

Pro

por

tion

exp

erie

nci

ng

≥1

ep

isod

e of

se

vere

hyp

ogly

cem

ia o

ver

9–

12

m

onth

s Insulin-‐treated paUents

0.8

0.6

0.4

0.2

0.0

Later stage T2DM patients (those who may be put on insulin therapy) have similar hypoglycemia risk to Type 1 patients.

23 UK Hypoglycemia study group. Diabetologia. 2007;50:1140–7.

THRESHOLDS FOR HYPOGLYCEMIA VARY WITH AGE*

Blo

od g

luco

se c

once

ntra

tion

(mm

ol/L

)

2.0

2.5

3.0

3.5

4.0

2.0

2.5

3.0

3.5

4.0

Men aged 23 ± 2 years (n=7)

Men aged 65 ± 3 years (n=7)

Hypoglycemic awareness

Greater reaction time

for corrective action

Onset of cognitive dysfunction

Hypoglycemic awareness

Onset of cognitive dysfunction

Less reaction time for

corrective action

Blo

od g

luco

se c

once

ntra

tion

(mm

ol/L

) With increasing age, potential reaction time between awareness

and onset of symptoms is decreased, contributing to an increased risk for asymptomatic hypoglycemia and greater

susceptibility to cognitive impairment*

*Based on data in nondiabetic patients with no family history of diabetes. Figure adapted from Zammitt NN, Frier BM. Diabetes Care. 2005;28(12):2948-61. Matyka K et al. Diabetes Care. 1997;20(2):135-41.

24

DEFECTIVE GLUCOSE COUNTERREGULATION LEADS TO HYPOGLYCEMIA UNAWARENESS

1. UK Hypoglycaemia Study Group. Diabetologia. 2007;50(6):1140-7; 2. Segel S et al. Diabetes. 2002;51(3):724-33; 3. Cryer PE. Hypoglycemia in Diabetes: Pathophysiology, Prevalence, and Prevention. Alexandria, VA: American Diabetes Association; 2009.

Plasma

Plasma glucose Individuals Insulin Glucagon Epinephrine

↓ Nondiabetic ↓ ↑ ↑ ↑

↓ Type 1 diabetes – – ↑

↓ Type 2 diabetes–early ↓ ↑ ↑ ↑

↓ Type 2 diabetes–late – – ↑

In paUents with T1DM and late-‐stage T2DM, physiologic changes in plasma levels of insulin, glucose, and epinephrine lead to defecUve glucose counterregulaUon and hypoglycemia

unawareness.

25

HYPOGLYCEMIA UNAWARENESS IS ASSOCIATED WITH A HIGHER RATE OF SEVERE HYPOGLYCEMIA

Severe hypoglycemia*

(episode

s/paUe

nt/year)

0

0.5

1.0

1.5

2.0

2.5

9-fold higher rate of severe hypoglycemia

0.22

2.15

Normal awareness

(n=144)

Impaired awareness

(n=13)

Severe hypoglycemia was defined as an episode requiring external assistance for recovery. Subjective changes in hypoglycemia symptom intensity were recorded by the participants based on a hypoglycemia awareness scale of 1 to 7, where 1 equals always aware and 7 equals never aware and a score of 4 or more correlates with impaired awareness.

* Based on data from a retrospective survey of 215 patients with T2DM treated with ≥2 injections of insulin daily for ≥1 year. Henderson et al. Diabetes Med. 2003;20(12):1016-21.

26

RELATIONSHIP BETWEEN SEVERE HYPOGLYCEMIA AND A1C

Incide

nce pe

r 100 person-‐years

Updated average A1C

6

5

4

3

2

1

0 6.0 7.0 8.0 9.0

Severe hypoglycemia correlated to poor control in intensively treated patients

PaUents may sUll experience hypoglycemia even if their A1C

is above target.

27 Miller ME et al. BMJ. 2010;340:b5444.

HYPOGLYCEMIA HAS A SIGNIFICANT IMPACT ON EMERGENCY DEPARTMENT UTILIZATION

•  Hypoglycemia* accounted for 5 million U.S. ER visits between 1993 and 2005

–  380,000 visits/year, 25% of which resulted in hospital admission

–  An estimated 68.6% of reported cases occurred in adults ≥45 years of age

•  Emergency department visits for severe hypoglycemia represent a small percentage of the total number of episodes

29

* Hypoglycemia was severe as identified by ICD-9 coding. ICD-9=International Classification of Diseases, 9th Edition. Ginde AA et al. Diabetes Care. 2008;31(3):511-513.

SEVERE HYPOGLYCEMIA INCREASES THE RISK FOR ADVERSE OUTCOMES

*Severe hypoglycemia is defined as blood glucose <2.8 mmol per litre with transient dysfunction of the CNS, without other apparent cause, during which the patient was unable to administer treatment (requiring help from another person). †Adjusted for multiple covariates: sex, duration of diabetes, treatment assignment, presence or absence of a history of macrovascular disease, presence or absence of a history of microvascular disease, and smoking status at baseline. Time-dependent covariates during follow-up included age; level of glycated hemoglobin; body mass index; creatinine level; ratio of urinary albumin to creatinine; systolic blood pressure; use or nonuse of sulfonylurea, metformin, thiazolidinedione, insulin, or any other diabetes drug; and use or nonuse of antihypertensive agents. ‡p<0.001. CI=confidence interval. Zoungas S. N Engl J Med. 2010;363(15):1410-18.

Clinical Outcome and Interval After Hypoglycemia

Hazard Ratio (95% CI)†

Microvascular events 2.07 (1.32-3.26)‡

Macrovascular events 3.45 (2.34-5.08)‡

Death from any cause 3.30 (2.31-4.72)‡

Death from non-CV cause 2.86 (1.67-4.90)‡

Death from CV cause 3.78 (2.34-6.11)‡

Hazard ratios represent the risk of an adverse cardiovascular outcome or death among patients reporting severe hypoglycemia (<2.8 mmol/L)* as

compared with those not reporting severe hypoglycemia

30

Link Between Hypoglycemia and Acute Cardiovascular Events in Type 2 Diabetes

•  RetrospecUve, observaUonal study assessing associaUon between hypoglycemic events and acute cardiovascular events

•  3.1% paUents had hypoglycemic events during evaluaUon period

•  PaUents with hypoglycemic events had 79% higher odds for acute cardiovascular events vs. paUents with no hypoglycemia

32 Johnston SS et al. Diabetes Care 2011; 34(5):1164-70.

IMPACT OF NON-SEVERE HYPOGLCYEMIC EVENTS ON PRODUCTIVITY

•  Absenteeism or lost time from work •  Reduced productivity while at work •  Out-of-pocket expenses (e.g. extra groceries,

extra test strips and lancets, transportation services)

•  Nocturnal hypoglycemia may impact one’s sense of well-being on the following day because of its impact on sleep quantity and quality

•  Patients with recurrent hypoglycemia have been found to have chronic mood disorders including depression and anxiety

34

Brod et al. Values in Health. 2011 In Press.,

Willis et al. Expert Rev Pharmacoeconomics Outcomes Res. 2013;13(1):123-130.

Seaquist et al. Consensus Report. Hypoglycemia. Diabetes Care Publish Ahead of Print, published online April 15, 2013

Impact of hypoglycemia on quality of life and acUviUes of daily living

•  ’Hidden' costs associated with hypoglycemia and fear of hypoglycemia

•  To try to reduce hypoglycemic events, many paUents with diabetes maintain their blood glucose levels with a 'safety margin' (i.e., at higher than recommended values) and maintain hyperglycemia

•  Approximately a third of the paUents were very worried about hypoglycemia, and a similar proporUon reported maintaining hyperglycemia

•  10% of the paUents reported that they had taken days off work because of hypoglycemia during the previous 12 months Willis et al. Expert Rev Pharmacoeconomics Outcomes Res. 2013;13(1):123-‐130.

Type 2 Diabetes—Hypoglycemia is Associated with Decreased Health-related QoL and

Treatment Satisfaction

Adapted from: Marrett E, et al. Diabetes Obes Metab. 2009; 11(12):1138-1144. A total of 1984 people with type 2 diabetes taking oral antihyperglycemic agents (OAHAs) participated in this internet survey to study the relationship between medication side effects SEs and patient-reported outcomes (PROs). Data were collected on hypoglycemia 6 months prior to the survey, which measured health-related quality of life (HRQoL). The patients also responded to a Treatment Satisfaction Questionnaire for Medication v.1.4 (TSQM) and the Hypoglycemia Fear Survey (HFS) II. a Treatment Satisfaction Questionnaire for Medication v.1.4; Side Effects. TSQM score range: 0-100 (greatest satisfaction). b Health Status Measure. EQ-5D score range: -0.038 to 1.0 (US preference-weighted index score). c Based on the t-test of the null hypothesis of no difference between patients with and without SEs. d Based on the F-test of the joint hypothesis of no association of SE severity and PRO scores.

Reported hypoglycemia p<0.0001c

Score

100

90

80

0 No

96.6

Yes

90.0

Severe

81.1

Mild

93.1

Moderate

89.3

Hypoglycemic severity p<0.0001d

TSQM SEa

Reported hypoglycemia p<0.0001c

Score

1.00

0.90

0.60

0 No

0.86

Yes

0.78

Severe

0.67

Mild

0.83

Moderate

0.77

Hypoglycemic severity p<0.0001d

EQ-‐5Db

0.80

0.70

FEARFULNESS OF HYPOGLYCEMIA IN PATIENTS WHO EXPERIENCED A PRIOR EPISODE

% p

atie

nts

rep

orti

ng

fea

r of

fu

ture

hyp

ogly

cem

ia 4

*46.5% (Type 1) and 58% (Type 2) of severe episodes are reported during sleep

Fear of hypoglycemia can be an impediment to effecUve management, 1 treatment saUsfacUon3 and can lead some paUents who have experienced severe hypoglycemia to deliberately

maintain a state of hyperglycemia2

40

1. Nakar S et al. J Diabetes Complications. 2007;21(4):220-6; 2. Frier BM. Diabetes Metab Res Rev. 2008;24(2):87-92; 3. Alvarez, Guisasola F et al. Diabetes Obes Metab. 2008;10(Suppl 1):25-32. 4. Leiter, Yale et al. Can J Diabetes. 2005;29(3):186-92.

Cost of Hypoglycemia

•  Missed work •  Reduced producUvity •  SubopUmal control and complicaUons •  Weight gain •  Hypoglycemia unawareness •  EMS/ hospitalizaUons

•  Difficult to esUmate the true cost of hypoglycemia

Strategies to Minimize Hypoglycemia and Glycemic Variability

•  IdenUfy causes •  Use agents that minimize hypoglycemia

– DPP4i/SGLT2i/GLP1i vs SU – Gliclazide vs glyburide –  Insulin analogues vs regular/ intermediate insulin

43

BASAL INSULIN ANALOGUES REDUCED NOCTURNAL HYPOGLYCEMIA VS. NPH

Philis-Tsimikas, 20 weeks2 Riddle 2003, 24 weeks1

*Based on biologically confirmed events.

1. Riddle et al. Diabetes Care. 2003;26(11):3080-‐6; 2. Phillis-‐Tsimikaset al. Clin Ther. 2006;28(10):1569–81.

Basal analogues may help reduce nocturnal hypoglycemia by approximately half.

NPH pm

Detemir pm

Glargine pm

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1 p<0.02 p<0.01 p<0.05 p<0.05

Rela

tive

risk

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0

Rela

tive

risk

24-hr Nocturnal 24-hr Nocturnal

44

Hypoglycemia Reported in ADOPT p < 0.05 glyburide vs. rosiglitazone

PaUe

nts p

resenU

ng with

hypo

glycem

ia ** (%

)

10

Rosiglitazone

39

Glyburide Me{ormin

12

** PaUents self-‐reporUng hypoglycemia (unconfirmed) Kahn et al (ADOPT Study). N Engl J Med 2006; 355:2427–43.

45

40

35

30

25

0

20

15

10

5

SGLT2 Inhibitor Durability compared to SU: Risk of hypoglycemia over 208 weeks

Rohwedder et al. EASD 2014. Poster 807-‐P.

Propor,on of pa,ents with at least 1 hypoglycemic event, by study period PaUe

nts w

ith ≥

1 hy

pogl

ycem

ic e

vent

(%)

Year 1 2 3 4

45 40 35 30 25 20 15 10 5 0

1.6 3.4

37.2

2.2

28.4

39.7

23.6

1.5

DAPA + MET (N=406) GLIP + MET (N=408)

DAPA + MET GLIP + MET

19 655

8 190

4 221

4 125

No. of events

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./012 345 67 89# 4:;: &!"!<-!-="'"! "'"*


•  Don’t just target an A1C-‐ Individualize targets •  Carbohydrate counUng •  Assess alcohol and acUvity •  Adjust insulin for acUvity •  Avoid injecUng in limbs before acUvity •  Avoid injecUng in lipohypertrophied areas •  Avoid stacking insulin

48


•  If using NPH-‐ mix well •  EducaUon sessions for hypo unawareness

– HypoCoMPASS trial

•  Avoid overtreatment of hypoglycemia •  Test o[en •  Glucose sensor-‐ CGM •  CSII-‐ Insulin pump +/-‐ CGM-‐ low glucose suspend •  Islet cell transplantaUon

49

Summary

•  Hypoglycemia is common in T1DM and T2DM •  O[en unreported and under-‐recognized

– Ask about it, try to determine the cause

•  Impact on QOL, work, fear •  Impacts glycemic control, risking complicaUons •  Use agents and strategies to minimize hypoglycemia

Quote

•  “I hope that everyone realizes that a low is much more than “just a number” and “needing glucose”. There are both physical and mental recovery to that number that most “non-‐diabeUcs” would never understand but hopefully will try to understand. They are different to each individual, but all the same – not fun.”

#diabetesmatters - the burden and impact of hypoglycemia - adams

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