Rémi Rabasa-Lhoret MD, PhDInstitut de Recherches Cliniques de Montréal (IRCM) :Professor of ResearchVP for Clinic and Clinical ResearchDiabetets clinic and research platform directorResearch chairs in diabetesJ-A DeSève et Lamarre GosselinUniversité de Montréal :Professor of MedicineCentre Hospitalier Universitaire de Montréal (CHUM) :Endocrinology division

Severe Hypoglycemia.A Canadian perspective

Hypoglycemia: definitions

*Note that some patients will have symptoms >3.1 mmol/L due to the counter hormonal release;**Functional brain failure; † Brain death.1. Zammitt NN, Frier BM. Diabetes Care 2005;28(12):2948-61.2. Diabetes Canada. Hypoglycemia: Low blood sugar in adults.

Symptoms of hypoglycemia evolve as blood glucose drops1,2

Glycemic thresholds for secretion of counterregulatory hormones and onset of physiological, symptomatic and cognitive changes in response to hypoglycemia

in the nondiabetic human.1

Diabetes Canada: Patient Educational

Sheet on Hypoglycemia

3

Bloo

d gl

ucos

e (m

mol

/L) 4.4 – 4.7 mmol/L: Decreased insulin secretion

3.6 – 3.9 mmol/L: Increased glucagon, epinephrine, cortisol and growth hormone secretion

2.8 – 3.1 mmol/L: Symptoms*< 2.8 mmol/L: Reduced cognition, aberrant behavior,

seizure, potential loss of consciousness and coma**

< 1.5 mmol/L: Neuronal death†

Diabetes Canada definitions of hypoglycemia

Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42(Suppl 1):S1-325.

Mildhypoglycemia• Autonomic symptoms are

present• Patient is able to self-

treat

4

Severehypoglycemia• Plasma glucose typically

Hypoglycemia Classification and Glycemic Threshold Values International Classification

1. American Diabetes Association. Diabetes Care. 2018;41(suppl 1):S55-S64.

2. International Hypoglycaemia Study Group. Diabetes Care. 2017;40(1):155-157.

LevelInternational Hypoglycaemia Study Group1,2

≤3.9 mmol/L

Severe hypoglycemia (SH):Frequency and Risk Factors

SH : current situation

Underestimated

Under reported

Limit Rxgoals

acheivements

Rx availablebut complex

7

A snapshot of SH in Canada

8*On insulin and/or a sulfonylurea. SH, severe hypoglycemia; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.1. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42(Suppl 1):S1-325.2. Ratzki-Leewing A, et al. BMJ Open Diabetes Res Care. 2018;6(1):e000503.

During a SH episode, the patient absolutely requires the assistance

of another person.1

Patients on insulin and/or sulfonylurea at greater risk include:1

Pre-schoolers

Adolescents Elderly

Average incidence rate for a Canadian

with diabetes* is~2.5

events/yearregardless of whether they

have T1DM or T2DM2

Every year, it affects:2

~5 in 10 Canadians with T1DM

~3 in 10 Canadians with T2DM*

The InHypo-DM Study: Strikingly high risk and rate of SH among Canadian adults with T1DM and T2DM treated with insulin and/or insulin secretagogues

SH, severe hypoglycemia; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.Ratzki-Leewing A, et al. BMJ Open Diabetes Res Care. 2018;6(1):e000503.

40.5%54.3%

38%

0%

20%

40%

60%

80%

100%

AllRespondents

(n=552)

T1DM (n=94) T2DM (n=456)

2.5 2.4 2.5

00.5

11.5

22.5

33.5

44.5

5

AllRespondents

(n=552)

T1DM (n=94) T2DM (n=456)

No difference in the odds of hypoglycemia between T1DM and T2DM

Risk of SH (≥1 Event) Annualized SH Rates

1-YEAR incidence proportion Incidence density (events/person year)

9

The InHypo-DM Study: In both T2DM and T1DM, SH was under-reported… which increased the risk of SH

SH, severe hypoglycemia; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.Ratzki-Leewing A, et al. Can J Diabetes 2018; 42(5): S52-53.

Only

34%of respondents said they always report SH

10

…

Those underreporting events were

1.9 timesmore likely to experience SH

(95% CI: 1.2 to 3.0, p=0.004)

The BETTER registry: Patients living withT1D (Québec)• 876 adults (64% women)• 47% using CSII• 78% using CGM• Hypoglycemia

– 6 values < 3.0 mmol/L in the last month– 13% patients with at least a SH in the last year

• Mean number of events 2.5 / yearUnpublished data by March 2020 from: https://type1better.com/en/home/PI : A-S Brazeau & R Rabasa-Lhoret

https://type1better.com/en/home/

High risk populationsFactors for which senior patients may be especially at risk

Patient characteristics that increase the risk of SH in people treated with sulfonylureas or insulin

• Prior episode of severe hypoglycemia

• Current low A1C (

Circumstances that increase the risk of SH

• SH, severe hypoglycemia.• Adapted from Diabetes Canada Clinical Practice Guidelines Expert Committee. Can

J Diabetes 2018;42(Suppl 1):S1-325.13

Missed meals / smaller meals Exercise

Alcohol intake Errors in insulin dose

Possible reasons for fear of hypoglycemia

Hendrieckx C, Halliday JA, Beeney LJ, Speight J. Diabetes and emotional health: a practical guide for healthcare professionals supporting adults with Type 1 and Type 2 diabetes. London: Diabetes UK, 2019, 2nd Edition (UK).

14

Limited understanding of how to recognize

and prevent it

Knowledge of having decreased

hypoglycemia awareness

Previous experience of a traumatic hypoglycemic

episode

Worry-prone personality

Hypoglycemia and Canadian healthcare costs

1. O'Reilly DJ, et al. Can J Diabetes 2018 ;42(6):659-663.2. Spaic, et al. Can J Diabetes 2016;40(S12):Abstract 31.

15

$2,901 per person

The total mean annual cost of hospitalizations, clinical visits, and work absenteeism associated

with hypoglycemia events1

189calls to Emergency

Medical Services (EMS) per 10,000 diabetes patients per year2

7.4%increase in rate of EMS

calls for a diabetic emergency from 2008-

2014 (p

Hypoglycemia can be Life Threatening, has or is associated with Negative Acute and Long-Term Consequences

Acute1 Long-term1,2

QoL= quality of life. 1. Frier BM. Nat Rev Endocrinol.2014;10(12):711-722. 2. Seaquist ER, et al. Diabetes Care. 2013;36(5):1384-1395. 3. Bonds DE, et al. BMJ. 2010;340:b4909. 4. Cryer PE. Diabetes Care. 2012;35(9):1814-1816.

Cognitive decline

Acute symptoms NeuroglycopenicAutonomic

Fear of hypoglycemia !

Cognitive impairment

Acute morbidityAccidents and injuriesComas and seizuresCardiovascular eventsCerebrovascular events

Mortality3 Mortality4

Reduced QoL

Driving and employment restrictions

Impaired work performance and social activities

Severe hypoglycemia (SH):Prevention and treatment

Strategies for preventing SH

SH, severe hypoglycemia.1. Yeoh E, et al. Diabetes Care 2015;38(8):1592-609; 2. Lind M, et al. JAMA 2017;317(4):379-38; 3. Aleppo G, et al. Diabetes Care 2017;40(4):538-545; 4. Reddy M, et al. Diabetes Technol Ther. 2018;20(11):751-757; 4. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42(Suppl 1):S1-325; 6. Pratley RE, et al. Diabetes Obes Metab. 2019;21(7):1625-1633.

• Comprehensive patient education, especially avoidance of risk factors and recognition of symptoms1

Patienteducation:

• Including:1-4

• continuous/flash glucose monitoring

• insulin pump therapy• sensor-augmented pump• hybrid closed-loop system

Technological interventions:

• Preferential use of anti-diabetic agents with lower potential for hypoglycemia (e.g., metformin, DPP-4i, SGLT-2i or GLP-1 RA)5

• Basal insulin dose adjustment• Lower rates with newer

analogue insulins (e.g., glargine-300, degludec)6

Medication adjustment:

18

Driving safety for patients with diabetes

19CGM, continuous glucose monitoring; FGM, flash glucose monitoring.1. Houlden RL, et al. Can J Diabetes 2018;42(Suppl 1):S150-153.

Check blood sugar

• Immediately before driving • At the first sign of hypoglycemia while driving

(STOP driving)• Every 4 hours while driving

1

If glucose

When doctors talked about driving safety with their patients with diabetes…

• Event rate fell from 4.49 to 2.71 events per 1,000 patients/year

• RR: 0.59 (95% CI 0.43-0.82)

A very large 3-year Ontario study shows that educating patients about safe driving works

Redelmeier DA, et al. N Engl J Med 2012;367:1228-36.

Study of the effect of medical warnings issued by Ontario physicians over a 3-year period, which including 518,104 patients with diabetes.

20

41%reductionin annual accident

rate

Treatment of SH*

*Treatment of SH is different than treatment of mild to moderate hypoglycemia; **Treatment with nasal glucagon 3 mg should also be considered.BG, blood glucose; IV, intravenous; SH, severe hypoglycemia.Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42(Suppl 1):S1-325.

20-15-15

1. Treat with 20 g of oral “fast sugar” (simple carbohydrate)

2. Retest in 15 minutes to ensure the BG > 4.0 mmol/L and retreat with a further 15 g of carbohydrate if needed

3. Eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein

In a conscious person:

1. Treat with 1 mg of glucagonsubcutaneously or intramuscularly**

2. Call 911

3. Discuss with diabetes health-care team

4. Once conscious, eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein

In an unconscious person with no IV access:

1. Treat with 10-25 g (20-50 mL of D50W) of glucose intravenously over 1-3 minutes

2. Retest in 15 minutes to ensure the BG >4.0 mmol/L and retreat with a further 15 g of carbohydrate if needed

3. Once conscious, eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein

In an unconscious person with IV access:

21

*Up to 4 years.Mitchell BD, et al. Endocr Pract. 2016;22(2):123-135.

T1DBasal-bolus insulin regimen(N=8336)

48.5%51.5%of participants filled

glucagon prescription

of participants did not fill glucagon prescription

Basal insulin regimen (N=23,310)

T2D

1.4% 98.6%of participants did not fill glucagon prescription

of participants filled glucagon

prescription

Basal-bolus insulin regimen (N=21,664) 96.4%

3.6% of participants did not fill glucagon prescription

of participants filled glucagon

prescription

People With T1D or T2D Initiated With Insulin Often Do Not Fill Prescription for GlucagonGlucagon: Low Prescription-Filling Rate*

To be used if patient is unconscious1-3

Kit must be stored per manufacturer’s specifications and able to be located easily2

Expiration dates must be checked and accounted for2

Injectable Glucagon: efficient but complex

1. Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2018;42(Suppl 1):S1-325; 2. Pearson T. Diabetes Educ 2008;34(1):128-34; 3. My Health Alberta website. Topic Overview page, Diabetes: How to give glucagon. Last updated July 25, 2018. Available at: https://myhealth.alberta.ca. Accessed August 27, 2019; 4. Eli Lilly and Company. http://uspl.lilly.com/glucagon/glucagon.html#ppi. Accessed August 20, 2019.

23

Administering injectable glucagon is a multistep process that requires attention and training on the part of the caregiver.

Preparation

Injecting

Dosing

Reconstitution

New option : Nasal Glucagon for Severe Hypoglycemia

Nasal glucagon is under development for the treatment of severe hypoglycemia in adults, children, and adolescents with diabetes.

Product still in development and not yet approved.Indication may vary slightly by geography.1. Yale JF, et al. Diabetes Technol Ther. 2017;19(7):423-432. 2. Sherr JL, et al. Diabetes Care. 2016;39(4):555-562. 3. Seaquist ER, et al. Diabetes Obes Metab. 2018;20(5):1316-1320. 4. Data on file, Eli Lilly and Company.

Ready to use; no reconstitution required1-3

Nasally administered dry powder (glucagon 3 mg)1-3

No need to inhale or breathe deeply1-3

Compact, portable, single-use drug-device combination1-3

Can be stored at room temperature (up to 30°C)4

©2018 Eli Lilly and Company

Percentages may not add up to 100% due to rounding. *Full dose for IM glucagon is delivered when ≥90% of the targeted 1-mg dose is administered; †Vs IM glucagon; ‡Full dose of nasal glucagon is delivered when plunger is fully depressed.Yale JF, et al. Diabetes Technol Ther. 2017;19(7):423-432.

Instructed Caregivers(N=16)

Non-InstructedAcquaintances(N=15)

No dose delivered(P

Randomized crossover noninferiority trial: A single 3-mg dose of nasal glucagon (NG) was as effective as intramuscular glucagon in reversing insulin-induced hypoglycemia

*From nadir concentration in participants with nadir glucose

The ease of use and efficacy of nasal glucagon were evaluated in the real world

Seaquist ER, et al. Diabetes Obes Metab 2018;20(5):1316-1320.

95.…of HEs resolved within

30 minutes of NG administration

69 patients experienced 157 hypoglycemic events (HEs)

Most caregivers reported that NG was

easy to use.

27

15They did so within

15 minutes.No additional

external medical help was required.

In every case of severe HEs (n=12) patients

awakened / returned to normal status.

Nasal glucagon was well tolerated1

Head/facial discomfort and nasal symptoms occurred more frequently with nasal glucagon, but most were transient.

IM, intramuscular.1. Rickels MR, Ruedy KJ, Foster NC, et al. Diabetes Care. 2016;39:264‐270

28

Participants (%)

9

25

0 20 40

Head/facial discomfort

Participants (%)

38

36

0 20 40

Nausea ± vomiting

Nasal glucagon (N=77)IM glucagon (N=76)

Participants (%)

1

18

0 20 40

Nasal symptoms

Nausea ± vomiting was transient and occurred at similar frequencies with

nasal and IM glucagon.

No serious adverse events were reported

Most common events by treatment visits

Free, readily available, Diabetes Canada healthcare provider & patient resourcesDiabetes Canada 2018 Clinical Practice Guidelines - Quick Reference Guide

HCP resource Patient resources

29

http://guidelines.diabetes.ca/docs/patient-resources/lows-and-highs-blood-sugar-levels.pdfhttp://guidelines.diabetes.ca/docs/patient-resources/hypoglycemia-low-blood-sugar-in-adults.pdfhttp://guidelines.diabetes.ca/docs/CPG-quick-reference-guide-web-EN.pdf%23page=6http://guidelines.diabetes.ca/docs/patient-resources/drive-safe-with-diabetes.pdf

SH: Conclusion & key points (1)• SH is frequent as on a yearly basis it can affect up to

(Canadian data)– 50% of patienst living with T1D– 30% of insulin and sulfonylurea-treated patients with T2D– In patients with a SH episode the mean number of episodes:

2.5/year

• SH have and is associated with devastating physical and psychological consequences

• Patients at higher risk for SH have specific characteristics 30

SH: Conclusion & key points (2)• Prevention

– Training +++– Low risk therapeutic options– Technology : CGM +++

• Treatment– Oral carbohydrate vs. Glucagon– Intramuscular vs. intra Nasal Glucagon

31

Thank-youMerci

The BETTER study aim to reduce hypoglycemia in persons living with Type 1 diabetes

https://type1better.com/en/home/

https://type1better.com/en/home/

Slide Number 1Slide Number 2Symptoms of hypoglycemia evolve as blood glucose drops1,2Diabetes Canada definitions of hypoglycemiaHypoglycemia Classification and Glycemic Threshold Values International ClassificationSlide Number 6SH : current situation A snapshot of SH in CanadaThe InHypo-DM Study: �Strikingly high risk and rate of SH among Canadian adults with T1DM and T2DM treated with insulin and/or insulin secretagoguesThe InHypo-DM Study: �In both T2DM and T1DM, SH was under-reported… �which increased the risk of SHThe BETTER registry: Patients living with T1D (Québec)Patient characteristics that increase the risk of SH �in people treated with sulfonylureas or insulinCircumstances that increase the risk of SH �Possible reasons for fear of hypoglycemiaHypoglycemia and Canadian healthcare costsHypoglycemia can be Life Threatening, has or is associated with Negative Acute and Long-Term ConsequencesSlide Number 17Strategies for preventing SHDriving safety for patients with diabetesA very large 3-year Ontario study shows that educating patients about safe driving worksTreatment of SH*Glucagon: Low Prescription-Filling Rate* Injectable Glucagon: efficient but complexNew option : Nasal Glucagon for Severe HypoglycemiaAdministration of Nasal Glucagon Had a Higher Success Rate vs IM Glucagon Among Non-Medically Trained PeopleRandomized crossover noninferiority trial: �A single 3-mg dose of nasal glucagon (NG) was as effective as intramuscular glucagon in reversing insulin-induced hypoglycemiaThe ease of use and efficacy of nasal glucagon were evaluated in the real world Nasal glucagon was well tolerated1Free, readily available, Diabetes Canada healthcare provider & patient resourcesSH: Conclusion & key points (1)SH: Conclusion & key points (2)Thank-you�Merci