Freeport Physicians’ Education DaysDr. Luciana Parlea

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A stepwise approach to diabetes management

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Freeport Physicians’ Education Days

Faculty: Dr. Luciana Parlea

• Relationships with financial sponsors:Member of Advisory Board: Abbott, NovoNordisk, Sanofi, Dexcom, LilyPayment from Organization: Abbott, NovoNordisk, Sanofi, Dexcom, Lily,

Boehringer-Ingelheim, Janssen, AstraZeneca

• Affiliation with a not-for-profit organization:Freeport Physicians’ Education Fund Honorarium

Presenter COI Disclosure

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Freeport Physicians’ Education DaysDr. Luciana Parlea

Disclosure of Financial Support

This program has received financial support from the following organizations in the form of unrestricted educational grants:

Bayer, Boehringer-Ingelheim, Dexcom, GSK, Janssen, Merck,

Novartis, Novo Nordisk, Pfizer

This program has received financial support from Grand River Hospital Foundation in the form of speaker honoraria. This program has received in-kind support from Grand River Hospital in the form of logistical support.

Potential for conflict(s) of interest:Dr. Luciana is receiving payment from the Freeport Physicians’ Education Fund for this presentation

Freeport Physicians’ Education DaysDr. Luciana Parlea

4

Mitigating Potential Bias:

• Recommendations for Drug Therapy will be based on peer reviewed journal articles and published guidelines

6

Objectives

• By the end of this session participants will

• Review the new Diabetes Canada guidelines for management of diabetes

• Discuss special considerations for diabetes management in the elderly

• Incorporate new treatment modalities in the treatment of diabetes in the elderly

7

Case 1

• 70 yo female Hba1c 7%, lives independently

• PMHx: CVA, HTN, DM2x 25 years, BMI 30

• GFR 45

• Current medications:

• sitagliptin/metformin xr 50/1000 once daily

• Ramipril 10mg, Atorvastatin 20mg, ASA 81mg

8

Case 2

• 69 yo male DM2 x 20 years, Hba1c 7.8%, lives independently

• PMHx: HTN, dyslipidemia, gout, obesity (BMI 35)

• GFR 50

• Current medications:

• Sitagliptin/metformin 50/1000 bid, dapagliflozin 10mg

• Perindopril 8mg, atorvastatin 40mg

9

Case 3• 80 yo female, HbA1C 9.5%, nursing home resident

• PMHx: DM2 x 40 years, Dementia, HTN

• GFR 35

• Current medications:

• sitagliptin/metformin 50/1000 1 tab bid, diamicron mr 60mg 1 tab bid, Lantus 20u qhs

• Atorvastatin 10mg, ramipril 2.5 mg

Guidelines State Importance of Choosing Cardioprotective Agents Independent of A1C

All the major guidelines have a statement about consideration of therapy with a GLP-1 RA or SGLT-2i with demonstrated cardiovascular disease benefit, independent of A1C

European Association forthe Study of Diabetes

(EASD)

Diabetes Canada

AmericanDiabetes Association

Diabetes Canada Clinical Practice Guidelines: 2020 Update

11Adapted from Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2020; 44:575−91.

• Assess glycemic control, CV and renal status, recent dietary patterns and weight change• Select individualized A1C target• Provide and/or refer for diabetes education• Start healthy behaviour interventions

GOAL:Attain A1C target by 3

months

Start metformin

(if A1C is >1.5% above target, start metformin + a

2nd agent)

Lifestyle changes expect to reduce blood

glucose levels

No pharmacotherapy

Symptomatic hyperglycemia and/or metabolic decompensation

Start insulin ± metformin

Start metforminAdjust or advance

therapy

Reassess A1C in 3-6 months

If A1C NOT at target at 3 months

Diabetes Canada Clinical Practice Guidelines: 2020 Update

Adapted from Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2020; 44:575−91.

Regular Review

• Assess glycemic control, cardiovascular and renal status

• Screen for complications (eyes, feet, kidneys)

• Review efficacy, side effects, safety and ability to take current

medications

• Reinforce and support healthy behaviour interventions

If A1C NOT at Targetand/or

Change in Clinical Status

Adjust or advance

therapy*

ASCVD, CKD or HF OR Age >60 with 2 CV risk factors A1C above target and glucose lowering required

ADD or SUBSTITUTE AHA with demonstrated cardiorenal benefitsADD or SUBSTITUTE AHA according to clinical priorities

start insulin for symptomatic hyperglycemia and/pr metabolic decompensation

Established Cardiovascular or Renal Disease Risk Factors

ASCVD CKD HF>60 yrs with CV

risk factors†

Low

er R

isks

Ob

serv

ed in

Ou

tco

me

Tria

ls

MACE

HHF

Progression of Nephropathy

GLP1-RAor

SGLT2i*

SGLT2i*

SGLT2i*

SGLT2i*or

GLP1-RA

SGLT2i*

SGLT2i*

SGLT2i*(and lower

CV mortality)

GLP1-RA

SGLT2i*

SGLT2i*

Highest level of evidence: Grade A Grade B Grade C or D

*Initiated only if eGFR >30 ml/min/1.73m2

PROVEN cardiorenal benefit in high-risk populations

CV safety, but NO proven cardiorenal benefit

RISK of HF

Weight lossGLP1-RA

dulaglutide, liraglutide, semaglutide

GLP1-RAexenatide ER, lixisenatide

SGLT2icanagliflozin, dapagliflozin

empagliflozin

Ertugliflozin (SGLT2i)

DPP4isitagliptin, linagliptin, alogliptin

Acarbose

Saxagliptin (DPP4i)

Tthiazolidinediones

Weight gainHypoglycemia

Sulfonylureas

Meglitinides

Insulin

Ffixed-dose combinations may be considered to reduce burden

Important:

A1C does not have to be

above target to use this

algorithm

Important:

DC guidelines

include clear list of

practical, traditional

CV risk factors for

use in this context

(see next slide)

Diabetes Canada Guideline Update 2020

13*Initiated only if eGFR >30 mL/min/1.73m2

Adapted from Diabetes Canada Clinical Practice Guidelines Expert Committee. Can J Diabetes 2020; 44:575−91.

Age >60 with ≥2 CV risk factors

ADD or SUBSTITUTE AHA with demonstrated cardiorenal benefits

Risk Factors

>60 yrs with CV risk factors†

Low

er R

isks

Ob

serv

ed in

O

utc

om

e Tr

ials

MACE

HHF

Progression of Nephropathy

Highest level of evidence: Grade A Grade B Grade C or D

GLP1-RA

SGLT2i*

SGLT2i*

CV risk factors• Smoking (tobacco use)• Hypertension

• Untreated BP ≥140/95 mmHg or

• Current antihypertensive therapy

• Dyslipidemia• Untreated LDL >3.4 mmol/L

OR HDL-C <1.0 mmol/L (men) or <1.3 mmol/L (women) OR triglycerides >2.3 mmol/L or

• Current lipid-lowering therapy• Central obesity

¶ In patients already initiated on therapy who meet the criterion of an eGFR < 30 mL/min/1.73 m2 with albuminuria >33.9 mg/mmol, therapy can be continued at 100 mg once daily.*Oral semaglutide PM indicates no dose adjustment for patients with renal impairment.Data from: Lipscombe L, et al. Can J Diabetes 2018;42(Suppl 1):S88-S103. Forxiga ® Product Monograph, Astra Zeneca Canada Inc. June 2020. Invokana ® Product Monograph, Janssen Canada Inc., May 2020. Jardiance ® Product Monograph. Boehringer Ingelheim (Canada) Ltd. April 2020. Ozempic® Product Monograph, Novo Nordisk Canada Inc. August 2020. Rybelsus®

Product Monograph, Novo Nordisk Canada Inc. March 2020.

Antihyperglycemic Agents and Renal Function

Use alternative agent Dose adjustment not requiredDose adjustment requiredCaution

CKD Stage

Acarbose

Dapagliflozin

Empagliflozin

Pioglitazone

Canagliflozin¶

Metformin

Linagliptin

Sitagliptin

Saxagliptin

Alogliptin

Exenatide

Liraglutide

Repaglinide

Gliclazide

Glyburide

Alpha-glucosidase

Inhibitors

Glimepiride

Biguanides

DPP-4

Inhibitors

SGLT2

Inhibitors

Insulin

Secretagogues

GLP-1

Receptor

Agonists

Insulins

RosiglitazoneThiazolidinediones

Dulaglutide

Exenatide QW

Lixisenatide

eGFR (mL/min/1.73 m2):

Semaglutide*

<15 15–29 30–44 ≥ 60

5 4 3b 1 or 2

25 100 mg daily

5050 mg daily25 mg daily

502.5 mg daily

500-1000 mg daily

50

50

Fluid retention

45-59

3a

30

45

15

15

30

30

30

15

30

30 60

60

60

60

60

60

30

15

6030 12.5 mg daily6.25 mg daily

60

30

45

30

30

3015

30

100 mg daily

30

Not recommended More intensive monitoring for glycemic and renal

biomarkers and signs and symptoms of renal dysfunction

60

16

Dapagliflozin

Empagliflozin

Canagliflozin¶

SGLT2

Inhibitors

25 100 mg daily 60

45

30

100 mg daily

30

60

Exenatide

Liraglutide

GLP-1

Receptor

Agonists

Dulaglutide

Exenatide QW

Lixisenatide

Semaglutide*

50

50

15

30

30

15

303015

Daily GLP-1RAs: Formulations & Administration

Prefilled multi-dose pen

(can deliver doses of 0.6, 1.2 or 1.8 mg)

Liraglutide (Victoza®)

1. Attach needle (not included

with device)

2. Dial dose

3. Inject

Note: pen priming required with

first dose

DAILY AGENTS

INJECTION STEPS:

Lixisenatide (Adlyxine™)

Prefilled multi-dose pen available in 10 µg/dose and 20 µg/dose

1. Attach needle (not included with device)

2. Pull injection button,

3. Inject; pen priming required with first dose

Note: pen priming required with first dose;

should be taken within 60 min before any meal

of the day

Oral Semaglutide(Rybelsus®)

ADMINISTRATION:

1. Take on an empty stomach at least 30

minutes before the first food, beverage or

other oral medications of the day.

2. Take with no more than half a glass of water

equivalent to 120 mL.

3. Swallow whole. Do not split, crush or chew.

3 mg, 7 mg and 14 mg tablets

GLP-1 RA = glucagon-like peptide receptor agonist1. Victoza® Product Monograph. Novo Nordisk Canada Inc. April 2020. 2. Adlyxine™ Product Monograph. Sanofi. May 2017 3. Rybelsus® Product Monograph. Novo Nordisk Canada Inc. March 2020 17

1. Uncap

2. Insert needle (included with device)

3. Set dose (if using multi-dose pen)

4. Inject

Note: does not require reconstitution

Prefilled single-dose pen (2 mg/dose)

Exenatide QW(Bydureon®)

Dulaglutide (Trulicity™)

Prefilled single-dose pen available in 0.75 and 1.5 mg

Semaglutide (Ozempic®)

Multidose pen (0.25 mg and 0.5 mg)Single-dose pen (1 mg)

1. Uncap and unlock

2. Inject

Note: does not require reconstitution

1. Attach needle (separate needle included)

2. Turn knob to click

3. Tap against palm 80 times or more

4. Inject

Note: requires reconstitution

GLP-1 RA = glucagon-like peptide receptor agonist1. Trulicity™ Product Monograph. Eli Lilly Canada, Inc. September 2020; 2. Bydureon® Product Monograph. AstraZeneca Canada Inc. January 2020.

3. Ozempic® Product Monograph. Novo Nordisk Canada Inc. August 202018

Weekly GLP-1RAs: Devices and Injection Steps

WEEKLY AGENTS

INJECTION STEPS:

Click on device/drug

for more information

GLP-1RAs: Dosing and TitrationGeneric Name Brand Name

MixingRequired

Dosing Titration Period Needles Included

Daily agents

Liraglutide Victoza® NoOD: 0.6 mg,

1.2 mg, 1.8 mg

0.6 mg x one week, increase to 1.2 mg after 1 week, then increase to 1.8 mg if

neededNo

Lixisenatide Adlyxine™ No OD: 10 µg, 20 µg 10 µg x 14 days, then 20 µg No

Semaglutide (Rybelsus®)Not applicable

(tablet)

OD: 3 mg, 7 mg and 14 mg

3 mg OD x 30 days, then increase to 7 mg OD; increase to 14 mg OD if additional

glycemic control needed after at least 30 days on 7 mg dose

Not applicable (tablet)

Weekly agents

Dulaglutide Trulicity™ NoQW: 0.75 mg,

1.5 mg0.75 mg then increase to 1.5 mg if needed Yes, part of device

Exenatide QW Bydureon® Yes QW: 2 mg None, only one dose Yes

Semaglutide Ozempic® NoQW: 0.25 mg, 0.5

mg, 1.0 mg

0.25 mg x 4 weeks, increase to 0.5 mg after 4 weeks, then increase to 1.0 mg if

neededYes

GLP-1 RA = glucagon-like peptide receptor agonist1. Adlyxine™ Product Monograph. Sanofi. May 2017 2. Bydureon® Product Monograph. AstraZeneca Canada Inc. January 2020. 3. Victoza® Product Monograph. Novo Nordisk Canada Inc. April 2020.

4. Trulicity™ Product Monograph. Eli Lilly Canada, Inc. September 2020; 5. Ozempic® Product Monograph. Novo Nordisk Canada Inc. August 2020. 6. Rybelsus® Product Monograph. Novo Nordisk

Canada Inc. March 2020.

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1. Injection site areas: abdomen, thigh, or upper arm

2. Show the patient the device, and have them complete

the first injection in the office

3. Rotate injection site with each injection, either within

the same area or in different areas of the body

Tips Regarding Injections

GLP-1RAs: Practical Considerations

If glucose reduction is less than expected once treatment has been initiated,

this could be due to improper injection. Review the injection technique with

the patient.*

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GLP-1 RA = glucagon-like peptide receptor agonistData from: Reid T. Clinical Diabetes 2013;31:148-157. FIT Forum for Injection Technique Canada. Recommendations for Best Practice in Injection

Technique 4th Edition. 2020. Available at: http://www.fit4diabetes.com/files/6816/0137/5707/Forum_for_Injection_Technique_Edition_4_2020.pdf Accessed October 13, 2020.

*Lapointe, G (Expert Opinion, Unpublished) 2020.

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SGLT2 available in Canada

• Empagliflozin 10mg, 25mg

• Dapagliflozin 5mg, 10mg

• Canagliflozin 100mg, 300 mg

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Diabetes management in older adults

• Diabetes is prevalent in adults > 65 years of age1.

• Older adults are susceptible to all the usual diabetes complications

• Age is an important contributor to major diabetes complications2.

• Older adults with diabetes comprise a very heterogeneous group

• Medical complexity

• Functional/cognitive status

• Individualized care is key!1. Defronzo RA. Diabetes 2009;58:773

2. LeRoith et al. JCEM 2019;104:1520

Moorhouse P, Rockwood K.

J R Coll Physicians Edinb 2012;42:333-340.

“Frailty is a medical condition of reduced function and health in older individuals”

Canadian Frailty Network

2018 Diabetes Canada CPG – Chapter 8. Targets for Glycemic Control

A1C Targets

≤6.5Adults with type 2 diabetes to reduce the risk of CKD

and retinopathy if at low risk of hypoglycemia

Avoid higher A1C to minimize risk of symptomatic hyperglycemia and acute and

chronic complications

≤7.0 MOST ADULTS WITH TYPE 1 OR TYPE 2 DIABETES

7.1

8.5

7.1-8.0%: Functionally dependent*

7.1-8.5%:

• Recurrent severe hypoglycemia and/or hypoglycemia

unawareness

• Limited life expectancy

• Frail elderly and/or with dementia**

* Based on class of antihyperglycemic medication(s) utilized and person’s characteristics

** see Diabetes in Older People chapter

A1C measurement not recommended. Avoid symptomatic

hyperglycemia and any hypoglycemiaEnd of life

2018

Glycemic targets in older people with diabetes

Status Functionally independent

Functionally dependent

Frail and/or with dementia

End of life

Clinical Frailty Index*

1-3 4-5 6-8 9

A1C targetLow risk hypoglycemia (ie. therapy does not include insulin or SU)

≤7.0% <8.0% <8.5% A1C measurement

not recommended.

Avoid symptomatic

hyperglycemia or any

hypoglycemia

A1C targetHigher risk hypoglycemia (ie. therapy includes insulin or SU)

7.1-8.0% 7.1-8.5%

CBGM Preprandial:Postprandial:

4-7 mmol/L5-10 mmol/L

5-8 mmol/L<12 mmol/L

6-9 mmol/L<14 mmol/L

Individualized

* See slide 5. CBGM = capillary blood glucose monitoring

Guideline recommendations for key clinical outcomes for older people with diabetes from Diabetes Canada (DC), American Diabetes Association (ADA) and International Diabetes Federation (IDF)

Measure ADA DC IDF

A1C Healthy:<7.5%

Complex/Intermediate:<8.0%

Very Complex/Poor Health:<8.5%

Functionally Independent: < 7.0%Functionally Dependent: 7.1-8.0%Frail and/or Dementia:7.1-8.5%End of Life: A1C measurement not recommended. Avoid symptomatic hyperglycemia and any hypoglycemia.

Functionally Independent: 7.0-7.5%Functionally Dependent: 7.0-8.0%Sub-level Frail: <8.5%Sub-level Dementia: <8.5%End of Life: avoid symptomatic hyperglycemia

Blood Pressure Healthy: <140/80 mmHg

Complex/Intermediate: <140/80 mmHg

Very Complex/Poor Health: <150/90 mmHg

Functionally independent with life expectancy > 10 yrs: <130/80 mmHg

Functionally dependent, orthostasis or limited life expectancy: individualize BP targets

Functionally Independent: <140/90 mmHgFunctionally Dependent: <140/90 mmHgSub-level Frail: <150/90 mmHgSub-level Dementia: <140/90 mmHgEnd of Life: strict BP control may not be necessary

LDL-C <1.8 mmol/L <2.0 mmol/L <2.0 mmol/L and adjusted based on CV risk

29

Cardiovascular trials in diabetes using SGLT2I and GLP1RA

Karagiannis et al. Diabetes Res and Clin Practice 2021; 174

30

SGLT2 use in older adults

• No difference in results for patients < 65 or > 65 for 3point MACE, all cause mortality, cvs death, and composite renal end point

Karagiannis et al. Diabetes Res and Clin Practice 2021; 174

Efficacy of SGLT2I in older adults with DM2

• Similar hba1c lowering ability in patients , 65 as > 65

• Similar weight loss for patients < 65 and > 65, and > 75

1. Karagiannis et al. Diabetes Res and Clin Practice 2021; 174

32

SGLT2 safety in older adults

• No increased risk of hypoglycemia when used in combination with insulin/su in patients < 65 vs. > 65

• Adjust therapy to minimize hypoglycemia risk

• No increased risk in Genitourinary tract infections in patients < 65, > 65 or > 75

• No increased risk of DKA < 65 vs > 65

• May see an increased risk of volume depletion in > 65 and on loop diureticsCustodio et al., Drugs and Aging 2020;37:399

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GLP 1 R Agonist use in older adults

Karagiannis et al. Diabetes Res and Clin Practice 2021; 174

34

GLP 1 R Agonist use in older adults

• Similar efficacy and safety profile for patients < 65 and > 65 years old

• Common side effects: nausea, vomiting, diarrhea• Start low and go slow

• Consider reducing metformin dose

• Watch out for dehydration (acute renal failure)

• Increased risk of hypoglycemia when combined with SU or insulin• Must adjust background therapy

Karagannis et al. Diabetes Res and Clin Practice 2021; 174

Hypoglycemia in the elderly

• Older adults are at higher risk of hypoglycemia

• Many need insulin therapy due to insulin deficiency

• CKD

• Cognitive impairment

• Varied appetite

36

Insulin use in older adults

• Single long acting insulin analogues reduce variability and hypoglycemia• Insulin glargine U300 (Toujeo)

• Insulin degludec (Tresiba) U100 and U200

• Flash glucose monitoring• Libre 2 – added alarms for hypo and hyperglycemia

37

Case 1

• 70 yo female Hba1c 7%, lives independently

• PMHx: CVA, HTN, DM2x 25 years, BMI 30

• GFR 45

• Current medications:

• sitagliptin/metformin xr 50/1000 once daily

• Ramipril 10mg, Atorvastatin 20mg, ASA 81mg

38

Case 2

• 69 yo male DM2 x 20 years, Hba1c 7.8%, lives independently

• PMHx: HTN, dyslipidemia, gout, obesity (BMI 35)

• GFR 50

• Current medications:

• Sitagliptin/metformin 50/1000 bid, dapagliflozin 10mg

• Perindopril 8mg, atorvastatin 40mg,

39

Case 3• 80 yo female, HbA1C 9.5%, nursing home resident

• PMHx: DM2 x 40 years, Dementia, HTN

• GFR 35

• Current medications:

• sitagliptin/metformin 50/1000 1 tab bid, diamicron mr 60mg 1 tab bid, Lantus 20u qhs

• Atorvastatin 10mg, ramipril 2.5 mg

45

Summary

• CVS protection should guide choice of antihyperglycemic agent• GLP 1 RA and SLGT 2 should be part of regimen for all patients with ASCVS, HF,

CKD or CVS risk.

• Glp1RA and SGLT2 show similar CVS protection in patients over 65 as in patients younger than 65

• Data suggests same effect for patients of 75, but this group remains under-represented in clinical trials.

• Individualization of care is important particularly in the older adults with diabetes.