the contemporary management of type 2 diabetes · 2020. 10. 13. · ppg, postprandial glucose. if...

The Contemporary Management of Type 2 Diabetes

Focus on the Evolving Role of GLP-1 Receptor Agonists: A Town Hall

This educational activity is sponsored by Postgraduate Healthcare Education, LLC and is supported by an

educational grant from NovoNordisk.

Faculty

Joshua J. Neumiller, PharmD, CDCES, FASCP, FADCES

Vice Chair & Allen I. White Distinguished Associate Professor, PharmacotherapyWashington State UniversitySpokane, WA

Dr. Neumiller is Vice Chair and the Allen I. White Distinguished Associate Professor in the Department of Pharmacotherapy at Washington State University. He is a Certified Diabetes Care and Education Specialist (CDCES), a Fellow of the Association for Diabetes Care and Education Specialists (ADCES), a Fellow of the American Society of Consultant Pharmacists, and a member of the WSU Geriatrics Team. Josh is a contributing author for the American Diabetes Association (ADA) books Medications for the Treatment of Diabetes and Practical Insulin. Josh recently served as Chairman of the ADA’s Professional Practice Committee, whose primary responsibility is revising the ADA Standards of Medical Care in Diabetes each year. Josh was awarded with the 2016 Albert B. Prescott Pharmacy Leadership Award and was named the 2021 ADCES Diabetes Educator of the Year for his work in diabetes care.

Faculty

Jennifer Trujillo, PharmD, FCCP, BCPS, CDCES, BC-ADM

Professor, Department of Clinical PharmacySkaggs School of Pharmacy and Pharmaceutical SciencesUniversity of Colorado Anschutz Medical CampusAurora, CO

Dr. Trujillo is a professor at the University of Colorado Skaggs School ofPharmacy and Pharmaceutical Sciences in Aurora, Colorado. She received herDoctor of Pharmacy at the University of Arizona and completed her pharmacy practice residency at Boston Medical Center. Dr. Trujillo currently practices as a clinical pharmacist and Certified Diabetes Care and Education Specialist at the UCHealth Diabetes and Endocrinology Clinic on the University of Colorado Anschutz Medical Campus. She is an active member of the American Diabetes Association’s Primary Care Advisory Group and “Diabetes Is Primary” program planning committee. She has published several book chapters and has authored more than 50 peer-reviewed journal articles in the field of diabetes.

Faculty

Heather P. Whitley, PharmD, BCPS, CDCES

Clinical Professor, Pharmacy Practice Auburn University Harrison School of Pharmacy Auburn, AL

Dr. Whitley is a Clinical Professor of Pharmacy Practice at Auburn UniversityHarrison School of Pharmacy. She earned her Doctor of Pharmacy degree from the Medical University of South Carolina and completed ASHP-accredited residency programs in Pharmacy Practice and Primary Care. She is also a Board Certified Pharmacotherapy Specialist (BCPS) and a Certified Diabetes Care and Education Specialist (CDCES). She has practiced in multiple locations in Alabama as a Clinical Pharmacy Diabetes Specialist, including family medicine practices in the rural Black Belt, FQHC facilities, and, since 2014, a family medicine residency program in Montgomery, Alabama. She has published nearly 40 manuscripts and presented in national and international arenas predominantly on her diabetes-related research.

Disclosures

Dr. Neumiller has disclosed that he has served as a consultant for Novo Nordisk.

Dr. Trujillo has disclosed that she has served as a consultant for Sanofi.

Dr. Whitley has disclosed that she has no actual or potential conflict of interest in relation to this program.

The clinical reviewer, Cynthia Moreau, PharmD, BCACP has disclosed that she has no actual or potential conflict of interest in relation to this program.

Susanne Batesko, RN, BSN, Robin Soboti, RPh, and Susan R. Grady, MSN, RN-BC, as well as the planners, managers, and other individuals, not previously disclosed, who are in a position to control the content of Postgraduate Healthcare Education (PHE) continuing education (CE) activities hereby state that they have no relevant conflicts of interest and no financial relationships or relationships to products or devices during the past 12 months to disclose in relation to this activity. PHE is committed to providing participants with a quality learning experience and to improve clinical outcomes without promoting the financial interests of a proprietary business.

Accreditation

Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

UAN: 0430-0000-20-101-H01-PCredits: 1.25 hour (0.125 CEU)Type of Activity: Application

• Explain the rationale for guideline recommendations on the use of GLP-1 receptor agonists in patients with type 2 diabetes

• Compare dosing, administration, clinical effects, and tolerability of currently available GLP-1 receptor agonists

• Discuss recent cardiovascular outcome trial (CVOT) findings with GLP-1 receptor agonists and implications in clinical practice

Learning Objectives

Part 1: Review of Current Guideline Recommendations for GLP-1 RA Use

Joshua J. Neumiller, PharmD, CDCES, FASCP, FADCES

Vice Chair & Allen I. White Distinguished Associate Professor, PharmacotherapyWashington State UniversitySpokane, WA

• “When do current guidelines recommend use of GLP-1 RAs?”

• “Should GLP-1 RAs be started for CV risk reduction in people with a ‘good’ A1C?”

• “How do you choose between an SGLT-2 inhibitor and a GLP-1 RA for CV risk reduction?”

• “What are the most important safety considerations when starting a GLP-1 RA?”

• “Which GLP-1 RA is best?”

• “How does oral semaglutide compare to injectable semaglutide?”

• “Which GLP-1 RA is best to provide CV protection?”

• “How long do patients need to be on a GLP-1 RA to gain CV benefit?”

Common Questions Received

Glucose-Lowering Medication Use in Type 2 Diabetes (T2D)

First line: Metformin + comprehensive lifestyle intervention (weight management & physical activity)

Preferably:• GLP-1 RA with

proven CVD benefit1

OR• SGLT-2 inhibitor

with proven CVD benefit,1 if eGFR adequate

If A1C above individualized target proceed as belowConsider independently of baseline A1C or individualized A1C target

Compelling need to minimize hypoglycemia:• DPP-4 inhibitor OR• GLP-1 RA OR• SGLT-2 inhibitor OR• TZD

Compelling need to minimize weight gain or promote weight loss:• GLP-1 RA with good

efficacy for weight loss3 OR

• SGLT-2 inhibitor

Cost a major issue:• Sulfonylurea OR• TZD

1 Proven CVD benefit = drug has a label indication for reducing CVD events2 Empagliflozin, canagliflozin and dapagliflozin have shown reduction in HF

and reduce CKD progression in CVOTs. Canagliflozin has primary renal outcome data from CREDENCE. Dapagliflozin has primary heart failure outcome from DAPA-HF.

3 semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide

Indicators of high-risk or established ASCVD, CKD, or HF?

NO

YES

• Established ASCVD

• Indicators of high ASCVD risk

• Particularly HFrEF(LVEF <45%)

• CKD: Specifically eGFR 30-60 mL/min or UACR >30 mg/g, particularly UACR >300 mg/g

Preferably:• SGLT-2 inhibitor with evidence of HF and/or

CKD benefit2

OR• If SGLT-2 not tolerated, contraindicated, or if

eGFR is less than adequate, add a GLP-1 RA with proven CVD benefit

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Preferably:• GLP-1 RA with proven CVD benefit1

OR• SGLT-2 inhibitor with proven CVD benefit,1 if eGFR adequate

Consider independently of baseline A1C or individualized A1C target


YES

• Established ASCVD

• Indicators of high ASCVD risk

• Particularly HFrEF(LVEF <45%)

• CKD: Specifically eGFR 30-60 mL/min or UACR >30 mg/g, particularly UACR >300 mg/g

Preferably:• SGLT-2 inhibitor with evidence of HF and/or CKD benefit2

OR• If SGLT-2 not tolerated, contraindicated or if eGFR is less than adequate, add a GLP-1 RA with proven CVD benefit

Key Change in 2020:

• For patients with indicators of high-risk or established ASCVD, CKD, or HF – use of agents with established evidence for risk reduction should be considered independently of current A1C and/or A1C target

American Diabetes Association. Diabetes Care. 2020;43(Suppl. 1):S98-110.

Glucose-Lowering Medication Use in T2D

If A1C above individualized target proceed as below

Compelling need to minimize hypoglycemia:• DPP-4 inhibitor OR• GLP-1 RA OR• SGLT-2 inhibitor OR• TZD

Compelling need to minimize weight gain or promote weight loss:• GLP-1 RA with good efficacy for weight loss3 OR

• SGLT-2 inhibitor

Cost a major issue:• Sulfonylurea OR• TZD


NO

In patients without indicators of high-risk or established ASCVD, CKD, or HF, GLP-1 RAs are recommended in patients requiring glucose lowering to minimize hypoglycemia and minimize weight gain/ promote weight loss


Glucose-Lowering Medication Use in T2D

Use of Injectable Glucose-Lowering Agents in T2D


FPG, fasting plasma glucose; PPG, postprandial glucose.

If injectable therapy is needed to reduce A1C

Consider GLP-1 RA in most patients prior to insulin

If A1C above target

Add basal insulin(basal analog or bedtime NPH)

If already on GLP-1 RA or if GLP-1 RA not appropriate OR insulin preferred

If A1C above targetDespite adequately titrated basal analog or

bedtime NPH OR once basal dose >0.5 IU/kg OR FPG at target

If on bedtime NPH, consider converting to a twice-daily NPH regimen

Add prandial insulinUsually one dose with the largest meal or

meal with greatest PPG excursion

If A1C above target

If A1C above target

Consider twice-daily premix insulin regimen

Consider self-mixed/ split insulin regimen

Stepwise additional injections of prandial

insulin

Proceed to full basal-bolus regimen

Use of Injectable Glucose-Lowering Agents in T2D

If injectable therapy is needed to reduce A1C

Consider GLP-1 RA in most patients prior to insulin

If A1C above target

Add basal insulin(basal analog or bedtime NPH)

If already on GLP-1 RA or if GLP-1 RA not appropriate OR insulin preferred

9.10 In patients with T2D who need greater glucose lowering than can be obtained with oral agents, GLP-1 RAs are preferred to insulin when possible. B


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Patient is >18 years old with T2D and ≥1 of the following:ASCVD, HF, DKD, at high risk for ASCVD

Address concurrently

Optimize guideline-directed medical therapy for prevention (lifestyle, BP, lipids, glucose, antiplatelet therapy)

Recommend starting SGLT-2 inhibitor or GLP-1 RA with proven CV benefit

depending on patient-specific factors

Discuss patient-clinician preferences and priorities

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2020 American College of Cardiology (ACC) Expert Consensus Decision Pathway

Reassess and consider addition of the other class if benefits outweigh risks

2020 ACC Expert Consensus Decision Pathway

Preference/priority Consider using a GLP-1 RA first when patient and clinician priorities include:

Consider using an SGLT-2 inhibitor first when patient and clinician priorities include:

MACE prevention +++ +++

HF prevention +++

Weight loss +++ +

CKD risk reduction + +++

Route of administration Subcutaneous (most) Oral

Considerations that may prompt use of another class

• Persistent nausea• History of gastroparesis• Active gallbladder disease• History of MEN2 or medullary thyroid cancer• History of proliferative retinopathy (caution

with semaglutide or dulaglutide)• Considering pregnancy• Breastfeeding

• Severely reduced kidney function• History of prior amputation, severe PAD, neuropathy, or

active foot ulcers (caution with canagliflozin)• History of recurrent genital candidiasis• History of diabetic ketoacidosis• History of fracture (caution with canagliflozin)• Considering pregnancy• Breastfeeding

MACE, major adverse cardiovascular event; MEN2, multiple endocrine neoplasia type 2; PAD, peripheral arterial disease. Das SR, et al. J Am Coll Cardiol. 2020;76(9):1117-45.

Considering Oral Therapies in Combination with Injectable Therapies

Davies MJ, et al. Diabetes Care. 2018;41(12):2669-701.DKA, diabetic ketoacidosis; DPP-4i, dipeptidyl peptidase 4 inhibitor; SU, sulfonylurea.

• GLP-1 RAs are given high priority in current clinical practice recommendations for improvement of glycemic control, weight loss, and reduction of CV risk

• When using a GLP-1 RA for CV risk reduction, consideration of use is recommended irrespective of A1C

• The ADA recommends that GLP-1 RAs be considered as the first glucose-lowering injectable agent in most people with T2D

• Major cardiology organizations, such as the ACC and others, are also recommending use of GLP-1 RAs and SGLT-2 inhibitors for CV risk reduction in appropriate, high-risk individuals

Key Summary Points

ADA, American Diabetes Association.

Part 1Questions & Answers

Part 2: Review of Current GLP-1 RA Products

Jennifer Trujillo, PharmD, FCCP, BCPS, CDCES, BC-ADM

Professor, Department of Clinical PharmacySkaggs School of Pharmacy and Pharmaceutical SciencesUniversity of Colorado Anschutz Medical CampusAurora, CO

GLP-1 RAs: Actions on Target Tissues

↓Glucose ↓Weight

• ↓Gastric emptying

Stomach

• ↑Satiety

Brain

GLP-1

Inactive GLP-1

DPP-4

t1/2 = 1–2 min

Food

Gut

• ↑Glucose-dependent insulin secretion

• ↓Glucose-dependent glucagon secretionPancreas

Comparison of GLP-1 RAs

Short-acting Long-acting

Exenatide (Byetta)

Lixisenatide(Adlyxin)

Liraglutide (Victoza)

Exenatide XR (Bydureon)

Dulaglutide(Trulicity)

Semaglutide(Ozempic)

Oral semaglutide(Rybelsus)

Base Exendin-4 Exendin-4 Human GLP Exendin-4 Human GLP Human GLP Human GLP

Homology to native GLP-1

53% 50% 97% 53% 90% 94% 94%

Glucose profile target

PPG PPG FPG/PPG FPG > PPG FPG > PPG FPG > PPG FPG > PPG

Antidrugantibodies

44% 70% 8.6% 42.2% 1.6% 1.0% 1.0%

Comparison of Phase 3 Studies of GLP-1 RAs

Exenatide (Byetta)




Dulaglutide (Trulicity)


Oralsemaglutide(Rybelsus)

Phase 3 clinical trial

AMIGO GetGoal LEAD DURATION AWARD SUSTAIN PIONEER

Backgroundtherapy

Drug naïve,metformin,

SU


SU, TZD, basal insulin


SU, TZD


SU, TZD

Drug naïvemetformin,

SU, TZD,bolus insulin

Drug naïve, metformin,

SU, TZD; basal, bolus,

premixed insulin

Drug naïve, metformin,

SU, TZD,SGLT-2i;

basal, bolus, pre-mixed

insulin

A1C lowering (%)*

-0.4 to -1.1 -0.46 to -0.99 -0.84 to -1.5 -1.48 to -1.9 -0.71 to -1.64 -1.1 to -2.2 -0.6 to -1.4

Weightlowering (kg)

-0.3 to -2.8 +0.3 to -2.96 +0.3 to -3.24 -2.0 to -4.0 +0.2 to -3.03 -1.4 to -6.5 -1.2 to -4.4

*Includes all doses studied

Documented Safety Issues

Drug Phase 3 clinical program

Nausea (%)^ Vomiting (%)^ Diarrhea (%)^ Injection-site reactions (%)

Exenatide AMIGO 8–44* 4–18* 6–18* 5.1

Lixisenatide GetGoal 25 10 8 3.9

Liraglutide LEAD 18–20 6–9 10–12 2.0

Exenatide XR DURATION 8.2 3.4 4 23.9

Dulaglutide AWARD 12.4–21.1 6–12.7 8.9–12.6 0.5

Semaglutide SUSTAIN 15.8–20.3 5–9.2 8.8–8.9 0.2

Oral semaglutide PIONEER 11–20 6–8 9–10 N/A

^averages from phase 3 trials taken from prescribing information; ranges based on different doses, except for exenatide

*ranges based on reported data from separate studies based on background therapy

Trujillo JM. “Glucagon-Like Peptide-1 Receptor Agonists.” In: White JR, Ed. 2019 Guide to

Medications for the Treatment of Diabetes Mellitus. American Diabetes Association;2019:190-210.

A1C Weight GI adverse effects

Exenatide (Byetta) Low Low Highest

Lixisenatide (Adlyxin) Low Low Intermediate

Liraglutide (Victoza) High High Intermediate


Intermediate Low Low

Dulaglutide (Trulicity) High Intermediate Intermediate/high

Semaglutide (Ozempic) Highest Highest High

Oral semaglutide(Rybelsus)

High/highest Highest Intermediate/high

Summary of Head-to-Head Trials

GI, gastrointestinal.

Comparison of Injectable GLP-1 RAs Short-acting Long-acting

Exenatide (Byetta)




Dulaglutide(Trulicity)


Dose

5 mcg twice daily for 1 month;

increase to 10 mcg twice daily

10 mcg once daily x 14 days;

increase to 20 mcg daily

0.6 mg once daily x 1 week;

increase to 1.2 mg daily x 1

week; increase to 1.8 mg daily

2 mg once weekly

0.75 mg once weekly; increase

to 1.5 mg; can increase to 3 mg

and 4.5 mg ifneeded, each after 4 weeks

0.25 mg once weekly x 4

weeks; increase to 0.5 mg x 4

weeks; increase to 1 mg once

weekly

Administration frequency

Twice daily Once daily Once daily Once weekly Once weekly Once weekly

Specificadministration requirements

Take within 60 minutes before

meals

Take within 60 minutes before morning meal

Take at same time each day

Take on same day each week

DeliveryMulti-use pen(2 strengths)

Multi-use pen(2 strengths)

Multi-use pen Single-use pen*Single-use pen (4 strengths)

Multi-use pen (2 pen options)

Renal dosing

CrCl <30 mL/min, not

recommended;CrCl 30–50

mL/min, use caution


recommendedNone


recommended;CrCl 30–50

mL/min, use caution

None None

*Requires reconstitution; 2 pen devices available (Bydureon and Bydureon BCise; both with different reconstitution and preparation requirements) CrCl, creatinine clearance.

• Take at least 30 minutes before the first food, beverage, or other oral medication of the day

• Take with no more than 4 ounces of plain water only

• Swallow tablets whole: do not crush or chew

• Start with 3 mg once daily for 30 days

• Increase to 7 mg once daily for 30 days

• Dose may be increased to 14 mg once daily if needed

Rybelsus (semaglutide) tablets [product information]. 2019.

Oral Semaglutide: Administration Requirements

Part 3: Review of CVOT Data with GLP-1 RAs

Heather P. Whitley, PharmD, BCPS, CDCES

Clinical Professor, Pharmacy Practice Auburn University Harrison School of Pharmacy Auburn, AL

GLP-1 RA Expanded FDA-Approved Cardiovascular Indications

Medication Expanded CV FDA indication

Liraglutide (Victoza) “…reduce the risk of major adverse CV eventsin adults with T2D and established CVD”

Semaglutide (Ozempic) “…to reduce the risk of major adverse CV eventsin adults with T2D and established CVD”

Semaglutide (Rybelsus) None

Exenatide XR (Bydureon, Bydureon BCise)

None

Dulaglutide (Trulicity) “…to reduce the risk of major adverse CV eventsin adults with T2D who have established CVD or multiple CV risk factors.”

Bydureon BCise [package insert]. 2020.; Ozempic [package insert]. 2020.; Rybelsus [package insert]. 2020.; Trulicity [package insert]. 2020.; Victoza [package insert]. 2020.

Overview of GLP-1 RA CVOTs

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2019;3

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121

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al; H

R, hazard

ratio.

Study identifierNo. of

patientsFollow-up

Time Study designPrimary

endpointResults

HR (95% CI)

ELIXA1

ACS <180 days; A1C 5.5%–11%

6,068 2.1 yLixisenatidePlacebo

4-pt MACE1.02 (0.89–1.17)

P<0.001 (non-inferiority)p=0.81 (superiority)

LEADER2

CV risk/CVD; A1C ≥7.0%

9,340 3.8 yLiraglutidePlacebo

3-pt MACE0.87 (0.78–0.97)

p=0.01 (superiority)

SUSTAIN 63

CVD; A1C ≥7.0%

3,297 2.1 ySemaglutide (SC)Placebo

3-pt MACE0.74 (0.58–0.95)


PIONEER 64

CVD or CKD 3,183 1.3 y

Semaglutide (PO)Placebo

3-pt MACE0.79 (0.57–1.11)

P<0.001 (non-inferiority)P=0.17 (superiority)

EXSCEL5

High CV risk/CVD; A1C 6.5%–10.0%

14,752 3.2 yExenatide XRPlacebo

3-pt MACE0.91 (0.83–1.00)

P<0.001 (non-inferiority)p=0.06 (superiority)

REWIND6

High CV risk; A1C ≤9.5%

9,901 5.4 yDulaglutidePlacebo

3-pt MACE0.88 (0.79–0.99)


Individual Components of 3-Pt MACE for GLP1-RA CVOTs

LEADER1

(liraglutide)

Hazard Ratio (95% CI)

SUSTAIN 62

(semaglutide SC)

PIONEER 63

(semaglutide PO)

EXSCEL4

(exenatide XR)

REWIND5

(dulaglutide)

1. Marso SP, et al. N Engl J Med. 2016;375(4):311-22.;2. Marso SP, et al. N Engl J Med.

2016;375(19):1834-44.; 3. Husain M, et al. N Engl J Med. 2019;381(9):841-51.; 4. Holman RR et

al. N Engl J Med 2017;377(13):1228-39.; 5. Gerstein HC, et al. Lancet. 2019;394(10193):121-30.

Implications for Practice

• Studies with long-acting GLP-1 demonstrated near consistent benefit for CV risk reduction for use in patients with T2D with and without ASCVD

• Considerations for product selection based on:• CV outcomes of interest

• Studied patient populations

• Additional benefits (A1C and weight reduction)

• ADE mitigation

• Route of administration

• Dose for CV risk reduction

ADE, adverse drug event.

Panel Discussion withQuestions & Answers

Thank You!

the contemporary management of type 2 diabetes · 2020. 10. 13. · ppg, postprandial glucose. if...

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