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Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals
GLP-1 Physiology and Evolving Clinical Data on GLP-1 Receptor Agonists for the Management of Type 2 Diabetes
Presented as a Live Webinar Tuesday, May 19, 2020 12:00 p.m. – 1:00 p.m. ET
On-demand Activity Recording of live webinar Available after May 23, 2020
This webinar is not accredited for continuing education.
FACULTY Curtis L. Triplitt, Pharm.D., CDCES Clinical Associate Professor, Medicine/Diabetes University of Texas Health Science Center at San Antonio Associate Director, Diabetes Research Texas Diabetes Institute, University Health System San Antonio, Texas
View faculty bio at https://www.ashpadvantage.com/t2d/glp1/
WEBINAR INFORMATION Visit https://www.ashpadvantage.com/t2d/glp1/ to find
• Webinar registration link• Group viewing information and technical requirements
Any referenced figures, tables and graphs are copyrighted works of their respective owners; used with permission.
ASHP Financial Relationship Disclosure Statement Planners, presenters, reviewers, ASHP staff, and others with an opportunity to control CE content are required to disclose relevant financial relationships with ACCME-defined commercial interests. All actual conflicts of interest have been resolved prior to the continuing education activity taking place. ASHP will disclose financial relationship information prior to the beginning of the activity. A relevant financial relationship is a defined as a financial relationship between an individual (or spouse/partner) in control of content and a commercial interest, in any amount, in the past 12 months, and products and/or services of the commercial interest (with which they have the financial relationship) are related to the continuing education activity. An ACCME-defined commercial interest is any entity producing, marketing re-selling, or distributing healthcare goods or services consumed by, or used on, patients. The ACCME does not consider providers of clinical serve directly to patients to be commercial interests—unless the provider of clinical service is owned, or controlled by, an ACCME-defined commercial interest.
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GLP‐1 Physiology and Evolving Clinical Data on GLP‐1 Receptor Agonists for the Management of Type 2 Diabetes
Curtis L. Triplitt, Pharm.D., CDCES
University of Texas Health Science Center at San AntonioTexas Diabetes Institute, University Health System
San Antonio, TexasProvided by ASHP Sponsored by AstraZeneca Pharmaceuticals
Curtis L. Triplitt ‐ Speakers bureau: AstraZeneca Pharmaceuticals; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novo Nordisk Inc.
All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant to this activity.
Disclosure of Relevant Financial Relationships
©2020 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Learning Objectives
At the conclusion of this educational activity, participants should be able to• Identify glucose homeostasis actions of GLP‐1 in T2D• Discuss potential CVD and renal benefits of GLP‐1 RAs fromCVOTs
• Differentiate recommended placement of GLP‐1 RA therapybased on comorbidities identified in national guidelines
GLP‐1=glucagon‐like peptide 1T2D=type 2 diabetesCVD=cardiovascular diseaseCVOTs=cardiovascular outcome trialsGLP‐1 RA=GLP‐1 receptor agonists
GLP‐1 Physiology and Evolving Clinical Data on GLP‐1 Receptor Agonists
• Content Overview– Brief Review of the Role of Incretins– Glucose Homeostasis and the Role of GLP‐1– GLP‐1 RA for the Treatment of Type 2 Diabetes
• Key Clinical Effects– GLP‐1 RA Actions Beyond A1C: Obesity Outcome Overview– GLP‐1 RA Actions Beyond A1C: Cardiovascular and Renal OutcomeOverview
– GLP‐1 RA to Maximize Effects on Body Weight
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Years
0
-15 -10 -5 0 5 10 15 20 25 30
200
150
100
50
250
Insulin resistance
Insulin levelR
ela
tive
Am
ou
nt
β-cell function
Incretin effect
Diagnoseddiabetes
Diabetes Onset
350
300
250
200
150
100
Postmeal glucose
Fasting glucose
Glu
co
se
(m
g/d
L)
50
Diabetes Is a Chronic and Progressive Disease1,2
*By the time diabetes is clinically diagnosed, β‐cell function may be reduced by ≥50%; subjects in the upper tertile of impaired glucose tolerance (IGT) are near‐maximally insulin resistant and have lost more than 80% of their β‐cell function1‐3Representative depiction of the natural progression of type 2 diabetes (time course and function)11. Adapted with permission (pending) from Kendall DM et al. Am J Med. 2009;122:S37‐S50; 2. Defronzo RA Diabetes. 2009; 58:773‐95;3. Holman RR. Diab Res Clin Prac. 1998;40(suppl):S21‐S25.
Pre Diabetes
50%–80% loss of β-cell function at diagnosis*
The Incretin Effect • Oral glucoseadministration isassociated with a greaterincrease in plasma insulinlevels than a similaramount of glucose givenintravenously1
• This phenomenon hasbeen dubbed the incretineffect, and accounts forapproximately 50%–70%of the total insulinsecreted after oralglucose administration1
*P≤0.05 between the oral glucose load and IV glucose loadIR=immunoreactive; IV=intravenous1.Baggio LL et al. Gastroenterology. 2007;132:2131‐57; 2.Nauck MA et al. J Clin Endocrinol Metab. 1986;63:492‐8.
Oral glucose load (50 g/400 mL)
IV glucose load (isoglycemic IV infusion)
180
0
100
200
Ven
ou
s P
lasm
a G
luco
se
(mg
/dL
)
Time (min)2
01 60 12002
IR In
suli
n (
mm
ol/
L)
Time (min)2
0102 60 120 180
0.0
0.2
0.4
0.6
0.8
*
**
** *
Incretin Effect2Incretin Effect2
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
General Characteristics of Incretin Hormones:GLP‐1 and GIP
GLP=glucagon‐like peptide; GIP=glucose‐dependent insulinotropic polypeptide or gastric inhibitory polypeptide; DPP=dipeptidyl peptidase1. Nauck MA. Eur J Intern Med. 2009;20:S303‐S308; 2. Kim W et al. Pharmacol Rev. 2008;60:470‐512.
GLP-11 GIP1
Structure 30 amino acids2 42 amino acids2
Source L-cells (distal jejunum, ileum, and colon)
K-cells (proximal small intestine)
Stimulus Glucose, fat, and neural inputs
Glucose and fat
Primary actionsGlucose-stimulated insulin secretion
Insulin biosynthesis β-cell proliferation Inhibition of β-cell apoptosis Fat metabolism in adipocytes Inhibition of glucagon Delay gastric emptying Satiety β-cell neogenesis
Metabolism DPP-4 DPP-4Half-life <2 min 5–7 minDefect in type 2 diabetes Reduced levels Reduced sensitivity
Common Actions
Distinct Actions of GLP-1
Glucose Homeostasis and the Role of GLP‐1
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Plasma Glucose
Hepatic Glucose Production Renal Glucose Production
and Reabsorption
Fasting State
Increase Decrease
Regulation of Glucose Homeostasis1,2
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐90; 2. Gerich JE. Diabet Med. 2010;27:136‐42.
Plasma Glucose
Food Intake
Gastric Emptying
Hepatic Glucose Production Renal Glucose Production
and Reabsorption
Fed State
Increase Decrease
Regulation of Glucose Homeostasis1,2
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐190. 2. Gerich JE. Diabet Med. 2010;27:136‐42.
©2020 American Society of Health-System Pharmacists, Inc. All rights reserved.
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Plasma Glucose
Food Intake
Gastric Emptying
Increase Decrease
Glucose Appearance
Key Hormones in the Regulation of Glucose Homeostasis1‐3
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐90;2. Gerich JE. Diabet Med. 2010;27:136‐42; 3. Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. 2007;132:2131‐57.
βα
GIP
GLP-1
Insulin
Plasma Glucose
Food Intake
Gastric Emptying
Increase Decrease
Glucose Appearance
GLP-1
Glucose Disappearance
Tissuesβα
Key Hormones in the Regulation of Glucose Homeostasis1‐3
GIP
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐90;2. Gerich JE. Diabet Med. 2010;27:136‐42; 3. Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. 2007;132:2131‐57.
©2020 American Society of Health-System Pharmacists, Inc. All rights reserved.
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Insulin
Plasma Glucose
Amylin
Food Intake
Gastric Emptying
Increase Decrease
GLP-1
Tissues
Glucose Disappearance
βα
Key Hormones in the Regulation of Glucose Homeostasis1‐3
GIP
Glucose Appearance
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐90;2. Gerich JE. Diabet Med. 2010;27:136‐42; 3. Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. 2007;132:2131‐57.
InsulinAmylin
Food Intake
Gastric Emptying
Glucagon
Increase Decrease
GLP-1
Plasma Glucose
Glucose Appearance
Tissuesβα
Key Hormones in the Regulation of Glucose Homeostasis1‐3
GIP
Glucose Disappearance
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐90;2. Gerich JE. Diabet Med. 2010;27:136‐42; 3. Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. 2007;132:2131‐57.
©2020 American Society of Health-System Pharmacists, Inc. All rights reserved.
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Amylin
Food Intake
Gastric Emptying
α
Glucagon
Leptin
Increase Decrease
Plasma Glucose
Glucose Appearance
Tissuesβα
Key Hormones in the Regulation of Glucose Homeostasis1‐3
1. Aronoff SL et al. Diabetes Spectr. 2004;17:183‐90; 2. Gerich JE. Diabet Med. 2010;27:136‐42; 3. Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. 2007;132:2131‐57; 4. Sadry SA et al. Nat Rev Endocrinol. 2013;9:425‐33.
GIP
GLP-1Insulin
Glucose Disappearance
Brain
Heart
Summary of Key Physiologic Actions of GLP‐1
GI=gastrointestinal; *GLP‐1 actions on liver and muscle are indirect.Drucker DJ. Cell Metab. 2006;3:153‐65.
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Insulin secretion
Glucagon secretion
Gastric emptying
Appetite
Cardioprotection
Cardiac output
Insulin biosynthesis
β-cell proliferation
β-cell apoptosis
Neuroprotection
Glucose production
Insulin sensitivity
GLP-1Pancreas
Stomach
GI tract
Muscle*
Liver*
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Summary: GLP‐1 Physiology
• Type 2 diabetes is a progressive disease associated with worsening β‐celldysfunction, increases in insulin resistance, and resultant hyperglycemia1
• Research conducted in the 1980s demonstrated an impaired “incretineffect” in individuals with type 2 diabetes2
• The widespread physiologic actions of incretin hormones, GIP and GLP‐1,occur in the pancreas, stomach, brain, bone, adipose tissue, liver, muscle,cardiovascular system, and central nervous system3
• Though the basic physiology of GLP‐1 effects are known, there is muchmore to learn
1. Kendall DM et al. Am J Med. 2009;122:S37‐S50; 2. Mudaliar S et al. Diabetologia. 2012;55:1865‐8;3. Baggio LL et al. Gastroenterology. 2007;132:2131‐57.
A key action of GLP‐1 is to
a. Increase glucagon secretionb. Increase insulin secretionc. Decrease GIP secretiond. Decrease DPP‐4 secretion
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
GLP‐1 Receptor Agonists for the Treatment of Type 2 Diabetes
GLP‐1 Receptor AgonismModulates Numerous Functions in Humans
1. Stonehouse A et al. Curr Diabetes Rev. 2008;4:101‐9; 2. Nielsen LL et al. Regul Pept. 2004;117:77‐88;3. Kolterman OG et al. J Clin Endocrinol Metab. 2003;88:3082‐3089; 4. Fehse F et al. J Clin Endocrinol Metab. 2005;90:5991‐5997.
GLP-1 Receptor Agonism1-4
Decreases food intake1,2
Slows gastricemptying1-3
Improves first-phase insulin response1,4
Suppresses glucagon secretion, decreasing glucose output1-3
Stimulates glucose-dependent insulin secretion1-4
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Continuously Infused GLP‐1 Nearly Normalized Blood Glucose in Patients With T2D
Healthy subjects, n = 6; patients with T2D, n = 7; mean data Rachman J et al. Diabetologia. 1997;40:205‐11.
0
100
200
300
SnackLunchBreakfast
Glu
cose
(m
g/d
L)
Continuous GLP-1 Infusion
T2D: Saline
Healthy subjects
T2D: Exogenous GLP-1
Time of Day (h)
12 AM 4 AM 8 AM 12 PM 4 PM
GLP‐1 Receptor Agonists for T2D
• GLP‐1 RAs are given subcutaneouslyor orally and bind to the nativeGLP‐1 receptor, and have similaractions as GLP‐1
• Indications:– In addition to diet/exercise to improve
glycemic control in patients with T2D1‐8
– To reduce MACE in patients with T2Dand established CVD (liraglutide5 andsemaglutide8) or in patients withmultiple cardiovascular risk factors(dulaglutide7)
MACE= major adverse cardiovascular events; MTC=medullary thyroid carcinoma1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI] Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020.
• These products differ in– Base molecule: exenatide or analog of
human GLP‐1– Half‐life of drug and frequency of dosing– Type of injection device
• Broadly speaking they can be groupedinto 2 groups– Intermittent GLP‐1 RAs1,4: No boxed
warning on MTC– Long‐acting GLP‐1 RAs2,3,5‐9: Boxed warning
on MTC in humans due to uncertainrelevance of preclinical findings
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Cautions
• Acute pancreatitis history– Not recommended– Weigh pros and cons
• Acute renal injury (ARI)– Careful attention to GI sideeffects in renal insufficiency
– Nausea/vomiting can putpatient at risk of ARI
• Gastroparesis– All GLP‐1 RAs can worsen– Not recommended
• Acute gallbladder– May contribute(cholecystitis or cholelithiasis)
1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI] Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020.
WarningsRisk of Thyroid C‐Cell Tumors
• GLP‐1 RAs cause an increased incidence in thyroid C‐cell tumors at clinicallyrelevant exposures in rats and or mice compared to controls. It is unknownwhether GLP‐1 RAs cause thyroid C‐cell tumors, including medullary thyroidcarcinoma (MTC), in humans, as human relevance could not be determined byclinical or nonclinical studies.
• GLP‐1 RAs contraindications– Patients with a personal or family history of MTC– Patients with multiple endocrine neoplasia syndrome type 2 (MEN 2)
• Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain valuein patients treated with GLP‐1 Ras– Counsel patients regarding the risk and symptoms of thyroid tumors
1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI] Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI] Plainsboro, NJ: Novo Nordisk Inc.; 2020.
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Intermittent and Long‐acting GLP‐1 RA Key Actions
Fineman MS et al. Diabetes Obes Metab. 2012;14:675‐88; Drucker DJ et al. Lancet. 2008;372:1240‐50.
Type 2Defects
IntermittentLong-Acting
Glucose-dependent Insulin Secretion
Fasting Insulin concentrations
1st and 2nd phase Insulin Secretion(Postprandial Insulin Secretion)
Glucose-dependent Glucagon Secretion
Fasting Glucagon concentrations
Postprandial Glucagon concentrations
Gastric Emptying
Food Intake
Exenatide BID1 Lixisenatide4 Liraglutide5 Exenatide QW2 Dulaglutide7 Semaglutide8 Oral Semaglutide9
Homology to GLP-1
53% 52% 97% 53% 97% 94% 94%
Half-life 2-3 hours 3 hours 13 hours
2-3 hours for exenatide;
microspheres continuously
release
5 days 7 days 7 days
Typical dosing 5- 10 mcg BID 10-20mcg daily 1.2-1.8mg daily 2mg weekly 0.75-1.5mg weekly 0.5-1.0mg weekly 7 or 14mg daily
Renalelimination
Yes No No Yes No* No** No**
RenalDo not recommend
CrCl<30 ml/min
Do not recommend eGFR <15
ml/min/1.73m2
Use caution w/ renal impairment
Do not recommend eGFR <45
ml/min/1.73m2
Monitor w/ renal impairment
Monitor w/ renal impairment
Monitor w/ renal impairment
General Pharmacokinetic/PharmacodynamicCharacteristics of Marketed GLP‐1 RAs
1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE: GlaxoSmithKline LLC; 2014; 7. Dula [PI]. Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2020. *data not found. ** <5% in urine.
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
General Clinical Characteristics of Marketed GLP‐1 RAs
1. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 2. ExQW [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 3. ExQWs [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2019; 4. Lixi [PI]. Bridgewater, NJ: Sanofi, LLC; 2016; 5. Lira [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2019; 6. Albi [PI]. Wilmington DE:GlaxoSmithKline LLC; 2014; 7. Dula [PI]. Indianapolis, IN; Lilly USA, LLC; 2020; 8. Sema [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2020; 9. Oral sema [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2020.
Exenatide BID1 Lixisenatide4 Liraglutide5 Exenatide QW2Exenatide QWs Auto-Injector3
Dulaglutide7 Semaglutide8Oral
Semaglutide9
TrialProgram
AMIGO GetGoal LEAD DURATION DURATION-NEO AWARD SUSTAIN PIONEER
Baseline A1C
7.8 to 8.6% 7.6 to 8.5% 7.1 to 8.6% 8.3 to 9.3% 8.4 and 8.5% 7.6 to 8.6% 8.0 to 8.4% 8.0 to 8.4%
A1Creduction
-0.6 to -0.9% -0.6 to -0.9% -0.8 to -1.5% -0.9 to -1.6% -1.1% & -1.4% -0.7 to -1.6% -1.2 to -1.7% -0.9 to -1.4%
Baseline weight
85 to 101 kg 66 to 94 kg 80 to 95 kg 88 to 93 kg 89 and 97 kg 85 to 96 kg 89 to 97 kg 85 to 93 kg
Weight -1.1 to -2.9 kg 0.3 to -2.7 kg 0.3 to -3.2 kg -0.9 to -3.7 kg -1.4 kg 0.2 to -3.1 kg -3.2 to -6.0 kg -2.2 to -4.4 kg
Nausea 8 to 44% 25% 18 to 20% 9 to 27% 8.2% 12 to 21% 16 to 20% 11 to 20%
Diarrhea 6 to 18% 8% 10 to 12% 6 to 20% 4% 9 to 13% ~9% 9 to 10%
Vomiting 4 to 18% 10% 6 to 9% ~11% 3.4% 6 to 13% 5 to 9% 6 to 8%
Summary
• GLP‐1 RAs address many coreglycemic defects in patients withT2D– Low risk of hypoglycemia whenused without an SU or insulin
• GLP‐1 RAs differ in– Base molecule: exenatide or analogof human GLP‐1
– Half‐life of drug and frequency ofdosing
– Type of injection device
• Intermittent GLP‐1 RAs– A1C reductions of ‐0.6 to ~‐1.0%– Mainly PPG
• Long‐acting GLP‐1 RAs– A1C reductions of ~‐1.0 to ~‐1.7%– Mainly FPG; generally greaterweight loss than intermittentGLP‐1 RAs
• Generally well‐tolerated with GIAEs the most frequent andtitration important in managing
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Obesity Outcome Overview
GLP‐1 RA Actions Beyond A1C
Currently, which GLP‐1 RAs are approved for weight loss?
a. Dulaglutide and exenatideb. Liraglutide and semaglutidec. Semaglutide and exenatided. Liraglutidee. None are currently approved
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Rationale for Using GLP‐1 RAs for Obesity
• GLP‐1 RAs activate GLP‐1 receptors in the brain involved in appetiteregulation and calorie intake
• Higher concentrations of GLP‐1 RAs have demonstrated substantial weightloss
GLP‐1 RAs Evaluated for Weight Loss
• Liraglutide 3 mg daily is approved for the treatment of obesity1
• Dulaglutide 3 mg and 4.5 mg have been studied for patients with T2D whoare overweight or obese2
• Semaglutide 2.4 mg is being studied in overweight and obese patients3
1. Lira 3mg [PI]. Plainsboro, NJ: Novo Nordisk Inc., 2018; 2. ClinicalTrials.gov Identifier: NCT03495102;3. ClinicalTrials.gov Identifier: NCT03552757.
General Clinical Characteristics of Marketed GLP‐1 RAs
1. Lira 3mg [PI]. Plainsboro, NJ: Novo Nordisk Inc.; 2018.
Liraglutide 3 mg1
Trial Program Study 1 Study 2 Study 3
Criteria ObesityT2D with obesity or
overweightObesity or overweight after >5% weight loss with diet
Baseline weight 106.2 kg 105.7 kg 100 kg
% Weight loss from baseline at 1y -7.4% -5.4% -4.9%
% pts losing ≥5% body weight 62.3% 49% 44.2%
% pts losing ≥10% body weight 33.9% 22.4% 25.4%
waist circumference-8.2 cm
(pts w/o T2D)-6 cm
(pts with T2D)
Side effects
Nausea 39.3%
Diarrhea 20.9%
Constipation 19.4%
Vomiting 15.7%
Warnings
• Boxed Warning: Risk of thyroid c-cell tumors• Acute pancreatitis suspected then discontinue promptly• Increased heart rate• Acute gallbladder disease• Caution when initiating in patients with renal impairment• Suicidal behavior and ideation
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Cardiovascular and Renal Outcome Overview
GLP‐1 RA Actions Beyond A1C
ELIXA ─
LEADER ─
EXSCEL ─
HARMONY ─
REWIND ─
SUSTAIN 6 ─
PIONEER 6 ─
Overall ─
ELIXA (ixi)
LEADER (lira)
EXSCEL (ExQW)
HARMONY (albi)
REWIND (dula)
SUSTAIN 6 (sema)
PIONEER 6 (oral sema)
Overall
Hazard Ratio (95% CI)
Favors GLP-1 RA Favors Placebo
0.87 (0.80, 0.96)
GLP1 RA MACE Overview
Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847.
0.5 0.8 1 1.2 1.4
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
GLP1 RA MACE Overview: Established CVD or Multiple Risk Factors
Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847.
LEADER ─
EXSCEL ─
REWIND ─
SUSTAIN 6 ─
PIONEER 6 ─
Overall ─
LEADER (lira)
EXSCEL (ExQW)
REWIND (dula)
SUSTAIN 6 (sema)
PIONEER 6 (oral sema)
Overall
0.94 (0.83, 1.07)
LEADER ─
EXSCEL ─
REWIND ─
SUSTAIN 6 ─
PIONEER 6 ─
Overall ─
Established CVD
Multiple Risk Factors
0.86 (0.80, 0.92)
Hazard Ratio (95% CI)
Favors GLP-1 RA Favors Placebo
0.4 0.8 1.4 2 2.60.5 1.21
GLP‐1 RA Renal Composite Overview:(new‐onset macroalbuminuria, sustained doubling of serum creatinine, or a 40% decline eGFR, end‐stage kidney disease, or death of renal cause)
Adapted from Zelniker TA et al. Circulation. 2019;139:2022–31.
Hazard Ratio (95% CI)
Favors GLP-1 RA Favors Placebo
ELIXA ─
LEADER ─
SUSTAIN 6 ─
EXSCEL ─
Overall ─
0.4 0.8 1.40.5 1.210.6
ELIXA (ixi)
LEADER (lira)
SUSTAIN 6 (sema)
EXSCEL (ExQW)
Overall
0.82 (0.75, 0.89)
1.6
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
REWIND‐eGFR and Albuminuria Effects
Gerstain HC. Lancet. 2019;394:131‐8.
EstimatedGlomerular Filtration Rate
Urinary Albumin Creatinine Ratio(geometric mean)
Summary of MACE and Renal Composite Data in T2D1‐6
Long‐acting GLP‐1 RA class has demonstrated
• Reductions in MACE in patients with established CVD (~13%)• Reductions in renal composite endpoint (~18%)
– Mostly reduction in macroalbuminuria, (EXSCEL and REWIND demonstrated effects in reduction ofeGFR)
Liraglutide & Semaglutide are indicated to
• To reduce the risk of MACE in adults with type 2 diabetes and establishedcardiovascular disease
Dulaglutide
• To reduce the risk of MACE in adults with type 2 diabetes who have establishedcardiovascular disease or multiple cardiovascular risk factors
1. Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847; 2. Gerstein HC et al. Lancet. 2019;394(10193):121‐30; 3. ZelnikerTA et al. Circulation. 2019;139:2022–31; 4. Zelniker T et al. Lancet. 2019; 393(10166):31‐9; 5. Gerstein HC et al. Lancet. 2019;394(10193): 131‐8; 6. Bethel MA et al. Presented at: American Diabetes Association 78th Scientific Sessions; June 22‐26, 2018; Orlando, FL.
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
First-Line Therapy is MET + Lifestyle Mod (inc. Weight Management + Physical Activity)
Indicators of High-Risk or Established ASCVD, CKD, or HF
Consider Independently of Baseline A1C or Individualized A1C Target
ASCVD Predominates Heart Failure or CKD Predominates
GLP-1 RA with proven CVD benefit*or
SGLT2-i with evidence of reducing HF and/or CKD progression in CVOTs if eGFR adequate
SGLT2-i with proven CVD benefit* if eGFR adequate
GLP-1 RA with proven CVD benefit*if eGFR is less than adequate
(if SGLT2-i not tolerated)
If A1C above target If A1C above target
If intensification required or not tolerating GLP-1 RA and/or SGLT2-i, choose agents with CV safety:• Pts on GLP-1 RA, consider adding SGLT2-I*• DPP-4i if not on GLP-1 RA• Basal Insulin• TZD• SU
• Avoid TZD in setting of HFChoose agents demonstrating CV safety:• Pts on SGLT2-I, consider adding GLP1-RA*• DPP-4i (not saxa) in setting of HF (if not on a
GLP-1 RA)• Basal Insulin• SU
ADA 2020 Standards of Care
Antihyperglycemic Medication in T2D: Focus with ASCVD,
CKD, & HF
Adapted from ADA Standards of Care [web annotation]. Diabetes Care. 2020; 43(suppl 1):S1‐S212.*Label indication of reducing CVD events.
Without Established ASCVD, CKD, or Heart Failure
Need to Minimize HypoglycemiaCompelling Need to
Minimize Weight Gain or Promote Weight Loss
Cost is a Major Issue
SGLT2-i GLP-1 RA TZD DPP-4i SGLT2-iGLP-1 RA
(good efficacy for weight loss)
SU TZD
GLP-1 RA SGLT2-i SGLT2-i SGLT2-iGLP-1 RA
(good efficacy for weight loss)
SGLT2-i TZD SU
DPP-4i TZD DPP-4i TZD
TZD GLP-1 RA
If A1C is above target:Continue addition of agents as listed above
If A1C is still above target:Later gen SU or basal insulin (w/ low hypo risk)
If quadruple therapy required or SGLT2-i or GLP-1 RA not
tolerated then use regimen with lowest risk of weight gaina
Insulin therapy (basal insulin)
OrConsider DPP-4i or SGLT2-i
ADA 2020 Standards of Care
Antihyperglycemic Medication in T2D: Focus w/o ASCVD,
CKD or HF
Adapted from ADA Standards of Care [web annotation]. Diabetes Care. 2020; 43(suppl 1):S1‐S212. aDPP‐4I (if not on GLP‐1 RA based on weight neutrality; if DPP‐4I not tolerated or contraindicated or patient already on GLP‐1 RA, cautious addition of SU, TZD, or basal insulin.
A1C
above goal
A1C
above goal
A1C
above goal
A1C
above goal
A1C
above goal
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22
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Adapted from Garber AJ et al. Endocr Pract. 2020;26:107‐39.
Individualize Goals
A1C ≤6.5%Patients w/o concurrent serious illness and low hypo risk
A1C >6.5%Patients w/ concurrent serious illness and risk for hypo
Lifestyle Modifications and Ongoing Glucose Monitoring (CGM preferred)
Independent of Glycemic Control, if Established or High ASCVD Risk and/or CKDRecommend SGLT2-I and/or Long-Acting GLP-1 RA
A1C < 7.5% A1C ≥ 7.5%-9.0% A1C > 9.0%
Monotherapy Dual Therapy Triple Therapy Symptoms
Metformin GLP-1 RA GLP-1 RA NO YES
GLP-1 RA SGLT2-i SGLT2-i
SGLT2-i DPP-4i TZD Dual Therapy DPP-4i TZD SU/GLN Insulin
±Other
Agents
TZD SU/GLN Basal Insulin OR
AGi Basal Insulin DPP-4i Triple Therapy
SU/GLN Colesevelam Colesevelam
Bromocriptine QR Bromocriptine QR
AG-i AG-i Add or Intensify Insulin
Refer to Insulin Algorithm
! !
!
Independent of Glycemic Control, If
Established or High Risk for ASCVD, CKD 3, or
HFrEF, Recommend
SGLT2-i and/or Long-Acting GLP-
1 RA with Proven Efficacy
!
!
!
!
!
3 M
on
ths
3 M
on
ths
MET + other agent! Use with caution
Few AEs or possible benefit
LEGEND
AACE/ACE 2020
Algorithm for Glycemic Management
If cardiovascular disease is present in T2D, 2020 ADA guidelines recommend GLP‐1 RA use
a. Before DPP‐4 inhibitorsb. As first choice after pioglitazonec. As first choice after metformind. After DPP‐4 inhibitors
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23
GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
Summary• T2D is a progressive disease associated with worsening β‐cell dysfunction,
increases in insulin resistance, and resultant hyperglycemia1
• Patients with T2D are also characterized by an impaired “incretin effect”2
• The first GLP‐1 RA for the treatment of diabetes was approved in 20053– Today GLP‐1 RAs are formulated for daily or weekly SC administration, as well as daily oral
administration• CVOTs have shown that these agents reduce MACE in patients with T2D and
established CVD or multiple cardiovascular risk factors4,5,6
• GLP‐1 RAs markedly reduce body weight• GLP‐1 RAs have been studied for other effects beyond glycemia (Parkinson’s
disease and Alzheimer’s disease)7
Kendall DM et al. Am J Med. 2009;122:S37‐S50; 2. Mudaliar S et al. Diabetologia. 2012;55:1865‐8; 3. ExBID [PI]. Wilmington, DE: AstraZeneca Pharm LP; 2018; 4. Giugliano D et al. Diabetes Obes Metab. 2019; doi: 10.1111/dom.13847; 5. Sheahan KH et al. Postgrad Med J. 2019; doi: 10.1136/postgradmedj‐2019‐137186; 6.Dula [PI]. Indianapolis, IN; Lilly USA, LLC; 2020; 7. Athauda D. et al. Drug Discov Today. 2016;21:802‐18.
Key Takeaways
• GLP‐1 RAs– Have physiological actions that help patients with type 2diabetes improve glycemic control
– Consider for patients who need• Weight loss• Low risk of hypoglycemia
– Consider strongly in type 2 diabetes with• High risk of CVD or current diagnosis• Renal insufficiency with albuminuria
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes
• Nauck MA et al. Incretin hormones: their role in healthand disease. Diabetes Obes Metab. 2018;20(suppl 1):5‐21.
• Sheahan KH et al. An overview of GLP‐1 agonists andrecent cardiovascular outcomes trials. Postgrad Med J.2020;96:156‐61.
Selected References
Thank you for joining us
• On‐demand activity cominglate May 2020
• Other live and on‐demandactivities in this serieswww.ashpadvantage.com/t2d
www.ashpadvantage.com/t2d
This activity is not eligible for CE Credit
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GLP-1 Physiology and Evolving Clinical Data on GLP-1 ReceptorAgonists for the Management of Type 2 Diabetes