GLP-1 Physiology and Evolving Clinical Data on GLP-1 Receptor … · 2020-05-18 · GLP‐1...

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

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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/

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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


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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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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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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.


7


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


GIP



8


Insulin

Plasma Glucose

Amylin

Food Intake

Gastric Emptying

Increase Decrease

GLP-1

Tissues


βα


GIP

Glucose Appearance


InsulinAmylin

Food Intake

Gastric Emptying

Glucagon

Increase Decrease

GLP-1

Plasma Glucose

Glucose Appearance

Tissuesβα


GIP




9


Amylin

Food Intake

Gastric Emptying

α

Glucagon

Leptin

Increase Decrease

Plasma Glucose

Glucose Appearance

Tissuesβα


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


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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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 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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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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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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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



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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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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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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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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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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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)



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.



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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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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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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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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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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• 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 Receptor … · 2020-05-18 · GLP‐1...

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