Cardiac mechanisms of GLP-1 receptor agonists · 2019-12-18 · Cardiac mechanisms of GLP-1 receptor agonists Filip K. Knop, MD PhD Professor, ... • Sanofi • Zealand Pharma. Contemporary

Cardiac mechanisms of GLP-1 receptor agonists

Filip K. Knop, MD PhD

Professor, Consultant Endocrinologist, Director of Center for Clinical Metabolic Research

Gentofte Hospital, University of Copenhagen

Denmark

Faculty Disclosure

I I have received a research grant(s)/ in kind support

A From current sponsor(s) YES NO

B From any institution YES NO

II I have been a speaker or participant in accredited CME/CPD

A From current sponsor(s) YES NO

B From any institution YES NO

III I have been a consultant/strategic advisor etc

A For current sponsor(s) YES NO

B For any institution YES NO

IV I am a holder of (a) patent/shares/stock ownerships

A Related to presentation YES NO

B Not related to presentation YES NO

Declaration of financial interests

For the last 3 years and the subsequent 12 months:

Professor Filip K. Knop, MD PhD, of Gentofte Hospital, University of Copenhagen,

Denmark has served on scientific advisory panels and/or been part of speaker’s

bureaus for, served as a consultant to and/or received research support from:

Disclosures

• Amgen

• AstraZeneca

• Boehringer Ingelheim

• Carmot Therapeutics

• Eli Lilly

• Gubra

• MedImmune

• MSD/Merck

• Munidpharma

• Norgine

• Novo Nordisk

• Sanofi

• Zealand Pharma

Contemporary CVOTs in diabetes and obesity

*Estimated enrolment; †Stopped early after a median follow-up of 57.4 months following futility analysis

Trials with filled boxes are completed. Trials with a white background are ongoing

AGI, alpha-glucosidase inhibitor; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; ER, extended release; GLP-1RA, glucagon-like peptide-1 receptor agonist; ITCA 650, continuous subcutaneous delivery of exenatide;

PPAR-αγ, peroxisome proliferator‐activated receptors-α and γ; OW, once weekly; SGLT-2i, sodium–glucose co-transporter 2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione

ClinicalTrials.gov.

2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024

DEVOTE

(Insulin degludec, insulin)

n=7637; duration ~2 yrs

Q2 2017 – RESULTS

EMPA-REG OUTCOME

(Empagliflozin, SGLT-2i)

n=7000; duration up to 5 yrs

Q3 2015 – RESULTS

CANVAS

(Canagliflozin, SGLT-2i)

n=4418; duration 4+ yrs

Q2 2017 – RESULTS

DECLARE-TIMI 58

(Dapagliflozin, SGLT-2i)

n=17,276; duration ~6 yrs

Q4 2018 – RESULTS

CANVAS-R



Q2 2017 – RESULTS

CREDENCE (cardio-renal)


n=4464; duration ~5.5 yrs

Q3 2018 – CANCELLED

(+ve efficacy)

VERTIS CV

(Ertugliflozin, SGLT-2i)


Completion Q3 2019

ELIXA

(Lixisenatide, GLP-1RA)

n=6068; follow-up ~2 yrs

Q1 2015 – RESULTS

REWIND

(Dulaglutide, OW GLP-1RA)


Q2 2019 RESULTS

FREEDOM

(ITCA 650, GLP-1RA in

DUROS)


Q2 2016 – TOP-LINE

RESULTS

EXSCEL

(Exenatide ER, OW GLP-

1RA)

n=14,752; follow-up ~3 yrs

Q3 2017 – RESULTS

LEADER

(Liraglutide, GLP-1RA)

n=9340; duration 3.5–5 yrs

Q2 2016 – RESULTS

HARMONY OUTCOMES

(Albiglutide, OW GLP-1RA)


Q3 2018 - RESULTS

PIONEER 6

(Oral semaglutide, GLP-1RA)


Q2 2019 RESULTS

EXAMINE

(Alogliptin, DPP-4i)

n=5380;

follow-up ~1.5 yrs

Q3 2013 – RESULTS

SAVOR-TIMI 53

(Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 yrs

Q2 2013 – RESULTS

TECOS

(Sitagliptin, DPP-4i)

n=14,671; duration ~3 yrs

Q4 2014 – RESULTS

CARMELINA

(Linagliptin, DPP-4i)


Q3 2018 – RESULTS

ALECARDIO

(Aleglitazar, PPAR-αγ)

n=7226; follow-up 2 yrs

Termin. Q3 2013 –

RESULTS

SCORED

(Sotagliflozin, SGLT-1i & SGLT-2i)

n=10,500*; duration ~4.5 yrs

Completion Q1 2022

SUSTAIN 6

(Semaglutide, OW GLP-

1RA)


Q3 2016 – RESULTS

CAROLINA

(Linagliptin, DPP-4i vs SU)


Q2 2019 RESULTS

TOSCA IT

(Pioglitazone, TZD)


Q4 2017† – RESULTS

ACE

(Acarbose, AGI)


Q2 2017 – RESULTS

AMPLITUDE-O

(Efpeglenatide, OW GLP-1RA)

n=4000*; duration ~3 yrs

Completion Q2 2021

Insulin

SGLT-2i

GLP-1RA

DPP-4i

PPAR-αγ

TZD

AGI

SOUL

(Oral semaglutide, OD GLP-1RA)

n=12,546*; duration ~3.5–5 yrs

Completion Q2 2024

SELECT

(Semaglutide, OW GLP-1RA)

n=17,500 *;

Duration: event driven, 1225 MACE

Completion Q3 2023

EXAMINE

Alo vs. Pbo

EMPA-REG Outcome

Empa vs. Pbo

ELIXA*

Lixi vs. Pbo

ORIGIN

Glargine U100 vs. SOC

SAVOR TIMI-53

Saxa vs. Pbo

CANVAS Program

Cana vs. Pbo

FREEDOM-CVO

ITCA 650 vs. Pbo

DEVOTE

Degludec vs.

Glargine U100

TECOS*

Sita vs. Pbo

DECLARE-TIMI 58

Dapa vs. Pbo

LEADER

Lira vs. Pbo

CARMELINA

Lina vs. Pbo

SUSTAIN-6

Sema vs. Pbo

EXSCEL

Exe OW vs. Pbo

HARMONY

Alb vs. Pbo

REWIND

Dul vs. Pbo

0,1 0,4 0,7 1,0 1,3

HR [95% CI]

Insulin

?

0,1 0,4 0,7 1,0 1,3 1,6

HR [95% CI]

GLP-1RA

0,1 0,4 0,7 1,0 1,3

HR [95% CI]

DPP-4i

0,1 0,4 0,7 1,0 1,3

HR [95% CI]

SGLT2i

Recent CVOTs with antidiabetic agentsPrimary composite endpoint: MACE

*MACE+

White et al. N Engl J Med 2013; 369:1327–35;

Scirica et al. N Engl J Med 2013;369:1317–26;

Green et al. N Engl J Med 2015;373:232–42;

McGuire et al. JAMA. 2019 Jan 1;321(1):69-79.

Zinman et al. N Engl J Med 2015; 373:2117-

28; Neal et al. N Engl J Med 2017;377:644–

57; Wiviott et al. N Engl J Med. 2019 Jan

24;380(4):347-357.

*MACE+

Pffefer et al. N Engl J Med 2015;373:2247–57; Intarcia press

release 06 May 2016; Marso et al. N Engl J Med 2016;375:311–22;

Marso et al. N Engl J Med 2016;375:1834–44; Holman et al. N

Engl J Med 2017;377:1228–39; Hernandez et al. Lancet. 2018 Oct

27;392(10157):1519-1529.; Gerstein et al. Lancet. 2019 Jun 10.

http://dx.doi.org/10.1016/S0140-6736(19)31149-3

Gerstein et al. N Engl J Med 2012;367:

319–28; Marso et al. N Engl J Med 2017;377:723–

32

Introduction to the incretin hormone GLP-1

K cells

L cells

GIP

GLP-1

GLP-1-positive endocrine L-cells in human

small intestine (Knop et al. Unpublished)

Glu

7

37

Lys

His Thr Thr SerPheGly Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Ala

Bell et al. Nature 19834

0

20

40

60

80

-30 0 30 60 90 120 150 180 210 240

Meal

Pla

sm

a G

LP

-1 (

pM

)

Time (min)

Knop et al. Am J Physiol Endocrinol Metab 20073

The incretin hormonesGlucose-dependent insulinotropic polypeptide (GIP)

Glucagon-like peptide-1 (GLP-1)

1. Brown JC, Dryburgh JR. Can J Biochem 1971;49:867–872; 2. Jörnwall H et al. FEBS Lett 1981;123:205–210;

3. Knop FK et al. Am J Physiol Endocrinol Metab 2007;292:E324–330; 4. Bell GL et al. Nature 1983;304:368–371

GLP-1 receptors are widely distributed in the human body

GLP-1, glucagon-like peptide-1

Drucker. Cell Metab 2016;24:15–30

Potential modes of action for GLP-1 receptor activation to

impact CV and/or renal disease

Mechanism for CV/CKD risk reduction is likely to be

multifactorial1–3

CV, cardiovascular; CKD, chronic kidney disease

1. Dalsgaard et al. Diabetes Obes Metab 2018;20:508–519; 2. Farr et al. Cardiovasc Haematol Disord Drug Targets 2014;14:126–36; 3. Yamamoto et al. J Clin Invest 2002;110:43–52

Glycaemia

Body weight

Blood pressure

Blood lipids

Effects on insulin and glucagon

cease alongside the occurrence

of normoglycaemia

Time (min)

*p<0.05

Glucose (mM)

5

0 60 120 180 240

15.0

12.5

10.0

7.5

Infusion of GLP-1

or placebo

*

**

** *

* **

* **

*

Placebo

GLP-1

*** *

n = 10 T2D

Insulin (pM)

Glucagon (pM)

150

5

250

200

100

50

20

15

10

0

GLP-1 receptor expression in the human pancreas

GLP-1R expression

GLP-1R, glucagon-like peptide-1 receptor

Jensen et al. Endocrinology 2018;159:665–75

GLP-1R identified in 50+ regions

GLP-1R

Brain access

*Significant difference between treatments analysed in individual brain regions using a false discovery rate value of 5%

to correct for multiple comparisons

AP, area postrema; ARH, arcuate hypothalamic nucleus; DMH, dorsomedial nucleus of the hypothalamus; GLP-1R,

glucagon-like peptide-1 receptor; i.v., intravenous; ME, median eminence; OV, vascular organ of the lamina terminalis;

NTS, nucleus of the solitary tract; PVH, paraventricular hypothalamic nucleus; PVp, periventricular hypothalamic

nucleus, posterior part; SF, septofimbrial nucleus; SFO, subfornical organ; SO, supraoptic nucleus; TU, tuberal

nucleus; VT750, VivoTag-S750 radiolabelled

Salinas et al. Sci Rep 2018;8:10310 i.v. injection of 0.1 mg/kg liraglutideVT750 in mice, n=6

Many untargeted GLP-1Rs

GLP-1R targeting in cerebral nuclei,

hypothalamus and hindbrain

32

16

128

64

2

1

8

4

DMHPVH SFO

APNTS

SFARH ME

OV PVp SOTU

Cerebral nuclei

Hypothalamus

Medulla

Fo

ld c

ha

ng

e

(lir

ag

luti

de

VT

750/v

eh

icle

)

*Significant difference between treatments analysed in individual brain regions using a false discovery rate value of 20% to

correct for multiple comparisons

AP, area postrema; ARH, arcuate hypothalamic nucleus; BLA, basolateral amygdalar nucleus; BST, bed nuclei of the stria

terminals; CeA, central amygdalar nucleus; LC, locus ceruleus; MTN, midline group of the dorsal thalamus; NTS, nucleus of

the solitary tract; PB, parabrachial nucleus; PSTN, parasubthalamic nucleus

Salinas et al. Sci Rep 2018;8:10310 c-Fos

Potential direct activation in:

• ARH (hypothalamus)

• AP and NTS (medulla)

Secondary activation in regions associated with control of

food intake

s.c. injection of 0.4 mg/kg liraglutide in mice, n=6

16

16

2

1

4

CeAMTN PB

BLABST ARH

PSTN LC APNTS

Cerebral cortex

Cerebral nuclei

Hypothalamus

Thalamus

Fo

ld c

ha

ng

e

(lir

ag

luti

de

/veh

icle

)

Pons

Medulla

Brain activation

Baseline to week 52: J2R-MI data (phase 2)

Change in body weight (%)

All randomised, effectiveness estimand. Graph is estimated mean data ± min/max

J2R-MI, jump-to-reference – multiple imputation; s.c., subcutaneous

O’Neil et al. Presented at: ENDO 2018: The Endocrine Society Annual Meeting; Chicago, IL; 17-20 March 2018. Abstract OR12-5

Ch

an

ge

in

bo

dy w

eig

ht

(%)

Semaglutide 0.05 mg

Semaglutide 0.1 mg

Semaglutide 0.2 mg

Semaglutide 0.3 mg

Semaglutide 0.4 mg

Placebo pool

Weeks

Liraglutide 3.0 mg

-6.0%

-8.6%

-11.6%

-11.2%

-13.8%

-2.3%

-7.8%

-15

-10

-5

0

0 2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 44 48 52

Semaglutide is not indicated for the treatment of overweight / obesity

Mechanism for CV risk reduction is likely to be

multifactorial1–3

CV, cardiovascular


Glycaemia

Body weight

Blood pressure

Blood lipids

Renal mode of action of GLP-1 therapy

GLP-1, glucagon-like peptide 1; GLP-1R, glucagon-like peptide 1 receptor

Pyke C et al. Endocrinology 2014;155:1280–1290

GLP-1R expression in cells of the

juxtaglomerular apparatus and in the wall

of afferent arterioles in kidney (non-

human primate)

GLP-1 suppresses the activity of the

sodium-hydrogen exchanger NHE3

– contributing to natriuresis

-> vasodilatation of afferent arteriole

Renal mode of action of GLP-1 therapy - natriuresis

GLP-1, glucagon-like peptide 1

Asmar A et al. JCEM. 2019 Jul 1;104(7):2509-2519.

S a lin e G L P -1

0

1 0 0

2 0 0

3 0 0

4 0 0

U r in a ry s o d iu m e x c re t io n

mm

ol/

18

0 m

in

S a lin e G L P -1

0

1 0 0

2 0 0

3 0 0

M e a n u r in a ry s o d iu m e x c r e t io n

mm

ol/

18

0 m

in

p = 0 .0 1 4

G lo m e ru la r f i lt ra t io n ra te

-2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

1 6 0

T im e (m in )

ml/

min

S a lin e

G L P -1

R e n a l p la s m a f lo w

-2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

T im e (m in )

ml/

min

S a lin e

G L P -1

3-hour GLP-1 infusion (1.5 pmol/kg/min)

increased natriuresis in lean, healthy

males during ECFV expansion with

isotonic NaCl (750 ml/h)

…without affecting renal

haemodynamics (as

assessed by 51Cr-EDTA

clearance; catherization of the

renal vein and the radial artery)

Renal mode of action of GLP-1 therapy - natriuresis

GLP-1, glucagon-like peptide 1

Asmar A et al. JCEM. 2019 Jul 1;104(7):2509-2519.

GLP-1 infusion had no effect on

circulating levels of natriuretic peptides

(proANP, ANP and BNP)

p ro A N P

-2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0

0

1 0 0

2 0 0

3 0 0

G L P -1

S a lin e

T im e (m in )

pg

/ml

p ro A N P A U C 0 -1 8 0 m in

G L P -1 S a lin e

-8 0 0 0

-6 0 0 0

-4 0 0 0

-2 0 0 0

0

p = 0 .5 3 2

pg

/ml

A N P

-2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0

0

2 0

4 0

6 0

8 0

G L P -1

S a lin e

T im e (m in )

pg

/ml

A N P A U C 0 -1 8 0 m in

G L P -1 S a lin e

-2 0 0 0

-1 0 0 0

0

1 0 0 0

2 0 0 0p = 0 .2 1 7

pg

/ml

B N P

-2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0

0

1 0 0

2 0 0

3 0 0

G L P -1

S a lin e

T im e (m in )

pg

/ml

B N P A U C 0 -1 8 0 m in

G L P -1 S a lin e

-1 0 0 0 0

-5 0 0 0

0

5 0 0 0

p = 0 .1 9 0

pg

/ml

…renin or aldosterone

Renin

-20 0 20 40 60 80 100 120 140 160 180

0

5

10

15

20

25Saline

GLP-1

Time (min)

mIU

/L

R e n in A U C 0 -1 8 0 m in

G L P -1 S a lin e

-2 0 0 0

-1 5 0 0

-1 0 0 0

-5 0 0

0

p = 0 .7 9 3

mIU

/L

Angiotensin II

-20 0 20 40 60 80 100 120 140 160 180

0

5

10

15

20Saline

GLP-1

Time (min)

pg

/ml

A n g io te n s in II A U C 0 -1 8 0 m in

G L P -1 S a lin e

-1 5 0 0

-1 0 0 0

-5 0 0

0

5 0 0

p = 0 .0 0 2

pg

/ml

Aldosterone

-20 0 20 40 60 80 100 120 140 160 180

0

20

40

60

80Saline

GLP-1

Time (min)

pg

/ml

A ld o s te ro n A U C 0 -1 8 0 m in

G L P -1 S a lin e

-2 0 0 0

-1 0 0 0

0

1 0 0 0

2 0 0 0

p = 0 .3 2 2

pg

/ml

but suppressed circulating ANG II levels

-4,7

-3,4

-2,5-2,0

-2,9

-1,2

-3,5

-2,5-2,9

-2,5

1,6

0,8

0,0

-2,8

-3,4

-4,7

-3,5

-6,2-5,8

-3,5

-2,8

-2,0-2,5

0,4

-2,1

0,6

-2,2

-4,6

-8,0

-6,0

-4,0

-2,0

0,0

2,0

Change in S

BP

fro

m b

aselin

e

(mm

Hg)

GLP-1RA reduce systolic blood pressure by ~4 mmHg

Only significant p-values are included. All legend colours depict the final dose in the treatment groups (some trials included up-titration to reach this maximum dose)

*To aid comparisons in this review, only the highest doses of the GLP-1RA in any given dosing schedule in this trial were included. Results from distinct trials

BID, twice daily; GLP-1RA, glucagon-like peptide-1 receptor agonist; NR, not reported; O2W, every second week; OD, once daily; OW, once weekly; SBP, systolic blood pressure

Dalsgaard et al. Diabetes Obes Metab 2018;20:508–19

128 130 132 134 130 128 134 132 NR NR 127 127 127 131 132 NR NR 132 133 126 NR NR 134 130 NR NR 134 (overall)Baseline

SBP

(mmHg)

Exenatide 2 mg OW

Exenatide 10 g BID

Liraglutide 0.9 mg OD


Lixisenatide 20 g OD

Albiglutide 30 mg OW

Albiglutide 50 mg O2W

Dulaglutide 0.75 mg OW


Semaglutide 1.0 mg OW

p=0.013

p=0.016

Ch

an

ge f

rom

baselin

e in

SB

P (

mm

Hg

)

Albiglutide was withdrawn from the worldwide market in July 2018


multifactorial1–3

CV, cardiovascular


Glycaemia

Body weight

Blood pressure

Blood lipids

-0.31

-0.10

-0.20

-0.09

-0.40

0.02

-0.15

-0.06 -0.06

-0.15

-0.04

-0.13

-0.03

0.01

-0.45

-0.18 -0.16

-0,8

-0,5

-0,3

0,0

0,3

GLP-1RAs reduce lipids (total cholesterol, fasted)

Only significant p-values are included. Results from distinct trials. All legend colours depict the final dose in the treatment groups (some trials included up-titration to reach this maximum dose)

*To aid comparisons in this review, only the highest doses of the GLP-1RA in any given dosing schedule in this trial were included. †Cholesterol was reported in mg/dL in the publication and so was converted to mmol/L for this figure (conversion factor: 0.0259)

BID, twice daily; GLP-1RA, glucagon-like peptide-1 receptor agonist; NR, not reported; O2W, every second week; OD, once daily; OW, once weekly

Dalsgaard et al. Diabetes Obes Metab 2018;20:508–519

DURATION-1 LEAD-6 DURATION-5† DURATION-6 HARMONY-7 AWARD-6Rosenstock

et al.*

Miyagawa

et al.

4.5 4.7 NR NR 4.7 5.1 4.6 4.5 NR NR NR NR 4.6 4.8 5.1 5.3 5.2

Baseline total

cholesterol

(mmol/L)

Exenatide 2 mg OW

Exenatide 10 g BID





Albiglutide 50 mg O2W



p<0.01

Ch

an

ge f

rom

baselin

e in

tota

l ch

ole

ste

rol (m

mo

l/L

)

Albiglutide was withdrawn from the worldwide market in July 2018

GLP-1RA (semaglutide) lowers postprandial lipid profilesObese individuals at fat-rich breakfast

Hjerpsted et al. Diabetes Obes Metab 2018;20(3):610-619

0,0

0,4

0,8

1,2

1,6

2,0

0 60 120 180 240 300 360 420 480

Se

rum

VL

DL c

ho

leste

rol

(mm

ol/L

)

Time planned since start of meal (min)

VLDL

0,0

0,2

0,4

0,6

0 60 120 180 240 300 360 420 480

Se

rum

fre

e fa

tty a

cid

s

(mm

ol/L

)

Free fatty acids

0,0

1,0

2,0

3,0

4,0

5,0

0 60 120 180 240 300 360 420 480

Se

rum

tri

gly

ce

rid

es

(mm

ol/L

)

Triglycerides

Semaglutide 1.0 mg (n=26) Placebo (n=28)

Apolipoprotein B48

0,00

0,01

0,02

0,03

0,04

0 60 120 180 240 300 360 420 480

Se

rum

a

po

lipo

pro

tein

B4

8 (

g/L

)

Time planned since start of meal (min)

Se

rum

ap

olip

op

rote

in B

48

(g/L

)


multifactorial1–3

CV, cardiovascular


Other potential

mechanisms:

Reduced atherosclerotic

burden?

Glycaemia

Body weight

Blood pressure

Blood lipids

Vehicle,

chowVehicle,

WD

Semaglutide

1 nmol/kg 3 nmol/kg 15 nmol/kg

Semaglutide attenuated plaque lesion area, partly independent of

body weight in LDLr-/- mice

ANOVA: p<0.05; *p<0.05; ***p<0.001

ANOVA, analysis of variance; LDLr –/–, low-density lipoprotein receptor knockout; WD, Western diet

Rakipovski et al. JACC Basic Transl Sci 2018;3:844–57; Rakipovski et al. Abstract 244-OR presented at the American Diabetes Association 77th Scientific Sessions; 9–13 June, 2017; San Diego, USA

Plaque lesion area

4 10

32

28

24

20

16

4

036

8620 12

Time (weeks)

14 16 18

Body weight

Bo

dy w

eig

ht

(g)

25

20

15

10

5

0

*** *** ***

Pla

qu

e a

rea (

%)

Semaglutide 1 nmol/kg, WD



Vehicle, chow

Vehicle, WD

• Analysis of macrophages for MΦ1 (pro-atherogenic) and MΦ2 (pro-resolving) macrophage markers,

showed that liraglutide modulates macrophage cell fate towards MΦ2 pro-resolving macrophages

• This coincided with decreased atherosclerotic

lesion formation

Liraglutide reduces atherosclerotic lesion formation via

modulation of macrophage cell fate in ApoE-/- mice

Bruen et al. Cardiovasc Diabetol 2017;16:143

MΦ

MΦ1

MΦ2

Macrophage

Pro-atherogenic

Pro-resolving

Atherosclerotic

lesion

• The gut-derived incretin hormone GLP-1 has potent and glucose-dependent insulinotropic and

glucagonostatic effects

-> GLP-1RA treatment improves glycaemic control without risk of hypoglycaemia

• GLP-1Rs are found in several areas of the brain; especially in appetite-regulating centres

-> GLP-1RA treatment reduces body weight and is associated with GI side effects (e.g. nausea)

• GLP-1 increases natriuresis (independently of net renal haemodynamics and circulating

concentrations of renin, aldosterone and natriuretic peptides; perhaps via suppression of ANG II)

• -> GLP-1RA treatment reduces systolic blood pressure and reduces risk of macroalbuminuria

• GLP-1RA treatment is associated with small reductions in circulating lipids

• In mouse models of atherosclerosis, GLP-1RA treatment reduces atherosclerotic plaque development

Potential cardiovascular and renal modes of action - summary

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Cardiac mechanisms of GLP-1 receptor agonists · 2019-12-18 · Cardiac mechanisms of GLP-1 receptor agonists Filip K. Knop, MD PhD Professor, ... • Sanofi • Zealand Pharma. Contemporary