cardiac mechanisms of glp-1 receptor agonists · 2019-12-18 · cardiac mechanisms of glp-1...
TRANSCRIPT
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
(Canagliflozin, SGLT-2i)
n=5826; duration ~3 yrs
Q2 2017 – RESULTS
CREDENCE (cardio-renal)
(Canagliflozin, SGLT-2i)
n=4464; duration ~5.5 yrs
Q3 2018 – CANCELLED
(+ve efficacy)
VERTIS CV
(Ertugliflozin, SGLT-2i)
n=8000; duration ~6 yrs
Completion Q3 2019
ELIXA
(Lixisenatide, GLP-1RA)
n=6068; follow-up ~2 yrs
Q1 2015 – RESULTS
REWIND
(Dulaglutide, OW GLP-1RA)
n=9622; duration ~6.5 yrs
Q2 2019 RESULTS
FREEDOM
(ITCA 650, GLP-1RA in
DUROS)
n=4000; duration ~2 yrs
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)
n=9574; duration ~4 yrs
Q3 2018 - RESULTS
PIONEER 6
(Oral semaglutide, GLP-1RA)
n=3183; duration ~1.5 yrs
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)
n=7003; duration ~4 yrs
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)
n=3297; duration ~2.8 yrs
Q3 2016 – RESULTS
CAROLINA
(Linagliptin, DPP-4i vs SU)
n=6103; duration ~8 yrs
Q2 2019 RESULTS
TOSCA IT
(Pioglitazone, TZD)
n=3028; duration ~10 yrs
Q4 2017† – RESULTS
ACE
(Acarbose, AGI)
n=6522; duration ~8 yrs
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
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
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
Liraglutide 1.8 mg OD
Lixisenatide 20 g OD
Albiglutide 30 mg OW
Albiglutide 50 mg O2W
Dulaglutide 0.75 mg OW
Dulaglutide 1.5 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
Mechanism for CV risk reduction is likely to be
multifactorial1–3
CV, cardiovascular
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
-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
Liraglutide 0.9 mg OD
Liraglutide 1.8 mg OD
Albiglutide 30 mg OW
Albiglutide 50 mg OW
Albiglutide 50 mg O2W
Dulaglutide 0.75 mg OW
Dulaglutide 1.5 mg OW
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
)
Mechanism for CV risk reduction is likely to be
multifactorial1–3
CV, cardiovascular
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
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
Semaglutide 3 nmol/kg, WD
Semaglutide 15 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