Cardiac mechanisms of GLP-1 receptor agonists Filip K. Knop, MD PhD - - PowerPoint PPT Presentation

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 agents

Primary 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 Ser Phe Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Ala

Bell et al. Nature 19834 20 40 60 80

• 30

30 60 90 120 150 180 210 240 Meal Plasma GLP-1 (pM) Time (min) Knop et al. Am J Physiol Endocrinol Metab 20073

The incretin hormones

Glucose-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

• f normoglycaemia

Time (min)

*p<0.05

Glucose (mM) 5 60 120 180 240 15.0 12.5 10.0 7.5 Infusion of GLP-1

• r placebo

* * * * * * * * * * * * * Placebo GLP-1 * * * * n = 10 T2D Insulin (pM) Glucagon (pM) 150 5 250 200 100 50 20 15 10

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 DMH PVH SFO AP NTS SF ARH ME OV PVp SO TU

Cerebral nuclei Hypothalamus Medulla

Fold change (liraglutideVT750/vehicle)

*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 CeA MTN PB BLA BST ARHPSTN LC AP NTS

Cerebral cortex Cerebral nuclei Hypothalamus Thalamus

Fold change (liraglutide/vehicle)

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

Change in body weight (%)

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

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

• f 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 1 0 0 2 0 0 3 0 0 4 0 0

U rin a ry s o d iu m e x c re tio n

m m o l/1 8 0 m in

S a lin e G L P -1 1 0 0 2 0 0 3 0 0

M e a n u rin a ry s o d iu m e x c re tio n

m m o l/1 8 0 m in

p = 0 .0 1 4 G lo m e ru la r filtra tio n ra te

• 2 0

2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 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 ) m l/m in S a lin e G L P -1

R e n a l p la s m a flo w

• 2 0

2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 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 ) m l/m in 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

2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 1 0 0 2 0 0 3 0 0 G L P -1 S a lin e T im e (m in ) p g /m l

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

p = 0 .5 3 2

p g /m l

A N P

• 2 0

2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 4 0 6 0 8 0 G L P -1 S a lin e T im e (m in ) p g /m l

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

1 0 0 0 2 0 0 0

p = 0 .2 1 7

p g /m l

B N P

• 2 0

2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 1 0 0 2 0 0 3 0 0 G L P -1 S a lin e T im e (m in ) p g /m l

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

5 0 0 0

p = 0 .1 9 0

p g /m l

…renin or aldosterone

Renin

• 20

20 40 60 80 100 120 140 160 180 5 10 15 20 25 Saline 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

p = 0 .7 9 3

m IU /L

Angiotensin II

• 20

20 40 60 80 100 120 140 160 180 5 10 15 20 Saline 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

5 0 0

p = 0 .0 0 2

p g /m l

Aldosterone

• 20

20 40 60 80 100 120 140 160 180 20 40 60 80 Saline 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

1 0 0 0 2 0 0 0

p = 0 .3 2 2

p g /m l

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 SBP from baseline (mmHg)

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 Change from baseline in SBP (mmHg)

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-6 Rosenstock 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 Change from baseline in total cholesterol (mmol/L)

Albiglutide was withdrawn from the worldwide market in July 2018

GLP-1RA (semaglutide) lowers postprandial lipid profiles

Obese 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 60 120 180 240 300 360 420 480 Serum VLDL cholesterol (mmol/L) Time planned since start of meal (min)

VLDL

0,0 0,2 0,4 0,6 60 120 180 240 300 360 420 480 Serum free fatty acids (mmol/L)

Free fatty acids

0,0 1,0 2,0 3,0 4,0 5,0 60 120 180 240 300 360 420 480 Serum triglycerides (mmol/L)

Triglycerides

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

Apolipoprotein B48

0,00 0,01 0,02 0,03 0,04 60 120 180 240 300 360 420 480 Serum apolipoprotein B48 (g/L) Time planned since start of meal (min) Serum apolipoprotein B48 (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, chow Vehicle, 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 36 8 6 2 12 Time (weeks) 14 16 18

Body weight

Body weight (g) 25 20 15 10 5 *** *** *** Plaque area (%) 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