and renal benefits of GLP-1 receptor agonists Filip Krag Knop, MD - - PowerPoint PPT Presentation

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The science behind vascular and renal benefits of GLP-1 receptor agonists Filip Krag Knop, MD Copenhagen, Denmark June 15, 2019 - Budapest, Hungary The science behind cardiovascular and renal benefits of GLP-1 receptor agonists Filip K.

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SLIDE 1

The science behind vascular and renal benefits of GLP-1 receptor agonists

Filip Krag Knop, MD Copenhagen, Denmark

June 15, 2019 - Budapest, Hungary
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SLIDE 2

The science behind cardiovascular and renal benefits

  • f GLP-1 receptor agonists
Filip K. Knop, MD PhD Professor, Consultant Endocrinologist, Head of Center for Clinical Metabolic Research Gentofte Hospital, University of Copenhagen Denmark
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SLIDE 3

Contemporary CVOTs in diabetes

*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. ClinicalTrials.gov (August 2018) 2019 2015 2020 2013 2014 2016 2017 2018 2021 Insulin DEVOTE (Insulin degludec, insulin) n=7637; duration ~2 yrs Q2 2017 – RESULTS SGLT-2i 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 Q3 2018 – RESULTS CANVAS-R (Canagliflozin, SGLT-2i) n=5826; duration ~3 yrs Q2 2017 – RESULTS CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) n=4401; duration 4.5 yrs Q3 2018 – TERMINATED (+ve efficacy) - RESULTS VERTIS CV (Ertugliflozin, SGLT-2i) n=8000*; duration ~6.3 yrs Completion Q3 2019 GLP-1RA ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q1 2015 – RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs Q2 2016 – TOPLINE RESULTS REWIND (Dulaglutide, QW GLP-1RA) n=10,010; duration ~6.5 yrs Q3 2018 –RESULTS SUSTAIN 6 (Semaglutide, QW GLP-1RA) n=3297; duration ~2.8 yrs Q3 2016 – RESULTS LEADER (Liraglutide, GLP-1RA) n=9340; duration 3.5–5 yrs Q2 2016 – RESULTS EXSCEL (Exenatide ER, QW GLP-1RA) n=14,752; follow-up ~3 yrs Q3 2017 – RESULTS HARMONY OUTCOMES (Albiglutide, QW GLP-1RA) n=9574; duration ~4 yrs Q2 2018 - RESULTS PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176*; duration ~1.5 yrs Q4 2018 - RESULTS DPP-4i TECOS (Sitagliptin, DPP-4i) n=14,671; duration ~3 yrs Q1 2015 – RESULTS SAVOR-TIMI 53 (Saxagliptin, DPP-4i) n=16,492; follow-up ~2 yrs Q2 2013 – RESULTS EXAMINE (Alogliptin, DPP-4i) n=5380; follow-up ~1.5 yrs Q3 2013 – RESULTS CAROLINA (Linagliptin, DPP-4i vs SU) n=6072; duration ~8 yrs Q3 2018 - RESULTS CARMELINA (Linagliptin, DPP-4i) n=7003; duration 4.5 yrs Q1 2018 - RESULTS ALECARDIO (Aleglitazar, PPAR-αγ ) n=7226; follow-up 2 yrs
  • Termin. Q3 2013 – RESULTS
PPAR-αγ 2022 SCORED (Sotagliflozin, SGLT-1i & SGLT-2i) n=10,500*; duration ~4.5 yrs Completion Q1 2022 TZD TOSCA IT (Pioglitazone, TZD) n=3028; duration ~10 yrs Q4 2017†– RESULTS AGI ACE (Acarbose, AGI) n=6522; duration ~8 yrs Q2 2017 – RESULTS AMPLITUDE-O (Efpeglenatide, GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021 SOLOIST-WHF (Sotagliflozin, SGLT-1i & SGLT-2i) n=4000*; duration ~2.7 yrs Completion Q1 2021
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SLIDE 4 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
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SLIDE 5

Renal outcomes in T2D CVOTs

CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; MDRD,
  • 1. Mann JFE et al. N Engl J Med 2017;377:839–848; 2. Marso SP et al. N Engl J Med 2016;375:1834–1844;
LEADER1 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 2 4 6 8 1 0 Patients with an event (%) HR: 0.78 95% CI (0.67; 0.92) p=0.003 Time since randomisation (months) Liraglutide Placebo Macroalbuminuria, doubling of serum creatinine and eGFR ≤45 mL/min/1.73 m2 per MDRD, ESRD or renal death SUSTAIN 62 2 4 6 8 10 8 16 24 32 40 48 56 64 72 80 88 96 104 Patients with an event (%) Time since randomisation (weeks) Semaglutide Placebo HR: 0.64 95% CI (0.46; 0.88) p=0.005 Macroalbuminuria, doubling of serum creatinine and eGFR ≤45 mL/min/1.73 m2 per MDRD or the need for continuous renal-replacement therapy REWIND3 New macroalbuminuria, 30% fall in eGFR or the need for continuous renal-replacement therapy HR: 0.85 95% CI (0.78; 0.93) p=0.0004
  • 3. Gerstein HC et al. Lancet 2019; Epub 2019 June 10
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SLIDE 6

Introduction to the incretin hormone GLP-1

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SLIDE 7 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
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SLIDE 8

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

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SLIDE 9

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
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SLIDE 10 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
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SLIDE 11 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)
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SLIDE 12 *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
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SLIDE 13 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
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SLIDE 14

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
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SLIDE 15
  • 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
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SLIDE 16

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)
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SLIDE 17

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
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SLIDE 18

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
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SLIDE 19

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
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SLIDE 20
  • 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
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SLIDE 21

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)
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SLIDE 22

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
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SLIDE 23 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
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SLIDE 24
  • 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 during ECFV expansion and NaCl loading (independent of net renal
haemodynamics and circulating concentrations of renin, aldosterone and natriuretic peptides (proANP, ANP and BNP); perhaps via suppression of ANG II
  • > GLP-1RA treatment reduces systolic blood pressure and reduces risk of macroalbuminuria
  • GLP-1R activation in the GI tract reduces GI motility
  • > 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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SLIDE 25

T h a t ’ si t f

  • l

k s !

filip.knop@regionh.dk
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SLIDE 26 GLP-1 20 40 60 80 100 120 140 10 20 30 40 50 60 Time (min) pmol/L * * * Glucose (75 g) + NaCl (6 g) Glucose (75 g) A n g io te n s in II 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 5 1 0 1 5 2 0 T im e (m in ) p g /m l * * G lu c o s e (7 5 g ) + S a lt (6 g ) G lu c o s e (7 5 g ) Orally ingested NaCl increases GLP-1 secretion – supporting a GLP- 1-mediated gut-renal axis for urinary sodium excretion Perhaps involving suppression of ANG II GLP-1, glucagon-like peptide 1 Asmar A et al. Diabetes June 2019 68(S1):1956-P