glp 1 edffect of cardiovascular system

GLP-1 Beyond blood sugar lowering effect

The effect of cardiovascular system

大里仁愛醫院新陳代謝科林文玉醫師

月眉福容 June 30, 2012

Introduction

IN-CRET-IN

INtestine seCRETion INsulin

Definition: gut derived factors that increase glucose stimulated

insulin secretion

Two hormones: (1) glucagon-like peptide-1 (GLP-1)

(2) glucose-dependent insulinotropic polypeptide (GIP)

Source :Creutzfeldt Diabetologia 28: 5645 1985

Discovery and identification of regulatory peptides in gastrointestional tract. Peptides may act as hormones, neurotransmitters, and growth factors. Sometimes 1 peptide acts in 2 or all of the 3 roles.

Physiological Reviews vol. 78, No 4, October 1998

Gut Hormones

Gut hormones signals the brain (hypothalamus) toachieve efficient nutrient digestion and

absorption: gut-brain interaction ( your brain in your gut

)

Melanocortin System and Regulation of Body WeightAnd Energy Expenditure

NTS

Central Melanocortin System and AgRP/NPY

• This system is involved in body weight regulation through its role in appetite and energy expenditure via leptin, grhelin and Agouti related protein. It receives inputs from hormone, nutrients and afferent neural inputs, and is unique in its composition of fibers which express both agonists and antagonists of melanocortin receptors.

• The melanocortin receptors, MC3-R and MC4-R, are directly positive linked to metabolism and negative to body weight control. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone) and antagonized by the agouti-related protein.

• Agouti-related protein also called Agouti-related peptide (AgRP) is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is only synthesised in NPY containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with Neuropeptide Y and works by increasing appetite and decreasing metabolism and energy expenditure ( increased weight ). It is one of the most potent and long-lasting of appetite stimulators

Regulation of gastric emptying

DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008

Regulation of Gastric Emptying

• Normally, the rate of gastric emptying is tightly regulated as a result of neural and hormonal feedback triggered by the interaction of nutrients within the small intestine known as the ileal break mechanism or “extrinsic pathway” of control. This feedback is caloric load dependent, relates to the length of small intestine exposed to nutrient, and regulates the overall rate of emptying to about 2–3 kcal/min.

• The intrinsic pathway is dependent upon the action of hyper- or hypoglycemia on gastric emptying. The increase in hIAPP and decrease in ghrelin both slow the gastric emptying rate by producing a parasympathetic signal. Ghrelin secretion enhances antropyloric coordination, a signal transmitted via the vagus nerve, which accelerates gastric emptying.

Rates of Remission of Diabetes

Adjustable

Gastric Banding

Roux-en-Y

Gastric Bypass

Biliopancreatic

Diversion

>95% (Immediate)48% (Slow) 84% (Immediate)

Foregut or Hindgut ?

• The “foregut hypothesis” raised by Rubino et al suggests that nutrient interactions in the duodenum are diabetogenic and, hence, bypassing the duodenum would reverse this defect. Their conclusions come from experiments in rodents that underwent jejunoileal bypass and subsequent refeeding through the bypassed intestine.

• The “hindgut hypothesis” raised by Cummings et al suggests that accelerated transit of concentrated nutrients (particularly glucose) to the distal intestine results in increased production of insulinotropic and appetite-controlling substances, which account for the reversal of hyperglycemia and obesity.

Improvement of Glycemia after Metabolic Surgery is Independent

of Body Weight Loss

In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion. In 1932, the name incretin was coined.

In 1986 Nauck demonstrated that a glucose infusion graded to achieve plasma glucose levels identical to those with oral load led

to a insulin response that was only one quarter as great.

J Clin Endocrinol Metab. 1986;63:492-498.

Nauck et al. Diabetologia. 1986

Incretin effect on insulin secretion

Oral glucose loadIntravenous glucose infusion

Time (min)In

sulin

(m

U/l)

80

60

40

20

0

18060 1200

Time (min)

Insu

lin (

mU

/l)

80

60

40

20

0

18060 1200

Incretin effect

Control subjects (n=8) People with Type 2 diabetes (n=14)

Diabetes care, Volume 34, Supplement 2, May 2011

Gastrointestinally mediated glucose disposal ( GIGD ): 20-80%, normal > 70%

If 25g iv glucose is required to copy a 75g oral glucose load ( glucose excursion ), The GIGD amounts to 100x (75-25)/75 = 66%

What is GLP-1?

Insulin response to oral glucose load (50 g/400 ml, ●) and during isoglycaemic i.v. glucose infusion (●)

IR-in

sulin

(m

U/l)

80

60

40

20

–10 –5 60 120 1800

** * * *

**

Time (min)

Incretineffect

• A 31 amino acid peptide• Cleaved from proglucagon in

L-cells in the GI-tract (and neurons in hindbrain/hypothalamus)

• Secreted in response to meal ingestion (direct luminal and indirect neuronal stimulation)

• Member of incretin family (GIP, GLP-1 and others)

• GLP-1 has following effects:

Nauck et al. Diabetologia 1986;29: 46–52, *p ≤ 0.05.

Increased insulin response Key observations

• Glucose-dependently stimulates insulin secretion and decreases glucagon secretion

• Delays gastric emptying

• Decreases food intake and induces satiety

• Stimulates -cell function and preserves or increases -cell mass in animal models

Glucose-lowering effect of GLP-1

Endocrine Review, April 2012, 33(2):187-215

Why not GIP ?

Because of its short half-life, native GLP-1 has limited clinical value

7

37

9

Lys

DPP-IV

His Ala Thr Thr SerPheGlu Gly Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Type 2 diabetes

Healthy individuals

i.v. bolus GLP-1 (15 nmol/l)

Inta

ct G

LP-1

(p

mol/l)

Time (min)

–5 5 15 35 45

0

500

1000

25

t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l)

Enzymatic cleavageHigh clearance (4–9 l/min)

Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.

GLP-1 enhancement

Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

GLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life:• exenatide• liraglutide

Injectables

Block DPP-4, the enzyme that degrades GLP-1:• Sitagliptin• Vildagliptin• Linagliptin

Oral agents

22

Pharmacokinetic Properties of DPP-4 Inhibitors

Sitagliptin

(Merck)1Vildagliptin (Novartis)2

Saxagliptin (BMS/AZ)3

Alogliptin (Takeda)5

Linagliptin(BI)6–9

Absorption tmax (median) 1–4 h 1.7 h 2 h (4 h for active

metabolite) 1–2 h 1.34–1.53 h

Bioavailability ~87% 85% >75 %4 N/A 29.5%Half-life (t1/2) at clinically relevant dose

12.4 h ~2–3 h 2.5 h (parent)3.1 h (metabolite)

12.4–21.4 h(25–800 mg)

113–131 h(1–10 mg)

Distribution 38% protein bound 9.3% protein bound Low protein binding N/A

Prominent concentration-

dependent protein binding:

<1 nM: ~99%>100 nM: 70%–80%

Metabolism ~16% metabolized69% metabolized

mainly renal(inactive metabolite)

Hepatic (active metabolite)

CYP3A4/5 <8% metabolized ~10% metabolized

Elimination Renal 87%(79% unchanged)

Renal 85%(23% unchanged)

Renal 75%(24% as parent; 36% as

active metabolite)

Renal(60%–71%unchanged)

Feces 81.5%(74.1% unchanged);

Renal 5.4%(3.9% unchanged)

DPP-4=dipeptidyl peptidase-4. 1. EU-SPC for JANUVIA, 2010. 2. EU-SPC for Galvus, 2010. 3. EU-SPC for Onglyza, 2010. 4. EPAR for Onglyza. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed May 4, 2011. 5. Christopher R et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840. 8. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62. 9. Blech S et al. Drug Metab Dispos.2010;38:667–678.

~ 5% of orally administered linagliptin is excreted via the

kidneys

The majority of Linagliptin is excreted unchanged via bile and gut

Metabolism

~90% transferred unchanged

~10% (inactive) metabolite

~ 95% of orally administered linagliptin is excreted via the

bile and gut

Excretion1:

~95% bound to plasma proteins(in essence DPP-4)

Absolute bioavailability: ~30%, with or without food

Tablet intake: 5mg QD, independent of food

Absorption

Source: US prescribing information

1 At steady state

Linagliptin is the first only DPP-4 inhibitor that does not require dose adjustment

5 m

g

100

mg

5 m

g

50 m

g2

5 mg

50 m

g BID

50 m

g QD

2.5

mg

Linagliptin(Trajenta®)

Sitagliptin(Januvia®)

Vildagliptin(Galvus®)

Saxagliptin(Onglyza®)

No renal issues

At risk of renal impairment

Mild renal impairment

Moderate renal impairment

Severe renal impairment

Influence of hepatic impairment on pharmacokinetics & exposure of Linagliptin

No dosage adjustment for linagliptin is necessary for patients with mild, moderate or severe hepatic impairment

0

0.5

1

1.5

Fo

ld in

cre

as

e in

ex

po

su

re r

ela

tiv

e t

o

no

rma

l he

pa

tic

fu

nc

tio

nF

old

Incr

eas

e in

exp

osu

re r

elat

ive

to n

orm

al h

epat

ic f

unct

ion

Source: Data on file

Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C)

Hepatic impairment (Child-Pugh classification)

n=7n=8 n=9 n=8

Patients with mild moderate and severe hepatic impairment(according to the Child-Pugh classification A-C)

Child-Pugh Grade Points

A Well-compensated disease 5-6

B Significant functional compromise

7-9

C Decompensated disease 10-15

Effect on Cardiovascular

System

GLP-1R expression in mouse cardiac and vascular tissue

Polycloal Anti-GLP-1R Ab Pre-absorption

Anti-SM (red )Anti-GLP-1 (green )Nuclear stain ( blue )In media SM

Endocardium

Circulation. 2008;117:2340-2350

Mesenteric arerty

Effects of GLP-1 in p’ts with AMI and LV dysfunction after successful reperfusion

• Glucose-insulin-potassium (GIK) infusions benefit patient with AMI, with enhancement of myocardial glucose uptake and oxidation and the efficacy of generating ATP.

• Dutch investigators reported beneficial effects of GIK therapy in patients with AMI s/p PCI, the benefits were limited to those in Killip class I. Patients with CHF (Killip class III–IV) exhibited an adverse trend with GIK therapy.

• Glucagon-like peptide-1 (GLP-1 [7–36] amide, with insulinotrophic and insulinmimetic effect, minimizing risks of hypoglycemia and the need for glucose infusion.

• If a continuous 72 hr infusion of GLP-1( post PCI ) improves global and regional ventricular function?

Lazaros A. Nikolaidis, Circulation 2004 109:962-965

Effects of GLP-1 in patients with AMI and LV dysfunction after successful reperfusion

Circulation 2004 109:962-965

Circulation 2004 109:962-965

The benefits of GLP-1 were independent of AMI location or history of Diabetes

GLP-1R Agonist liraglutide: cardioprotective pathways, treated before ischemic episode

• Whether liraglutide exerts cardioprotective actions in a preclinical murine model of experimental ischemia after coronary artery occlusion.

• If treatment with liraglutide before induction of ischemia leads to activation of prosurvival kinases and cytoprotective genes in the heart and limits infarct size, expansion, and cardiac rupture in the normal and diabetic heart?

• Moreover, liraglutide increases cAMP and reduces apoptosis in a GLP-1R–dependent manner in murine cardiomyocytes cultured in vitro.

Mohammad Hossein Noyan-Ashraf, Diabetes 58: 975-983, 2009

Non-diabetic

Diabetic

GLP-1R Agonist Improves Outcomes After Experimental Myocardial Infarction in Mice


blood sugar lowering

( n=20 )

) ( n=35 )( n=60)

( n=60)( Lir75 + WL, n= 25 )

Cardiac Rupture Post-MI


Diabetes vol. 58, April 2009

After weight correction,

No percent difference between.


Forskolin is commonly used to raise levels of cAMP in the study and research of Cell physiology.

Liraglutide increases cAMP and reduces apoptosis in a GLP-1R–dependent mannerIn murine cardiomyocytes in vitro.

Indian Coleus: Forskoin ( adenylate cyclase activator )


Lira 200 for 7 d, Killed before MI ( wild type ) 4 days after MI

• Liraglutide administration induces changes in the expression of cardioprotective proteins in normal non-AS murine heart, by phosphorylation of Akt and GSK3β and increased expression of Nrf2, PPAR- β/ δ and HO-1.

• Reduced levels of MMP-9 and cleaved caspase 3 in the infarct region at day 4 post-MI.

Extracellular signal-regulated kinases

Endocrine Review, April 2012, 33(2): 187-215

Direct Effects of GLP-1 on Myocardial Contractivity and Glucose Uptake

in Normal and Postischemic Rat Heart

• GLP-1 increased heart rate and blood pressure in intact rodents through sympathostimulatory effect ( Barragan 1994, 1996; Yamamoto, 2002 ).

• But depressed myocardial contractivity in isolated rat ventricular myocytes ( Vila petroff, 2001 ).

• GLP-1 enhanced recovery of LV function after transient coronary occlusion. Whether it is from GLP-1 direct effects and/or from increased myocardial glucose uptake ( like insulin effect ).

Tingcun Zhao, JPET 317:1106-1113, 2006

GLP-1 or insulin on LV dev. P, LV dP/dt, heart rate and coronary flow ( normal heart rat )

JPET 317:1106-1113, 2006

The effect of GLP-1 or insulin on myocardial glucose uptake and myocardial lactate

production (normal heart rat )

JPET 317:1106-1113, 2006

GLP-1 increased myocardial glucose uptake through a non-Akt-1-dependent mechanism,

distinct from insulin

JPET 317:1106-1113, 2006

The effect of GLP-1 or insulin on coronary flow, LV dev. P, LV dP/dt and LVEDP during 30 min of low flow

ischemia ( 5% baseline ) and 30 min of reperfusion

JPET 317:1106-1113, 2006

After 30 min of low flow ischemia, the change of myocardial glucose uptake

and lactate production

JPET 317:1106-1113, 2006

Myocardial signal transduction with increased myocardial glucose uptake

in postischemic myocardium

JPET 317:1106-1113, 2006

• GLP-1 and insulin has comparable effects on myocardial glucose uptake, but via different cellular mechanism. Insulin-mediated glucose uptake was associated with Akt-1 phosphorylation and GLUT-4 translocation. In contrast, GLP-1 did not increased Akt-1 and GLUT-4, but did result in increased GLUT-1 expression in sacrolemma.

• The benefits of GLP-1 and insulin to improve postischemic contractile dysfunction are related simply to enhanced glucose uptake.

Extracellular signal-regulated kinases


GLP-1R expression in mouse cardiac and vascular tissue

Polycloal Anti-GLP-1R Ab Pre-absorption Anti-SM (red )

Anti-GLP-1 (green )

Nuclear stain ( blue )In media SM

Endocardium

Loading control: GADPH, beta-actin

Cardioprotective and Vasodilatory Actions of GLP-1 Receptor Are Mediated Through Both GLP-1

Receptor-Dependent and –Independent Pathways

Circulation. 2008;117:2340-2350

Functional recovery after I/R injury in WT and Glp 1r-/- hearts with GLP-1 (9-36).

Circulation. 2008;117:2340-2350

GLP-1 ( 9-36 ) Vasodilatory effect might be through NO release

Circulation. 2008;117:2340-2350

Only GLP-1 (7-36)Rae GLP-9-26

1. Both GLP-1 and GLP-1(9-36) produced increased coronary flow in constant-pressure perfused isolated hearts and vasodilatation of resistance-level mesenteric arteries from WT and Glp1r -/- mice. Furthermore, this vasodilatory effect correlated with presumably NO-dependent cGMP release. But exendin-4 did not in that exendin-4 cannot bind to novel receptor of GLP-1 (9-36 )--- GLP-1 independent pathway.

What about endothelium?

GLP-1 Prevents Reactive Oxygen species-Induced Endothelial Cell Senescence

Arteriolscle Thromb Vasc Biology 2010; 30: 1407-1414

The PI3K/Akt Survival pathway Is Not required for the GLP-1Protective Effect in HCAEC


H89: inhibitor of Forkolin

GLP-1 Protective effect Is cAMP/PKA Dependent


Liraglutide attenuates induction of PAI-1 and vascular adhesion molecules

Journal of endocrinology ( 2009 ) 201, 59-66

Real-time Q-PCR of the effects of Liraglutide treatment on Nur77 mRNA expression

Journal of endocrinology ( 2009 ) 201, 59-66

• GLP-1 administration attenuates endothelial cell dysfunction in diabetic patients and inhibits TNF -mediated PAI-1 induction in human vascular endothelial cells.

α

Conclusion

Ongoing Trials

With or without metformin background therapy (including patients with contraindication to Metformin use in renal

impairment)

n= 6,000; approx. 6-7 year follow up

Inclusion if at least one of the following is fulfilled

1. Previous vascular complications

2. Evidence of end organ damage such as e.g. albuminuria

3. Age > 70 years

4. Two or more specified traditional CV risk factors

Primary endpoint: Time to the first occurrence of the primary composite endpoint:

1. CV death (including fatal stroke and fatal MI)

2. Non-fatal MI

3. Non-fatal stroke

4. Hospitalization for unstable angina pectoris

Glimepiride 1-4mg1Linagliptin 5mg vs.

1 16 weeks titration phase of glimepiride up to 4mg/day

CAROLINA will evaluate CV safety of Linagliptin in patients with T2DM at high CV risk

Rosenstock J., et al. ADA 2011 Poster 1103-PClinicaltrial.gov NCT01243424

Thanks for your attention!!

glp 1 edffect of cardiovascular system

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