GLP‐1 and metabolic syndrome.Bench to bedside.

Kevin Niswender MD, PhDVanderbilt University School of MedicineVanderbilt University School of Medicine

The incretin effect.Control Subjects

(n=8)

L

0.6

0.5

80

60

Incretin Effect

sulin

, mU

/L nmol / L

0.4

0.3

60

40

IR In

s

L

0.2

0.120

Oral glucose load Time min

00

18060 1200g

Intravenous (IV) glucose infusionTime, min

Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

The Incretin Axis

Hormonal signals• GLP-1• GIP

Glucagon(GLP-1)

alpha alpha cellscellsbbeta cellseta cells

Pancreas

Neural signals

GutInsulin

(GLP-1,GIP)Nutrient signals

Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag.Drucker DJ. Diabetes Care. 2003;26:2929–2940.Kieffer T et al. Endocr Rev. 1999;20:876–913.Nauck MA et al. Diabetologia. 1993;36:741–744.

Adiposity Negative Feedback SignalingAdiposity Negative Feedback Signalingi.e. regulation of “metabolic drive”

Schwartz MW et al., Nature 2000

Does GLP-1 work in a similar way?Does GLP-1 work in a similar way?

GLP-1 given ICV lowers food intake..GLP 1 given ICV lowers food intake..

Turton et al., Nature 1996

and blunts NPY induced feeding…and blunts NPY induced feeding.

Turton et al., Nature 1996

Reward CircuitryReward Circuitry

Cami NEJM 2003

GLP-1 analogue decreases candy and increases chow intake.(and decreases weight gain)

Raun et al., Diabetes 2007

GLP-1 as an adiposity signal?GLP 1 as an adiposity signal?

• GLP-1 can act in hypothalamic areas toGLP 1 can act in hypothalamic areas to control feeding.

• In rodent models this is not required for• In rodent models, this is not required for an effect on feeding and weight gain.GLP 1 i t d d i ti t f t• GLP-1 is not produced in proportion to fat mass.

• Rather, energy in the form of food stimulates GLP-1 production.

Feeding occurs in meals: ti ti d l t i tisatiation and meal termination.

Schwartz MW et al., Nature 2000

CCK reduces meal sizeCCK reduces meal size

Geary Phys. Beh. 2004

GLP-1 induces satiety and reduces meal size

4*

(MJ)

4

take

(

2

rgy

int

saline GLP-10en

er

Flint et al., JCI 1990

GLP-1 works in periphery as aGLP 1 works in periphery as a satiety factor.

Williams et al., Endocrinology 2008

Energy homeostasis and GLP-1:potential sites/mechanisms of actionpotential sites/mechanisms of action

GLP-1

GLP-1

GLP-1

GLP-1

Schwartz MW et al., Nature 2000

GLP‐1 and GIP Are Degraded by DPP‐4

Meal

Intestinal GIP and GLP-1 release

DPP-4Enzymerelease Enzyme

GIP-(1–42) GIP-(3–42)( )GLP-1(7–36)

Intact

( )GLP-1(9–36)Metabolites

Rapid Inactivation

Half-life*GLP-1 ~ 2 minutes

GIP and GLP-1 Actions

GLP-1 2 minutesGIP ~ 5 minutes

Deacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.

Therapeutic approaches: exenatide and liraglutide.

GLP-1 (amidated form)HisAlaGluGlyThrPheThrSerAspValSerSerTyrLeuGluGlyGlnAlaAlaLysGluPheIleAlaTrpLeuValLysGlyArg amide

Proteolytic inactivation (DPP-4)

7 10 15 20 25 30 35 36

GLP 1 (amidated form)

HisGlyGluGlyThrPheThrSerAspLeuSerLysGlnMetGluGluGluAlaValArgLeuPheIle GluTrpLeuLysAsnGlyGlyProSerSerGlyAlaProProProSeramide

Exenatide

HisAlaGluGlyThrPheThrSerAspValSerSerTyrLeuGluGlyGlnAlaAlaLysGluPheIle AlaTrpLeuVal ArgGlyArgGly

Liraglutide

Glu

C-16 free fatty acidAlbumin

Does the promise translate: glucose?Does the promise translate: glucose?0

Liraglutide Exenatide

0 5(%)

LiraglutideBaseline 8·2%

ExenatideBaseline 8·1%

–0·5

ge in

HbA

1C(

–1·0Chan

g

–1·5

p<0·0001

Buse et al., Lancet 2009

Does the promise translate: weight?Does the promise translate: weight?98 Liraglutide

Exenatide

(kg) 94

96

odyw

eigh

t

90

92

Bo

88

90

086

2 4 6 8 10 12 14Time (weeks)

16 18 20 22 24 26

Buse et al., Lancet 2009

Liraglutide (Victoza) and obesity

Astrup, Lancet 2009

Does the promise translate: Lipids?Liraglutide Exenatide Estimated treatment

difference(liraglutide–exenatide)(95% CI)

p value

Islet function

Fasting insulin (pmol/L) 12·43 (6·93) –1·38 (6·92) 13·81 (0·94 to 26·68) 0·0355

Fasting C-peptide (nmol/L) 0·05 (0·05) –0·02 (0·05) 0·07 (–0·02 to 0·16) 0·1340

Fasting proinsulin-to-insulinratio

0·00 (0·03) –0·02 (0·03) 0·02 (–0·03 to 0·08) 0·4309

HOMA-B 32·12% (6·75%) 2·74% (6·75%) 29·37% (16·81% to <0·000141·93%)

Fasting glucagon (ng/L) –19·44(5·18) –12·33 (5·12) –7·12 (–16·66 to 2·43) 0·1436

Blood pressure

Systolic blood pressure(mm Hg)

–2·51 (1·15) –2·00 (1·18) –0·51 (–2·66 to 1·64) 0·6409

Diastolic blood pressure(mm Hg)

–1·05 (0·71) –1·98 (0·71) 0·93 (–0·37 to 2·23) 0·1610

Lipid profiles

Total cholesterol (mmol/L) –0·20 (0·07) –0·09 (0·07) –0·11 (–0·23 to 0·02) 0·0946

LDL cholesterol (mmol/L) –0·44 (0·06) –0·40 (0·06) –0·04 (–0·15 to 0·06) 0·4412

VLDL cholesterol (mmol/L) 0·20 (0·04) 0·27 (0·04) –0·07 (–0·13 to –0·01) 0·0277

HDL cholesterol (mmol/L) –0·04 (0·02) –0·05 (0·02) 0·01 (–0·02 to 0·04) 0·5105

Triglycerides (mmol/L) –0·41 (0·10) –0·23 (0·10) –0·18 (–0·37 to 0·00) 0·0485

Free fatty acids (mmol/L) –0·17 (0·02) –0·10 (0·02) –0·07 (–0·11 to –0·03) 0·0014

Apolipoprotein B (g/L) –0·06 (0·02) –0·03 (0·02) –0·02 (–0·05 to 0·01) 0·1119Apolipoprotein B (g/L) 0 06 (0 02) 0 03 (0 02) 0 02 ( 0 05 to 0 01) 0 1119

Data are least square means (SE). HOMA-B=homoeostasis model assessmentβ-cell function. LDL=low-densitylipoprotein. HDL=high-density lipoprotein.VLDL=very low-density lipoprotein.

Change in indicesof islet function and cardiovascular risk from baseline to week 26Buse et al., Lancet 2009

Does the promise translate: exenatide 82 weeks?

234

Quartile I II III IV

Systolic BP

Quartile I II III IV

Diastolic BP

Hg) 2

34

mH

g)

–3–2–1

01

ysto

lic B

P (m

m

–3–2–1

01

ΔD

iast

olic

BP

(mm

–6–5–4

ΔS

–6–5–4Δ

Triglycerides HDL C

Quartile I II III IV Quartile I II III IV

–20

0

Triglycerides

/dl)

789

HDL-C

–80

–60

–40

Trig

lyce

ride

(mg/

234567

ΔH

DL

(mg/

dl)

–120

–100Δ

012

Blonde, DOM 2006