GLP-1 and use with insulin

Giorgio Sesti

University “Magna Graecia” of Catanzaro

T2DM anti-hyperglycaemic therapy: general recommendations

Diabetes Care 2012;35:1364-1379; Diabetologia 2012;55:1577-1596.

T2DM anti-hyperglycaemic therapy: general recommendations

Diabetes Care 2012;35:1364-1379; Diabetologia 2012;55:1577-1596.

Why treating with a combination of a glucagon-like peptide 1 (GLP‑1) receptor agonist and

long-acting insulin ?

Butler et al. Diabetes 2003’52:102-110.

ND IFG T2DM ND T2DM.000

.500

1.000

1.500

2.000

2.500

3.000

3.500

Obese Lean

-50%

-63%

β-ce

ll vo

lum

e (%

)

Mean relative β-cell volume in obese non-diabetic, IFG and diabetic subjects and lean subjects

Butler, A. et al Diabetes 52: 102-110, 2003Butler AE et al. Diabetes 52:102–110,2003

β-cell apoptosis was 3- fold increased in obese with type 2 diabetes and 10-fold increased in lean with type 2 diabetes vs. their respective control groups

(P <0.05)

(P <0.05)

Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype

of T2DM

Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195. *Shown in rodents or in vitro models only.

LiraglutideGLP-1

Compound (nM)

Apop

toti

c b-

cells

(%

of c

ontr

ol)

0

25

50

75

100

0 1 10 100 1000

**

* **

**ND

*p < 0.01, **p < 0.005

Bregenholt et al. Biochem Biophys Res Commun 330: 577–584, 2005

Cytokine-induced apoptosis

0

25

50

75

100

0 1 10 100 1000ND

*

****

** *

*

Fatty-acid-induced apoptosis in neo-natal rat

islets

Compound (nM)

Liraglutide inhibits beta-cell apoptosis in isolated neo-natal rat islets

UKPDS 34. Lancet 1998:352:854–865

6.2% – upper limit of normal range

8.0

6.0

7.5

7.0

6.5

Time (years)

00 2 3 4 51

Rosiglitazone Metformin Glibenclamide

Rosiglitazone vs. metformin–0.13 (–0.22 to –0.05), p=0.002Rosiglitazone vs. glibenclamide–0.42 (–0.50 to –0.33), p<0.0016.0

7.0

8.0

9.0

Med

ian

HbA

1c (

%)

Years from randomisation

ConventionalGlibenclamideMetforminInsulin

Recommended treatment

target ≤7.0%

2 4 6 8 100

ADOPTUKPDS

7.5

8.5

6.5

Over time, glycaemic control deteriorates

Kahn et al. N Engl J Med 2006;355:2427–43

UKPDS 16. Diabetes 1995;44:1249-1258; Lebovitz 1999;7:139-153.

Years from diagnosis

-ce

ll fu

ncti

on (

%, H

OM

A)

Diabetes diagnosis

β-cell function progressively declines

ADOPTUKPDS

0

20

40

60

80

100

Diet (n=110)Sulphonylurea (n=511)

Metformin (n=159)

–5 –4 –3 –2 –1 0 1 2 3 4 5 6

Extrapolation of β-cell function prior to diagnosis

0 1 2 3 4 50

60

70

80

90

100

Rosiglitazone: -2.0 (-2.6 to -1.3)Metformin: -3.1 (-3.8 to -2.5)Glyburide: -6.1 (-6.8 to -5.4)

Annualised slope (95% CI)

Treatment difference (95% CI) Rosiglitazone vs. metformin, 5.8 (1.9 to 9.8); p=0.003 Rosiglitazone vs. glyburide, -0.8 (-4.7 to 3.1)); p=0.67

Time (years)β-

cell

func

tion

(%

)

Kahn et al. N Engl J Med 2006;355:2427-2443.

Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype

of T2DM

*Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.

Vilsbøll et al. Diabet Med 2008;25:152-156.

First-phase insulin

secretionMean

change vs. baseline

(pmol/l/hr)

p=0.05

Placebo(n=5)

0.65 mg/day(n=5)

1.25 mg/day(n=9)

1.90 mg/day (n=6)

p<0.02

0

5

10

15

20

Liraglutide increased first-phase insulin secretion

Normals, n=11; Type 2 diabetes, n=12.Muller WA et al. N Engl J Med. 283:109–115, 1970.

Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes

-60 0 60 120 180 240

360330300270240110

80

140130120110100

90

120906030

0

Glucose (mg%)

Insulin (μ/ml)

Glucagon (μIμ/ml)

Meal

(minutes)

Type 2 diabetes

Normals

Delayed/depressedinsulin response

Non-suppressed glucagon

Glucagon secretion

Pancreatic cells: -cell -cell -cell

Hepatic glucose production

Insulin secretion

Excessive hepatic glucose production

Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype

of T2DM

*Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.

Liraglutide significantly reduced the 24-h AUC of glucagon in T2DM

Placebo

Liraglutide

Degn KB et al. Diabetes 53:1187–1194, 2004

Garber et al. Diabetes Obes Metab 2011;13:348-356.

Change in FPG over time: LEAD-3 2-year completers

0 8 16 24 32 40 48 56 64 72 80 88 96 1046.06.57.07.58.08.59.09.5

10.0

Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride 8 mgTime (weeks)

FPG

(m

mol

/l)

Observed mean±2SE, no imputation for missing values.

7.45 mmol/l7.58 mmol/l

8.54 mmol/l

0

Jones KL, et al. J Nucl Med 37:1643-1648, 1996

Gastric emptying rate is an important determinant of PPG in early Type 2 Diabetes

Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype

of T2DM

*Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.

Gastric emptying is inhibited in a dose-dependent manner by GLP‑1 administration

Meier J J et al. J. Clin. Endocrinol. 88: 2716–2725, 2003

Flint et al. Adv Ther 2011;28:213-226.

PPG profile of liraglutide 1.8 mg (baseline corrected)

Chan

ge fr

om b

asel

ine

(mm

ol/l)

Time since start of meal (hours)

-1

2

1

0

3

4

5

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Liraglutide 1.8 mgPlacebo

GLP-1

Energy intake

SatietyGastric emptying

GLP-1 action on the GI and central nervous systems

• In the arcuate nucleus, mRNA expression of the anorectic neurotransmitter CART was significantly increased following liraglutide treatment.

• Liraglutide prevented the increase in orexigenic NPY mRNA seen in weight-matched (food-restricted) rats.

CART

0

2.5

0.5

1.0

Gen

e ex

pres

sion

(a

rbit

rary

uni

ts)

Vehicle Liraglutide

2.0

1.5

Weight-matched

P<0.05P<0.05

0

2.5

0.5

1.0

Gen

e ex

pres

sion

(a

rbit

rary

uni

ts)

Vehicle Liraglutide

2.0

1.5

Weight-matched

p<0.05p<0.05NPY

Vrang et al. Diabetes 59 (Suppl 1) 583 P, 2010

Liraglutide increases anorectic neurotransmitter CART mRNA expression and prevents fasting induced orexigenic NPY mRNA

expression in rats

0 8 16 24 32 40 48 56 64 72 80 88 96 104

-4

-3

-2

-1

0

1

2

3

4

Liraglutide 1.8 mg Liraglutide 1.2 mg

Chan

ge in

bod

y w

eigh

t (k

g)

-2.8 kg-2.3 kg

+1.0 kg

Time (weeks)

Change in body weight over time — 2-year completers of LEAD-3

Observed mean±2SE (standard error), no imputation for missing valuesGarber et al. Diabetes Obes Metab 2011;13:348–56 (LEAD-3 2-year extension)

Pratley RE et al. Lancet 375: 1447–1456, 2010

Liraglutide vs. sitagliptin for type 2 diabetes patients who did not have adequate glycaemic control with metformin: Change in body

weight

–3.38 kg

–2.86 kg

–0.96 kg

Dose–response relationships for the effects of GLP-1

Holst JJ et al Trends in Mol Med 2008

Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in

addition to metformin vs. placebo: At least one event of overall hypoglycaemia (odds ratio)

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012

Series10

2

4

6

8

10

12

14

16

18

20

8.86000000000001

10.51

0.45 0.4

1.12999999999999 0.92

4.77

17.78

SU Glinides TZDs Acarbose DPP-4 GLP-1 Basal Biphasic

inhibitors agonists insulin insulin

At le

ast

one

even

t of

ove

rall

hypo

glyc

aem

ia (

odds

ra

tio)

The combination of basal insulin and GLP‑1-based therapies addresses complimentary targets such as:

Fasting and pre-prandial glucose by suppressing hepatic glucose production and improving β-cell function

Post-prandial glucose by decelerating gastric emptying

…and may help alleviate some of the problems of insulin therapy:

Weight gain

Hypoglycaemia

Elevated doses of insulin

In clinical practice, combination therapy could arise:

1. By adding insulin to pre-existing GLP-1RA therapy 2. By adding GLP-1RAs to established insulin therapy

Clinical outcomes

DeVries et al. Diabetes Care 2012;35:1446-1454.

IDet + liraglutide 1.8 mg (n=162)

Liraglutide 1.8 mg (n=161)

Adults 18–80 years with T2DM

HbA1c: 7.0–10.0% (MET only)

7.0–8.5% (MET + SU)

MET (≥1500 mg)or MET (≥1500 mg) + SU (≤50% max. dose)

for ≥3 months

Open-label study with two randomised and one non-randomised

treatment arm

Conducted in 7 European countries,

Canadaand the US

Liraglutide 1.8 mg

Run-in period:12 weeks

Randomisation

Liraglutide 1.8 mg (n=498)

Liraglutide 0.6 mg 1 week

HbA1c <7.0%Observational group

Randomised period: 26 weeks

IDet, insulin detemir; MET, metformin; SU, sulphonylurea

Liraglutide 1.2 mg1 week

Metformin ≥1500 mg/day; SU discontinued

DeVries et al. Diabetes Care 2012;35:1446-1454.

39% of run-in completers had

HbA1c ≥7.0%

61% of run-in completers had

HbA1c <7.0%

HbA1c ≥7.0% (1:1 randomisation)

Randomised treatment group

Randomised control group

Trial design

Mean (2SE); data are from the FAS, no imputation.

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Randomised control group (RC; MET + liraglutide 1.8 mg)Randomised treatment group (RT; MET + IDet + liraglutide 1.8 mg)Observational group (O; MET + liraglutide 1.8 mg)

Chan

ge in

HbA

1c (

%)

Time (weeks)

Run-in(Weeks -12 to 0)

Randomised period(Weeks 0 to 26)

RC: 8.29RT: 8.22O: 7.72

RC: -0.66RT: -0.60

O: -1.34

(final value 7.5)RC: -0.76

(final value 7.1)RT: -1.13

(final value 6.6)O: -1.12

Mean change in HbA1c by week

DeVries et al. Diabetes Care 2012;35:1446-1454.

456789

10111213

Mean (2SE); data are from the FAS, no imputation. p-values are for treatment differences in changes from randomisation (Week 0) for the meal (FAS LOCF)

Self-

mea

sure

d pl

asm

a gl

ucos

e (m

mol

/l)

p=0.0003

Randomisation (Week 0)Randomised control group (metformin+liraglutide 1.8 mg)Randomised treatment group(metformin+IDet+liraglutide 1.8 mg)

0

p=0.0244 p=0.0141

Week 26Randomised control group (metformin+liraglutide 1.8 mg)Randomised treatment group(metformin+IDet+liraglutide 1.8 mg)

Before breakfast

90 min afterbreakfast

Before lunch

Before dinner

90 min afterlunch

90 min afterdinner

Bedtime

Seven-point glucose profiles

DeVries et al. Diabetes Care 2012;35:1446-1454.

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

-6

-5

-4

-3

-2

-1

0

Randomised control group (RC; metformin+liraglutide 1.8 mg)Randomised treatment group (RT; metformin+IDet+liraglutide 1.8 mg)

Mean (2SE); data are from the FAS, no imputation.

Chan

ge in

bod

y w

eigh

t (k

g)

Time (weeks)

Run-in(Weeks −12 to 0)

Randomised period(Weeks 0 to 26)

Baseline:RC: 98.6RT: 99.5O: 99.0

RC: 3.46RT: 3.53

O: 4.35RC: 4.74O: 4.78

RT: 4.00

Mean body weight change by week

DeVries et al. Diabetes Care 2012;35:1446-1454.

Clinical outcomes

In clinical practice, combination therapy could arise:

1. By adding insulin to pre-existing GLP-1RA therapy 2. By adding GLP-1RAs to established insulin therapy

Buse et al. Ann Intern Med 2011;154:103-112.

Insulin Titration

FPG Algorithm (mmol/l)

Dose Change

(U)<3.1b −4

3.1-3.9b −24.0-5.5c 05.6-6.6c +26.7-7.7c +47.8-9.9c +6

≥10c +8

BID, twice daily (≤60 min before morning and evening meals); FPG, fasting plasma glucose; OAMs, oral antihyperglycaemic medications (metformin and/or pioglitazone); T, telephone call. aInsulin titrated to FPG of <5.6 mmol/l 5 weeks after randomisation and throughout remainder of study using "Treat to Target" algorithm adapted from Riddle et al. Diabetes Care 2003;26(11):3080-3086. bValues for at least 1 FPG since the last assessment. cBased on the average of FPGs during the last 3 to 7 days. Note: The increase in the total daily dose should not exceed more than 10 U/day or 10% of the current total daily dose, whichever is greater.

*

Screening Randomisation

5 µg BID

Insulin glargine + OAMscontinued throughout study

Endpoint

Placebo (volume equivalent)

10 µg BID

T T T

VisitWeek of treatment

1

2

3

0

5

4

4

2

6

6 30

13

10

8

14

9

18

10

22

11 12

268

72

1

T T T T T T T

+

T T

1

2

3

0

5

4

4

2

6

6 30

13

10

8

14

9

18

10

22

11 12

268

72

1

1

2

3

0

5

4

4

2

6

6 30

13

10

8

14

9

*

Exenatide

+

Exenatide

(volume equivalent)

T T T

1 3

0

5

4

4

2

6

6 30

13

10

8 9

18

10

22

11 12

268

72

T T T T T T TT T

1 3

0

5

4

4 6

6 30

138 9

Placebo

Insulin Titration

−

Study design

Buse et al. Ann Intern Med 2011;154:103-112.

Baseline 18 30-2.5

-2

-1.5

-1

-0.5

00

-1.83-

1.74000000000002

-0.9500000000

00001 -1.04

Exenatide BID + GlarginePlacebo BID + Glargine

Weeks

HbA

1c (

%)

Data are mean±95% CI.

Difference in HbA1c at 30 weeks: -0.69% (95% CI -0.93 to -0.46%; p<0.001)

HbA1c reduction: patients taking exenatide or placebo with insulin glargine

Buse et al. Ann Intern Med 2011;154:103-112.

Data are mean±95% CI.

Body weight change over 30 weeks (p<0.001; all time points)

0 2 4 6 8 10 14 18 22 26 30-3

-2

-1

0

1

2

0

-0.45 -0.7500000000000

07-1.17

-1.47-1.62

-1.74

-2.26-1.86

-1.6900000000000

1-1.78

0-0.07 0.04 -0.21

-0.05-0.25

0.13 0.02

0.630000000000008

1.01 0.960000000000001

Exenatide BID + GlarginePlacebo BID + Glargine

Weeks

Body

wei

ght

chan

ge (

kg)

Body weight change: patients taking exenatide or placebo with insulin glargine

Buse et al. Ann Intern Med 2011;154:103-112.

Insulin glargine+exenatideInsulin glargine+placebo

Categoria 10

5

10

15

20

25

30

35

25

17

0

2926

1

Prop

orti

on o

f pat

ient

s ex

peri

enci

ng h

ypog

lyca

emia

(%

)

Minor Minor nocturnal Major

Hypoglycaemic events

Buse et al. Ann Intern Med 2011;154:103-112.

Between-group Difference -6.5 (95% CI 12.3 to 0.8); p=0.030

Categoria 10

5

10

15

20

25

30

13

26

Chan

ge in

insu

lin d

ose

(U/d

)

Insulin glargine+exenatide Insulin glargine+placebo

Increase insulin dosage from baseline was greater in the placebo group

Buse et al. Ann Intern Med 154:103-112, 2011

Overall conclusions

Adding basal insulin to pre-existing GLP-1RA therapy or adding GLP-1RAs to established insulin therapy may help improve glycaemic control and reduce glycaemic excursions

Improvement in HbA1c by combining GLP-1RAs with insulin is associated with:

Weight loss

No increased risk of hypoglycaemia

Reduction in insulin doses

THANK YOU !

Sesti lecture