GLP-1 Agonists And Insulin Therapy - Denver, Colorado · GLP-1 Agonists . And. Insulin Therapy....

GLP-1 Agonists And

Insulin Therapy

Steven V. Edelman, MDProfessor of Medicine

University of California San Diego School of MedicineVeterans Affairs Medical Center

Founder and Director, Taking Control of Your Diabetes, 501(c) 3

T2D –

Type 2 Diabetes A1C –

HbA1c or Glycated hemoglobin (1)

Abstract 0278-OR presented at ADA’s 71st Scientific Sessions in June 2011, and published online in Diabetes, Obesity and Metabolism on May 30, 2012

(2) Adapted from IMS data

3) Includes all types of basal insulinsLixisenatide was in-licensed from Zealand Pharma A/S. Lyxumia®

is the intended trademark for lixisenatide. Lixisenatide is currently not approved or licensed anywhere in the world

Riccardo Perfetti, MD, PhD

In patients controlled with basal insulin, PPG –

not FBG –

is the major contributor to

hyperglycaemia

42 41 42 43 48

58 59 58 57 52

0

10

20

30

40

50

60

70

80

90

100

<6.5 6.5–˂7.0 7.0–˂7.5 7.5–˂8.0 ≥8.0

% o

f pat

ient

s

HbA1c (%)

Basal hyperglycaemia

Postprandial hyperglycaemia

Relative contributions of FBG and PPG hyperglycaemia to overall hyperglycaemia at Week 24/28 in patients receiving insulin glargine (N=1699)

Riddle et al. Diabetes Care 2011;34:2508–14

Targeting FBG and PPG control is essential for optimal clinical outcomes

Data are pooled from six similarly designed, randomized, controlled trials of patients with T2DM suboptimally controlled on OADs

Options for additional control beyond basal insulin

Prandial insulin

Advantages Disadvantages

Effective in controlling PPG Increased risk of hypoglycaemia

Weight gain

GLP-1 receptor agonists

Advantages Disadvantages

Low rates of hypoglycaemia Nausea mainly on initiation

Weight loss in some patients

Effective in controlling PPG

The Goals For T2D Management Today Include

•

Optimal glucose control – A1c, FPG, PPG

•

Minimal hypoglycemia •

Weight loss or no weight gain

Exenatide Added to Insulin Glargine-Treated Patients with Type 2 Diabetes

Richard M Bergenstal, MD; John B Buse, MD, PhD; Leonard C Glass, MD; Cory R Heilmann, PhD; Michelle S Lewis, PhD; Anita YM Kwan, MS;

Byron J Hoogwerf, MD; Julio Rosenstock, MD

Study ObjectivesPrimary ObjectiveExenatide BID plus optimized titration of basal insulin, glargine, (OG+EXE BID) is superior to placebo plus optimized titration of basal insulin, glargine, (OG+PLB BID) as measured by change in A1C from baseline to Week 30

Secondary Endpoints•7-Point self-monitored blood glucose (SMBG) profiles•1,5-Anhydroglucitol•Change in body weight•Change in insulin dose•Self-reported hypoglycemic episodes and treatment-emergent adverse events (TEAEs)

Screening

Insulin Glargine + OAMs

Randomization

OG+EXE BID

OG+PLB BID

Weeks of treatment0 4 30

5μg EXE 10μg EXE

Study End

Study Design

-2

Baseline

Characteristics (ITT)EXE BID PLB BID

N 137 122Female (n [%]) 67 (49) 44 (36)Age (y) 59 ±

9 59 ±

10Weight (kg) 95.4 ±

20.4 93.4 ±

21.2BMI (kg/m2) 33.8 ±

5.8 33.1 ±

6.2A1C (%) 8.32 ±

0.85 8.50 ±

0.96Diabetes duration (y) 12 ±

7 12 ±

7FBG (mmol/L) 7.9 ±

2.1 8.3 ±

2.3Insulin Dose (U/kg) 0.51 ±

0.28 0.50 ±

0.24Systolic BP (mmHg) 130.0 ±

15.9 128.1 ±

13.4Diastolic BP (mmHg) 75.8 ±

9.8 74.5 ±

8.7OAMs (n [%])

NoneMetforminPioglitazoneMetformin+Pioglitazone

21 (15)91 (66)

2 (2)23 (17)

17 (14)91 (75)6 (5)8 (7)

-2

-1.5

-1

-0.5

0

0.5

0 18 30

Axis Tit

le 7.41 0.09%

6.70 0.09%

A1C Change from Baseline

LSMean ±

SE

A1C

Cha

nge

(%)

Weeks

OG+EXE BID (Baseline 8.3

0.1%)OG+PLB BID (Baseline 8.5

0.1%)

**

*

**

**

†

**

OG+EXE BID baselineOG+EXE BID endpoint

OG+PLB BID baselineOG+PLB BID endpoint

7-point Glucose ProfilesG

luco

se (m

mol

/L)

LSMean ±

SE*p<0.001. †p<0.01 and **p<0.05 for between-treatment comparison

‐1.78

0.96

‐3

‐2.5

‐2

‐1.5

‐1

‐0.5

0

0.5

1

1.5

2

0 2 4 6 8 10 14 18 22 26 30

** * * *

** * *

Change in Weight from BaselineW

eigh

t Cha

nge

(kg)

Weeks

OG+EXE BID (Baseline 95.4

1.7 kg)OG+PLB BID (Baseline 93.8

1.8 kg)

LSMean ±

SE *p<0.001 between-treatment comparison

*

-4 -3 -2 -1 1 2 3 4-15

-10

-5

5

10

15

0

0

-4 -3 -2 -1 1 2 3 4-15

-10

-5

5

10

15

0

0

OG+EXE BID OG+PLB BID

46% 8%

41% 5%

1%

4%

31%

64%

Weight Change vs. A1C Change

Values are for Week 30 completers

A1C Change (%) A1C Change (%)

Wei

ght C

hang

e (%

)

Wei

ght C

hang

e (%

)

Insulin Dose EXE BID PLB BID

Baseline (U/day)

Endpoint (U/day)

49 ±

2

62 ±

2

47 ±

3

69 ±

2

Baseline (U/kg)

Endpoint (U/kg)

0.51 ±

0.02

0.66 ±

0.02

0.51 ±

0.02

0.71 ±

0.02

LSMean ± SE

Change in Insulin Dose from Baseline

EXE BID PLB BIDMinor Hypoglycemia (n [%])

Overall incidence* 34 (25%) 35 (29%)

Rate (episodes/patient/year)* 1.4 1.2Adverse Events

(n [%])

Nausea† 56 (41%) 10 (8%)

Diarrhea† 25 (18%) 10 (8%)

Vomiting† 25 (18%) 5 (4%)

Headache† 19 (14%) 5 (4%) Constipation† 14 (10%) 2 (2%)

One patient in the placebo arm had 2 episodes of major nocturnal

hypoglycemia *No significant differences between groups†

p<0.05, between-group comparison

Safety and Adverse Events

EXE BID PLB BID P-value*

Systolic BP (mmHg)EndpointChange

125.8 ±

1.2-2.7 ±

1.2130.2 ±

1.3+1.7 ±

1.3 0.011

Diastolic BP (mmHg)Endpoint Change

73.3 ±

0.7-1.7 ±

0.776.7 ±

0.7+1.7 ±

0.7 <0.001

Heart Rate (bpm) Endpoint Change

76.7 ±

0.8+2.3 ±

0.873.8 ±

0.8-0.7 ±

0.8 0.008

Change in Blood Pressure and Heart Rate

Data presented as LSMean ±

SE; *

between-group comparison

Lixisenatide, a novel once-daily GLP-1 receptor agonist for the treatment of Type 2 diabetes:

an ideal candidate for combination with basal insulin

Riccardo Perfetti, MD, PhDVice President, Global Medical Affairs

Diabetes Division, Sanofi

Mea

n ch

ange

from

pre

-mea

l pl

asm

a gl

ucos

e (m

g/dL

) SE

M

–30

0

30

60

90

Time after study drug administration (h)4.53.52.52.01.51.0

LIXISENATIDEDay –1 Day –28

LIRAGLUTIDEDay –1 Day –28

Test meal

0.5

Test drug

0 4.03.0

Difference in PPG effect by GLP-1 analogues: lixisenatide versus liraglutide1

26

Study PDY10931 compared the effects of lixisenatide versus liraglutide on PPG in 148 adults with T2DM insufficiently controlled (HbA1c

6.5−9.0%) on ≥1.5 g/day of metformin1

Greater reduction of PPG area under the curve with lixisenatide (129%) compared with liraglutide (41%)

Overall incidence of AEs (mainly gastrointestinal [GI]) lower with lixisenatide (58%) versus liraglutide (73%)

1. Kapitza et al. Abstract D-0740; Presented at IDF 2011, Dubai

SEM=standard

error of the mean; AE=adverse events

Lixisenatide GetGoal clinical trial programme

Study Objectives # of pts

ClinicalTrials.gov Identifier

GetGoal-Mono Efficacy and safety of monotherapy(1-

or 2-step dose increase) 361 NCT00688701

GetGoal-Mono Japan Safety and efficacy of monotherapy in Asian patients (1-

or 2-step dose increase) 69 NCT00905255

GetGoal-M Efficacy and safety in combination with MET 680 NCT00712673

GetGoal-M-Asia Efficacy and safety in combination with MET (+

SU) 391 NCT01169779

GetGoal-F1 Efficacy and safety in combination with MET

(1 or 2-step dose increase) 482 NCT00763451

GetGoal-S Efficacy and safety in combination with SU (+

MET) 859 NCT00713830

GetGoal-P Efficacy and safety in combination with pioglitazone (+

MET) 484 NCT00763815

GetGoal-X Efficacy and safety head-to-head vs exenatide (+

MET) 634 NCT00707031

GetGoal-L Efficacy and safety in combination with basal insulin (+

MET) 496 NCT00715624

GetGoal-L Asia Efficacy and safety in combination with basal insulin (+

SU) 311 NCT00866658

GetGoal-Duo1 Efficacy and safety in combination with insulin glargine + MET (± TZDs) 446 NCT00975286

10 µg

15 µg

10 µg

15 µg

20 µg

20 µg

GetGoal-L-Asia: study design

Lixisenatide + basal insulin ±SU (n=154)

Placebo + basal insulin ±SU (n=157)

Diet and lifestyle counselling every 3 monthsScreening criteria:Asian patients with

T2DM for ≥1 year on stable basal insulin with HbA1c 7–10%, stratified by HbA1c

and SU use

n=311

Seino et al. Diabetes Obes Metab 2012 doi: 10.1111/j.1463-1326.2012.01618.x

R=randomization; ClinicalTrials.gov identifier NCT00866658

R

–3 0–1 1 2 6 8 24

Screening Run-in

4 12 16 20

Primary endpoint

Double-blind period of 24 weeks

Visit week

0.2 +0.1%

–0.8%

0

–0.2

–0.4

–0.6

–0.8

–1.0

LS m

ean

chan

ge in

HbA

1c(%

)

Week 24 LOCF*

p<0.0001

GetGoal-L-Asia primary efficacy endpoint: change in HbA1c

from baseline to Week 24Placebo + basal insulin (n=154)


Modified intent-to-treat (mITT) population; *LOCF (on treatment value available) analysis for least squared mean or mean change at Week 24

Lixisenatide + basal insulin (n=146)

8.8

Week

8.6

8.4

8.2

8.0

7.8

7.6

7.4

7.2

7.0Baseline 4 8 12 16 20 24

Mea

n H

bA1c

(%) ±

SE

Week 24 LOCF*

8.6%

7.6%

LS mean difference vs placebo: –0.9%

(95% CI: –1.1 to –0.7)

GetGoal-L-Asia: change in 2-hour PPG and glucose excursion at 24 weeks

Placebo + basal insulin (n=142)Lixisenatide + basal insulin (n=131)


mITT population, LOCF (on treatment value available) analysis for least squared mean change at Week 24; *After a standardized breakfast meal test of Ensure Plus®

Drink (Abbot; contains 600 kilocalories with 54% carbohydrate, 17% protein and 29% fat); †2-hour PPG –

plasma glucose 30 minutes prior to meal test (before study drug administration)

LS mean difference vs placebo: –7.8 mmol/L

(95% CI: –8.9 to –6.8)LS mean difference vs placebo: –7.2 mmol/L

(95% CI: –8.3 to –6.2)

2-hour PPG*1

0

–1

–2

–3

–4

–5

–6

–8

–7

p<0.0001 p<0.0001

Glucose excursion†1

0

–1

–2

–3

–4

–5

–6

–8

–7

GetGoal-L-Asia: change in body weight 24 Weeks

1.

Data on file2.


mITT population; LS Mean Change from baseline to Week 24 (LOCF)

0

0.2

–2.0

–4.0

p=0.0857

LS m

ean

chan

ge (k

g)


GetGoal-L-Asia: adverse events over 24 weeks

Adverse event, n (%)

Lixisenatide + basal insulin

(n=154)

Placebo + basal insulin

(n=157)

Any TEAE 137 (89.0) 110 (70.1)

Serious TEAE 10 (6.5) 9 (5.7)

TEAE leading to death 0 1 (0.6)

TEAE leading to discontinuation 14 (9.1) 5 (3.2)

GI disorders (all)NauseaVomitingDiarrhoea

94 (61.0)61 (39.6) 28 (18.2) 10 (6.5)

23 (14.6)7 (4.5 ) 3 (1.9)4 (2.5)


Data are for the safety population (all patients who received ≥1 dose of study treatment); TEAE=treatment-emergent adverse event

GetGoal-L-Asia: symptomatic hypoglycaemia

All patients


91

Patients not receiving SU


•No episodes of severe hypoglycaemia reportedData are for the safety population (all patients who received ≥1 dose of study treatment)

n=13 n=15n=37 n=66

10 µg

15 µg

10 µg

15 µg

20 µg

20 µg

GetGoal-L: study design

Lixisenatide + basal insulin ± metformin (n=329)

Placebo + basal insulin ± metformin (n=167)

Diet and lifestyle counselling every 3 months

Screening Criteria:T2DM for ≥1 year on stable basal insulin with HbA1c 7–10%, stratified by HbA1c

(<8%/≥8%) and metformin use

n=496

Riddle et al. Abstract 983-P; Presented at ADA 2012. Philadelphia, PA

R

Double-blind period of 24 weeks

–3 0–1

Screening Run-In

24

Primary endpoint

1 2 6 84 12 16 20(Phone call visit)

Visit week

ClinicalTrials.gov Identifer NCT00715624

GetGoal-L primary efficacy endpoint: change in HbA1c

from baseline to Week 24

mITT population; *LOCF (on treatment value available) analysis for least squared mean or mean change at Week 24

Lixisenatide + basal insulin (n=304) Placebo + basal insulin (n=158)


8.6

8.4

8.2

8.0

7.8

7.6

7.4

Mea

n H

bA1c

(%) ±

SE

7.2

Week0 4 8 12 16 20 24 Week 24

LOCF*


(95% CI: –0.6 to –0.2)

8.1%

7.8%

0

–0.2

–0.4

–0.6

–0.8

LS m

ean

chan

ge in

HbA

1c(%

)

Week 24 LOCF*

p<0.001

GetGoal-L: change in 2-hour PPG and glucose excursion at 24 weeks

Lixisenatide + basal insulin (n=235)

2-hour PPG*

–1.7

–5.5

Glucose excursion†

–0.3

–4.1

0

–1

–2

–3

–4

–5

–6

0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

–4.0

–4.5







(95% CI: –4.6 to –3.0)

Placebo + basal insulin (n=123)Lixisenatide + basal insulin (n=233)Placebo + basal insulin (n=123)

p<0.0001 p<0.0001

GetGoal-L: change in body weight at Week 24



LS mean difference vs placebo: –1.3 kg

(95% CI: –1.8 to –0.7)

0

–0.5

–1.0

–1.5

–2.0p<0.0001

LS m

ean

chan

ge (k

g)


GetGoal-L: adverse events over 24 weeks


Lixisenatide + basal insulin

(n=328)

Placebo + basal insulin (n=167)

Any TEAE 241 (73.5) 114 (68.3)

Any serious TEAE 12 (3.7) 7 (4.2)

Death 1 (0.3) 0

TEAE leading to discontinuationGastrointestinal disorders

25 (7.6)14 (4.3)

8 (4.8)2 (1.2)


132 (40.2)86 (26.2) 27 (8.2) 24 (7.3)

34 (20.4)14 (8.4) 1 (0.6)9 (5.4)

Data are for the safety population (all patients who received ≥1 dose of study treatment)


GetGoal-L: symptomatic hypoglycaemia over 24 weeks


Type, n (%)Lixisenatide

+ basal insulin (n=328)Placebo

+ basal insulin (n=167)Symptomatic hypoglycaemia

Blood glucose <60 mg/dL91 (27.7)87 (26.5)

36 (21.6)35 (21.0)

Severe symptomatic hypoglycaemia Blood glucose <60 mg/dL

4 (1.2)3 (0.9)

00


GetGoal-Duo1: study design

Rosenstock et al. Abstract 062-OR; Presented at ADA 2012, Philadelphia, PA

*This was changed from ≤126 mg/dL in July 2010; ClinicalTrials.gov Identifer: NCT00975286; MET=metformin

2-weekscreening

Screening Criteria:•T2DM for ≥1 year •MET ≥1.5 g/day ±TZDs ± SU or Glinide•HbA1c

: ≥7.0%

and ≤10%

N=1470

n=898

Glargine titrated to FPG target 80–100 mg/dL

10

15

10

15

20

20

Glargine + metformin + PLACEBO

± TZDs

Glargine + metformin + LIXISENATIDE

± TZDs

12-week

Run-In

Rn=446

n=825

Glargine + metformin (±TZDs) Randomized if criteria met:

• HbA1C

≥7% and ≤9%• Mean FPG ≤140 mg/dL* (7 days end of Run-in)

Lixisenatide titration Lixisenatide maintenance

(n=223)

(n=223)

24-week-double-blind period

Glargine weekly titration;target FPG 80–100 mg/dL

GetGoal-Duo1 primary efficacy endpoint: change in HbA1c

from baseline to Week 24

mITT population; * LOCF (on treatment value available) analysis for least squared mean or mean change at Week 24; SCR=screening

Placebo + insulin glargine + metformin (n=221)Lixisenatide + insulin glargine + metformin (n=215)


Mea

n H

bA1c

(%) ±

SE

SCR–12 24Week

6.66.8

–8 –4 –1 4 8 16

7.07.27.47.67.88.08.28.4

8.8

0

8.6

7.6

7.6

Glargine + MET (±TZDs) Lixisenatide OR placebo + MET (±TZDs)

Week 24 LOCF*

7.3%

7.0%


(95% CI: –0.5 to –0.2)

0

–0.2

–0.4

–0.6

–0.8

LS m

ean

chan

ge in

HbA

1c(%

)

Week 24 LOCF*

p<0.0001

GetGoal-Duo1: change in 2-hour PPG and glucose excursion at 24 weeks





2-hour PPG*+0.1

–3.1

Glucose excursion†

–0.3

–3.4

LS m

ean

chan

ge (m

mol

/L)

0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

LS m

ean

chan

ge (m

mol

/L)




(95% CI: –3.8 to –2.3)

p<0.0001

1.2

0.3

0

0.2

0.4

0.6

0.8

1.0

LS m

ean

chan

ge (k

g)1.2

1.4 p=0.0012

GetGoal-Duo1: change in body weight at Week 24



LS mean difference vs placebo: –0.9 kg

(95% CI: –1.4 to –0.4)


GetGoal-Duo1: adverse events over 24 weeks


Lixisenatide + insulin glargine +

metformin

(n=223)

Placebo + insulin glargine +

metformin

(n=223)

Any TEAE 178 (79.8) 152 (68.2)

Serious TEAE 17 (7.6) 10 (4.5)

TEAE leading to death 0 2 (0.9)

TEAE leading to discontinuationNausea and vomiting

19 (8.5)9 (4.0)

8 (3.6)0


89 (39.9)61 (27.4) 21 (9.4) 15 (6.7)

36 (16.1)11 (4.9)3 (1.3)7 (3.1)

Increases in pancreatic enzymes (lipase and/or amylase) or pancreatitis

Pancreatitis

5 (2.2)

0

10 (4.5)

1 (0.4)

Calcitonin increase (≥20 ng/L) during the on-treatment period 0 2 (0.9)

Injection site reactions 15 (6.7)* 5 (2.2)

*Two patients (0.9%) discontinued due to injection site reactions; Data are for the safety population (all patients who received

≥1 dose of study treatment)


GetGoal-Duo1: symptomatic hypoglycaemia over 24 weeks

Type

Lixisenatide + insulin glargine + metformin

(n=223)

Placebo + insulin glargine + metformin

(n=223)Blood glucose <60 mg/dL

Number of patients with events, n (%) 45 (20.2) 26 (11.7)

Number of events/patient/year 0.80 0.44

Severe hypoglycaemia

Number of patients with events, n (%) 1 (0.4) 0

Number of events 1 0



I ned to get these slides

61%

43% of 39%

17% of 39%n=987

n=498

n=162

n=161

Glycemic efficacy, changes in body weight, and insulin detemir doses.

DeVries J H et al. Dia Care 2012;35:1446-1454

Copyright ©

2011 American Diabetes Association, Inc.

Conclusions: GLP-1 Agonists And Insulin Therapy Works Well Together And Makes Physiologic Sense

Thank You Very [email protected]

Reduce A1cImprove fasting and postprandial glycemiaWeight neurtral

or weight loss

Minimal hypoglycemia

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