are all glp-1 analogs created equal · not all glp-1 receptor agonists are the same glp-1 receptor...

Are all GLP-1 Analogs Created equal ?

Dror Dicker

Internal Medicine D & Obesity Clinic

Hasharon Hospital RMC

ISRAEL HEALTH PROFILE

WHO 2013

ENDOCRINE PRACTICE Vol 19 No. 2 March/April 2013

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Not all GLP-1 receptor agonists are the same

GLP-1 receptor agonists can be classified in several ways

Structure: GLP-1-based Exendin-4-based

Pharmacokinetic profile: Short-acting Long-acting

Actions on gastric emptying, FPG, and PPG: Non-prandial – modest gastric emptying delay - reduces FPG Prandial – strong gastric emptying delay – reduces PPG

Strategies employed to develop GLP-1 receptor agonists with prolonged in vivo half-lives

Meier, J. J. (2012) Nat. Rev. Endocrinol

Pharmacologic characteristics of currently available GLP-1 receptor agonists and lixisenatide

Horowitz M. Adv Ther ( 2013 )

Receptor binding studies

Median inhibitory concentration ( IC50 ) of:

lixisenatide for the human GLP-1 receptor is 1.4 nM , which is

approximately four-fold greater than the affinity of GLP-1 ) 0.35 nM (.

liraglutide has an IC50 of 0.11 nM

Exenatide has an IC50 of 0.55 nM

Blood glucose concentrations and postprandial glucose in response to standardized meals at breakfast , lunch and dinner at baseline and Day 28 in

M . Lorenz et al . Regulatory Peptides 2013





Actions on gastric emptying, FPG, and PPG:

Overview of Lixisenatide Development

Efficacy HbA1c FPG PPG

Body Weight

Hypoglycemia

Lixisenatide in the treatment of Type 2 diabetes

Diet and exercise

1 OAD

2 OADs

Basal insulin ± OADs

GetGoal-Mono

Monotherapy

GetGoal-Mono Japan

Monotherapy

GetGoal-F1

Add-on to MET

GetGoal-X

Add-on to MET

GetGoal-M

Add-on to MET GetGoal-P

Add on to pioglitazone ± MET

GetGoal-M-Asia

Add on to MET± SU

GetGoal-S

Add on to SU ± MET

GetGoal-L-Asia

Add on to basal insulin ± SU

GetGoal-Duo1

Add on to insulin glargine ± MET

GetGoal-L

Add on to basal insulin ± MET

Craig W ,Spellman,JAOA;2012

-92 -15 -0.9



Body Weight


Lixisenatide - 2.0



Body Weight

Hypoglycemia

Symptomatic hypoglycemia defined as symptoms considered to result from a hypoglycemic episode with plasma glucose <60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate intake

0 10 20 30 40 50

Incidence (%) 0 1 2 3 4 5 6

Relative risk (95% CI)

MET (EFC6019) Exenatide = 46/316

Lixisenatide = 16/318

0.20 0.60

0.35

SU + MET (EFC6015) Placebo = 44/239

Lixisenatide = 107/486 1.20

1.64 0.87

1.49

SU (EFC6015) Placebo = 7/46


0.68 3.27

MET (EFC10743 + EFC6014) Placebo = 16/330

Lixisenatide = 58/832 1.44 0.84 2.46

1.02

Monotherapy (EFC6018) Placebo = 2/122


0.19 5.50

Placebo Lixisenatide

Values left of line favor lixisenatide

Significantly fewer

hypoglycemic episodes vs exenatide

Lixisenatide Associated with Low Risk of Hypoglycemia

Exenatide

Rationale for Combination of Basal Insulin plus a GLP-1 Agonist

Basal insulin analogues Suppress hepatic glucose production

Control nocturnal and FPG

Improve β-cell function

Weight re-gain ~1–3 kg

Less hypoglycemia risk vs NPH

Simple titration algorithms available

Avoid clinical inertia

Differential impacts on both FPG,PPG

Improve insulin release and sensitivity to insulin

Decrease gastric emptying

No independent increase in hypoglycaemia

Weight loss ~1–3 kg

Simple to use

GLP-1 receptor agonists

Complementary and potentially synergistic effects

Optimise HbA1c control, safely

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine

RIDDLE MC. Diabetes Care 2013

Mean seven-point SMPG ( mmol/L ) at baseline and week 24 Before and after treatment profiles for the insulin glargine plus metformin ( with or without TZDs ) plus lixisenatide group

RIDDLE MC. Diabetes Care 2013

Lixisenatide – Summary

Comprehensive phase III clinical development program in >5000 patients

Once-daily dosing with one-step dose-increase regimen provides a simple treatment option

Enhanced glycemic control Significant reduction in HbA1c with low risk of hypoglycemia Pronounced PPG-lowering effect

Benefits of body weight reduction

Good safety and tolerability profile Mild and transient GI effects: reduced episodes of nausea vs

exenatide Long-term safety and efficacy data (≥76 weeks) will be

forthcoming

Study Design

R A N D O M I S A T I O N

Key inclusion criteria T2D patients: • Age: 37–74 years • Treated with metformin

(≥1.5 g/day) • HbA1c

: 6.5%–9.0%

Ope

n la

bel

Mul

ticen

tre

Para

llel g

roup

Lixisenatide 10 μg weeks 1–2 20 μg thereafter

Liraglutide 0.6 mg week 1 1.2 mg week 2

1.8 mg thereafter

28 days

Blood sampling Day -1/1, Day 28/29

2-week screening

n=71

n=77

Dosing 30 minutes before breakfast*

Kapitza et al. Diabetes Obes Metab 2013 Jan 31. doi: 10.1111/dom.12076.

Endpoints Primary • Change in plasma glucose concentration-time curve from baseline to Day 28

in 4-hour period after start of standardised breakfast test meal (AUC0:30–4:30 h) Secondary Changes from baseline to Day 28 in: • Maximum PPG excursion in the 4-hour period after start of standardised breakfast test

meal • Pre-meal-corrected AUC0:30–4:30 h for serum insulin • Serum C-peptide • Plasma glucagon levels (6-point profile, including pre-meal value) • 24-hour plasma glucose (15-point profile) • Mean HbA1c


Demographics and baseline characteristics


Lixisenatide vs. Liraglutide: Differences in percentage of patients with 2-hour PPG < 7.7 mmol/L

69.3%

29.4%

0

10

20

30

40

50

60

70

80

Lixisenatide n=75

Liraglutide n=68

Proportion of Patients

(%)

Proportion of Patients with 2-Hour PPG<7.7 mmol/L


Lixisenatide vs. Liraglutide: Glycaemic Control at Day 28

-0.32

-0.51

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Lixisenatide(n=76)

Liraglutide(n=68)

Cha

nge

in H

bA1c

(%) -0.3

-1.3

-1.5

-1

-0.5

0

Lixisenatide(n=76)

Liraglutide(n=68)

Cha

nge

in F

PG (

%)

p<0.01

Change in HbA1c Change in FPG

p<0.0001


Lixisenatide vs. Liraglutide: Body Weight Change From Baseline at Day 28

-1.6

-2.4

-3

-2.5

-2

-1.5

-1

-0.5

0

Lixisenatide(n=76)

Liraglutide(n=68)

Cha

nge

in b

ody

wei

ght (

kg)

p<0.01


Plasma Glucose 24-hour Profiles


15

14

13

12

11

10

9

8

7

6

5

0 0.5 1.5 2.5 3.5 4.5 6.5 8.5 10.5 12.5 14.5 24

Plas

ma

gluc

ose

(mm

ol/L

)

Time after study drug administration(h)

Lixisenatide (Baseline)

Lixisenatide (Day 28)

Liraglutide (Baseline)

Liraglutide (Day 28)

Comparative effects of lixisenatide and liraglutide on post-prandial glucose

Adapted from Kapitza et al. Diabetes Obes Metab 2013 Jan 31. doi: 10.1111/dom.12076.

Lixisenatide also provides a greater decrease in post-meal glucagon than liraglutide

Adapted from Kapitza et al. Diabetes Obes Metab 2013 Jan 31. doi: 10.1111/dom.12076.

Summary of the interdependent relationships of gastric emptying , incretin hormones , and postprandial glycemia .

MARATHE CS. DIABETES CARE 2013

Relationships Between Gastric Emptying , Postprandial Glycemia , and Incretin Hormones


Summary of the interdependent relationships of gastric emptying , incretin hormones , and postprandial glycemia .


American Journal of Physiology - Endocrinology and Metabolism 1997

Effect of GLP-1 analogs on Gastric Empting

Meier JJ et al. Diabetes 2005

Tachyphylaxis

Effect of GLP-1 analogs on Gastric Empting -Tachyphylaxis

Nauck MA et al.Diabetes 2011

Study in rats demonstrating tachyphylaxis in the slowing of gastric emptying

Jelsing J , et al . Diabetes Obes Metab . 2012

The Effect of Ex ogenous GLP-1 on Food Intake is Lost in Male Truncally Vagotomized Subjects with Pyloroplasty

Plamboeck A.Am J Physiol Gastrointest Liver Physiol. May 2013

Meier JJ. Nature Reviews Endocrinology 2012;

Long-acting GLP-1 RA

Fasting Glucose

Glucagon

Insulin

Appetite

Nausea

Long-acting GLP-1 RA: Biological Effects

Meier JJ. Nature Reviews Endocrinology 2012;

Short-acting GLP-1 RA

Appetite

Nausea

Glucagon

Transpyrolic Flow

Gastric motility

Short-acting GLP-1 RA: Biological Effects

Intestinal glucose

absorption ↓

Postprandial Glucose Insulin

Effects of GLP-1 analogs on Gastric Empting summery

GLP-1 analogues slow gastric emptying – the magnitude of this effect is dependent on the baseline rate of gastric emptying

Reduction in postprandial glycaemia by GLP-1 analogues related to slowing of gastric emptying

Slowing of gastric emptying induced long-acting’ GLP-1 analogues probably diminishes with time tachyphylaxis

Lixisenatide has a sustained effect to markedly delay gastric emptying, although information about the latter is limited

Vital sign measurements


Glucagon-Like Peptide-1 ( GLP-1 ): Effect on Kidney Hemodynamics and Renin-Angiotensin Aldosterone System in Healthy Men

Skov J.J Clin Endocrinol Metab 2013

Na + / H + exchangers structure

Alexander RT; The Journal of Experimental Biology 2009

DPP4 i + GLP-1 Na+

Na+ Na+ Na+

Glucagon-Like Peptide-1 ( GLP-1 ): Effect on Kidney Hemodynamics and Renin-Angiotensin Aldosterone System in Healthy Men

Skov J.J Clin Endocrinol Metab 2013

Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

Wohlfart et al . Journal of Translational Medicine 2013

GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure

Drucker D.Nature Medicine 2013

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76 78 79 79 80

24 22 21 21 20

0

20

40

60

80

100

<8.0 8.0–<8.5 8.5–<9.0 9.0–<9.5 ≥9.5

Tota

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ycem

ia (%

)

PPG FPG On OADs, fasting hyperglycemia

dominates over a wide range of HbA1c

With treatment intensification (24/28 weeks), FPG contributes >40% to overall hyperglycemia

42 41 42 43 48

58 59 58 57 52

0

20

40

60

80

100

Tota

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ycem

ia (%

)

HbA1c <6.5 6.5–<7.0 7.0–<7.5 7.5–<8.0 ≥8.0

PPG FPG

HbA1c

Addressing FPG and PPG contributions by HbA1C Level

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

FPG= fasting plasma glucose PPG = postprandial glucose

Comparison of short-acting versus long-acting GLP-1 receptor agonists

Meier, J. J. (2012) Nat. Rev. Endocrinol

Thank You

are all glp-1 analogs created equal · not all glp-1 receptor agonists are the same glp-1 receptor...

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