GLP-1 Receptor Agonists

ADEA CASE SERIES

Merlin ThomasGary KilovNicole Frayne Giuliana Murfet

Facilitator: Rachel McKeown,Professional Services Manager, ADEA (NSW)

Motivated/adherentGood self-careShort durationLow hypo riskLong life expectancy No co-morbidityGood resources

Non-compliantPoor self-careLongstanding

High hypo riskShort life expectancy

Co-morbidityLimited resources

<7 COMPROMISETARGET

Adapted from Inzucchi et al Diabetes Care 2012

The right target...

Motivated/adherentGood self-careShort durationLow hypo riskLong life expectancy No co-morbidityGood resources

Non-compliantPoor self-careLongstanding

High hypo riskShort life expectancy

Co-morbidityLimited resources

Standard ?Adapted from Inzucchi et al Diabetes Care 2012

….with the right agent

How does GLP-1 lower glucose levels in diabetes?

1. BACKGROUND

α

β

Incretins in -cell biology3,4

L

MEAL

GLPRGLP-1

Distal small intestine ileum and colon

Pancreas

• Amplified insulin secretion

• Improved glucose sensitivity

• -cell proliferation/neogenesis

• Reduced -cell apoptosis

3. Campbell & Drucker. Cell Metabolism (2013); 4. Diakogiannaki, et al. Physiol. Behav. (2012).

carbohydrate protein, fatty &

bile acids

vagal

Up to 70% of total post-prandial insulin production is determined by incretins

The effect and contribution varies with the size of the glucose challenge / the meal composition

vagal

AMPLIFIER

SIGNAL AMPLIFICATION OUTPUT

GLUCOSE GLP-1 increasedFOOD AMPLIFICATION INSULIN*

(incret-ins) of glucose/meal-stimulatedinsulin secretion

Incretins regulate a proportional response

What happens to theincretin effect in diabetes?

As a consequence of hyperglycaemia and/or other metabolic manifestations of diabetes itself incretin effect is reduced by ~50% in diabetes8

Normal secretion of GLP-1, but.. Down-regulation of GLP-1 receptor8

Less substrate to act on (β-cells, δ-cells, etc) Gastroparesis8

Resistance to GLP-1 (which needs pharmacological doses to overcome it)8,10

8. Nauck et al. Diabetologia (2013); 9. De Frionzo Diabetes (2009) 10. Vilsbøll T, et al. Diabetologia. (2002)

AMPLIFIER

NO SIGNAL AMPLIFICATION NO OUTPUT

No GLUCOSE NO MORENO FOOD INSULIN GLP1

Incretins and hypoglycaemia

Reduced risk of hypoglycaemia

No increase in insulin when glucose levels are low during a

continuous infusion of GLP-11

7. Nauck et al. JCEM (2002)

What happens to -cells in diabetes?

8. Defronzo. Diabetes (2009)

Diabetes is associated with the blunting of hyperglycaemia or postprandial suppression of glucagon secretion

Reduced incretin effect Hyperplasia of -cells Increased sensitivity to glucagon

Contributes to the inappropriately increased rate of hepatic glucose output characteristic of T2DM

=ALPHA CELL ANARCHY

α

β

GLP-1 in -cell biology3,4

L

MEAL

carbohydrate protein, fatty &

bile acids

GLPRGLP1

Distal small intestine ileum and colon

Pancreas

• Augmented suppression of glucagon release

• Partly via increased insulin

• Partly via somatostatin (?)

3. Campbell & Drucker. Cell Metabolism (2013); 4. Diakogiannaki, et al. Physiol. Behav. (2012).

vagal

vagal

No impairment of glucagon response (which protects against hypoglycaemia)

during an infusion of GLP-1

7. Nauck et al. JCEM (2002)

ControlGLP-1

Incretins in the stomach

L

MEAL

GLPRGLP1

Distal small intestine ileum and colon

Stomach

11. Shah & Vella Rev Endocr Metab Disord (2014); 12. Marathe et al. Diabetes Care (2013)

carbohydrate protein, fatty &

bile acids

FULL

vagal afferents

Reduced gut motility Delayed stomach emptying Delayed digestion and

absorption of carbohydrates2

Exenatide slows emptying of the stomach as measured by the half-life of a 99TC -labelled meal13

13. Linnebjerg et al. Regl Pept (2008)

Placebo Exenatide (5µg) Exenatide (10µg)0

1

2

3

4

5

6

T(50

) h o

f lab

elle

d m

eal

*

*

L

MEAL

GLPRGLP1

Distal small intestine ileum and colon

brain

Enhanced glucose disposal Increased satiety/fullness Reduced appetite Reduced food intake

2. Campbell & Drucker. Cell Metabolism (2013); 11. Shah & Vella Reviews in Endocrine and Metabolic Disorders (2014)

carbohydrate protein, fatty &

bile acidsvagal

Incretins in the brain

Incretin biology and DPP4

L

MEAL

GLPRGLP1

Distal small intestine ileum and colon

2. Campbell & Drucker. Cell Metabolism (2013);

carbohydrate protein, fatty &

bile acids

vagal

• Pancreas

• Stomach

• Liver

• Brain

DPP4

Short circulating half life (<2 min)

Resistant to DPP4

GLP1 has a 1-4 min half-life (designed for grazing?)

GLP1 (amidated form)

Rationale for GLP analoges1,2

DPP4

EXENATIDE

plasma half-life of 2.4 hours and an action time of about 6-8 hours

The Gila monster

“I want some of that (adaptation) for my patients”

From Lizard Saliva to Diabetes Drug

All lower the HbA1c by approximately the same amount when added-on metformin40 RCT (n=17795): 6-12 months trials, added-on after MFM failure

McIntosh B et al. Open Med 2011; 5:E35-E48

Series1

-1

-0.5

0

0.5

+0.1 +0.1+0.2

-0.4*-0.5

† -0.6‡

-0.8*-0.9†

-0.8‡

Exenitide lowers HbA1cin both dual and triple therapy

N 113 110 113

Baseline 8.2 8.3 8.2

123 125 129

8.7 8.5 8.6

247 245 241

8.5 8.5 8.5

Ch

an

ge

in

Hb

A1c

*P<0.001 vs placebo †P<0.0002 vs placebo

30-week data; mean .

Placebo BID Exenatide 5 μg BID Exenatide 10 μg BID

‡P<0.0001 vs placebo

1. DeFronzo RA ,et al. Diabetes Care 2005;28:1092–100. 2. Buse JB, et al. Diabetes Care 2004;27:2628–35. 3. Kendall DM, et al. Diabetes Care 2005;28:1083–91.

Pivotal phase 3 clinical studies—combined intent-to-treat (ITT)

MET1 SU2 MET + SU3

Exenatide was as effective as insulin at lowering HbA1c

Abbreviations: BL, baseline; MET, metformin, SU, sulphonylurea; TZD, thiazolidinedione

1. Nauck MA, et al. Diabetologia 2007; 50(2): 259–67. 2. Heine RJ, et al. Ann Intern Med 2005; 143(8): 559–69. 3. Barnett AH, et al. Clin Ther 2007; 29(11): 2333–48. 4. Davies MJ, et al. Diabetes Obes Metab 2009; 11(12): 1153–62. 5. Bunck MC, et al. Diabetes Care 2009; 32(5): 762–8.

Primary endpoint: Change in HbA1c (%)

Series1

-1.5

-1

-0.5

0

-1.0%-1.1%

-1.4% -1.3%

-0.8%-0.9%

-1.1%

-1.4% -1.3%

-0.7%

MET + SU1MET, SU, TZD

(combination of 2 or 3)4

n=253BL=8.6%

n=248BL=8.6%

n=275BL=8.2%

n=260BL=8.3%

N=68BL= 8.9%

n=118BL= 8.7%

n=116BL=8.5%

n=36BL= 7.6%

n=33BL= 7.4%

exenatide 10 µg BID plus orals Insulin aspart 70/30 Insulin glargine

Background

Ch

an

ge

in H

bA

1c

N=70BL= 9%

52 weeksMET + SU2

26 weeksMET or SU3

16 weeks 26 weeksMET5

52 weeks

Starting GLP-1R agonistsCASE#1

Laboratory parameters HbA1c 7.9% Total cholesterol: 3.8 mmol/L Normal albuminuria and

eGFR

Graham presents to his GPPatient history• Age 50 years• Married, 3 children• Works as a taxi driver• BP 132/85 mmHg• BMI 30 kg/m2

• Non-smoker• Diet and exercise not optimal

Medical history• Diabetes diagnosed 18 months ago

• Dyslipidaemia and hypertension diagnosed 3 years ago

Graham, aged 50

Current Medications• Metformin 1500 mg/day• Rosuvastatin 20 mg/day• Telmisartan/hydrochlorothiazide

80/12.5 mg fixed dose combination

What are Graham’s treatment priorities?

Weight Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

What are Graham’s treatment priorities?

Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Weight

Cost

Question 1. How well will he tolerate an GLP-1R agonist?

Tolerability

Common side effectsNausea (20-30%)

Vomiting (~10%)

Diarrhoea (~10%)

Injection site reactions

(10-20%)

Nausea and vomiting with exenatide

Exenatide Exenatide LAR

attenuates slowly (weeks to months) attenuates rapidly (4-8 weeks)

30

Tricks for tolerability

• Cautious dose escalation 5µg bd to 10µg bd

• Reducing the size as well as the fat content of meals can sometimes help get patients through.

• Although exenatide can be injected at any time within 60 minutes of meal, starting off at ~15 minutes prior meal and slowly extending this depending on tolerability can also help. Question 1a. What other tricks do you

have?

What are Graham’s treatment priorities?

Weight Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Question 2. What about driving on a GLP-1RA?

Meta-analysis: Overall hypoglycemia

for medications added-on metformin34 RCT (n=16704): 6-12 months trials, added-on after metformin failure

McIntosh B et al. Open Med 2011; 5:E35-E48

33

GLP-1 actions on the β cell are normally tightly coupled to the level

of ambient glucose. The insulinotropic actions of GLP-1 are rapidly terminated once the plasma glucose falls into the normal range

7 6 5 4 3 2 1

GLP1 doesn’t cause hypoglycemia

34

Closer to the edge, reduced food intake as well as

uncoupling of GLP-1 from its glucose dependence by

sulphonylureas

But they do make it easier for SUs to cause hypoglycemia

7 6 5 4 3 2 1

GLP-1RA

35

Byetta added to metformin does not increase the risk of hypoglycaemia; with

SU consider dose reduction

0

10

20

30

40

EX + SU + MET3

(n=733; ITT population)

EX + SU1

(n=337; ITT population)

EX + MET2

(n=336; ITT population)

Inci

den

ce o

f h

ypo

gly

caem

ia (

%)

3%

14%

36%

13%

19%

28%

5% 5%

Placebo

30-Week, randomised, placebo-controlledExenatide 5 g

5%

Exenatide 10 g

1. Buse JB, et al. Diabetes Care. 2004; 27: 2628–35. 2. DeFronzo RA, et al. Diabetes Care. 2005; 28: 109–100. 3. Kendall DM, et al. Diabetes Care. 2005; 28: 1083–91.

De Heer et al Diabetes 2007

GLP-1 in the presence of a sulfonylurea agent leads to enhanced insulin secretion

and suppressed glucagon even at normal or low glucose concentrations

GLP1

control

What are Graham’s treatment priorities?

Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Question 3. How will GLP-1R agonist affect his weight?

Weight Loss

Meta-analysis: Body weight change

for medications added-on metformin30 RCT (n=15265): 6-12 months trials, added-on after MFM failure

McIntosh B et al. Open Med 2011; 5:E35-E48

Exenatide 10 μg BID provided long-term glycaemic control without weight gain over 156 weeks*†

Changes in body weight1

-1

-2

-3

-4

-5

-6

-7

-8

-9

-10

0 26 52 78 104 130 156

‡P<0.0001

Mean baseline body weight: 99 ± 18 kg

reduction from baseline

-1.6 kgat week 12

reduction from baseline

-5.3 kgat 3 years

N=217

Ch

an

ge

in

bo

dy

we

igh

t (k

g)

Treatment (weeks)

*Of 527 subjects, 217 completed 156 weeks of the study, of which 84% lost weight and 50% lost at least 5% of baseline body weight.1

†Exenatide is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.

• Weight loss >1.5 kg per week has been observed in patients treated with exenatide2

• Weight loss of this rate may have harmful consequences2

‡

1. Klonoff DC et al. Curr Med Res Opin 2008; 24: 275–86. 2. Byetta Approved Product information 17 September2012 .

> 85% patients lose weight

Potential for weight loss with Exenatideversus weight gain with insulin glargine

-3

-2

-1

0

1

2

Insulin glargineExenatide

Chan

ge in

bod

y w

eigh

t (kg

)

0 2 4 8 12 18 26Insulin glargine n = 267 266 261 253 251 246 244Byetta n = 281 277 275 261 245 235 231

*P < 0.0001 compared with insulin glargine measure at the same time point.

Weeks

**

**

**

Adapted from Heine RJ, et al. Ann Intern Med 2005; 143(8): 559–69.

†Exenatide is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.

(Mean baseline body weight 87.5 kg)

(Mean baseline body weight 88.3 kg)

What are Graham’s treatment priorities?

Weight Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Q4. How well will an GLP-1RA keep working?

50 y.o.

42

Exhaustion (nike effect)Sustainability – the NIKE effect

Exenatide 10 μg BID provides sustained HbA1c reduction over 156 weeks*

Mean change in HbA1c from baseline10

9

8

7

6

5

4

3

2

1

0 26 52 78 104 130 156

†P<0.0001

Mean baseline HbA1c: 8.2%

reduction from baseline

-1.1%at week 12

reduction from baseline

-1.0%at 3 years

†

Me

an

Hb

A1c

(%

)

Treatment (weeks)

Adapted from Klonoff DC, et al. Curr Med Res Opin 2008; 24: 275–86.

*Of 527 subjects, 217 completed 156 weeks of the study, of which 46% achieved HbA1c of ≤7%.

N=217

44

Five-Year Efficacy and Safety Data of Exenatide Once Weekly

DURATION1. Mayo Clin Proc (2015)

What are Graham’s treatment priorities?

Weight Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Question 5. Will a GLP1RA protect his heart?

CV Outcomes and GLP-1RA

2015 20172016 2018 201920132012 2014

ELIXALixisenatide(N = 6000)

LEADERLiraglutide (N = 9341)

EXSCELExenatide (N = 9500)

REWINDDulaglutide (N = 9622)

SUSTAIN-6Semaglutide (N = 3260)

What are Graham’s treatment priorities?

Weight Sustainability

No HYPO

Lower HbA1c

Cost

Compliance

Tolerability

CVD risk

Question 5. Is it subsidised?

GLP-1RA in addition to insulin

CASE#2

Laboratory parameters HbA1c 8.2% Total cholesterol: 5.8 mmol/L eGFR 125 ml/min/1.73m2

Kevin presents to his GPPatient history• Age 50 years• BP 142/75 mmHg• BMI 37 kg/m2

• Non-smoker• Diet and exercise not optimal

Medical history• Diabetes diagnosed 5 years ago• Failed oral therapy

Now on insulin injections

• But control is still suboptimal

Kevinaged 50

Current Medications• Metformin 2g/day• Insulin 100U/day• Rosuvastatin 20 mg/day• Telmisartan/hydrochlorothiazide

80/12.5 mg fixed dose combination

What are Kevin’s treatment priorities?

Weight Sustainability

No HYPO

Lower HbA1c

CVD Risk

Compliance

Tolerability Cost

Q 6. How well will an GLP1RA work for Kevin(on top of his insulin regimen)?

Over the past 3 years, however, the effectiveness of combining GLP-1 receptor agonists (both

shorter-acting and newer weekly formulations) with basal insulin has been demonstrated, with most studies showing equal or slightly superior

efficacy to the addition of prandial insulin, and with weight loss and less hypoglycemia.

The available data now suggest that either a GLP-1 receptor agonist or prandial insulin could be used

in this setting, with the former arguably safer, at least for short-term outcomes

Inzucchi Diabetes (2015)

1. Buse JB, et al. Ann Intern Med 2011; 154: 103–12 ;

Exenatide lowers HbA1c when used in combination with basal insulin1

Exenatide

1. Buse JB, et al. Ann Intern Med 2011; 154: 103–12.;.

No increased risk of weight gain or hypoglycaemia when exenatide is added to basal insulin1,2**†

Change in weight* Minor hypoglycaemia

Exenatide

THANK YOU FOR YOUR PARTICIPATION

ADEA CASE SERIES

Merlin ThomasGary KilovNicole Frayne