Pathophysiology in the Treatment of Type 2

Diabetes

Newer AgentsPart 4 of 5

Exenatide

– Exendin-4, isolated from Gila monster saliva, shares 53% of its amino acid identity with GLP-11

• Exenatide is a synthetic version of exendin-41

– In in vitro assays, exendin-4 and GLP-1 have equivalent binding affinities for the GLP-1 receptor2-4

– In in vitro studies, the degree of GLP 1 receptor ‑activation by exenatide is at least equivalent to that of native GLP-15,6

1. Nielsen LL, et al. Regul Pept. 2004;117:77-88; 2. Raufman JP. Regul Pept. 1996;61:1-183. Fehmann HC, et al. Peptides. 1994;15:453-456; 4. Thorens B, et al. Diabetes. 1993;42:1678-16825. Parkes D, et al. Drug Dev Res. 2001;53:260-267; 6. Göke R, et al. J Biol Chem. 1993;268:19650-19655

Exenatide– Mono or Adjunctive therapy, depended on patient’s needs

or desires (not approved for combination with insulin)– BID subcutaneous– Start 5 mcg injected 0-60 minutes before am and pm meal for 1

month (decreased risk nausea if take with first bite)– Or, dose with two largest meals*– Decrease nausea risk by advising patient to stop eating when full– Increase to 10 mcg as needed, and then tolerated

with first bite

• Don’t use if creatinine clearance < 30 ml/min• Don’t use in gastroparesis or GI motility disorders

Exenatide: Change in A1c and Weight

(vs Placebo)

Add on to: Duration

Exenatide10 μg bid

A1C Change in

% (baseline)

Weight change in

kg(baseline)

Monotherapy 24 weeks -0.7 (7.8) -1.5 (86.2)

Metformin 30 weeks -0.9 (8.2) -2.4 (100.9)

Sulfonylurea 30 weeks -1.0 (8.6) -0.9 (95.2)

Metformin + sulfonylurea

30 weeks -1.0 (8.5) -0.7 (98.4)

Glitazone ± metformin 16 weeks -0.9 (7.9) -1.5 (97.5)

Exenatide prescribing information. Amylin Pharmaceuticals Inc; 2009.

Exenatide Lowered PPG and FPG Concentrations in Large Phase 3 Clinical

Studies: Combined Data

30-wk pivotal studies; Patients with T2D; Evaluable standard meal tolerance test cohorts; Placebo, n = 44 Exenatide 5 µg BID, n = 42; Exenatide 10 µg BID, n = 52; Mean ± SE; * Least squares (LS) mean difference at Wk 30, P<0.0001; ITT population; Placebo, n = 483; Exenatide 5 µg, n = 480; Exenatide 10 µg, n = 483; Mean ± SE; *P<0.0001 vs placebo; † LS mean difference at Wk 30. Data on file, Amylin Pharmaceuticals, Inc.

-30 0 30 60 90 120 150 180100

150

200

250

300

Time (min)

Pla

sma

Glu

cose

(m

g/d

L)

Exenatide or PlaceboMeal

Difference From Placebo: -75 to -80 mg/dL *

Placebo Exenatide 5 µg BID Exenatide 10 µg BID

Δ F

PG

Fro

m B

asel

ine

(mg/

dL)

**

Difference From Placebo: -20 to -23 mg/dL *†

-20

-10

0

10

20

Exenatide 3-Year Completers: A1c and Weight

PBO-Controlled Open-Label Uncontrolled

N = 217; Mean (- SE); P < 0.0001 from baseline to 30 weeks and baseline to 3 years.No diet and exercise regimen was provided.

0 26 52 78 104 130 1564

5

6

7

8

9

10

Time (wk)

(Bas

elin

e A

1C

= 8

.2%

)

-1.0 ± 0.1%-1.1 ± 0.1%

% Achieving A1C ≤ 7%

A1C

(%

)

Klonoff DC, et al. Current Medical Research and Opinion. 2008;24:275–286.

-7

-6

-5

-4

-3

-2

-1

0

1

Ch

an

ge

in b

od

y w

eigh

t (kg)

(Bas

eline W

eigh

t = 9

9 kg

)

-5.3 ± 0.4 kg

A1CWeight

54 46

Changes in Glycemia and Weight in 3 Head-to-Head Studies Exenatide vs. Insulin

Heine R, et al. Ann Int Med. 2005;143:559-569.Barnett A, et al. Clin Thera. 2007;29(11):2333-2348. Nauck M, et al. Diabetologia. 2007;50(2):259-267.

EXENATIDEAND NO undue HYPOglycemia

Added by Dr S

Relative differences- sitagliptin vs exenatide

• ~50% experience nausea or other GI events

– Early in course, decrease over time

– ~5% stop therapy due to nausea or vomiting

– To minimized –

• Start low dose bid for 4 weeks, then titrate to 10 μg bid

• administer exenatide just before meals until well tolerated

• SU-related hypoglycemia can be increased

– SU dose when initiating therapy with exenatide

• Antibodies of unclear significance

• Pancreatitis – rare

• Renal failure – rare

Exenatide: Adverse Events

Pancreatitis With Exenatide and Sitagliptin: Large Database Analysis

• Analysis of data from large US commercial health insurance database

• Active drug safety surveillance system• June 2005 through June 2008 • No increased risk for patients treated with exenatide or sitagliptin

compared with metformin (MET) or glyburide (GLY)

Dore DD, et al. Curr Med Res Opin. 2009;25:1019-1027.

0.0 0.5 1.0 1.5 2.0 2.5

Relative Risk (95% confidence interval)

EXN (n = 27,996) vs

MET or GLY (n = 27,983)

SITA (n = 16,267) vs

MET or GLY (n = 16,281)

Pancreatitis Occurrence

0.13% of exenatide-treated patients

0.12% of sitagliptin-treated patients

Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences

Properties/Effect Exenatide1 DPP-4 Inhibitor1 Liraglutide, Exenatide-OW2,3

Glucose-dependent insulin secretion Yes Yes Yes

Glucose-dependent glucagon Yes Yes Yes

Slows gastric emptying Yes No Little or no

Effect on body weight Weight loss Weight neutral Weight loss

Effect on A1c ~1% <1% >1%

Effect on fasting glucose Modest Modest Good

Effect on postprandial glucose Good Modest Modest

Effect on CVD risk factors Improve (with weight loss)

No consistent change Improve

Side effects Nausea (?pancre-atitis, CRF)

~ None observed(pancreatitis)

Less nausea, skin, (?pancreatitis, ?

CRF, ?MTC)

Administration SubcutaneousTwice daily

OralOnce daily

SubcutaneousDaily or weekly

1. Amori RE, et al. JAMA. 2007;298:194-206.2. Exenatide LAR (once weekly): Drucker DJ, et al. Lancet. 2008;372:1240-1250. 3. Liraglutide: Buse JB, et al. Lancet. 2009;374:39-47.

Dr G – Needs to be redesigned/edited if kept