ceftaroline: a new cephalosporin with activity …...materia medica volume 1, issue 2 july 2012 2 (p

MATERIA MEDICA Volume 1 Issue 2 July 2012 1

INSIDE THIS ISSUE THE PIOGLITAZONE CONTROVERSY PRACTICE

IMPLICATIONS

BYDUREONreg A NEW ONCE-WEEKLY GLP-1 AGONIST FOR TYPE 2 DIABETES

s of 2010 there were over 256 million people in the United States with a diagnosis of type 2 diabetes mellitus (T2DM)1 This is concerning

given persons with diabetes live with an increased risk of serious macrovascular and microvascular complica-tions Fortunately there are many different classes of medications currently on the market for treatment Current national recommendations list metformin as initial therapy for T2DM followed by addition of insu-lin or another oral medication2 Lately the use of one class of oral medications in particular the thiazoli-dinediones (TZDs) has been surrounded by contro-versy potentially limiting the number of oral diabetes medication options for some patients As a result of post marketing safety reports the FDA has released warnings regarding an increased risk of cardiovascular disease associated with the use of one of the two TZDs rosiglitazone and now restricts its use and pre-scribing3

The other TZD pioglitazone (Actos) does not have the same restrictions as rosiglitazone however there are recent warnings from the FDA regarding po-tential increased risks of congestive heart failure and bladder cancer45 Despite these warnings pioglitazone is still an appropriate choice of add-on therapy for many patients with T2DM and should not be discount-

ed all together This review will discuss the literature supporting these warnings as well as when pioglita-zone therapy is and is not appropriate

Pioglitazone was approved in 1999 with an indica-tion for the treatment of T2DM6 Current national rec-ommendations list it as a tier 2 medication to be used after lifestyle modifications and metformin2 Pioglita-zone is indicated for monotherapy or as add-on thera-py with metformin andor a sulfonylurea On average pioglitazone can achieve an A1c reduction of 05-13 as compared to insulin which can reduce A1c by 1-25

Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) receptor agonist The medi-cation enters the cell nucleus to activate PPARγ which controls multiple transcription factors Pioglitazone can stimulate glucose uptake into cells via activation of GLUT4 transcription which results in increased insulin sensitivity Due to a mechanism of action reliant on gene regulation full effects of pioglitazone are often not apparent until after 4 weeks of therapy5

The Pioglitazone Controversy Practice Implications

Chelsea Deronde PharmD

A

Volume 1 Issue 2 July 2012

Editorrsquos Summary Pioglitazone Controversy

Background

Pioglitazone a thiazolidinedione is a commonly used

agent for the treatment of type 2 diabetes

Recommended as 2nd-tier therapy after metformin

Key Points

Pioglitazone has been associated with an increased

risk of heart failure exacerbation and should not be used in patients with NYHA Class III or IV heart failure or symptomatic heart failure

Pioglitazone may be associated with an increased risk

of bladder cancer particularly with long-term (gt 2 year) use and should be avoided in those with a history of bladder cancer or those at increased risk for develop-ing bladder cancer

PIOGLITAZONE BACKGROUND

M

ATERIA

EDICA


(plt00001) The pioglitazone group also had an in-crease in median body weight from baseline to end of follow up of 36kg compared to a decrease in median body weight in the placebo group of 05 kg (plt00001) The weight gain with pioglitazone may be partly at-tributable to fluid retention which could have contrib-uted to the increased risk of CHF7

A retrospective cohort study designed to examine the risk of CHF with TZDs collected data from a health insurance claims database from 1995 to 20018 Patients who had any claims processed for a TZD were included in the ldquoexposedrdquo group and were each matched with five randomly selected ldquounexposedrdquo pa-tients who had received a different oral anti-hyperglycemic medication Patients were excluded if they had any claims associated with a diagnosis of heart failure in the year prior to TZD initiation The study population included 5441 patients in the ldquoexposedrdquo group and 28103 in the ldquounexposedrdquo group The pri-mary outcome was CHF diagnosis indicated by a hos-pitalization or outpatient visit with associated CHF di-agnosis The results showed an increased risk with TZD use with an adjusted hazards ratio of 17 (plt0001 Table)8

The choice to use pioglitazone should always take into account the patientrsquos risk for CHF Patients with pre-existing risk factors for CHF or who already have CHF may not be good candidates for this medication However many patients with T2DM especially young-er patients do not have risk factors for CHF and can benefit from glycemic control with pioglitazone Given fluid retention and edema tends to worsen when pa-tients are just starting pioglitazone or after dose in-creases monitoring for weight gain edema and symp-toms of CHF is particularly important during those time periods5

The most recent warning from the FDA regarding pioglitazone was concerning for a potential increased risk of bladder cancer from the medication4 Pioglita-zone exerts its affects on blood glucose via the PPARγ receptor This receptor has been identified in bladder

Pioglitazone is taken orally and dosed once daily without regard to meals which makes it attractive to patients However weight gain and edema are com-mon adverse effects that limit the use of this agent The weight gain is partly attributed to fluid retention Patients are also at a higher risk of bone fracture when on pioglitazone This adverse effect is important to consider for patients with osteoporosis or who already have a high risk of fracture More serious adverse ef-fects include CHF liver failure and possible increased risk of developing bladder cancer5 Because of these concerns recommended monitoring for patients on pioglitazone includes bone mineral density tests liver function tests at baseline and with any symptoms of liver injury weight checks and signs or symptoms of worsening or new onset CHF5

Pioglitazone holds a black box warning for causing or worsening CHF which is thought to be due to fluid retention caused by the medication With increased fluid retention the heart becomes increasingly stressed and cannot compensate for the increased volume lead-ing to CHF The medication is contraindicated in NY-HA Class III or IV heart failure and not recommend-ed for use in patients with symptomatic heart failure Patients should be carefully monitored for signs or symptoms of heart failure especially after starting pioglitazone or after a dose increase5

Much of the data related to CHF and pioglitazone come from results of the PROactive trial7 This study was a randomized double blind trial including 5238 patients with T2DM and macrovascular disease The primary outcome was time to first occurrence of all cause mortality non-fatal MI stroke acute coronary syndrome coronary or leg revascularization or ampu-tation above the ankle The data did not show a signifi-cant difference in the primary endpoint between pioglitazone and placebo However there was a signifi-cant increase in CHF with pioglitazone use compared to placebo An emergent heart failure event was report-ed by 11 of patients treated with pioglitazone com-pared to 8 of patients treated with placebo

PIOGLITAZONE amp BLADDER CANCER

PIOGLITAZONE amp CHF

Table | Incidence of CHF and weight change in PROactive trial8

Adverse Event Placebo (N=2633) Actos (N=2605)

At least one hospitalized CHF event 108 (41) 149 (57)

Fatal CHF event 22 (08) 25(10)

Median body weight change from baseline to final follow-up -05 kg +36 kg


tumors and also in some healthy uroepithelial tissue When TZDs bind to the PPARγ receptors in the cell nucleus they can alter cellular replication Thus mech-anistically TZDs could plausibly affect cancer cell lines9

Preclinical studies of pioglitazone demonstrated an increase in bladder tumors in male rats receiving pioglitazone compared to placebo Further the PRO-active study found an increase of bladder tumors in human patients treated with pioglitazone7 Although the difference was not statistically significant the FDA requested a safety analysis regarding the risk of bladder cancer with pioglitazone use in humans

This ongoing longitudinal cohort study is being conducted by GlaxoSmithKline the drugrsquos manufac-turer9 Data are being collected from Kaiser Perma-nente Northern Californiarsquos (KPNC) health records system Patients eligible for inclusion met one of the following criteria 1) as of 1197 patients had a diag-nosis of T2DM were gt 40 years old and were a KPNC member 2) diagnosis of T2DM turned 40 years old between 1197 and 123102 and were a KPCN member at that time or 3) were gt40 years old when joined the KPCN between 1197 and 123102 Patients with a previous diagnosis of blad-der cancer or diagnosis within 6 months of joining KPCN were excluded from the study

The study compares pioglitazone ldquoever userdquo to ldquonever userdquo There are 30173 patients in the ldquoever userdquo category and 162926 patients in the ldquonever userdquo category ldquoEver userdquo is defined as filling at least 2 pre-scriptions within a 6 month period with all other pa-tients categorized as ldquonever userdquo Cumulative duration of treatment is also taken into account Patients are being followed until 43008 or until death from any cause membership or prescription benefits were void for at least 4 months or a diagnosis of bladder cancer is made The primary outcome of the study is inci-dence of bladder cancer in these patients regardless of cancer histology

While the final report is still in progress the results of the April 2011 interim report included 881 cases of newly diagnosed bladder cancer Of these cases 90 were in the ldquoever userdquo group and 791 in the ldquonever userdquo group The median bladder cancer incidence rate was 815 per 100000 person years in the ldquoever userdquo group compared to 688 in the ldquonever userdquo group However there was no significant difference in inci-dence (HR 12 95 CI 09-15) Rates of bladder can-cer were also higher in patients in the ldquoever userdquo group However the hazard ratios adjusted for sex and age as well as adjusted for other known confounding

variables were not statistically significant (12 with 95 CI 09-15 for both ratios) The subgroup analysis did demonstrate a significantly higher risk of bladder cancer in patients taking pioglitazone longer than 24 months The relative risk was 40-50 higher in pa-tients taking pioglitazone for the longer duration This risk increased to 70 higher when the observation pe-riod was extended to gt48 months of exposure In the overall study population thus far no significant in-creased risk of bladder cancer was found with pioglita-zone use however a significant increased risk was ob-served in patients treated with pioglitazone for gt 2 years

One limitation to this study is the uncertainty of whether patients were included with undiagnosed blad-der cancer at the start of the trial In addition many confounding variables may affect the incidence of bladder cancer such as smoking renal function or other cancer diagnoses at baseline910 Unfortunately data collection was not complete for all of the baseline characteristics and certain variables such as occupa-tional exposures (including workers exposed to dyes rubber aluminum leather pesticides) were not all ac-counted for Significant differences in baseline data for these characteristics could bias the results

Until the final report is published the interim in-formation should be applied to clinical practice judi-ciously to prevent patient harm Pioglitazone may not be an appropriate choice for some patients who are already at an increased risk of developing bladder can-cer given pioglitazonersquos mechanism of action may be additive Higher risk patients include those with a his-tory of bladder cancer current smokers10 history of exposure to occupational carcinogens (eg paint met-al rubber leather and miner workers)11 or previouscurrent use of cyclophosphamide12 For patients at low risk for bladder cancer pioglitazone may be appropri-ate for blood glucose control Given that a significant increase in risk was seen after 2 years of use risks and benefits of the medication should be reassessed as pa-tients approach that point in therapy

As is the case with any medications the choice of using pioglitazone for treatment in T2DM patients comes down to risks versus benefits Risks of uncon-trolled T2DM include stroke MI renal failure reti-nopathy and neuropathy2 If pioglitazone decreases a patientrsquos chance of these serious complications the benefits may outweigh the risks of the medication Pioglitazone should not be used in patients with NY-

CONCLUSION


HA Class III or IV heart failure symptomatic heart failure or those at high risk for bladder cancer osteo-porosis or with pre-existing edema5 The decision to use pioglitazone must be patient specific with a thor-ough evaluation of the risks of CHF and bladder can-cer

REFERENCES

1 National Diabetes Information Clearinghouse US Depart-ment of Health and Human Services Available at httpdiabetesniddknihgovdmpubsstatistics Accessed 51112

2 American Diabetes Association Standards of Care in Diabe-tes 2012 Diabetes Care 2012 35(1)S11-S63

3 FDA Drug Safety Communication Avandia (rosiglitazone) labels now contain updated information about cardiovascular risks and use in certain patients US Food and Drug Admin-istration Available at httpwwwfdagovDrugsDrugSafetyucm241411htm Accessed 42812

4 Actos (pioglitazone) Ongoing Safety Review - Potential In-creased Risk of Bladder Cancer US Food and Drug Admin-istration Available at httpwwwfdagovSafetyM e d W a t c h S a f e t y I n f o r m a t i o n SafetyAlertsforHumanMedicalProductsucm226257htmutm_campaign=Google2amputm_source=fdaSearchamputm_medium=websiteamputm_term=pioglitazone bladder can-ceramputm_content=1 Accessed 41512

5 Actos [package insert] Deerfield Takeda Pharmaceuticals America Inc 2012

6 FDA approved drug products US Food and Drug Admin-istration Available at httpwwwaccessdatafdagovs c r i p t s c d e r d r u g s a t f d a i n d e x c f m fuseaction=SearchDrugDetails Accessed 51912

7 Dormandy JA Charbonnel B Eckland DJ et al Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) a randomised con-trolled trial Lancet 20053661279-89

8 Delea TE Edelsberg JS Hagiwara M et al Use of thiazoli-dinediones and risk of heart failure in people with type 2 dia-betes a retrospective cohort study Diabetes Care 2003262983-9

9 Lewis JD Ferrara A Peng T et al Risk of bladder cancer among diabetic patients treated with pioglitazone interim report of a longitudinal study Diabetes Care 201134916-22

10 Freedman ND Silverman DT Hollenbeck AR Schatzkin A Abnet CC Association between smoking and risk of bladder cancer among men and women JAMA 2011306737

11 Kogevinas M Mannetje A Cordier S et al Occupation and bladder cancer among men in Western Europe Cancer Caus-es Control 200314907

12 Talar-Williams C Hijazi YM Walther MM et al Cyclophos-phamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis Ann Intern Med 1996124477

iabetes places patients at a higher risk for car-diovascular morbidity and mortality as well as complications including retinopathy neurop-

athy and nephropathy Achieving target A1c and blood glucose levels are an essential part of therapy to reduce these macrovascular and microvascular complications1 Several pharmacologic options are available for treat-ment of type 2 diabetes The new 2012 ADA guide-lines continue to recommend metformin and lifestyle modifications as first line therapy for those without contraindications2 Step 2 therapy for those who fail to achieve glycemic control is individualized for each pa-tient These new guidelines emphasize the importance of patient specific considerations for drug therapy be-yond metformin2 Factors to consider when choosing the best adjunct to metformin include concomitant diseases concurrent medications dosing frequency route of administration drug tolerability and cost

Currently five drug classes are recommended as step 2 therapy for type 2 diabetes sulfonylureas (SU) thiazolidinediones (TZD) glucagon like peptide-1

Bydureonreg A New Once-Weekly GLP-1 Agonist for Type 2 DM

Lisa Hong PharmD Candidate

D

Editorrsquos Summary Exenatide ER (Bydureonreg)

Description amp Indication

GLP-1 agonist also known as an incretin mimetic

Indicated for treatment of type 2 diabetes as a 2nd-tier

agent after metformin

Dosing

2 mg subcutaneously once every 7 days

Not recommended if CrCL lt 30 mLmin

Exenatide ER has not been studied concomitantly with

insulin

Efficacy

The DURATION trial series suggest exenatide ER is

non-inferior compared with metformin pioglitazone and sulfonylureas and possibly superior to sitagliptin

May be less effective than liraglutide based on prelimi-

nary results of the DURATION-6 trial

Safety

Generally similar safety profile to twice-daily exenatide

(Byettareg)


(GLP-1) agonists dipeptidyl peptidase-4 (DPP-4) in-hibitors and insulin2 The GLP-1 agonists currently available include liraglutide(Victozareg) exenatide (Byettareg) and exenatide extended-release (Bydureonreg) Bydureonreg is manufactured by Amylin Pharmaceuticals Inc and is the newest drug in this class gaining FDA approval on January 27 20123 The-se agents are indicated as adjuncts to improve glycemic control in patients with type 2 diabetes and are not ap-propriate for patients with type 1 diabetes4 GLP-1 ag-onists are preferred in those who are overweight be-cause they are the only recommended adjuncts to met-formin which can cause weight loss2 Additionally the-se drugs alone do not cause hypoglycemia and carry low side effect profiles2

Exenatide is usually dosed twice daily before meals and liraglutide is a once daily injection The new-est agent exenatide extended-release (ER) is attractive because it is only administered once weekly This once weekly dosing allows for increased adherence and con-venience compared to once or twice daily injections required with other agents in this class The purpose of this article is to discuss the pharmacology of exenatide ER as well as the clinical trials which assessed the med-icationrsquos safety and efficacy

GLP-1 is an endogenous incretin hormone which plays an important role in glucose homeostasis15 This hormone is secreted by the small intestine in response to food intake In type 2 diabetes the incretin effect is diminished leading to reduced insulin secretion5 GLP-1 agonists are incretin mimetics which control hyper-glycemia via multiple mechanisms These medications increase glucose-dependent insulin secretion suppress inappropriate increases in glucagon and slow gastric emptying which reduces appetite and increases sa-tiety35 The glucose-dependent effects on insulin and glucagon only occur during hyperglycemia significantly reducing risk of hypoglycemia GLP-1 agonists may reduce A1c by up to 2913 Additionally these agents reduce both fasting and post-prandial glucose but have a larger effect on post-prandial levels7 Although GLP-1 is secreted following meals previous studies support a role of basal GLP-1 concentrations on fast-ing blood glucose (FBG) levels (Figure) The findings from these studies provided a rationale to explore GLP-1 agonists with prolonged pharmacokinetic profiles12 Continuous delivery and exposure to exenatide with the extended-release formulation provides significantly greater reduction in FBG levels and thus A1c compared

to twice daily exenatide7 The gradual release of ex-enatide with the ER formulation eliminates the need for dose titration15

Additionally endogenous GLP-1 is rapidly inacti-vated by dipeptidyl peptidase-4 (DPP-4) The half-life of endogenous GLP-1 is less than 2 minutes16 Ex-enatide is a synthetically derived GLP-1 agonist with an amino-acid alteration at the N-terminus of the com-pound which reduces susceptibility to degradation by DPP-4515 This resistance to DPP-4 allows for three to four times greater GLP-1 activity compared to normal physiologic activity5 The increased GLP-1 activity is responsible for the effects on satiety and gastric empty-ing which are not seen at physiologic GLP-1 concen-trations5 These effects may contribute to the benefits seen on blood pressure and fasting lipids (Table 1) In the extended-release formulation of exenatide sur-face-bound exenatide is initially released followed by continuous release of the drug from biodegradable pol-ymeric microspheres over approximately ten weeks314

During this time two peaks occur in exenatide plasma

CLINICAL PHARMACOLOGY

Figure | Once-weekly exenatide ER causes greater reductions in fasting blood glucose but smaller re-ductions in post-prandial glucose compared to twice-daily exenatide

7

Table 1 | Exenatide lipid and BP effects7

Parameter Exenatide BID Exenatide QW

TG -11 -15

HDL -003 mmolL -002 mmolL

LDL -013 mmolL +003 mmolL

SBP -34 mmHg -47 mmHg

DBP -17 mmHg -17 mmHg

TG = triglycerides HDL = high-density lipoproteins LDL = low-density lipoproteins SBP = systolic blood pressure DBP = diastolic blood pressure Not a statistically significant change from baseline


concentrations representing hydration and erosion of the microspheres respectively3 Steady state is reached after six to seven weeks of drug administration how-ever improvements in glucose control may be seen as early as two to four weeks after the first dose711 Ex-enatide ER has a constant volume of distribution of 283 liters3 This medication is not extensively metabo-lized by the liver and is primarily eliminated via glo-merular filtration with subsequent proteolytic degrada-tion3 The mean clearance of the drug is 91 Lh inde-pendent of the dose3 Plasma concentrations fall below detectable levels at about ten weeks after discontinua-tion of the medication The pharmacokinetics of ex-enatide ER are summarized in Table 2

The following drug interactions are based on stud-ies which used exenatide (Byettareg) but given the same active ingredient in exenatide ER (Bydureonreg) drug interactions are expected to be similar between these medications Post-marketing reports with exenatide have demonstrated that concurrent use of warfarin may result in elevated INR and increased risk of bleed-ing Slowed gastric emptying from exenatide use may result in reduced absorption rate of orally administered drugs Oral medications should be taken at least one hour before exenatide is injected5 Dosing oral contra-ceptives 30 minutes after exenatide administration may result in a 20 increased mean trough concentration and 45 reduction in the Cmax of ethinyl estradiol as well as a delayed Tmax of ethinyl estradiol by 3 hours These effects are less pronounced when oral contra-ceptives are dosed one hour prior to exenatide admin-istration

DRUG INTERACTIONS

Table 2 | Pharmacokinetics of exenatide ER3

Absorption

Tmax Initially peak 2 weeks 2

nd peak 6-7 weeks (steady state

~300pgmL)

Distribution Vd=283L and remains unchanged

Metabolism Not metabolized in the liver

Excretion Glomerular filtration and proteolytic

degradation Mean CL=91 Lh independent of dose

The DURATION series was conducted to assess the safety and efficacy of exenatide ER compared to other agents commonly used in the treatment of type 2 diabetes These trials are summarized in Table 3

All trials except DURATION-2 and -4 were open-label in design Each study population consisted of patients with type 2 diabetes a baseline A1c between 7 and 11 and a BMI between 25 and 45 kgm2 The primary outcome for each trial was change in A1c from baseline A common limitation across the studies is the lack of assessment in hard outcomes such as cardiovas-cular morbidity and mortality Additionally each study was only conducted for a short duration which limits the ability to evaluate adverse effects and glycemic control long-term

DURATION-1

DURATION-1 was a randomized open-label non-inferiority trial assessing the safety and efficacy of once weekly exenatide ER compared to twice daily ex-enatide7 The 295 patients included in the study were at least 16 years of age and were currently on metformin a SU a TZD or any combination of two of these medications All patients included had a baseline FBG less than 16 mmolL (288 mgdl) Reduction of A1c from baseline was significantly greater with exenatide ER (-19) compared to exenatide (-15 p=00023 for the comparison between the two treatment arms) The difference in change of A1c from baseline between the two treatment arms was -033 (95 CI -054 to -012) Mean FBG was also reduced significantly more with exenatide ER with a difference between groups of 09 mmolL (162 mgdl) at the end of the 30-week study (plt00001) A significantly greater proportion of patients taking exenatide ER (77) reached target A1c of lt7 compared to those on twice-daily exenatide (61 p=00039) Weight loss was similar between both groups and averaged approximately 36 to 37 kg The study considered exenatide ER non-inferior to exenatide if the difference in change of A1c between both groups was lt04 Superiority was satisfied if the confidence interval fell entirely below zero Therefore exenatide ER was superior to exenatide in glycemic control with similar weight loss and without increase in hypoglycemia however the incidence of hypoglycemia was greater in both groups when given concomitantly with a SU

After 30 weeks those in the exenatide twice daily group switched to exenatide ER once weekly for an additional 22-week follow-up totaling a 52-week study

CLINICAL TRIALS


Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

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duration6 During the subsequent assessment period A1c FBG and weight loss were maintained in those who originally received exenatide ER and similar glu-cose control was achieved in those who switched from twice daily to once weekly exenatide

Limitations of this study include the open label design although blinding of A1c and FBG results was maintained throughout the 30-week period in attempt to minimize bias Also the majority of the population was white which reduces the external validity of the study to other ethnic groups This study was spon-sored by Amylin Pharmaceuticals and Eli Lilly and Company who were involved in design protocol de-velopment and analysis of the data The lack of com-parison to other therapies limits the ability to assess relative efficacy as compared to other pharmacologic agents Additionally adherence was not assessed be-tween the two groups and given the difference in dos-ing frequency adherence may have contributed to the differences seen The secondary outcomes were ana-lyzed using on-treatment change within each treatment arm but no comparison between treatments was per-formed

DURATION-2

The DURATION-2 trial a 26-week randomized double-blinded placebo-controlled superiority trial studied 500 patients at least 18 years of age already treated with metformin8 The study compared opti-mized doses of exenatide ER sitagliptin (a DPP-4 in-hibitor) and pioglitazone (a TZD) as adjunctive thera-py The results showed that A1c was reduced by 11 05 and 09 in each group respectively if baseline A1c was lt9 For patients with a baseline A1c ge 9 A1c was reduced by 2 13 and 15 in each group respectively The difference between exenatide ER and pioglitazone was only significant in those with an A1c ge 9 whereas the difference in A1c reduction between exenatide ER and sitagliptin was significant regardless of baseline A1c Significantly more patients reached an A1c of lt 7 in those taking exenatide ER (59) com-pared to sitagliptin (30) and pioglitazone (43) The p-values for comparison to exenatide ER were 00001 and 00015 for sitagliptin and pioglitazone respective-ly

Secondary outcomes included FBG weight BP and lipid changes Patients in the exenatide ER group had a 09 mmolL (162 mgdl) greater reduction in FBG compared with patients treated with sitagliptin (p=00038) Additionally 60 of patients receiving exenatide ER achieved a FBG of lt 7 mmolL (126 mgdl) whereas only 35 of patients receiving T

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sitagliptin reached this FBG goal (plt00001 for the comparison between exenatide ER and sitagliptin) No significant difference in FBG reduction was observed between exenatide ER and pioglitazone At week 26 those receiving exenatide ER lost an average of 23 kg whereas those receiving sitagliptin only lost about 08 kg and those receiving pioglitazone gained approxi-mately 28 kg Exenatide ER caused favorable changes in all lipid parameters though pioglitazone provided greater increases in HDL and greater reduction of TGs Exenatide ER reduced SBP by close to 4 mmHg and 11 mmHg in those with normal and abnormal (gt130 mmHg) SBP respectively This finding of blood pressure reduction was statistically significantly greater when comparing exenatide ER to sitagliptin but not pioglitazone Exenatide ER administered once weekly was superior to optimized doses of sitaglipitin and pioglitazone from the standpoint of patients achieving target A1c and weight loss

In a subsequent 26-week assessment period all patients in the sitagliptin and pioglitazone treatment arms were switched to once weekly exenatide ER9 Those who switched from pioglitazone or sitalgliptin had further improvement in glycemic control whereas those originally receiving exenatide ER had sustained glycemic control Also by the end of the additional 26 weeks a small but significant improvement in HDL from baseline was reported in the exenatide ER treat-ment group (0017 mmolL [03 mgdl] plt005)

Amylin and Eli Lilly and Company funded the study and played a role in all aspects of the study in-cluding data analysis and interpretation However bias was minimized by use of a double-blinded study de-sign Another limitation is the lack of comparison with other potential adjunctive therapies such as insulin SU or liraglutide another GLP-1 agonist

DURATION-3

DURATION 3 was a randomized open-label study conducted over 26 weeks10 The trial compared once weekly exenatide ER to insulin glargine (a long-acting basal insulin) titrated to a goal FBG of 4 to 55 mmolL (72 to 99 mgdl) This population included 456 adults age 18 or older who failed to achieve glu-cose control with metformin or metformin in combi-nation with a SU The dose of metformin had to be at least 1500 mg for 8 weeks or longer prior to enroll-ment After 26 weeks exenatide ER caused a signifi-cantly greater reduction in A1c from baseline (-15) compared to insulin glargine (-13 p=0017 for the comparison between treatments) Although insulin provided a 07 mmolL (126 mgdl) greater decrease

in FBG (p=0001 for the difference between treatment groups) exenatide ER demonstrated greater reductions in PPG excursions after morning (p=0001) and even-ing meals (p=0033) Compared to insulin exenatide ER caused significant weight loss (-26 kg vs 14 kg plt00001) and a significantly lower incidence of hypo-glycemia (plt00001 with metformin only and p=0009 with concomitant use of metformin and SU) The au-thors concluded that exenatide ER is a reasonable ad-junct if adherence obesity and risk of hypoglycemic events are of particular concern

The generalizability of this trial is limited as the population studied was predominantly white Funding was provided by Amylin Pharmaceuticals and Eli Lilly and Company who were involved in the study design protocol development collection review and analysis of data Most authors were employees of Eli Lilly and Company which could potentially inject bias Addition-ally the open-label design due to inability to mask fixed-dose exenatide and daily titration of insulin al-lows for potential bias in the results This potential for bias was minimized by masking investigators responsi-ble for analyzing data to treatment assignments The lack of adherence assessment is another limitation of this study

DURATION-4

DURATION-4 was a randomized double-blind open-label non-inferiority trial which assessed the safety and efficacy of metformin exenatide ER sitagliptin and pioglitazone as monotherapy in 740 patients naiumlve to antihyperglycemic medications Each group received diet and exercise counseling in addition to treatment After 26 weeks the mean A1c reduction from baseline was -153 in those taking exenatide ER -148 with metformin (non-inferior compared to exenatide ER) -1-63 with pioglitazone (superior to exenatide ER) and -115 in the sitagliptin group (inferior compared to exenatide ER) Within each treatment group 63 55 61 and 43 of patients achieved an A1c of lt7 respectively The sitagliptin treatment arm was the only group that was statistically different from exenatide ER (plt0001 for the compari-son between both groups for both the proportion of patients reaching A1c lt7 and FBG) FBG was re-duced by -23 mmolL (414 mgdl) -2 mmolL (36 mgdl) -26 mmolL (468 mgdl) and -11 mmolL (198 mgdl) for each group respectively Exenatide ER caused similar weight loss (2 kg) compared to met-formin however reduction in weight with exenatide ER was statistically greater than that seen with pioglita-


zone and sitagliptin (plt0001 for the comparison of exenatide ER to both pioglitasone and sitagliptin)

By the end of the 26-week study exenatide ER metformin and pioglitazone treatment arms had a mean A1c of lt7 The results with pioglitazone are inconsistent with results from the DURATION-2 study which demonstrated superiority with exenatide ER over pioglitazone however DURATION-2 used these agents as adjuncts to metformin and not as mon-otherapy Glucose control was much less with sitagliptin supporting that DPP-4 inhibition is less ef-fective compared to GLP-1 receptor agonism The da-ta with metformin support the ADA recommendation of using metformin as first line therapy however ex-enatide ER and pioglitazone demonstrated similar re-duction in A1c Thus exenatide ER and pioglitazone may potentially be alternative options for treatment-naiumlve patients The study recognized metformin as a first line recommendation but concluded that ex-enatide ER and metformin provide similar glycemic control with weight loss as well as a minimal risk of hypoglycemia Therefore exenatide ER may be consid-ered first line as monotherapy if a patient has contrain-dications for the use of metformin

This study did not assess adherence and provided a very limited description of how non-inferiority and superiority were determined

DURATION-5

The DURATION-5 trial was a randomized open-label study which compared exenatide and exenatide ER in 252 patients over a 24-week period11 Patients were at least 18 years of age and treated with metfor-min and either a SU or a TZD Baseline FBG was lt155 mmolL (280 mgdl) At the end of the study exenatide ER provided greater A1c reduction (-16 vs -09 plt00001) and FBG lowering (-35 mgdl vs -12 mgdl p=00008) compared to exenatide The ex-enatide ER treatment arm also had a greater propor-tion of patients who reached target A1c of lt7 com-pared to exenatide (581 vs 301 plt00001) In those receiving exenatide ER BP was reduced by 29 mmHg (95 CI -52 to -07) from baseline if baseline SBP was lt 130 mmHg and 79 mmHg (95 CI -113 to -45) if baseline SBP was ge130 mmHg In those tak-ing exenatide twice daily BP was only significantly re-duced if hypertension was uncontrolled (mean SBP change -77 mmHg 95 CI -113 to -40) BP reduc-tions were significantly greater in those treated with exenatide ER Exenatide ER also significantly reduced LDL (-64 mgdl) and total cholesterol (-154 mgdl) Weekly exenatide ER provided superior glycemic con-

trol with greater A1c and FBG reduction less GI side effects and similar weight loss and hypoglycemic risk

The authors of this study were employees and stockholders of Amylin Pharmaceuticals Inc who sponsored the trial but bias was minimized by blinding sponsors from the data throughout the 24 weeks

DURATION-6

DURATION-6 was a 26-week randomized multi-centered open-label non-inferiority study which ran-domized 911 patients to one of two treatment arms once-weekly exenatide ER (n=461) or once-daily lirag-lutide (n=450)21 Patients included were already treated with metformin a SU andor pioglitazone Exenatide ER was considered non-inferior to liraglutide if the upper limit of the 95 confidence interval for the dif-ference between groups in A1c reduction from baseline was lt025 Although the full results of the DURA-TION-6 trial are not yet published results from a pub-lished abstract suggest that by week 26 liraglutide re-duced A1c from baseline by 148 compared to 128 in those who received exenatide ER The difference between groups of 021 did not meet the non-inferiority criteria with a 95 confidence interval of 0008 to 034 (the upper 95 CI level of 034 being gt025) Additionally 602 of patients taking lirag-lutide achieved A1c lt7 whereas only 523 of pa-tients taking exenatide ER reached this goal (p=0008 for comparison between treatment groups) Weight loss between groups was statistically different with -358 kg and -268 kg for liraglutide and exenatide ER respectively (mean difference of 09 kg 95CI 040 to 141) The incidence of hypoglycemia and the magni-tude of BP lowering were similar between both treat-ment arms Exenatide ER caused less GI side effects compared to liraglutide The study concluded that li-raglutide provides greater reductions in A1c and weight but more GI side effects than exenatide ER The effi-cacy results for exenatide-ER were less impressive in DURATION-6 compared to other studies in the DU-RATION series

Contraindications

As with all GLP-1 agonists exenatide ER carries a black box warning for the risk of thyroid C-cell tumors and should not be used in patients with a personal or family history of medullary thyroid carcinoma or multi-ple endocrine neoplasia syndrome type 2 (MEN 2) The proposed mechanism for the development of the-se carcinomas is that GLP-1 stimulates calcitonin re-

SAFETY amp ADVERSE EFFECTS


lease which may upregulate calcitonin gene expression leading to C-cell hyperplasia19 Administration of ex-enatide in humans does not appear to affect the con-centration of calcitonin11 The FDA does not recom-mend routine monitoring of serum calcitonin or thy-roid ultrasounds in patients treated with exenatide ER3 Although the findings of thyroid C-cell tumors were in rats and clinical relevance in humans is uncer-tain use is only recommended if benefits outweigh this potential risk Patientsrsquo should be encouraged to report symptoms such as a lump in the neck dysphagia or dyspnea

Warnings and Precautions

Safety and efficacy of exenatide has not been es-tablished in children Therefore use in the pediatric population is not recommended4 Exenatide falls into pregnancy category C Animal (rat) studies demon-strated that exenatide may cause cleft palate reduced fetal growth and irregular skeletal ossification Due to potential harm to the fetus exenatide should only be used during pregnancy if benefit outweighs risk3 Ex-cretion of exenatide in breast milk is unclear Studies in mice have found presence of exenatide at concentra-tions le 25 of serum concentrations The potential risk of tumorigenicity should be weighed against bene-fits of the drug3

Adverse Effects

A comparison of the incidence of adverse effects between different pharmacologic agents is displayed in Table 4 The table was compiled from the DURA-TION series

The most common adverse events (AE) with ex-enatide (immediate or extended-release) are gastroin-testinal (GI) side effects such as nausea vomiting diar-rhea and indigestion4 Of these GI side effects nausea is the most common with a lower incidence in those taking exenatide ER (14 to 264) compared to those taking exenatide (345 to 35)711 These GI effects may occur upon initiating therapy but are generally transient45

Injection site reactions are the second most com-mon AEs seen with either formulation of exenatide following GI side effects The incidence of injection site reactions is greater with exenatide ER (13 to 176) compared with twice-daily exenatide (10 to 103) but injections are administered less frequently with the former drug711

Post-marketing data with exenatide showed an as-sociation with hemorrhagic or necrotizing acute pan-creatitis3 Although exenatide ER was not studied in

patients with a history of pancreatitis and risk of pan-creatitis while on this medication is unknown alterna-tive options should be considered if a patient has a his-tory of pancreatitis3 Exenatide should be used with caution if there is a history of gallstones alcoholism or high triglyceride levels4 GLP-1 agonists can potentially mask signs of pancreatitis as signs and symptoms can include abdominal pain which may or may not radiate to the back nausea and vomiting4

Antibodies to exenatide can develop in those tak-ing the medication3 Although antibodies are often measured and detected in patients who have taken ex-enatide ER it is usually not associated with blunted response or reduced glycemic control3 Alternative agents should be considered if glycemic control is lost

Hypersensitivity reactions including anaphylaxis and angioedema have been noted in post-marketing reports3 Patients who experience these reactions should discontinue exenatide and seek immediate med-ical attention

Hypoglycemia may occur when exenatide is used in combination with insulin SUs or meglitinides The dose of the SU may require reduction particularly if glucose levels are close to goal range because these agents cause non-glucose dependent insulin secretion Patients taking these medications in combination with exenatide need to be educated regarding recognition and management of signs and symptoms of hypoglyce-mia (shaking sweating weakness tachycardia head-ache and hunger)

Exenatide ER is administered as a 2 mg subcutane-ous injection into the upper arm abdomen or thigh every 7 days3 Unlike exenatide exenatide ER can be administered at any time of day with or without food3 Eating slowly and stopping when full will reduce risk of nausea and vomiting5 Additionally exenatide ER does not require dose titration

In patients with renal impairment and creatinine clearance of 30 to 50 mLmin GLP-1 agonists should be used with caution3 Use of these agents is contrain-dicated in those with stage 4 or 5 CKD (CrCl lt30 mLmin)3 Therefore prudence should be exercised in the elderly population Administration of these medica-tions in those with renal dysfunction prolongs the half-life and reduces clearance of the drug increasing the incidence of nausea vomiting or diarrhea which can lead to dehydration and kidney failure This risk can be reduced by ensuring adequate fluid intake3

DOSING amp ADMINISTRATION


If a dose is missed it should be administered as soon as possible as long as the next scheduled dose is at least three days away4 The weekly schedule is then continued as before On the other hand if the next dose is in one to two days the missed dose is skipped and dosing is resumed at the next scheduled dose4 The day of the week chosen for administration can be changed so long as the last dose was 3 or more days ago4

Exenatide ER should be protected from light and stored in the refrigerator (36-46˚F) up to the expiration date4 The medication should not be frozen or used if it has been frozen previously4 Storage at room tem-perature (lt 77˚F) is acceptable for up to 4 weeks4 Pa-

Table 4 | Incidence of adverse effects in exenatide ER clinical trials47-1120-21

Side effect incidence BID

Exenatide ER

Exenatide Insulin

Glargine Sitagliptin PIO Metformin Lirag-lutide

Nausea 338-35 5-27 1 37-108 43-96 69 204

Injection site pruritis 14-10 5-182 2 5 1 na na

Nasopharyngitis na 5-13 17 23-98 43-86 45 na

Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131

Influenza na 4 4 na na na na

Arthralgia na 4-52 3 18 31 12 na

Back pain na 24-4 2 31 43 57 na

Oropharyngeal pain na 3 3 na na na na

Vomiting 89-186 37-108 1 18-38 26-31 33 10

Hypertension na 12-2 3 18 74 12 na

Musculoskeletal pain na 2 3 na na na na

Bronchitis na 2 3 na na na na

Constipation 62 3-108 2 2-25 1-18 33 na

Gastroenteritis 55 2 -88 2 na na na na

Hypoglycemia 11 0-1 26 3-37 31 41 na

GERD 41 74 na na na na na

Dyspepsia 21 73-74 na 15-18 49-61 33 na

Fatigue 34 61 na 0 9 na na

Injection site hematoma 110 54 na na na na na

URTI 41-172 59-81 na 46-5 4-61 na na

Injection site erythema 24 54-74 na na na na na

Dizziness 65 23 na na na na na

Peripheral edema na 0-1 na 06-3 74-8 04 na

Sinusitis na 3 na 1 7 na na

Angina na 0 na 0 1 na na

Coronary artery occlusion na 0 na 0 2 na na

Urinary tract infection 83 34-101 na 46 61 na na

Injection site bruising 103 47 na na na na na

PIO = pioglitazone na = no data available

tients should always check that diluents are clear how-ever the suspension is cloudy after mixing Each dose should be administered immediately after the powder is suspended in the diluents within the syringe3 The injection site should be rotated weekly staying within the same region (upper arm abdomen or thigh)3

As with all diabetes patients those taking exenatide ER should be encouraged to perform self blood glu-cose monitoring at appropriate intervals exercise regu-larly and maintain a healthy diet All patients should be educated regarding recognition and management of signssymptoms of hypoglycemia which may include shaking sweating hunger tachycardia and headache


Exenatide ER should not be used concomitantly with exenatide Patients currently taking exenatide should discontinue this agent upon initiation of ex-enatide ER3 When switching from exenatide to ex-enatide ER transient elevations of serum glucose may be seen but these elevations in blood glucose are ex-pected to improve within the first two weeks of thera-py3 This transient interruption of glycemic control occurs because of the differences in pharmacokinetics between the two formulations of exenatide exenatide displays more immediate effects while the effects of exenatide ER requires weeks for drug concentrations to plateau and reach steady state

Exenatide ER is slightly more expensive compared to exenatide however the benefit of once weekly ver-sus twice daily dosing may be worth the difference in price for some patients Both agents are significantly less costly in comparison to liraglutide the other GLP-1 agonist on the market Table 5 displays the cost of other commonly prescribed medications for type 2 dia-betes

Treating diabetes is important to reduce cardiovas-cular risk blindness amputations and kidney failure The prevalence of diabetes and obesity is increasing worldwide and the majority of patients with diabetes are overweight Many options for glucose control can cause weight gain but GLP-1 agonists are the only pre-ferred agents which facilitate weight loss Weight loss

COST

Table 5 | Cost comparison for common diabetic medications

Medication

Cash Price for 30-Day Supply ($)

University Of Colorado King Soopers

Exenatide 10 mcg (Byetta) 32026 34249

Exenatide ER 2 mg (Bydureon) 36014 36489

Liraglutide 18 (Victoza) 51399 47529

Metformin 1000 mg 8330 400

Glipizide XL 10 mg 2674 2309

Pioglitazone 45 mg 29377 34899

Sitagliptin 100 mg 22424 23799

Insulin glargine (Lantus) vial 14901 13319

Lantus Solostar (1 pack 3 pens) 25810 23079

Insulin aspart (Novolog) vial 14956 13379

Novolog pens (1 pack 3 pens) 27783 26659

CONCLUSION

may subsequently reduce cardiovascular risks factors including hyperlipidemia and hypertension These agents are particularly attractive for their efficacy (reduction in A1c up to 2) and safety profile which keeps weight gain and hypoglycemia to a minimum The newest GLP-1 agonist Bydureonreg contains a new extended-release form of exenatide that offers the convenience of once weekly dosing Bydureonreg is an appropriate option for consideration when obesity adherence and risk of hypoglycemia are of concern

REFERENCES

1 Holman RR Paul SK Bethel MA et al10-year follow-up of intensive glucose control in type 2 diabetes N Engl J Med 2008359(15)1577-89

2 Inzucchi SE Bergenstal RM Buse JB et al Management of Hyperglycemia in Type 2 Diabetes A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care 201235(6)1364-79

3 Bydureonreg [package insert] San Diego CA Amylin Phar-maceuticals Inc 2012

4 Bydureonreg [medication guide] San Diego CA Amylin Pharmaceuticals Inc 2012

5 Triplitt CL Reasner CA Chapter 83 Diabetes Mellitus In Talbert RL DiPiro JT Matzke GR Posey LM Wells BG Yee GC eds Pharmacotherapy A Pathophysiologic Approach 8th ed New York McGraw-Hill 2011 http


wwwaccesspharmacycomcontentaspxaID=7990956 Accessed June 10 2012

6 Buse JB Drucker DJ Taylor KL et al DURATION-1 exenatide once weekly produces sustained glycemic con-trol and weight loss over 52 weeks Diabetes Care 201033(6)1255-61

7 Drucker DJ Buse JB Taylor K et al Exenatide once weekly versus twice daily for the treatment of type 2 dia-betes a randomized open-label non-inferiority study Lancet 2008372(9645)1240-50

8 Bergenstal RM Wysham C Macconell L et al Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2) a randomised trial Lan-cet 2010376(9739)431-9

9 Wysham C Bergenstal R Malloy J et al DURATION-2 efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide Dia-bet Med 201128(6)705-14

10 Diamant M Van Gaal L Stranks S et al Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3) an open-label randomised trial Lancet 2010375(9733)2234-43

11 Blevins T Pullman J Malloy J et al DURATION-5 ex-enatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes J Clin Endocrinol Metab 201196(5)1301-10

12 Raskin P Mohan A Comparison of once-weekly with twice-daily exenatide in the treatment of type 2 diabetes (DURATION-1 trial) Expert Opin Pharmacother 201011(13)2269-71

13 Kim D MacConell L Zhuang D et al Effects of once-weekly dosing of a long-acting release formulation of ex-enatide on glucose control and body weight in subjects with type 2 diabetes Diabetes Care 200730(6)1487-93

14 Malone J Trautmann M Wilhelm K et al Exenatide once weekly for the treatment of type 2 diabetes Expert Opin Investig Drugs 200918(3)359-67

15 Aroda VR DeYoung MB Clinical implications of ex-enatide as a twice-daily or once-weekly therapy for type 2 diabetes Postgrad Med 2011123(5)228-38

16 Nauck MA Incretin-based therapies for type 2 diabetes mellitus properties functions and clinical implications Am J Med 2011124(1 Suppl)S3-18

17 Klonoff DC Buse JB Nielsen LL et al Exenatide effects on diabetes obesity cardiovascular risk factors and hepat-ic biomarkers in patients with type 2 diabetes treated for at least 3 years Curr Med Res Opin 200824(1)275-86

18 Fineman M Flanagan S Taylor K et al Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing Clin Pharmacokinet 201150(1)65-74

19 Bjerre Knudesen L Madsen LW Andersen S et al Gluca-gon-like Peptide-1 receptor agonists activate rodent thy-roid C-cells causing calcitonin release and C-cell prolifera-tion Endocrinology 2010151(4)1473-86

20 Russel-Jones D Cuddihy RM Hanefeld M et al Efficacy and safety of exenatide once weekly versus metformin

pioglitazone and sitagliptin used as monotherapy in drug-naiumlve patients with type 2 diabetes (DURATION-4) a 26-week double-blind study Diabetes Care 2012 35(2)252-8

21 Buse JB Nauck MA Forst T et al Efficacy and safety of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6) a randomized open-label study Diabetologia 201154[Suppl1]S38

MATERIA MEDICA

A publication of the Department of Clinical Pharmacy Skaggs School of Pharmacy and

Pharmaceutical Sciences

University of Colorado

Editor Steven M Smith PharmD MPH

Associate Editor Katy E Trinkley PharmD

The material contained in this newsletter has been prepared by the Skaggs School of Pharmacy for informational purposes only The articles are the work product of the individual authors to whom each article is attributed The articles contained herein should not be used without proper permission or citation Should you have questions about any of the content in this newsletter please contact the Editor


(plt00001) The pioglitazone group also had an in-crease in median body weight from baseline to end of follow up of 36kg compared to a decrease in median body weight in the placebo group of 05 kg (plt00001) The weight gain with pioglitazone may be partly at-tributable to fluid retention which could have contrib-uted to the increased risk of CHF7

A retrospective cohort study designed to examine the risk of CHF with TZDs collected data from a health insurance claims database from 1995 to 20018 Patients who had any claims processed for a TZD were included in the ldquoexposedrdquo group and were each matched with five randomly selected ldquounexposedrdquo pa-tients who had received a different oral anti-hyperglycemic medication Patients were excluded if they had any claims associated with a diagnosis of heart failure in the year prior to TZD initiation The study population included 5441 patients in the ldquoexposedrdquo group and 28103 in the ldquounexposedrdquo group The pri-mary outcome was CHF diagnosis indicated by a hos-pitalization or outpatient visit with associated CHF di-agnosis The results showed an increased risk with TZD use with an adjusted hazards ratio of 17 (plt0001 Table)8

The choice to use pioglitazone should always take into account the patientrsquos risk for CHF Patients with pre-existing risk factors for CHF or who already have CHF may not be good candidates for this medication However many patients with T2DM especially young-er patients do not have risk factors for CHF and can benefit from glycemic control with pioglitazone Given fluid retention and edema tends to worsen when pa-tients are just starting pioglitazone or after dose in-creases monitoring for weight gain edema and symp-toms of CHF is particularly important during those time periods5

The most recent warning from the FDA regarding pioglitazone was concerning for a potential increased risk of bladder cancer from the medication4 Pioglita-zone exerts its affects on blood glucose via the PPARγ receptor This receptor has been identified in bladder

Pioglitazone is taken orally and dosed once daily without regard to meals which makes it attractive to patients However weight gain and edema are com-mon adverse effects that limit the use of this agent The weight gain is partly attributed to fluid retention Patients are also at a higher risk of bone fracture when on pioglitazone This adverse effect is important to consider for patients with osteoporosis or who already have a high risk of fracture More serious adverse ef-fects include CHF liver failure and possible increased risk of developing bladder cancer5 Because of these concerns recommended monitoring for patients on pioglitazone includes bone mineral density tests liver function tests at baseline and with any symptoms of liver injury weight checks and signs or symptoms of worsening or new onset CHF5

Pioglitazone holds a black box warning for causing or worsening CHF which is thought to be due to fluid retention caused by the medication With increased fluid retention the heart becomes increasingly stressed and cannot compensate for the increased volume lead-ing to CHF The medication is contraindicated in NY-HA Class III or IV heart failure and not recommend-ed for use in patients with symptomatic heart failure Patients should be carefully monitored for signs or symptoms of heart failure especially after starting pioglitazone or after a dose increase5

Much of the data related to CHF and pioglitazone come from results of the PROactive trial7 This study was a randomized double blind trial including 5238 patients with T2DM and macrovascular disease The primary outcome was time to first occurrence of all cause mortality non-fatal MI stroke acute coronary syndrome coronary or leg revascularization or ampu-tation above the ankle The data did not show a signifi-cant difference in the primary endpoint between pioglitazone and placebo However there was a signifi-cant increase in CHF with pioglitazone use compared to placebo An emergent heart failure event was report-ed by 11 of patients treated with pioglitazone com-pared to 8 of patients treated with placebo

PIOGLITAZONE amp BLADDER CANCER

PIOGLITAZONE amp CHF

Table | Incidence of CHF and weight change in PROactive trial8

Adverse Event Placebo (N=2633) Actos (N=2605)

At least one hospitalized CHF event 108 (41) 149 (57)

Fatal CHF event 22 (08) 25(10)

Median body weight change from baseline to final follow-up -05 kg +36 kg











CONCLUSION



REFERENCES


















D






Dosing




insulin

Efficacy





Safety


(Byettareg)










7



TG -11 -15









DRUG INTERACTIONS


Absorption



~300pgmL)







DURATION-1



CLINICAL TRIALS


Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

1

∆

FB

G (

mm

olL)

-21

(-378

mgd

l) v

s

-28

(-

504

mgd

l)

p=

00

01

Hyp

ogly

cem

ia (

)

8 v

s 26

hig

her

in b

oth

gro

ups w

S

U

420

Phase I

II R

D

B n

on

-in

feriority

stu

dy

Dura

tion

26

weeks

E

xenatid

e E

R w

eekly

+ o

ral

pla

ce

bo d

aily

(N

=222)

M

etf

orm

in B

ID titra

ted

we

ekly

to

2 g

md

ay +

SQ

pla

cebo w

eekly

(N

=22

2)

P

ioglit

azo

ne t

itra

ted w

eekly

to

45 m

gd

ay +

SQ

pla

ceb

o w

eek-

ly (

N=

148)

S

itaglip

tin

10

0 m

g d

aily

+ S

Q

pla

ce

bo w

eekly

N=

148)

ge 1

8 y

o u

ncontr

olle

d t

yp

e

2 D

M

naiumlv

e t

o a

ntih

yp

er-

gly

cem

ic a

gents

A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 2

6 exenatid

e E

R v

s

metform

in v

s

pio

glit

azon

e v

s sita

glip

tin re

spective

ly

∆

A1c f

rom

baselin

e-

15

vs

-14

8 (

983

C

I -

02

6 t

o 0

17)

vs

-16

3 (

983

C

I -0

15 t

o

03

5)

vs

-11

5 (

983

C

I -0

62 t

o -

01

3)

w A

1clt

7

6

3 v

s

55 v

s

61 v

s 43

(plt

00

01)

∆

FB

G (

mm

olL)

-23

(4

14

mgd

l) v

s

-2 (

36

mgd

l p

=0

15

5)

vs

-26

(46

8 m

gd

l p

=01

53)

vs

-11

(198

mgd

l p

lt00

01)

W

t (k

g)

-2 v

s

-2 (

p=

08

92)

vs 15

(plt

00

01)

vs

-08

(plt

00

01)




DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA

















CONCLUSION



REFERENCES


















D






Dosing




insulin

Efficacy





Safety


(Byettareg)










7



TG -11 -15









DRUG INTERACTIONS


Absorption



~300pgmL)







DURATION-1



CLINICAL TRIALS


Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

1

∆

FB

G (

mm

olL)

-21

(-378

mgd

l) v

s

-28

(-

504

mgd

l)

p=

00

01

Hyp

ogly

cem

ia (

)

8 v

s 26

hig

her

in b

oth

gro

ups w

S

U

420

Phase I

II R

D

B n

on

-in

feriority

stu

dy

Dura

tion

26

weeks

E

xenatid

e E

R w

eekly

+ o

ral

pla

ce

bo d

aily

(N

=222)

M

etf

orm

in B

ID titra

ted

we

ekly

to

2 g

md

ay +

SQ

pla

cebo w

eekly

(N

=22

2)

P

ioglit

azo

ne t

itra

ted w

eekly

to

45 m

gd

ay +

SQ

pla

ceb

o w

eek-

ly (

N=

148)

S

itaglip

tin

10

0 m

g d

aily

+ S

Q

pla

ce

bo w

eekly

N=

148)

ge 1

8 y

o u

ncontr

olle

d t

yp

e

2 D

M

naiumlv

e t

o a

ntih

yp

er-

gly

cem

ic a

gents

A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 2

6 exenatid

e E

R v

s

metform

in v

s

pio

glit

azon

e v

s sita

glip

tin re

spective

ly

∆

A1c f

rom

baselin

e-

15

vs

-14

8 (

983

C

I -

02

6 t

o 0

17)

vs

-16

3 (

983

C

I -0

15 t

o

03

5)

vs

-11

5 (

983

C

I -0

62 t

o -

01

3)

w A

1clt

7

6

3 v

s

55 v

s

61 v

s 43

(plt

00

01)

∆

FB

G (

mm

olL)

-23

(4

14

mgd

l) v

s

-2 (

36

mgd

l p

=0

15

5)

vs

-26

(46

8 m

gd

l p

=01

53)

vs

-11

(198

mgd

l p

lt00

01)

W

t (k

g)

-2 v

s

-2 (

p=

08

92)

vs 15

(plt

00

01)

vs

-08

(plt

00

01)




DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA









REFERENCES


















D






Dosing




insulin

Efficacy





Safety


(Byettareg)










7



TG -11 -15









DRUG INTERACTIONS


Absorption



~300pgmL)







DURATION-1



CLINICAL TRIALS


Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

1

∆

FB

G (

mm

olL)

-21

(-378

mgd

l) v

s

-28

(-

504

mgd

l)

p=

00

01

Hyp

ogly

cem

ia (

)

8 v

s 26

hig

her

in b

oth

gro

ups w

S

U

420

Phase I

II R

D

B n

on

-in

feriority

stu

dy

Dura

tion

26

weeks

E

xenatid

e E

R w

eekly

+ o

ral

pla

ce

bo d

aily

(N

=222)

M

etf

orm

in B

ID titra

ted

we

ekly

to

2 g

md

ay +

SQ

pla

cebo w

eekly

(N

=22

2)

P

ioglit

azo

ne t

itra

ted w

eekly

to

45 m

gd

ay +

SQ

pla

ceb

o w

eek-

ly (

N=

148)

S

itaglip

tin

10

0 m

g d

aily

+ S

Q

pla

ce

bo w

eekly

N=

148)

ge 1

8 y

o u

ncontr

olle

d t

yp

e

2 D

M

naiumlv

e t

o a

ntih

yp

er-

gly

cem

ic a

gents

A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 2

6 exenatid

e E

R v

s

metform

in v

s

pio

glit

azon

e v

s sita

glip

tin re

spective

ly

∆

A1c f

rom

baselin

e-

15

vs

-14

8 (

983

C

I -

02

6 t

o 0

17)

vs

-16

3 (

983

C

I -0

15 t

o

03

5)

vs

-11

5 (

983

C

I -0

62 t

o -

01

3)

w A

1clt

7

6

3 v

s

55 v

s

61 v

s 43

(plt

00

01)

∆

FB

G (

mm

olL)

-23

(4

14

mgd

l) v

s

-2 (

36

mgd

l p

=0

15

5)

vs

-26

(46

8 m

gd

l p

=01

53)

vs

-11

(198

mgd

l p

lt00

01)

W

t (k

g)

-2 v

s

-2 (

p=

08

92)

vs 15

(plt

00

01)

vs

-08

(plt

00

01)




DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA
















7



TG -11 -15









DRUG INTERACTIONS


Absorption



~300pgmL)







DURATION-1



CLINICAL TRIALS


Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

1

∆

FB

G (

mm

olL)

-21

(-378

mgd

l) v

s

-28

(-

504

mgd

l)

p=

00

01

Hyp

ogly

cem

ia (

)

8 v

s 26

hig

her

in b

oth

gro

ups w

S

U

420

Phase I

II R

D

B n

on

-in

feriority

stu

dy

Dura

tion

26

weeks

E

xenatid

e E

R w

eekly

+ o

ral

pla

ce

bo d

aily

(N

=222)

M

etf

orm

in B

ID titra

ted

we

ekly

to

2 g

md

ay +

SQ

pla

cebo w

eekly

(N

=22

2)

P

ioglit

azo

ne t

itra

ted w

eekly

to

45 m

gd

ay +

SQ

pla

ceb

o w

eek-

ly (

N=

148)

S

itaglip

tin

10

0 m

g d

aily

+ S

Q

pla

ce

bo w

eekly

N=

148)

ge 1

8 y

o u

ncontr

olle

d t

yp

e

2 D

M

naiumlv

e t

o a

ntih

yp

er-

gly

cem

ic a

gents

A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 2

6 exenatid

e E

R v

s

metform

in v

s

pio

glit

azon

e v

s sita

glip

tin re

spective

ly

∆

A1c f

rom

baselin

e-

15

vs

-14

8 (

983

C

I -

02

6 t

o 0

17)

vs

-16

3 (

983

C

I -0

15 t

o

03

5)

vs

-11

5 (

983

C

I -0

62 t

o -

01

3)

w A

1clt

7

6

3 v

s

55 v

s

61 v

s 43

(plt

00

01)

∆

FB

G (

mm

olL)

-23

(4

14

mgd

l) v

s

-2 (

36

mgd

l p

=0

15

5)

vs

-26

(46

8 m

gd

l p

=01

53)

vs

-11

(198

mgd

l p

lt00

01)

W

t (k

g)

-2 v

s

-2 (

p=

08

92)

vs 15

(plt

00

01)

vs

-08

(plt

00

01)




DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA










DRUG INTERACTIONS


Absorption



~300pgmL)







DURATION-1



CLINICAL TRIALS


Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

1

∆

FB

G (

mm

olL)

-21

(-378

mgd

l) v

s

-28

(-

504

mgd

l)

p=

00

01

Hyp

ogly

cem

ia (

)

8 v

s 26

hig

her

in b

oth

gro

ups w

S

U

420

Phase I

II R

D

B n

on

-in

feriority

stu

dy

Dura

tion

26

weeks

E

xenatid

e E

R w

eekly

+ o

ral

pla

ce

bo d

aily

(N

=222)

M

etf

orm

in B

ID titra

ted

we

ekly

to

2 g

md

ay +

SQ

pla

cebo w

eekly

(N

=22

2)

P

ioglit

azo

ne t

itra

ted w

eekly

to

45 m

gd

ay +

SQ

pla

ceb

o w

eek-

ly (

N=

148)

S

itaglip

tin

10

0 m

g d

aily

+ S

Q

pla

ce

bo w

eekly

N=

148)

ge 1

8 y

o u

ncontr

olle

d t

yp

e

2 D

M

naiumlv

e t

o a

ntih

yp

er-

gly

cem

ic a

gents

A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 2

6 exenatid

e E

R v

s

metform

in v

s

pio

glit

azon

e v

s sita

glip

tin re

spective

ly

∆

A1c f

rom

baselin

e-

15

vs

-14

8 (

983

C

I -

02

6 t

o 0

17)

vs

-16

3 (

983

C

I -0

15 t

o

03

5)

vs

-11

5 (

983

C

I -0

62 t

o -

01

3)

w A

1clt

7

6

3 v

s

55 v

s

61 v

s 43

(plt

00

01)

∆

FB

G (

mm

olL)

-23

(4

14

mgd

l) v

s

-2 (

36

mgd

l p

=0

15

5)

vs

-26

(46

8 m

gd

l p

=01

53)

vs

-11

(198

mgd

l p

lt00

01)

W

t (k

g)

-2 v

s

-2 (

p=

08

92)

vs 15

(plt

00

01)

vs

-08

(plt

00

01)




DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA








Tab

le 3

| D

UR

AT

ION

tri

al

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

17

Phase I

II R

M

C O

L

non

-in

feriority

D

ura

tion 3

0

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=14

8)

E

xenatid

e 5

mcg B

ID x

28

da

ys

then 1

0 m

cg S

Q B

ID (

N=

14

7)

D

ura

tion

30 w

eeks

ge 1

6 y

o ty

pe 2

DM

tr

eat-

ed w

die

t e

xerc

ise

m

et-

form

in S

U T

ZD

or

com

-bo o

f an

y 2

meds x

ge 2

m

o A

1c 7

1-1

1

F

BG

lt

16

mm

olL (

lt288

mgd

l)

BM

I 25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 3

0 E

xena

tide E

R v

s exenatid

e

∆

A1c f

rom

baselin

e-

19

vs

-15

p

=00

02

3

w A

1clt

7

7

7 v

s

61

p=

00

039

∆F

BG

(m

molL)

-23

(-4

1 m

gd

l) v

s

-14

(-

252

mgd

l)

plt

00

001

Wt (k

g)

-37

vs

-36

p

=0

89

Hyp

ogly

cem

ia 0 v

s 11

H

yp

ogly

cem

ia w

S

U 1

45

vs 15

4

29

Phase I

II

MC

R

D

B

PC

sup

eri-

ority

tria

l D

ura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

ee

kly

+

ora

l p

lace

bo (

N=

170)

S

itaglip

tin

10

0m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

P

ioglit

azo

ne 4

5m

g d

aily

+ S

Q

pla

ce

bo w

eekly

(N

=17

2)

ge18 y

o T

ype 2

DM

tr

ea

t-m

ent w

m

etf

orm

in ge

2

month

s A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

p

atients

w

A

1c lt

7

F

BG

w

eig

ht

hyp

og

lycem

ia

Week 2

6 exenatid

e E

R v

s

sitag

liptin v

s

pio

glit

azon

e re

sp

ectively

∆A

1c (

base

line lt

9

) -

11

-0

5

-09

∆A

1c (

base

line ge

9

) -

2

-13

-1

5

w A

1c lt

7

5

9 3

0 p

=00

001

43

p

=

00

015

∆F

BG

(m

molL)

-18

(-3

24

mgd

l)

-09

(-1

62

m

gd

l) p=

00

03

8

-15

(27 m

gd

l) p=

03

72

9

w F

BG

le7 m

molL 6

0 3

5 p

lt00

01

52

p=

01

024

Wt (k

g)

-23

-0

8

p=

00

00

2 28

p

lt00

00

1

310

Phase I

II

MC

R

O

L

para

llel

stu

dy

Dura

tion 2

6

weeks

E

xenatid

e E

R 2

mg S

Q w

eekly

(N

=23

3)

In

sulin

gla

rgin

e (

10 u

nits S

Q

titr

ate

d to

go

al F

BG

of

4-5

5

mm

olL)

(N=

22

3)

ge 1

8 y

o ty

pe 2

DM

un-

contr

olle

d d

esp

ite o

pti-

miz

ed d

oses o

f m

etf

orm

in

or

metform

in +

SU

for

ge 3

m

onth

s m

etf

orm

in d

ose

ge 1

500 m

gd

ay f

or

ge 8

w

eeks A

1c 7

0-1

1

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c le

7

FB

G

we

igh

t

hyp

og

lycem

ia

Week 2

6 exenatid

e v

s

insulin

gla

rgin

e

∆

A1c f

rom

baselin

e

-15

vs

-13

p=

00

17

w

A

1c lt

7

6

0 v

s 48

p=

01

0

∆

Wt (k

g)

-26

vs

14

kg p

lt00

00

1

∆

FB

G (

mm

olL)

-21

(-378

mgd

l) v

s

-28

(-

504

mgd

l)

p=

00

01

Hyp

ogly

cem

ia (

)

8 v

s 26

hig

her

in b

oth

gro

ups w

S

U

420

Phase I

II R

D

B n

on

-in

feriority

stu

dy

Dura

tion

26

weeks

E

xenatid

e E

R w

eekly

+ o

ral

pla

ce

bo d

aily

(N

=222)

M

etf

orm

in B

ID titra

ted

we

ekly

to

2 g

md

ay +

SQ

pla

cebo w

eekly

(N

=22

2)

P

ioglit

azo

ne t

itra

ted w

eekly

to

45 m

gd

ay +

SQ

pla

ceb

o w

eek-

ly (

N=

148)

S

itaglip

tin

10

0 m

g d

aily

+ S

Q

pla

ce

bo w

eekly

N=

148)

ge 1

8 y

o u

ncontr

olle

d t

yp

e

2 D

M

naiumlv

e t

o a

ntih

yp

er-

gly

cem

ic a

gents

A

1c 7

-11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c fro

m b

ase-

line

2deg

pro

port

ion

of

patie

nts

achie

vin

g t

ar-

get

A1c lt

7

F

BG

w

eig

ht

Week 2

6 exenatid

e E

R v

s

metform

in v

s

pio

glit

azon

e v

s sita

glip

tin re

spective

ly

∆

A1c f

rom

baselin

e-

15

vs

-14

8 (

983

C

I -

02

6 t

o 0

17)

vs

-16

3 (

983

C

I -0

15 t

o

03

5)

vs

-11

5 (

983

C

I -0

62 t

o -

01

3)

w A

1clt

7

6

3 v

s

55 v

s

61 v

s 43

(plt

00

01)

∆

FB

G (

mm

olL)

-23

(4

14

mgd

l) v

s

-2 (

36

mgd

l p

=0

15

5)

vs

-26

(46

8 m

gd

l p

=01

53)

vs

-11

(198

mgd

l p

lt00

01)

W

t (k

g)

-2 v

s

-2 (

p=

08

92)

vs 15

(plt

00

01)

vs

-08

(plt

00

01)




DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA










DURATION-2



ab

le 3

(co

ntrsquo

d)

|

DU

RA

TIO

N t

rial

seri

es7

-112

02

1

Stu

dy

D

esig

n

Tre

atm

en

t arm

s

Inclu

sio

n C

rite

ria

E

nd

po

ints

R

esu

lts

511

Phase I

II

R M

C

OL

stu

dy

Dura

tion

24

weeks

E

xenatid

e E

R w

eekly

(N

=12

9)

E

xenatid

e 5

mcg x

4 w

ks

then 1

0 m

cg x

20 w

ks

(N=

12

3)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

optim

ized m

etf

or-

min

S

U T

ZD

or

com

bi-

nation f

or

ge 2

month

s A

1c

70

-11

F

BG

lt2

80 m

g

dl B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

F

BG

lt

12

6 m

gd

l

weig

ht B

P

hyp

og

lycem

ia

Week 2

4 exenatid

e E

R v

s

exenatid

e

∆

A1c f

rom

baselin

e

-16

vs

-09

p

lt0

00

01

w

A1c lt

7

5

81

vs 3

01

p

lt00

001

∆F

BG

(m

gd

l)

-35 v

s

-12

p=

00

008

w

F

BG

lt1

26 m

gd

l 5

04

vs 3

09

p=

00

008

∆W

t (k

g)

-23

vs

-14

(d

iffe

rence 0

95 9

5

CI

-19

to

00

1)

∆

BP

(m

mH

g)

from

baselin

e

-29

(9

5

CI -

52

to -

07

) vs

-12

(9

5

CI

-35

to 1

2)

If

baselin

e S

BP

ge 1

30 m

mH

g

-79

(-1

13

to -

45

) vs

-77

mm

Hg (

-113

to -

40

)

621

Phase I

II R

M

C O

L

stu

dy

Lirag

lutid

e 1

8 m

g S

Q d

ai-

ly (N

=4

50)

E

xenatid

e E

R 2

mg S

Q

weekly

(N

=46

1)

ge18 y

o ty

pe

2 D

M tr

eat-

ed w

m

ax tole

rate

d d

os-

es o

f m

etf

orm

in S

U m

et-

form

in +

SU

or

metf

orm

in

+ p

iog

lita

zon

e

A1c 7

0-

11

B

MI

25

-45 k

gm

2

1deg

cha

nge

in

A

1c f

rom

base-

line

2deg

A1c lt

7

F

BG

w

eig

ht

BP

h

ypo

gly

-cem

ia

W

eek 2

6 lir

aglu

tide v

s exe

natide E

R

∆

A1c f

rom

baselin

e

-14

8 v

s

-12

8 (

diffe

rence

02

1

95

CI 0

08 t

o 0

34

)

w

A1c lt

7

6

02

vs 5

23

p

=00

08

∆W

t (k

g)

-35

8 v

s

-26

8 (

diffe

rence 0

9

95

CI

04

0 t

o 1

41)

H

yp

ogly

cem

ia (

)

89

vs

108

p

=03

74

R

= r

andom

ized M

C =

m

ulti-cente

r O

L =

open-la

bel D

B =

double

-blin

d

PC

= p

lacebo-c

ontr

olle

d

FB

G =

fastin

g b

lood g

lucose

BP

= b

lood p

ressure

S

BP

= s

ysto

lic B

P

All

p-v

alu

es r

eport

ed a

re for

com

parison t

o e

xenatid

e E

R

N

ot

sta

tistically

diffe

rent fr

om

exe

natid

e E

R





DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA











DURATION-3




DURATION-4






DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA











DURATION-5




DURATION-6


Contraindications







Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA











Adverse Effects

















Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA












Exenatide ER

Exenatide Insulin


Nausea 338-35 5-27 1 37-108 43-96 69 204



Headache 48 -81 47-10 7 9-92 4-8 122 na

Diarrhea 41-131 61-162 4 55-10 37-78 126 131



Back pain na 24-4 2 31 43 57 na


Vomiting 89-186 37-108 1 18-38 26-31 33 10




Constipation 62 3-108 2 2-25 1-18 33 na


Hypoglycemia 11 0-1 26 3-37 31 41 na


Dyspepsia 21 73-74 na 15-18 49-61 33 na



URTI 41-172 59-81 na 46-5 4-61 na na
















COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA











COST


Medication














CONCLUSION


REFERENCES

























MATERIA MEDICA


























MATERIA MEDICA







ceftaroline: a new cephalosporin with activity …...materia medica volume 1, issue 2 july 2012 2 (p

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