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DARIFENACIN (ENABLEX): A
NEW OPTION FOR TREATMENT
OF OVERACTIVE BLADDER

Ryan Roberts, Pharm.D. Candidate



Overactive bladder (OAB) is a chronic and po-
tentially debilitating condition that affects approxi-
mately 16% of the adult population in the U.S. and
Europe. According to the National Overactive Blad-
der Evaluation (NOBLE) program, an estimated 34
million Americans have symptoms of OAB.1 Over-
active bladder is a common condition in both men
and women of all ages, but is more prevalent in the
elderly population.2 In 2000, the combined direct
and indirect costs associated with OAB were $12.6
billion, which is similar to the economic impact of
asthma and osteoporosis.3 However, due to low phy-
sician consultation rates, estimated costs are likely to
be grossly underestimated, and the economic burden
of OAB may be much larger. As the world's popula-
tion continues to grow and age, the economic impact
of this condition will continue to expand. By the year
2020, population growth estimations predict that
there will be 44% more people over the age of 65,
and that costs will escalate in line with this aging
population.2
The International Continence Society has defined
OAB as urinary urgency with or without urge incon-
tinence, usually with frequency and nocturia without
proven infection or other pathology.2 These symp-
toms are believed to be caused by inappropriate con-
tractions of the detrusor muscle during the filling
phase of the micturition cycle.4 Muscarinic receptors


play important roles in cholinergic mediated func-
tions throughout the body, including stimulating con-
tractions of urinary bladder smooth muscle.5 Block-
ade of muscarinic receptors on the detrusor muscle
with anticholinergic medications has become the
most common and effective pharmacologic treatment
for patients suffering from OAB.6 Anticholinergic
therapy results in fewer and less forceful inappropri-
ate bladder contractions, which allows for enhanced
bladder capacity.4 Blockade of other muscarinic re-
ceptors located in the GI, CNS, myocardium, sali-
vary glands, and eye, however, are associated with
many adverse effects that may affect adherence. For
thirty years, immediate release oxybutynin, a non-
selective muscarinic antagonist, has been the "gold
standard" for treatment of OAB, but its use has been
limited by side effects.7 More selective agents, such
as darifenacin, are being marketed for OAB. Newer
agents offer a cleaner side effect profile compared to
oxybutynin without sacrificing therapeutic efficacy.
Darifenacin (dir i fen' a sin)(Enablex[6 na'
bl6ks]) is a new M3 selective receptor antagonist ap-
proved by the FDA for OAB and its symptoms in
December 2004 and is marketed by Novartis. In con-
trast to oxybutynin, darifenacin demonstrates a
higher degree of selectivity for M3 receptors than M1,




INSIDE THIS ISSUE:
DARIFENACIN (ENABLEX'): A NEW OPTION FOR
TREATMENT OF OVERACTIVE BLADDER
SITAGLIPTIN (JANUVIA"): A DIPEPTIDYL PEPTIDASE
IV INHIBITOR FOR DIABETES MELLITUS TYPE 2

l,^


am


SPharmaNote


VOLUME 22, ISSUE 2 NOVEMBER 2006


Volume 22, Issue 2 November 2006


PharmaNote







M2, M4, and M5 receptors (9 and 12-fold greater for
M3 compared to M1 and M5, respectively and 59-fold
greater affinity for M3 to M2 and M4). 8 This article
will examine the safety, efficacy, and tolerability of
darifenacin.

Pharmacology and Pharmacokinetics
Muscarinic receptors are responsible for mediat-
ing the effects of the parasympathetic nervous sys-
tem.9 Five subtypes have been identified and are
designated M1 through M5, each having a specific
physiological role in the tissue in which it is found. 10
M3 receptor subtype is primarily responsible for
parasympathetic mediated detrusor contractions and
the symptoms of overactive bladder, though M2 re-
ceptors are the predominant receptor type in the blad-
der.11 Other receptors and their functions include:
M1 and M3 receptors, which drive secretion from
salivary glands; M1 receptors in the brain are in-
volved in learning and memory cognitive impair-
ment; M2 receptors modulate pacemaker activity, AV
conduction, and force of contraction; and M3 and M5
receptors on the ciliary muscle of the eye are in-
volved in contraction of the pupil. When these recep-
tors are blocked by a non-selective blocker, un-
wanted side effects may occur.
Darifenacin's peak plasma concentration (Cmax) is
reached approximately seven hours after multiple
dose oral administration and steady state plasma con-
centrations are achieved by day six. There is no af-
fect of food on absorption. Darifenacin is approxi-
mately 98% bound to plasma proteins, mainly alpha-
1-acid glycoprotein, and is extensively metabolized
in the liver. Metabolism is mediated by CYP2D6 and
CYP3A4 and no metabolites contribute to its clinical
effect. A small subset of individuals (7% Caucasians
and 2% African Americans) are poor metabolizers
(PMs) of CYP2D6, while people with normal
CYP2D6 activity are extensive metabolizers (EMs).
In PMs, metabolism will be mediated by CYP3A4
only and thus the Cmax and AUC will be increased by
90% and 70%, respectively compared to EMs. Fur-
thermore, potent inhibitors of CYP3A4
(ketoconazole, itraconazole, ritonavir, nelfinavir,
clarithromycin, and nefazodone) will extensively in-
crease serum levels of darifenacin and the daily dose
of 7.5 mg should not be exceeded in patients taking
these medications. Other medications that induce
CYP3A4 (ex. rifampin, carbamazepine, phenytoin)
may also affect darifenacin serum levels. Caution
should be used when darifenacin is combined with


medications that are substrates of CYP2D6 and have
narrow therapeutic windows (ex. flecainide, thiori-
dazine, and TCA's) as drug interaction studies have
shown several fold increases in the serum levels of
these drugs.8 Oral bioavailability of darifenacin 7.5
mg and 15 mg is 15% and 19%.12 Estimated clear-
ance is 40 L/h for EMs and 32 L/h for PMs. The
elimination half-life (tl/2) following chronic dosing
is 12-19 hours. No dosing adjustments are required
based on age, gender, or renal insufficiency. How-
ever, patients with moderate hepatic impairment
should not exceed 7.5 mg daily and those with severe
impairment should avoid this medication altogether.
Since darifenacin is 98% protein bound, a decrease
in serum proteins due to moderate hepatic dysfunc-
tion will increase unbound darifenacin exposure by
4.7 fold over patients with normal liver function.8

Clinical Trials
OAB
Several studies have investigated the safety and
efficacy of darifenacin for the treatment of OAB.
These studies include: dosing-ranging studies4'13,
comparison studies14, and safety trials.5'15 Several
other important trials have been conducted using
darifenacin (Table 1).

Dosing-ranging studies
Several double-blinded, placebo-controlled trials
evaluated darifenacin's effect on OAB and its symp-
toms. Steers et al.4 evaluated the efficacy, safety, and
tolerability of a flexible dosing strategy in a multi-
center, double-blind, 12 week study (n=395). The
primary endpoint was change from baseline in the
number of incontinence episodes per week at the
ends of weeks 2 and 12. Patients were randomized
and received darifenacin 7.5 mg once daily or pla-
cebo. After two weeks, efficacy, tolerability, and
safety were assessed and the dose was increased to
15 mg, if clinically necessary. Results showed a sig-
nificant improvement in the primary endpoint at the
end of weeks 2 and 12. Median % changes from
baseline for darifenacin vs. placebo were 43% vs. -
28.6% (p=0.042) and -62.9% vs. 48.1% (p=0.035).
Patients that required a dose escalation to 15 mg had
lower response rates at 2 weeks than those that con-
tinued with 7.5 mg. However, at week 12, patients
taking 15 mg showed the most marked improvement
in the study's primary endpoint. Darifenacin was
well-tolerated as only 6% of patients in the
darifenacin group discontinued the study as a result


PharmaNote Volume 22, Issue 2 November 2006


Volume 22, Issue 2 November 2006


PharmaNote






Table 1. Summary of important clinical trials involving darifenacin
Study group Demographics Design Dose N Primary endpoint
% reduction of incontinence
1-88 (8 -Randomized episodes/week:
Haa et a1. 7 -DB, PC, PG 3.75mg 53 58.8*
Haab,etalwith OAB symp -Fixed dose 7.5mg 229 67.7 (p=0.010)**
toms > 6 months
-12 weeks 15mg 115 72.8 (p=0.017)**
placebo 164 55.9
% reduction of incontinence
-Pooled subgroup episodes/week:
F >5 y w analysis 7.5mg vs. 97 66.7 (p<0.001)**
is M/F >65 yo with 72 .- ^
Foote, et al.8 -Randomized placebo 72 34.8
OAB symptoms -DB, PC
-DB, PC
-12 weeks 15mg vs. 109 75.9 (p<0.001)**
placebo 108 44.8
-Randomized
Increase in mean warning
M/F > 18 yo with -DB, PC, PGcrease n mean warning
time:
Zinner, et al.19 OAB symptoms > -Fixed dose 15mg 212 0.68 minutes
months -Community setting placebo 220 0.36 minutes
placebo 220 0.36 minutes
-12 weeks
M =male; F female; DB double-blind; PC= placebo-controlled; PG parallel group
*statistical analysis not performed; **significance vs. placebo; # not significant


of treatment related AE's compared with 2% in the
placebo group. The most common AE's were consti-
pation, dry mouth, and headache.
Another dose-ranging study by Hill et al.13 ran-
domized 439 patients to darifenacin 7.5 mg (n=108),
15 mg (n=107), 30 mg (n=115), or placebo (n=109).
After 12 weeks of treatment, patients receiving
darifenacin showed a dose-related decrease from
baseline in the number of incontinence episodes per
week, with median percentage reductions of 68.7%
(p=0.007), 76.5% (p<0.001), and 77.3% (p<0.001).
A significant reduction in incontinence episodes was
seen as early as week 2 of treatment for all doses of
darifenacin. Improvements in secondary endpoints
paralleled the improvement in the primary endpoint.
Darifenacin treatment resulted in dose-related im-
provement when compared with placebo in a broad
range of OAB symptoms including: fewer micturi-
tions and urgency episodes per day, decreased sever-
ity of urgency, and increased bladder capacity.
These improvements were statistically superior to
placebo for darifenacin 15 and 30 mg and numeri-
cally superior for the 7.5 mg dose. The overall inci-
dence of all-cause adverse events was 57.4%, 68.2%,
and 80% in the 7.5mg, 15mg, and 30mg darifenacin
groups. The most commonly reported adverse
events, dry mouth and constipation, showed a dose-
related trend among patients randomized to
darifenacin. Adverse CNS and cardiovascular events
were similar for all darifenacin treatment groups and
placebo.


Darifenacin vs. Oxybutynin
Zinner and colleagues14 evaluated darifenacin's
efficacy in reducing symptoms of OAB compared to
the non-selective anticholinergic oxybutynin and pla-
cebo. This study was a randomized, double-blind,
placebo-controlled, four-way crossover study de-
signed to assess the efficacy, tolerability, and safety
of darifenacin compared to oxybutynin. Each patient
received two weeks each of darifenacin 15 mg daily,
30 mg daily, oxybutynin 5 mg TID, and placebo in a
random sequence at 10 day intervals. The primary
outcome was an overall decrease in OAB symptoms
broken down into four outcome variables: Mean
number of incontinence episodes/week; mean num-
ber of urgency episodes/day; mean severity of ur-
gency episodes; and mean number of micturitions/
day. A total of 76 patients were randomized to re-
ceive one of the four treatments, but 16 withdrew
before the study's end (only 5 because of AE's),
leaving 58 patients in the final efficacy analysis.
Darifenacin 15 mg daily was comparable to oxybu-
tynin in overall improvement in OAB symptoms
(p<0.05), meaning that both agents significantly re-
duced the number of incontinence episodes/week and
the number and severity of urgency episodes at week
2 (Table 2). Sixty-one of the 76 patients were evalu-
ated for drug tolerability. Rates of dry mouth were
higher in patients taking darifenacin 15 mg compared
with placebo, but were not significant. Dry mouth
occurred in 13.1% of patients on darifenacin 15 mg
compared to 34.4% in oxybutynin 5 mg TID


PharmaNote Volume 22, Issue 2 November 2006


Volume 22, Issue 2 November 2006


PharmaNote







(p<0.05). Rates of constipation were higher among
active treatments compared to placebo, but were
comparable between darifenacin 15 mg and oxybu-
tynin 5 mg TID at 9.8% and 8.2%. Blurred vision
and dizziness occurred in 3.3% and 1.6 % of patients
receiving oxybutynin, but did not occur with
darifenacin or placebo.

Safety Trials
In the past decade, the most common cause of
withdrawal or restriction of an approved and mar-
keted drug has been the prolongation of the QT inter-
val, which is associated with torsade de pointss.6
Because of this, increased regulatory scrutiny has
focused on noncardiac drugs that affect cardiac func-
tion. Since anticholinergic agents have the potential
to cause palpitations and tachycardia due to blockade
of M2 receptors in the myocardium, the possibility of
effects at cardiac ion channels, and the subsequent
change in cardiac conduction must be ruled out be-
fore these drugs are marketed.5 Serra et al.5 con-
ducted a 7-day randomized, parallel-group study (n =
188) measuring the QT/QTc interval in healthy vol-
unteers taking darifenacin at steady-state therapeutic
(15 mg daily) and supratherapeutic (75 mg daily)
doses. Patients were compared to control groups re-
ceiving placebo or moxifloxacin (positive control,
400 mg daily). No significant increase in QTc inter-
val was found with either dose of darifenacin when
compared with placebo. Mean changes form baseline
at Tmax vs. placebo were -0.4 (p =0.842) and -2.2 (p
=0.400) milliseconds in the darifenacin 15 mg and 75
mg groups. The positive control (moxifloxacin 400
mg daily), showed an increase of 11.6 milliseconds
(p<0.01). The results of this study demonstrate that
darifenacin, even at supratherapeutic doses, does not
significantly prolong QT/QTc interval.
Another concern associated with anticholinergic
medications is their potential to cause adverse CNS


effects. Older patients are more vulnerable due to
reduced brain muscarinic receptor density and an in-
creased sensitivity to antimuscarinic effects. Kay et
al.15 compared darifenacin with oxybutynin ER on
memory in patients > 60 years old. This 3-week mul-
ticenter, double-blind, double dummy, parallel group
study compared oxybutynin ER (10 mg once daily,
increasing to 20 mg once daily by week 3) with
darifenacin (7.5 mg once daily in weeks 1 and 2,
then 15 mg in week 3). The primary end-point was
accuracy on a delayed recall Name-Face Association
Test at the end of week 3. Results showed no signifi-
cant difference between darifenacin and placebo on
delayed recall by the end of week three (mean differ-
ence, -0.06, p = 0.908). Oxybutynin ER, however,
resulted in significant memory impairment, with
lower scores than placebo and darifenacin for de-
layed recall (mean differences, -1.30, p = 0.011 and
-1.24, p = 0.022). The magnitude of effect on mem-
ory impairment in the oxybutynin ER patients is
comparable to 10 years of brain aging.

Dosing and Administration
Darifenacin doses ranging from 3.75-30 mg/day
in a once daily dosing regimen have been investi-
gated in clinical trials for treatment of OAB. The
dose-response relationship begins to flatten at 15 mg/
day, while the frequency of adverse effects increases.
Data supports the manufacturer's recommended
maximum daily dosage of 15 mg/day, since efficacy
at 30 mg/day is minimally improved at the cost of a
large increase in adverse events. The recommended
starting dose of darifenacin is 7.5mg once daily.
Based on response, the dose may be increased to 15
mg once daily after 2 weeks of therapy.8 The major-
ity of the therapeutic effect is apparent by about 6
weeks of treatment, though some symptomatic im-
provement can be seen immediately.17 No studies
have evaluated the use of darifenacin in combination


Table 2. Outcome variables at week 214
Darifenacin Oxybutynin
Outcome variable 15 mg daily 30 mg daily 5 mg TID Placebo
Mean no. of inconti-
Mean no. of inconti- 10.93* 8.82* 9.45* 14.64
nence episodes/week
Mean no. of urgency 795* 7.59* 8.12* 8.71
episodes/day
Mean severity of ur- 1.93* 1.84* 1.89* 2.03
agency episodes
Mean no. of micturi-
9.33 8.85* 9.24* 9.62
tions/day
*P <0.05 vs. placebo, accounting from multiplicity by the least significant difference method; TID indicates three times daily
*All values are adjusted for sequence and period from the crossover analysis of variance

PharmaNote Volume 22, Issue 2 November 2006





Table 3. Adverse events* reported in > 3% of patients treated with darifenacin4
Adverse Event Darifenacin 7.5/15 mg, N = 268
Constipation 56 (20.9%)
Dry Mouth 50 (18.7%)
Headache 18 (6.7%)
Dyspepsia 12 (4.5%)
Nausea 11 (4.1%)
Urinary Tract Infection 10 (3.7%)
Accidental Injury 8 (3.0%)
Flu Syndrome 6 (3.0%)


*Regardless of causality


with other drugs used to treat OAB.

Toxicity and Safety
Data collected from Steers and colleagues4,
showed adverse events of constipation, dry mouth,
headache, dyspepsia, and nausea in patients receiv-
ing darifenacin once daily (Table 3). Other adverse
events reported in phase III studies include abnormal
vision, back pain, dry skin, vomiting, weight gain,
sinusitis, and rash. These adverse effects occurred in
> 1% of patients.8 Three different trials11'14'15 demon-
strated that the incidence of dry mouth is signifi-
cantly less frequent in patients taking darifenacin
than those taking oxybutynin. Despite this, the most
common reasons for discontinuation of darifenacin
remain dry mouth and constipation.

Cost
Pricing data for darifenacin was obtained from
averaging the cost of a one month prescription from
three pharmacies located in Gainesville, FL. The
average monthly cost (30 tablets) for both 7.5 mg
and 15 mg is $112.64 (range $108.95 $118.99).

Summary
Darifenacin is a novel agent that selectively in-
hibits M3 receptors and is indicated for the treatment
of OAB. Darifenacin appears to be as effective as
immediate release oxybutynin, in OAB treatment,
while having a lower incidence of dry mouth and ad-
verse CNS effects. It is unknown how darifenacin
compares to other anticholinergic agents used for
OAB, such as tolterodine or solifenacin, as no head-
to-head trials have been completed. However, with
the data available, darifenacin seems to have a place
in the treatment of patients suffering from overactive
bladder.

References
1. Coyne KS, et al. The impact of urinary urgency and
frequency on health-related quality of life in overac-


tive bladder: results from a national community sur-
vey. Value in Health Vol. 7(4) 2004.
2. Kelleher CJ. Economic and social impact of OAB.
Eur Urol 2002 (Suppl 1): 11-16.
3. Hashim H, Abrams P. Drug treatment of overactive
bladder: efficacy, cost, and quality-of-life considera-
tions. Drugs 2004;64:1643-56.
4. Steers W, Corcos J, Foote J, Kralidis G. An investiga-
tion of dose titration with darifenacin, an M3-
selective receptor antagonist. BJU Int. 2005;95:580-6.
5. Serra DB, et al. QT and QTc interval with standard
and supratherapeutic doses of darifenacin, a mus-
carinic M3 selective receptor antagonist for the treat-
ment of overactive bladder. J Clin Pharmacol
2005;45:1038-47.
6. Staskin DR. Overactive bladder in the elderly: A
guide to pharmacological management. Drugs Aging
2005;22:1013-28.
7. Staskin DR, MacDiarmid SA. Using anticholinergics
to treat overactive bladder: the issued of treatment
tolerability. Am J Med 2006;119:9-15.
8. Enablex [package insert]. East Hanover, NJ. Novartis
Pharmaceuticals Corp. 2006.
9. Porth CM. Pathophysiology: Concepts of Altered
Health States 6th Edition. Lippincott Williams and
Wilkins, 2002. pg 1086.
10. Andersson KE. Potential benefits of muscarinic M3
receptor selectivity. Eur Urol 2002 (Suppl 1):23-28.
11. Chapple CR, Abrams P. Comparison of darifenacin
and oxybutynin in patients with overactive bladder:
assessment of ambulatory urodynamics and impact on
salivary flow. Eur Urol 2005;48:102-9.
12. Croom KF, Keating GM. Darifenacin in the treatment
of overactive bladder. Drugs Aging 2004:21:885-92.
13. Hill S, Khullar V, Wyndaele JJ, Lheritier K. Dose
response with darifenacin, a novel once-daily M3 se-
lective receptor antagonist for the treatment of over-
active bladder: results of a fixed dose study. Int
Urogynecol J Pelvic Floor Dysfunct 2006;17:239-47.
14. Zinner N, Tuttle J, Marks L. Efficacy and tolerability
of darifenacin, a muscarinic M3 selective receptor
antagonist (M3 SRA), compared with oxybutynin in
the treatment of patients with overactive bladder.
World J Urol 2005;23:248-52.


Phama~te olue 2, Isue2 Nvemer 00


Placebo, N = 127
10 (7.9%)
11 (8.7%)
7 (5.5%)
2 (1.6 %)
2 (1.6%)
4 (3.1%)
3 (2.4%)
3 (2.4%)


Volume 22, Issue 2 November 2006


PharmaNote






15. Kay G, et al. Differential effects of the antimuscarinic
agents darifenacin and oxybutynin ER on memory in
older subjects. Eur Urol 2006;50:317-26.
16. Roden DM. Drug-induced prolongation of the QT
interval. N Engl J Med 2004;350:1013-22.
17. Haab F, Stewart L, Dwyer P. Darifenacin, an M3
selective receptor antagonist, is an effective and well-
tolerated once-daily treatment for overactive bladder.
Eur Urol 2004;45:420-9.
18. Foote J, Glavind K, Kralidis G, Wyndaele J. Treat-
ment of overactive bladder in the older patient:
pooled analysis of three phase III studies of
darifenacin, an M3 Selective Receptor Antagonist.
Eur Urol 2005;48:471-77.
19. Zinner N, et al. Efficacy, tolerability and safety of
darifenacin, an M3 selective receptor antagonist: an
investigation of warning time in patients with OAB.
Int J Clin Pract 2006;60:119-26.



SITAGLIPTIN: A DIPEPTIDYL
PEPTIDASE IV INHIBITOR FOR
DIABETES MELLITUS TYPE 2

Kelli Rudisill, Pharm.D. Candidate


In recent years, the incidence of type 2 diabetes
has steadily increased and the CDC now estimates
there are approximately 20.8 million people with dia-
betes in the United States comprising 7% of the
population. Globally, the burden of diabetes is ex-
pected to climb to 336 million by 2030.1 Chronic hy-
perglycemia can give rise to a number of serious
complications including heart disease, stroke, hyper-
tension, blindness, kidney disease, and nervous sys-
tem damage. The direct medical cost of these com-
plications is estimated around $24.6 billion annually
in the U.S.2
Despite a number of medication options, control-
ling diabetes remains a huge challenge to health care
professionals. Currently available oral options in-
clude sulfonylureas, thiazolidinediones, biguanides,
meglitinides, and alpha-glucosidase inhibitors. The
use of some of the oral agents is limited by side ef-
fects such as weight gain and hypoglycemia or con-
traindications including renal insufficiency or
chronic heart failure. Due to the limitations of cur-
rently available medications, there is a need for addi-
tional options to manage patients with difficult to

PharmaNote


control diabetes or for those with contraindications
or side effects to traditional options.
Incretin hormones have recently become a target
for treating diabetes. These hormones stimulate the
release of insulin in response to elevated plasma glu-
cose levels.3 Glucagon-like peptide 1, or GLP-1, is
an incretin that is released from the small intestine in
response to the ingestion of food.3 GLP-1 regulates
glucose homeostasis by increasing insulin secretion
and synthesis as well as by inhibiting glucagon re-
lease.4 Additionally, GLP-1's effects on glucose ho-
meostasis and insulin release are glucose dependant,
thus minimizing the likelihood of having hypoglyce-
mia.5 Based on the benefits of GLP-1 augmentation,
research has focused on creating a drug to increase
GLP-1 levels in the body. One limitation to supple-
menting GLP-1 is that it has an extremely short half
life due to rapid degradation in vivo by the enzyme
dipeptidyl peptidase IV (DPP-IV).6
Sitagliptin is a novel medication that targets the
DPP-IV enzyme and inhibits it from inactivating
GLP-1. By inhibiting DPP-IV, the half-life of GLP-1
is increased; thus, allowing GLP-1 to regulate glu-
cose homeostasis more efficaciously.
Sitagliptin (sit a glip' tin) is being marketed by
Merck and Co. under the brand name Januvia (ja
noo' ve a). The FDA approved sitagliptin on October
17, 2006.33
This article will review the mechanism of action
for sitagliptin as well as the pharmacokinetics,
safety, and efficacy

Pharmacology and Pharmacokinetics
The regulation of glucose levels via insulin is a
complex mechanism involving many factors. Incretin
hormones are one of the factors that play a central
role in regulating the secretion of insulin. When glu-
cose is administered orally, an increased secretion of
insulin occurs as opposed to when it is administered
intravenously. This increased response of insulin sec-
ondary to oral glucose administration is known as the
incretin effect and is estimated to account for 50-
70% of the insulin secreted by the body.7 The two
incretin hormones most often associated with the in-
cretin effect are GLP-1 and glucose-dependent insu-
linotropic peptide (GIP).8 Studies show that patients
with type 2 diabetes have normal GIP concentrations
but decreased levels of GLP-1.9 GLP-1 is associated
with stimulating insulin synthesis and secretion, in-
hibiting glucagon release, slowing gastric emptying,


Volume 22, Issue 2 November 2006







and reducing appetite.10 Additionally, GLP-1 has
been associated with positive effects on beta cell
function and thus may play a role in beta cell restora-
tion and prevention of type 2 diabetes.10'32'28 The sig-
nificance of the effects of GLP-1 are not fully under-
stood; however, the observation that people with
type 2 diabetes have decreased levels of GLP-1
stimulated research to correct these levels as an ap-
proach to managing diabetes. One challenge in in-
creasing GLP-1 levels is that it is rapidly degraded in
vivo by dipeptidyl peptidase-IV (DPP-IV), an en-
zyme that is primarily located in the brush border
membrane of the intestines and kidneys.1 As a re-
sult, GLP-1 has a half life of less than 2 minutes.11
Inhibition of this enzyme should promote improve-
ments in glucose homeostasis by increasing the con-
centration of GLP-1.
Sitagliptin is a selective, competitive, reversible
inhibitor of the DPP-IV enzyme, which causes de-
creased deactivation of the incretin hormone GLP-1.
Sitagliptin's effects are meditated through a number
of mechanisms. The primary mechanism of action
for sitagliptin is amplifying the effect of the incretin
GLP-1 which in turn increases insulin biosynthesis
and secretion and inhibits glucagon release. Si-
tagliptin also plays a potentially beneficial role on
the function of beta cells and may have the potential
to prevent or delay type 2 diabetes.10'12 GLP-1 slows
gastric emptying and suppresses appetite.2 Si-
tagliptin also inhibits T-cell activity in vitro and has
been shown to affect substance P, certain chemoki-
nes, and neuropeptide Y, although the implications
of these actions are currently unknown.30
Most of the pharmacokinetic studies conducted
to date for sitagliptin were performed in patients
without diabetes. Bergman et al.13 conducted a mul-
tiple oral dose trial with sitagliptin in 70 healthy sub-
jects (Table 1). This study demonstrated that si-
tagliptin inhibited the DPP-IV enzyme dose depen-
dently. As a result, GLP-1 concentrations increased
in a manner proportional to the dose. In this trial, the
terminal half-life (t12) was 11.8-14.4 hours. The renal


clearance, averaged across all doses (25-600 mg
daily), was 349 mL/min, which is greater than the
GFR indicating that an active secretion process is
involved. This study concluded that sitagliptin exhib-
ited pharmacokinetic/pharmacodynamic parameters
consistent with a once daily dosing schedule.
Sitagliptin is readily absorbed following oral ad-
ministration, with a bioavailability of 87%.31 Food
does not interfere with the pharmacokinetics of si-
tagliptin.31 About 75% of sitagliptin is excreted in
the urine unchanged.13 Steady state is achieved after
3 days.14 Additionally, the pharmacokinetics of si-
tagliptin are independent of age, gender, and obe-
sity.16
Renally impaired patients experienced increased
exposure to sitagliptin and thus will require a dose
reduction.17 Hepatic impairment has no effect on the
time to maximum concentration (Tmax), t1/2, renal
clearance, or fraction of the oral dose excreted in the
urine.18

Clinical Trials
Several clinical trials have been conducted to
date on sitagliptin (Table 2). These studies were in-
volved in the pre-marketing approval of sitagliptin
and many are only available in abstract form. These
articles include trials on: safety, dose-ranging, effi-
cacy as monotherapy, combination therapy, and drug
interaction studies.
In a randomized, double blind, placebo-
controlled, 3-period, single-dose, crossover study,
the safety, tolerability and glucose lowering ability
of sitagliptin was evaluated in 56 type 2 diabetics.
Oral glucose tolerance tests performed 2 hours after
administration of sitagliptin demonstrated that the
AUC was reduced by 22% and 26% for the 25mg
and 200mg doses, respectively (p<0.001). Addition-
ally, GLP-1 concentrations were doubled by both
sitagliptin doses, plasma insulin levels increased
22% and 23% (p<0.001), and plasma glucose levels
were decreased 8% (p=0.015) and 14% (p<0.001) for
the 25mg and 200mg doses.19


Table 1. Pharmacokinetics of sitagliptin on day 10 in healthy men1


Parameter 50 mg daily of sitagliptin, N=8 100 mg daily of sitagliptin, N=8
AUCo-t (mmol/Lh) 3.7 8.5
Cmax (nmol/L) 366 941
Tmx (h) 2.5 3.0
T1/2 (h) 14.2 14.4
fe,o-t 0.70 0.76
C1R (ml/min) 369 363
CR renal clearance
fe,o-t the amount of sitagliptin excreted unchanged in the urine over the dosing interval
PharmaNote Volume 22, Issue 2 November 2006







Raz et al.21 studied 521 people with type 2 diabe-
tes who took sitagliptin to evaluate its efficacy as
monotherapy in reducing hemoglobin Alc (A1C)
levels. Patients had A1C levels between 7-10% at
baseline. Patients either received 100mg daily,
200mg daily, or placebo for 18 weeks. The patients
receiving sitagliptin had decreased A1C levels when
compared with the placebo group. The reductions in
A1C were -0.60% [95% CI -0.82 to -0.39] and -
0.48% [95% CI -0.70 to -0.26] for the 100mg and
200mg groups respectively. The group that received
the greatest reduction was the patients who had a
baseline A1C > 9%. Overall, sitagliptin was well tol-
erated.
Sitagliptin was compared to glipizide in a 12
week, double-blind, placebo-controlled, dose-range
finding study conducted in 743 people with type 2
diabetes.24 Patients were randomized to receive ei-
ther sitagliptin 5mg, 12.5mg, 25mg, 50mg BID or
glipizide 5mg titrated to 10, 15, and then to 20mg/
day for 12 weeks. The reduction in A1C for si-
tagliptin was dose dependant and ranged from -0.4 to
-0.8% (p values not reported), while the reduction in
A1C in the glipizide group was -1.0% (p value not
reported). However, the glipizide group experienced
a mean weight gain of 1.1 kg, while the sitagliptin
group did not. Additionally, the incidence of hypo-
glycemia was much higher in the glipizide treated
group than in the sitagliptin treated group.
Karasik et al.23 examined sitagliptin as add-on
therapy to metformin. This trial had 701 patients in-
adequately controlled on doses of metformin
>1500mg/day alone. Patients were randomized to
receive either sitagliptin 100mg daily or placebo for
24 weeks. The addition of sitagliptin provided an ad-
ditional -0.65% (p<0.001) decrease in A1C. Fasting
glucose levels improved (-25.4mg/dL, p<0.001) in
the metformin plus sitagliptin group versus the met-
formin plus placebo group. Weight gain was not dif-
ferent between the sitagliptin group and the placebo
treated patients, and the addition of sitagliptin was
not associated with an increase in the hypoglycemic
events compared to placebo.
The efficacy of sitagliptin in combination with
pioglitazone for inadequately controlled diabetes was
studied in a 24 week study by Rosenstock.22 Patients
with an A1C between 7-10% were randomized to
receive either 100mg of sitagliptin or placebo in ad-
dition to pioglitazone therapy. The addition of si-
tagliptin to pioglitazone resulted in a -0.70% decease


in the A1C versus pioglitazone alone (p<0.001) and
fasting plasma glucose levels decreased 17.7mg/dL
(p<0.001) in the patients on combination therapy.
Additionally, almost double the patients in the si-
tagliptin group achieved their goal A1C (<7%) ver-
sus the placebo group (45% versus 23%, p<0.001).

Dosing and Administration
A number of trials have been conducted evaluat-
ing the pharmacokinetics of sitagliptin. In these tri-
als, several different doses were evaluated and the
percent inhibition of DPP-IV recorded. An ideal dose
of sitagliptin should inhibit at least 80% of DPP-IV
enzyme activity.25 Bergman et al.13 demonstrated that
50, 100, and 200 mg daily inhibited DPP-IV at levels
greater than 80%. Doses of 25, 50 and 100 mg were
approved by the FDA. A starting dose of 100 mg
daily is recommended for monotherapy or add-on
therapy in patients with normal renal function.34 Al-
though, doses up to 600 mg were well tolerated in
healthy male subjects, the maximum approved dose
is 100 mg daily.31
The majority of sitagliptin (>75%) is really ex-
creted unchanged and kinetic studies indicate that
accumulation occurs in really compromised pa-
tients. As such, lower doses are recommended for
patients with renal insufficiency. Patients with mod-
erate renal insufficiency (CrCl < 50 ml/min) should
take 50 mg daily, while in severe renal insufficiency
(CrCl < 30 ml/min), the 25 mg dose is suggested.26'34
Sitagliptin is administered once daily due to a favor-
able pharmacokinetic profile consistent with once
daily administration.13

Toxicity and Safety
Sitagliptin appears to exhibit a promising side
effect profile, especially when compared to many of
the older oral antidiabetic medications. There are
currently no contraindications to sitagliptin and the
only warning in the package insert is for a dose re-
duction in patients with renal impairment.34 Addi-
tionally, in the numerous pharmacokinetic trials per-
formed, sitagliptin was associated with very few hy-
poglycemic events. The absence of hypoglycemia is
expected since GLP-1 is dependant on glucose to
stimulate the release of insulin.5 Sitagliptin has an
appetite suppressant effect20 and it initially was be-
lieved that it might possess weight loss properties.
Clinical trials have failed to show weight loss in
study participants; however, sitagliptin does appear


m:m
PharmaNote Volume 22, Issue 2 November 2006


Volume 22, Issue 2 November 2006


PharmaNote







Table 2. Summary of sitagliptin trials
Trial Design Patients Treatment Duration Outcome Adverse effects
TT T> T->n N=5T ^ c-AUC for glucose
Herman R DB N=56 Single for glucose No hypoglycemia re-
(2005)19 PC, CO T2DM SIT 25mg or 200mg x 1 ddecreased 22% and ed
26%
hypoglycemia and GI
Raz R, DB, N=521 SIT 100mg or 200mg qd A1C decreased adverse events no diff.
(2006)21 PC, PGS T2DM vs. Pbo 0.60% & 0.48% than placebo. SIT
weight neutral.
Hypoglycemia no diff.
Aschner R, DB, N=741 SIT 100mg or 200mg qd A1C decreased Hypoglycemia no diff.
24 weeks than placebo; weight
(2006)28 PCS T2DM vs. Pboweeks 0.79% & 0.94% than placebo; weight
neutral
0.6% to 1.1% de- One event of hypogly-
Herman R, DB, N=552 1 of 5: Pbo, SIT 25, 50, crease in A1C for cemia in each si-
(2005)29 PC, PGS T2DM 100mg QD or 50mg BID 100mg depending on tagliptin group; no wt.
the initial A1C gain
1 DB 1 of 6: Pbo, SIT 5, 12.5, 0.4 to 0.8% decrease No weight gain in si-
Scott 4 N=743 25, 50mg BID, or GLIP 12 weeks in A1C (up to 50mg tagliptin groups; 1.lkg
(2005)24 PS T2DM 5mg QD titratedd to bid); 1.0% A1C de- weight gain for
PGS
20mg/d) crease in glipizide glipizide.
Decrease in A1C of
Nonaka R, DB, N=151 0.65% as compared No weight gain or hy-
(2006)2 PC, PGS T2DM SIT 100mg qd vs. Pbo 12 weeks with a 0.41% in- poglycemia reported
crease in placebo
Incidence of hypogly-
N=353 Addition of SIT to cemia similar to Pbo.
Rosenstock R, DB, PIO + SIT 100mg qd vs.
nso22 PR T2DM on Pqdvs. 24 weeks PIO caused A1C to Slightly more abdomi-
(2006) R, PC PIO + Pbo
PIO decrease 0.7% nal pain. No change in
body weight
Addition of SIT to No change in body
N=701 MET caused A1C to weight or increased
Karasik R, DB, MET + SIT 100omgqdvs.
( 6 2 R, DB, T2DM on MET + 24 weeks decrease 0.65% hypoglycemia or GI
(2006) PC MET + Pbo
MET when compared with adverse events when
placebo compared with placebo
AC= active control; CO= crossover; DB= double-blind; GLIP= glipizide; MET= metformin; PC= placebo controlled; PGS= parallel group study; Pbo= placebo;
PIO-pioglitazone; QD= once daily; R= randomized; SIT=sitagliptin; T2DM= type 2 diabetes


to be weight neutral.27 28,29
Sitagliptin's effect on inhibiting T-cell activity
initially raised concerns that immune function might
be compromised as a consequence. However, data
from clinical trials in humans have failed to confirm
this and to date this effect has only been exhibited in
vitro.30
The most common adverse effects from treat-
ment with sitagliptin reported in the package insert
are nasopharyngitis (5.2% vs. 3.3% in placebo), up-
per respiratory tract infections (6.3% in patients re-
ceiving sitagliptin plus pioglitazone versus 3.4% in
patients receiving pioglitazone alone), and headache
(5.1% in patients receiving sitagliptin plus pioglita-
zone versus 3.9% in patients receiving pioglitazone
alone).34 Additionally, the incidence of gastrointesti-
nal adverse events does not appear to be higher than
placebo (abdominal pain: 2.3% in sitagliptin; 2.1% in
placebo, nausea: 1.4% in sitagliptin; 0.6% in pla-


cebo, and diarrhea: 3.0% in sitagliptin; 2.3% in pla-
cebo).34

Drug Interactions
Limited data is currently available concerning
sitagliptin's drug interaction profile. Sitagliptin does
not appear to be metabolized by the CYP450 en-
zymes. Sitagliptin has been studied in pharmacoki-
netic trials with pioglitazone and metformin and did
not show any significant interactions with either.22' 23
When digoxin was administered concomitantly with
sitagliptin for ten days, a slight increase in the area
under the curve (AUC) for digoxin was observed.
However, no dosage adjustment is recommended
when sitagliptin is administered with digoxin.34 Si-
tagliptin has also been studied with warfarin35, gly-
buride36, rosiglitazone37, cyclosporine38, and simvas-
tatin39 and no significant drug interactions were iden-
tified. In the future, additional trials are needed to


Phara~ot Volme 2, Isue Novmber200


Volume 22, Issue 2 November 2006


PharmaNote







assess the interaction between sitagliptin and other
drugs commonly used in diabetic patients.

Cost
Pricing data for sitagliptin was obtained for a one
month prescription from three pharmacies located in
Gainesville, FL. The average monthly cost (30 tab-
lets) for all strengths was $191 (range $180 $203).

Summary
Sitagliptin is a novel oral medication that
raises levels of the naturally occurring incretin hor-
mone, GLP-1, which functions to increase insulin
secretion and inhibit glucagon release in a glucose-
dependant manner. Sitagliptin provides up to a 1%
A1C decrease, depending on the patient's baseline.
Sitagliptin has a favorable side effect profile when
compared to available second line oral agents, since
it is weight neutral and induces minimal to no hypo-
glycemia. While sitagliptin's exact place in therapy
is not yet established, it appears to be efficacious as
either monotherapy or combination therapy with
metformin or pioglitazone. Additional trials will aid
in defining sitagliptin's role in treating type 2 diabe-
tes, but it appears that it will provide a useful option
for patients with contraindications to traditional oral
antidiabetic medications or for those wishing to
minimize hypoglycemia or weight gain.


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PharmaNote







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