The medical letter on drugs and therapeutics february 17 2014

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IN THIS ISSUE (starts on next page)

Dapagliflozin (Farxiga) for Type 2 Diabetes.................................................p 13
Macitentan (Opsumit) for Pulmonary Arterial Hypertension................... p 15

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On Drugs and Therapeutics
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Volume 56 (Issue 1436)
February 17, 2014

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ALSO IN THIS ISSUE

Table 2. Pharmacology

Macitentan (Opsumit) for Pulmonary Arterial
Hypertension................................................ p 15

Class

Sodium-glucose co-transporter 2 (SGLT2)
inhibitor

Formulation

5-, 10-mg tablets

Dapagliflozin (Farxiga) for Type 2

Diabetes
Dapagliflozin (dap” a gli floe’ zin; Farxiga – Bristol-Myers
Squibb/AstraZeneca), an SGLT2 (sodium-glucose cotransporter 2) inhibitor, has been approved by the FDA
for oral treatment of type 2 diabetes. Dapagliflozin is the
second SGLT2 inhibitor to be approved for this indication; canagliflozin (Invokana) was the first.1
Table 1. SGLT2 Inhibitors
Drug

Cost1

Dosage
2

Canagliflozin –
Invokana

100-300 mg once/d

Dapagliflozin –
Farxiga

5-10 mg once/d3

$289.10
289.20

1. Approximate wholesale acquisition cost (WAC) for 30 days’ treatment.
Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) February 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved.
©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices
may be higher.

2. Taken before the first meal of the day. Maximum dose is 100 mg in patients
who have an eGFR of 45 to 59 mL/min/1.73 m2. Should not be used in patients with an eGFR <45 mL/min/1.73 m2.
3. Taken in the morning with or without food. Should not be used in patients with
an eGFR <60 mL/min/1.73 m2.

View our detailed online table: SGLT-2 Inhibitors
MECHANISM OF ACTION — SGLT2, a membrane
protein expressed mainly in the kidney, transports filtered glucose from the proximal renal tubule into tubular epithelial cells. SGLT2 inhibitors decrease renal
glucose reabsorption and increase urinary glucose excretion, resulting in a reduction in blood glucose levels.
CLINICAL STUDIES — In randomized, double-blind
clinical trials in patients with type 2 diabetes (see
Table 3), dapagliflozin significantly reduced HbA1c
compared to placebo when used as monotherapy
in treatment-naive patients or as add-on therapy in
patients with inadequate glycemic control on metformin, glimepiride, pioglitazone, sitagliptin, or insulin.

Route

Oral

Tmax

2 hrs (fasting); 3 hrs (high-fat meal)

Metabolism

Glucuronidation, primarily by UGT1A9

Elimination

Urine (75%); feces (21%)

Half-life (terminal)

12.9 hrs (10-mg dose)

In other studies, addition of dapagliflozin to metformin was non-inferior to addition of an active control
(glipizide), and initial treatment with dapagliflozin
plus metformin was more effective than metformin
alone. Treatment with dapagliflozin also resulted in
systolic blood pressure reductions of 3-5 mm Hg and
weight loss of 2-4 kg.2-10
Extensions of the clinical trials found that addition of
dapagliflozin to metformin for up to 102 weeks resulted
in sustained reductions in HbA1c and body weight.11,12
Adding dapagliflozin to insulin for up to 104 weeks improved glycemic control, stabilized insulin dosing, and
reduced weight; addition of placebo was associated with
use of higher doses of insulin and with weight gain.13
ADVERSE EFFECTS — Like canagliflozin, dapagliflozin has been associated with an increased risk of
genital mycotic infections and urinary tract infections. In
clinical studies, genital mycotic infections occurred in
about 7.6% of women and 2.7% of men taking dapagliflozin, compared to 1.5% of women and 0.3% of
men taking placebo. Urinary tract infections occurred in
about 5.0% of patients taking dapagliflozin versus 3.7%
of those taking placebo. Dapagliflozin has a diuretic effect, which can lead to dehydration, hypovolemia, and
hypotension, particularly in elderly patients with renal
dysfunction and in those taking loop diuretics.
In patients treated with dapagliflozin as monotherapy,
there were no reports of minor or major hypoglycemia.
Minor episodes of hypoglycemia occurred more often

with dapagliflozin than with placebo when combined
with a sulfonylurea (5.7% vs. 2.1%) or insulin (41.9%
vs. 34.0%).

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13


Revised 2/28/14: In the Drug Interactions paragraph, the second sentence about dapagliflozin exposure has been rewritten.

Table 3. Some Dapagliflozin Clinical Studies
Study
Design

Drug
Regimen

HbA1c
Change (%)1

Monotherapy in Treatment-Naive Patients
24 weeks2
(n=485)†

Dapagliflozin 5 mg
10 mg
Placebo

-0.77

-0.89
-0.23

24 weeks3
(n=282)†

Dapagliflozin 5 mg
Placebo

-0.82
+0.02

Initial Combination Therapy in Treatment-Naive Patients
24 weeks4
(n=638)

Dapagliflozin 5 mg
+ Metformin ~2000 mg
Dapagliflozin 5 mg
Metformin ~2000 mg

-2.05
-1.19
-1.35

24 weeks4
(n=603)

Dapagliflozin 10 mg
+ Metformin ~2000 mg

Dapagliflozin 10 mg
Metformin ~2000 mg

-1.98
-1.45
-1.44

24 weeks5
(n=546)†

Metformin >1500 mg
+ Dapagliflozin 5 mg
10 mg
+ Placebo

-0.70
-0.84
-0.30

52 weeks6
(n=814)

Metformin 1500-2500 mg
+ Dapagliflozin ~10 mg
+ Glipizide ~20 mg

-0.52
-0.52

24 weeks7

(n=597)†

Glimepiride 4 mg
+ Dapagliflozin 5 mg
10 mg
+ Placebo

-0.63
-0.82
-0.13

24 weeks8
(n=420)

Pioglitazone 30 or 45 mg
+ Dapagliflozin 5 mg
10 mg
+ Placebo

-0.82
-0.97
-0.42

24 weeks9
(n=432)

Sitagliptin 100 mg
(+ Metformin >1500 mg)
+ Dapagliflozin 10 mg
+ Placebo

-0.5
0.0

Add-on Therapy

24 weeks10
(n=808)

Insulin11
+ Dapagliflozin
+ Placebo

5 mg
10 mg

-0.89
-0.96
-0.39

†

Some patients were taking <5 mg/day of dapagliflozin; results for these doses
are not included here.
1. Mean change from baseline.
2. E Ferrannini et al. Diabetes Care 2010; 33:2217.
3. CJ Bailey et al. Diabetes Obes Metab 2012; 14:951.
4. RR Henry et al. Int J Clin Pract 2012; 66:446.
5. CJ Bailey et al. Lancet 2010; 375:2223.
6. MA Nauck et al. Diabetes Care 2011; 34:2015.

7. K Strojek et al. Diabetes Obes Metab 2011; 13:928.
8. J Rosenstock et al. Diabetes Care 2012; 35:1473.
9. SA Jabbour et al. Diabetes Care 2014 Jan 15 (epub).
10. JP Wilding et al. Ann Intern Med 2012; 156:405.
11. Insulin >30 units/day with 0-2 oral antidiabetic agents.

Increases from baseline in LDL cholesterol were reported
in patients taking dapagliflozin 10 mg (2.9% vs. -1.0%
with placebo). Hyperphosphatemia, increased serum
creatinine, decreased estimated glomerular filtration rate
(eGFR), and renal failure have also occurred. Use of dapagliflozin in patients with moderate renal impairment (eGFR
30 to <60 mL/min/1.73 m2) did not improve glycemic control and was associated with increased serum concentra14

tions of dapagliflozin and an increased risk of renal-related
adverse reactions and bone fractures.
In clinical trials, patients treated with dapagliflozin had
a higher incidence of bladder cancer (10/6045; 0.17%)
than those treated with placebo (1/3512; 0.03%).
When patients treated for less than one year before
diagnosis were excluded, there were 4 cases of bladder cancer with the active drug and none with placebo.
PREGNANCY — For use during pregnancy, dapagliflozin is classified as category C (developmental toxicity in animals; no adequate studies in women).
DRUG INTERACTIONS — Dapagliflozin is metabolized primarily by UGT1A9. Mefenamic acid (Ponstel), a
UGT1A9 inhibitor, increased dapagliflozin exposure
(AUC) by about 50%, but the dose of dapagliflozin does
not have to be reduced if the drugs are taken concurrently. Taking dapagliflozin with insulin or a sulfonylurea
increases the risk of hypoglycemia.
DOSAGE AND ADMINISTRATION — The recommended starting dose of dapagliflozin is 5 mg once
daily, taken in the morning with or without food. The
dose can be increased to 10 mg if needed for glycemic
control. Patients with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m2) should not be treated with dapagliflozin. The package insert also states

that the drug should not be used in patients with active
bladder cancer and that the benefits and risks should
be considered when it is used in patients with a prior
history of bladder cancer.
CONCLUSION — Dapagliflozin (Farxiga), like canagliflozin (Invokana), is modestly effective in reducing
HbA1c. Both of these drugs can lower systolic blood
pressure and reduce body weight, but genital mycotic
infections can occur, and their long-term safety is unknown. □
1. Canagliflozin (Invokana) for type 2 diabetes. Med Lett Drugs Ther
2013; 55:37.
2. E Ferrannini et al. Dapagliflozin monotherapy in type 2 diabetic
patients with inadequate glycemic control by diet and exercise: a
randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010; 33:2217.
3. CJ Bailey et al. Dapagliflozin monotherapy in drug-naïve patients
with diabetes: a randomized-controlled trial of low-dose range.
Diabetes Obes Metab 2012; 14:951.
4. RR Henry et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomized controlled trial. Int
J Clin Pract 2012; 66:446.
5. CJ Bailey et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a
randomised, double-blind, placebo-controlled trial. Lancet 2010;
375:2223.
6. MA Nauck et al. Dapagliflozin versus glipizide as add-on therapy in
patients with type 2 diabetes who have inadequate glycemic con-

The Medical Letter • Volume 56 • Issue 1436 • February 17, 2014


trol with metformin: a randomized, 52-week, double-blind, activecontrolled noninferiority trial. Diabetes Care 2011; 34:2015.
7. K Strojek et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes
Obes Metab 2011; 13:928.

8. J Rosenstock et al. Effects of dapagliflozin, an SGLT2 inhibitor, on
HbA(1c), body weight, and hypoglycemia risk in patients with type
2 diabetes inadequately controlled on pioglitazone monotherapy.
Diabetes Care 2012; 35:1473.
9. SA Jabbour et al. Dapagliflozin is effective as add-on therapy to
sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care
2014 Jan 15 (epub).
10. JP Wilding et al. Long-term efficacy of dapagliflozin in patients with
type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012; 156:405.
11. J Bolinder et al. Dapagliflozin maintains glycaemic control while
reducing weight and body fat mass over 2 years in patients with
type 2 diabetes mellitus inadequately controlled on metformin.
Diabetes Obes Metab 2013 Aug 1 (epub).
12. CJ Bailey et al. Dapagliflozin add-on to metformin in type 2 diabetes
inadequately controlled with metformin: a randomized, double-blind,
placebo-controlled 102-week trial. BMC Med 2013; 11:43.
13. JP Wilding et al. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab 2013 Aug 1 (epub).

Macitentan (Opsumit) for Pulmonary
Arterial Hypertension
The FDA has approved macitentan (ma” si ten’ tan; Opsumit – Actelion), for oral treatment of pulmonary arterial
hypertension (PAH). Macitentan is the second nonselective
endothelin receptor antagonist approved for PAH. It is a derivative of bosentan (Tracleer), which is also manufactured
by Actelion, and is scheduled to become available generically in 2015. Riociguat (Adempas), another new drug for
this indication, will be reviewed in a future issue.
DRUGS FOR PAH — Current management of PAH
usually includes warfarin (Coumadin, and others)
and furosemide (Lasix, and generics). Oral drugs
approved specifically for PAH include the phosphodiesterase 5 (PDE5) inhibitors sildenafil (Revatio,
and generics) and tadalafil (Adcirca),1 bosentan, and

ambrisentan (Letairis), a selective endothelin type A
receptor antagonist.2 Patients with more advanced
disease can be treated with multiple daily inhalations
of a systemic prostacyclin such as iloprost (Ventavis)
or treprostinil (Tyvaso), or continuous intravenous
infusions of epoprostenol (Flolan, and generics) or
treprostinil (Remodulin); treprostinil can also be given as a continuous subcutaneous infusion.3
MECHANISM OF ACTION — Macitentan prevents the
binding of endothelin (ET)-1 to both ETA and ETB receptors. Macitentan has high affinity for ET receptors in hu-

Table 1. Pharmacology
Class

Endothelin receptor antagonist

Route

Oral

Formulation

10-mg tablets

Tmax

8 hrs

Metabolism

Primarily hepatic by CYP3A4, and to a minor

extent by CYP2C19

Elimination

Urine (50%); feces (24%)

Elimination half-life

16 hrs (active metabolite 48 hrs)

man pulmonary arterial smooth muscle cells and may
cause less liver toxicity than bosentan.3-5
CLINICAL STUDY — Approval of macitentan was
based on a clinical trial (SERAPHIN) in 742 patients
randomized to placebo or to 3 mg or 10 mg of the active drug once daily. The composite primary endpoint
was time from treatment initiation to the first occurence
of death, atrial septostomy, lung transplantation, use of
injectable prostanoids, or worsening of pulmonary hypertension. More than 60% of patients were on stable
PAH therapy, primarily with oral PDE5 inhibitors.6
After a median treatment duration of 115 weeks (the
incidence of death was followed to 129 weeks), 31.4%
of patients taking macitentan 10 mg/day experienced a
primary endpoint event, compared to 46.4% of patients
taking placebo (P<0.001). The beneficial effect of macitentan was mostly attributable to a lower incidence of
clinical worsening of PAH, which was defined as >15%
reduction in 6-minute walk distance, worsening of PAH
symptoms, and need for additional PAH treatment. The
authors state that macitentan significantly reduced
morbidity and mortality, but the trial did not show an
effect on mortality alone.

At 6 months, the secondary endpoint of 6-minute walk
distance had increased by 7.4 meters and 12.5 meters
in the 3-mg and 10-mg groups, respectively, and had
decreased by 9.4 meters with placebo.
ADVERSE EFFECTS — Adverse events that occurred at
a rate at least 3% higher with macitentan 10 mg than with
placebo included headache, nasopharyngitis, bronchitis,
and anemia. Decreases in hemoglobin and hematocrit
have also occurred in patients taking other endothelin receptor antagonists. Macitentan is not recommended for
patients with severe anemia.
Aminotransferase elevations, hepatotoxicity and liver
failure have also occurred with other endothelin receptor
antagonists. In the macitentan clinical trial, the incidence
of elevated aminotransferases >3× the upper limit of
normal (ULN) was similar with both doses of macitentan
and with placebo, but the incidence of elevated amino-

The Medical Letter • Volume 56 • Issue 1436 • February 17, 2014

15


transferases >8x ULN was 2.1% with macitentan 10 mg
and 0.4% with placebo.
A decrease in sperm count has occurred with other
endothelin receptor antagonists and may also occur in
men taking macitentan.
PREGNANCY — Macitentan is teratogenic in animals.
It is contraindicated for use during pregnancy (category
X) and is available for women only through a restricted

access program. Pregnancy should be excluded before
starting treatment and prevented during treatment and
for one month afterwards.
DRUG INTERACTIONS — Strong CYP3A4 inducers
such as rifampin can lower serum concentrations of
macitentan, and strong CYP3A4 inhibitors such as ketoconazole and ritonavir can increase them. Concomitant use of macitentan with strong CYP3A4 inducers
and inhibitors should be avoided.7
DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of macitentan is 10 mg once daily.
Aminotransferases should be monitored before starting macitentan and as needed during treatment. The
drug should be discontinued for clinically significant
aminotransferase elevations or when elevations are accompanied by an increase in bilirubin >2x ULN or by
symptoms of hepatotoxicity. Patients with pulmonary
veno-occlusive disease should not take macitentan.
The cost of 1 month’s treatment with macitentan is
$6840.8
CONCLUSION — Macitentan (Opsumit) can decrease
morbidity in patients with pulmonary arterial hypertension, but the claim that it has been shown to decrease
mortality is misleading. □
1
2.
3.
4.
5.

6.
7.
8.

16

Tadalafil (Adcirca) for pulmonary arterial hypertension. Med Lett
Drugs Ther 2009; 51:87.
Ambrisentan (Letairis) for pulmonary arterial hypertension. Med
Lett Drugs Ther 2007; 49:87.
Y Wu et al. An update on medical therapy for pulmonary arterial
hypertension. Curr Hypertens Rep 2013; 15:614.
W Diller. Opsumit label and pricing suggest Actelion’s gamble
ready to pay off. The Pink Sheet October 28, 2013.
MH Bolli et al. The discovery of N-[5-(4-bromophenyl)-6-[2-[(5bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide
(macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem 2012; 55:7849.
T Pulido et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369:809.
Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
Approximate wholesale acquisition cost (WAC). Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™)
February 5, 2014. Reprinted with permission by FDB, Inc. All rights
reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy.
Actual retail price may be higher.

Coming Soon in The Medical Letter:
Afatinib (Gilotrif) for Lung Cancer
Riociguat (Adempas) for PAH
Tobramycin Inhalation (Bethkis) for Cystic Fibrosis
Coming Soon in Treatment Guidelines:
Drugs for Diabetes
Drugs for Hypertension

The Medical Letter

®

On Drugs and Therapeutics
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The Medical Letter • Volume 56 • Issue 1436 • February 17, 2014


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Online Continuing Medical Education
To take CME exams and earn credit, go to:
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Issue 1436 Questions
(Correspond to questions #19-24 in
Comprehensive Exam #70, available July 2014)

Dapagliflozin (Farxiga) for Type 2 Diabetes
1.

Dapagliflozin decreases renal glucose reabsorption and increases:

a. insulin production
b. insulin sensitivity
c. urinary glucose excretion
d. glucagon synthesis

2.

Adverse effects of dapagliflozin include:
a. urinary tract infection
b. weight gain
c. severe hypoglycemia
d. all of the above

3.

A 56-year-old man with recent onset of type 2 diabetes has
not responded adequately to metformin monotherapy and asks
you to prescribe Farxiga. You could tell him that:
a. there are no studies showing that it actually
lowers HbA1c
b. comparative studies have shown that other drugs
are more effective when added to metformin
c. it has caused severe injection reactions
d. its long-term safety is unknown

Macitentan (Opsumit) for Pulmonary Arterial Hypertension
4.

In the clinical trial comparing macitentan to placebo, the active drug:
a. reduced morbidity

b. lowered the incidence of clinical worsening of PAH
c. increased the 6-minute walking distance
d. all of the above

5.

Adverse effects of macitentan have included:
a. anaphylaxis
b. anemia
c. reversible posterior leukoencephalopathy
d. none of the above

6.

Use of macitentan during pregnancy:
a. has been found to be safe
b. is contraindicated
c. should be discontinued after the first trimester
d. may be reasonable if the benefit is thought to
outweigh the risk

ACPE UPN: Per Issue Exam: 0379-0000-14-436-H01-P; Release: February 17, 2014, Expire: February 17, 2015
Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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Physician Assistants: The National Commission on Certification of Physician Assistants (NCCPA) accepts AMA
PRA Category 1 Credit(s)™ from organizations accredited by ACCME. NCCPA also accepts AAFP Prescribed credits
for recertification. The Medical Letter is accredited by both ACCME and AAFP.
Physicians in Canada: Members of The College of Family Physicians of Canada are eligible to receive Mainpro-M1
credits (equivalent to AAFP Prescribed credits) as per our reciprocal agreement with the American Academy of Family
Physicians.
Physicians, nurse practitioners, pharmacists, and physician assistants may earn 1 credit with this exam.
MISSION:
The mission of The Medical Letter’s Continuing Medical Education Program is to support the professional development
of healthcare professionals including physicians, nurse practitioners, pharmacists, and physician assistants by providing
independent, unbiased drug information and prescribing recommendations that are free of industry influence. The program
content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms
of action, clinical trials, dosage and administration, adverse effects, and drug interactions. The Medical Letter delivers
educational content in the form of self-study material.
The expected outcome of the CME Program is to increase the participant’s ability to know, or apply knowledge into
practice after assimilating, information presented in materials contained in The Medical Letter.
The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and
activities. The Medical Letter aims to be a leader in supporting the professional development of healthcare professionals
through Core Competencies by providing continuing medical education that is unbiased and free of industry influence.
The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.
GOAL:
Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and
timely educational content that they will use to make independent and informed therapeutic choices in their practice.
LEARNING OBJECTIVES:
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and
other treatment modalities. Activity participants will be able to select and prescribe, or confirm the appropriateness
of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific

attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient
management. Activity participants will make independent and informed therapeutic choices in their practice.
Upon completion of this program, the participant will be able to:
1. Review the efficacy and safety of dapagliflozin (Farxiga) for treatment of type 2 diabetes.
2. Review the efficacy and safety of macitentan (Opsumit) for treatment of pulmonary arterial hypertension.
Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy. We do not sell any
of your information. Secure server software (SSL) is used for commerce transactions through VeriSign, Inc. No credit
card information is stored.
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Microsoft IE 6.0+, Mozilla Firefox 2.0+ or any other compatible Web browser. Dial-up/high-speed connection.
Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: