CLINICAL

REVIEW ARTICLE

New and Emerging Drugs and Targets for

Type 2 Diabetes: Reviewing the Evidence
Brien Rex Miller, DO; Hanh Nguyen, DO; Charles Jia-Haur Hu, DO; Chihyi Lin, DO; Quang T. Nguyen, DO,
FACP, FACE, FTOS

Stakeholder Perspective,
page 462
Am Health Drug Benefits.
2014;7(8):452-463
www.AHDBonline.com
Received September 29, 2014
Accepted in final form October 28, 2014
Disclosures are at end of text
BACKGROUND: Diabetes is a deadly and costly disease. The number of adults in the United States with
newly diagnosed diabetes has nearly tripled from 1980 to 2011. At the current pace, 1 in 3 US adults will
have diabetes in their lifetime. Currently, 14 classes of drugs are available to treat type 2 diabetes mellitus,
but only 36% of patients with type 2 diabetes achieve glycemic control with the currently available thera-
pies. Therefore, new treatment options are desperately needed.
DISCUSSION: Despite the availability of many pharmacotherapies, in 2011 an estimated 3.1 million
(14.9%) patients with type 2 diabetes still reported not taking medications to treat their diabetes. Patient
compliance is a major obstacle facing practicing clinicians on a daily basis. New treatment options are
desperately needed, but efficacy and tolerability are no longer the only criteria contributing to the success
of a drug. Ease of administration, convenient dosing frequency, being weight control friendly, and having
a low risk for hypoglycemia are important factors for the survival of a new drug in the US healthcare sys-
tem. The present review is focused on important new drugs and drug classes in the pipeline, as well as
on recently approved drugs, including sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1
agents, and new insulin therapies, as well as on the technologic improvements in the delivery and dosing
frequency of some of the currently available drugs.
CONCLUSIONS: In the United States, diabetes can be expected to continue to wreak significant
human and financial tolls. The associated complications will continue to climb if they are not controlled
and stopped. New therapies for diabetes are clearly needed that will better address these unmet
needs. The common threads among the emerging therapies are their convenience of administration
and dosing frequency, which are important to the improvement of patient adherence.

T
ype 2 diabetes mellitus is an ongoing medical
problem that clinicians deal with on a daily basis.
The necessity of treating diabetes adequately is
essential because of the many comorbidities and compli-
cations associated with uncontrolled diabetes. These
comorbidities are very costly to the healthcare system
and to the patient. In 2012, 28.9 million adult patients
in the United States were diagnosed or undiagnosed with
diabetes; of these, 15.5 million were men and 11.2 mil-
lion were aged ≥65 years.1 The number of newly diag-
nosed patients with diabetes in 2012 was approximately
1.7 million, the majority of whom were aged 45 to 64
Dr Miller is Resident, Department of Internal Medicine,
Valley Hospital Medical Center, Las Vegas, NV; Dr H.
Nguyen is Resident, Department of Internal Medicine, Valley
Hospital Medical Center, Las Vegas, NV; Dr Hu is
Resident, Department of Internal Medicine, Valley Hospital
Medical Center, Las Vegas, NV; Dr Lin is Resident,
Department of Internal Medicine, Valley Hospital Medical
Center, Las Vegas, NV; Dr Q.T. Nguyen is Medical
Director, Las Vegas Endocrinology, Clinical Associate
Professor, Clinical Education, AZCOM, Adjunct Associate
Professor of Endocrinology, Touro University Nevada.
years.1 The prevalence of diabetes is still increasing. The
number of US adults (aged 18-79 years) with newly diag-
nosed diabetes has nearly tripled in the past few decades,
from 493,000 in 1980 to more than 1.5 million in 2011.2
At the current pace, approximately 1 in 3 US adults will
have diabetes in their lifetime.1
The numerous comorbidities associated with diabe-
tes include, but are not limited to, kidney failure, obe-
sity, coronary artery disease, peripheral vascular dis-
ease, hypertension, stroke, and amputations.1 In the
years 2003-2006, cardiovascular (CV) disease mortali-
ty rates were approximately 1.7 times higher among
adults aged ≥18 years with diagnosed diabetes than
among adults without diagnosed diabetes.1 In 2010,
after adjusting for population age differences, hospital-
ization rates for heart attack and stroke were 1.8 times
and 1.5 times higher, respectively, among adults aged
≥20 years with diagnosed diabetes than among adults
without diagnosed diabetes.1 The estimated total cost
for type 2 diabetes mellitus was $245 billion in 2012,
of which $176 billion was in direct medical expendi-
tures.1 With these trends, the cost and debilitating ef-
fects of this disease are only going to escalate, unless
better glycemic control is achieved.

452 l American Health & Drug Benefits l www.AHDBonline.com November 2014 l Vol 7, No 8
 New and Emerging Drugs and Targets for Type 2 Diabetes
The older medications for diabetes, especially insulin
and sulfonylureas, are associated with the common side
effects of weight gain and hypoglycemia, which can be
costly to the healthcare system. A retrospective study
evaluated the incidence and cost of hypoglycemic events
in patients with type 2 diabetes during 4 years.3 The
analysis showed that the mean cost per 1 inpatient ad-
mission was $17,564, including $1387 for an emergency
department visit and $394 for an outpatient visit. The
total direct medical cost of hypoglycemia during the
4-year study was $52,223,675, which accounted for ap-
proximately 1% of all the inpatient costs, 2.7% of emer-
gency department costs, and 0.3% of outpatient costs.3
The annual medical cost of obesity is currently esti-
mated to be approximately $147 billion.4 Using drugs for
the treatment of diabetes that can aid in weight loss
rather than increase weight gain is cost-effective and can
aid in patient adherence. In one study, researchers esti-
mated that 1% of weight loss in 1 year could decrease a
patient’s total healthcare cost by approximately $213 per
patient who is using antidiabetic medications.5 Another
study ascertained that patients with type 2 diabetes mel-
litus who lost weight with a treatment regimen are more
likely to adhere to their regimen than patients who gain
weight with their medication.6 Increased adherence to
oral antihyperglycemic agents has been shown to be asso-
ciated with reduced healthcare utilization as well as cost.7
As many as 14 classes of drugs are currently available
for the treatment of type 2 diabetes mellitus.8 Despite the
availability of pharmacotherapies, an estimated 3.1 mil-
lion (14.9%) US adults with type 2 diabetes were still
not taking a medication for diabetes in 2011.9 According
to the 1999-2000 National Health and Nutrition Exam-
ination Survey, only approximately 36% of patients with
type 2 diabetes achieve glycemic control—defined as a
hemoglobin (Hb)A1c level of <7%—with the currently
available therapies.10 New medications with different
mechanisms of action or with novel approaches to ther-
apy are needed to improve patient outcomes and to re-
duce the clinical burden of this condition.
The current article reviews some of the newly ap-
proved therapies by the US Food and Drug Administra-
tion (FDA), as well as those that are currently being
tested as new options for the treatment of type 2 diabetes
mellitus. Most drugs in this review have voucher and
coupon programs provided by the manufacturer to offset
the cost of the medications (Table).
The risks and benefits of each drug discussed in this
article should be weighed appropriately when a drug regi-
men is chosen for a particular patient with diabetes. In
addition, because many of these drugs have only recently
become available in the United States, long-term evi-
dence from real-world utilization is lacking. Furthermore,
Vol 7, No 8 l November 2014 www.AHDBonline.com
KEY POINTS
➤ The number of US adults with newly diagnosed
diabetes has nearly tripled from 1980 to 2011 and
continues to rise.
➤ Despite the many drugs available for treating type 2
diabetes, only 36% of patients in the United States
achieve glycemic control; patient adherence is a
major obstacle.
➤ Efficacy and tolerability are no longer the only
criteria for the success of a new drug; ease of
administration, convenient dosing frequency,
being weight control friendly, and having a low
hypoglycemic risk are important factors for new
antidiabetes drugs.
➤ New oral drug classes have recently been approved
by the FDA and more are in development, most of
which are once-daily agents.
➤ All new injections for diabetes are now in a pen
format to improve patient adherence.
➤ Significantly, the new agents being introduced to
the market are either weight-friendly or can induce
weight loss, and have lower risks for hypoglycemia.
➤ At a mean total cost of $17,564 per hypoglycemic
episode requiring hospitalization, this can be a
meaningful improvement to the healthcare system
as a whole.
the FDA has requested postmarketing studies for some of
these new agents, to investigate the potential risks for pa-
tients with diabetes to ensure that these new classes of
drugs are safe for long-term use in this patient population.
Sodium Glucose Cotransporter-2 Inhibitors
The most recent class to be approved by the FDA for
the treatment of type 2 diabetes mellitus is sodium glu-
cose cotransporter-2 (SGLT-2) inhibitors. SGLT-2
proteins are primarily found in the proximal convolut-
ed tubule of the kidneys and are responsible for reab-
sorbing approximately 90% of the glucose that is fil-
tered through the kidneys.11 By inhibiting SGLT-2,
urinary glucose excretion is increased, thereby lowering
the plasma glucose concentration. This drug class can
be used as monotherapy or in combination with other
antihyperglycemic agents as a result of its distinct
mechanism of action.12
Canagliflozin
The first SGLT-2 inhibitor to be approved by the
FDA was canagliflozin (Invokana), which received
FDA approval in March 2013. Canagliflozin is indicat-
l American Health & Drug Benefits l 453
 CLINICAL

ed as an adjunct to diet and exercise for the improve- plasma glucose (FPG), 2-hour postprandial glucose,
ment of glycemic control in adult patients with type 2 body weight, and systolic blood pressure.
diabetes mellitus.13 Supplied as tablets for oral adminis- There were few adverse events in the groups receiving
tration, the recommended starting dose of canagliflozin canagliflozin, including genital mycotic infections, uri-
is 100 mg once daily, taken before the first meal of the nary tract infections, and osmotic diuresis, which can
day. In patients tolerating canagliflozin 100 mg once lead to orthostatic hypotension and syncope. The inci-
daily and who have an estimated glomerular filtration dence of hypoglycemia was low across all groups. Over-
rate (eGFR) of ≥60 mL/min/1.73 m2 and require addi- all, treatment with canagliflozin improved glycemic
tional glycemic control, the dose can be increased to control and was generally well-tolerated in patients with
300 mg once daily. type 2 diabetes who had inadequate glycemic control
Clinical results. In a randomized, double-blind, with diet and exercise.14
placebo-controlled study over 26 weeks, 584 patients Canagliflozin was also assessed in a randomized, dou-
were randomized to canagliflozin 100 mg, canagliflozin ble-blind, active-controlled study of 755 patients inade-
300 mg, or placebo, administered once daily.14 At quately controlled on the combination of metformin and
week 26, there was a significant reduction of HbA1c a sulfonylurea.15 Patients received canagliflozin 300 mg
from baseline with canagliflozin 100 mg and 300 mg in combination with metformin and a sulfonylurea or
compared with placebo (−0.77%, −1.03%, and sitagliptin 100 mg in combination with metformin and a
+0.14%, respectively; P <.001).14 In addition, both sulfonylurea. At week 52, canagliflozin 300 mg demon-
doses of canagliflo­ zin significantly reduced fasting strated superiority to sitagliptin 100 mg in reducing
HbA1c (−1.03% vs −0.66%, respectively). Combination
Table E merging Therapies for the Treatment of Patients with therapies including canagliflozin also demonstrated
Diabetes: Monthly Costs greater reductions in FPG, body weight, and systolic
Drug class Monthly Monthly cost Date of FDA blood pressure than those with sitagliptin (P <.001).15
and name cost, $ with voucher, $ approval The overall adverse event rates were similarly low
SGLT-2 inhibitors with canagliflozin and sitagliptin (76.7% vs 77.5%, re-
spectively), but higher incidences of genital mycotic in-
Canagliflozin 324.51-348.81 0 for commercial March 2013 fections and osmotic diuresis were reported with canagli-
(Invokana) insurance
flozin, which led to 1 patient’s discontinuation of the
Dapagliflozin 324.43-348.72 0 for cash and January 2014 drug.15 The trial’s findings demonstrate that canagliflozin
(Farxiga) commercial is superior to sitagliptin in providing glycemic control
insurance
and body-weight reduction in patients with type 2 diabe-
Empagliflozin 313.19-325.93 0 for commercial August 2014 tes who are already using metformin plus a sulfonylurea.15
(Jardiance) insurance
Considering its site of action at the renal SGLT-2
Ipragliflozin Not available Not available Approved in transporters, canagliflozin is not expected to be effective
(Suglat) in the US in the US Japan only, in patients with severe renal impairment (estimated glo-
January 2014
merular filtration rate [eGFR] <30 mL/min/1.73 m2),
Tofogliflozin Not available Not available Not yet those with end-stage renal disease, or those who are un-
(CSG452) approved dergoing dialysis, even though studies have not been
GLP-1 conducted on these patient populations.
Exenatide pen 454.31-473.80 25 for March 2014 The efficacy and safety of canagliflozin were evaluated in
(Bydureon) commercial a randomized, double-blind, placebo-controlled study that
insurance included 269 patients with moderate renal impairment
Albiglutide 338.62-352.58 10 for April 2014 (eGFR ≥30 to <50 mL/min/1.73 m2).16 These patients had
(Tanzeum) commercial less overall glycemic efficacy at 26 weeks and a higher inci-
insurance dence of adverse events related to reduced intravascular
Dulaglutide Data not yet Data not yet September 2014 volume (ie, postural dizziness and orthostatic hypotension),
(Trulicity) available available renal-related adverse reactions, and decreases in eGFR
Technosphere insulin compared with patients with mild renal impairment or with
normal renal function (eGFR ≥60 mL/min/1.73 m2). Pa-
Afrezza Not available Not available June 2014 tients using canagliflozin 300 mg were also more likely to
FDA indicates US Food and Drug Administration; GLP-1, glucagon- experience an elevation in potassium. Hence, the assess-
like peptide-1; SGLT-2, sodium-glucose cotransporter-2. ment of renal function is recommended before the initia-
Source: www.Goodrx.com, which compares local prescription drug costs. tion of canagliflozin, and periodically thereafter.16

454 l American Health & Drug Benefits l www.AHDBonline.com November 2014 l Vol 7, No 8
 New and Emerging Drugs and Targets for Type 2 Diabetes
Finally, among the ongoing postmarketing studies re-
quired by the FDA for these agents is the phase 3 clinical
trial Canagliflozin Cardiovascular Assessment Study
(CANVAS) that is set to compare canagliflozin with
placebo regarding CV events, including CV-related
death, myocardial infarction, and stroke.17 A total of 4330
patients with type 2 diabetes whose diabetes was not
well-controlled at the beginning of the study and who
had a history of, or were at a high risk for, CV events were
enrolled; they will be followed up for up to 9 years.
In January 2013, preliminary data from the CANVAS
trial suggested that canagliflozin was not associated with
an increased risk for CV events. Canagliflozin also caused
a slight increase in low-density lipoprotein cholesterol,
but the mechanism for this has yet to be elucidated.17
Dapagliflozin
In January 2014, dapagliflozin (Farxiga) was the sec-
ond SGLT-2 inhibitor to receive FDA approval to im-
prove glycemic control, along with diet and exercise, in
adult patients with type 2 diabetes.18 Similar to canagli-
flozin, dapagliflozin works in the renal tubules by inhib-
iting SGLT-2 transporters, resulting in the removal of
excess glucose and its associated calories in the urine.
Dapagliflozin has been studied as a monotherapy and in
combination with other therapies for type 2 diabetes,
including metformin, pioglitazone, glimepiride, sita-
gliptin, and insulin.19,20
Clinical results. One major study assessing the safe-
ty and efficacy of dapagliflozin monotherapy was a 24-
week, parallel-group, double-blind, placebo-controlled
phase 3 trial involving 558 patients with type 2 diabe-
tes.19 Patients were divided into 2 groups based on their
HbA1c levels: 485 patients were in the main cohort
with an HbA1c of 7% to 10%, and 73 patients were in
the group with an HbA1c of 10.1% to 12%. The pa-
tients with an HbA1c of 7% to 10% were randomly as-
signed to 1 of 7 arms to receive placebo or 2.5-mg,
5-mg, or 10-mg dap­agliflozin once daily in the morning
(main cohort) or evening (exploratory cohort). The
patients with an HbA1c of 10.1% to 12% (the high-
HbA1c exploratory cohort) were randomly assigned to
receive placebo or 5-mg or 10-mg dapagliflozin once
daily in the morning.
At week 24, the mean HbA1c changes from baseline
in the main cohort were −0.23% with placebo and
−0.58, −0.77, and −0.89% with 2.5-mg, 5-mg (P = .005),
and 10-mg dapagliflozin, respectively (P <.001). Data
from exploratory cohorts yielded similar and consistent
results. No major episodes of hypoglycemia were report-
ed with dapagliflozin, but urinary tract infections and
genital infections were more common in the arms receiv-
ing dapagliflozin than with placebo.19
Vol 7, No 8 l November 2014 www.AHDBonline.com
In another randomized, double-blind, active-­
controlled, multicenter 52-week trial, dapagliflozin was
compared with glipizide as an add-on therapy in diabet-
ic patients who had inadequate glycemic control with
metformin.20 Sulfonylureas are known to cause hypo-
glycemia and weight gain, and to have poor glycemic
durability, although they are initially effective. The
study aimed to assess whether dapagliflozin causes fewer
of these adverse events.
A total of 814 patients with type 2 diabetes were di-
vided into 2 groups to receive either dapagliflozin and
metformin or glipizide and metformin.20 The mean
HbA1c reduction in the dapagliflozin cohort (–0.52%)
was statistically noninferior at week 52 compared with
glipizide (–0.52%). In addition, dapagliflozin produced a
significant weight loss of 3.2 kg compared with a weight
gain of 1.2 kg with glipizide (P <.001). Furthermore, only
3.5% of patients receiving combination therapy with
dapagliflozin and metformin had hypoglycemic episodes
compared with 40.8% of patients in the glipizide group
(P <.001). However, genital infections and lower urinary
tract infections were more frequent with dapagliflozin
than with glipizide, but patients with these infections
responded to standard treatment and this rarely led to
study discontinuation.20
Before its approval by the FDA, dapagliflozin was de-
clined twice by the FDA, in July 2011 and January 2012,
because of insufficient data on the drug’s safety profile.
The concern was of an increased number of bladder can-
cers diagnosed among dapagliflozin users in the initial
trials.21 At the time of the July 2011 Endocrinology and
Metabolic Drugs Advisory Committee meeting,9 total
patients who were diagnosed with bladder cancer were
receiving dapagliflozin (0.06 per 100 patient-years), and
1 patient with bladder cancer was in the control group
(0.03 per 100 patient-years).22 The drug manufacturer
argued that the increase in bladder cancers seen in pa-
tients taking dapagliflozin resulted from preexisting can-
cers. Nonetheless, at this time, the drug’s manufacturer
and the FDA do not recommend dapagliflozin for pa-
tients with active bladder cancer.18,23
Similar to canagliflozin, dapagliflozin should not be
used in patients with moderate or severe renal impair-
ment, patients with end-stage renal disease, or patients
on dialysis. Dapagliflozin can also cause dehydration,
leading to hypotension, dizziness, fainting, and a decline
in renal function.
The FDA is requiring 6 postmarketing studies to be
conducted by the manufacturers of dapagliflozin, in-
cluding further investigation on its CV risk, bladder
cancer risk, effects on urinary flow and composition
changes on bladder tumor promotion in rodents, effica-
cy and safety in pediatric patients, risk of liver damage,
l American Health & Drug Benefits l 455
 CLINICAL
and pregnancy outcomes. These postmarketing studies
will likely provide better insight into dapagliflozin’s
benefit-risk profile.23
Empagliflozin
In August 2014, empagliflozin (Jardiance) became the
third SGLT-2 inhibitor to receive FDA approval for the
treatment of type 2 diabetes as an adjunct to diet and ex-
ercise. Used as a tablet for oral administration, the recom-
mended dose is 10 mg once daily in the morning, taken
with or without food. In patients tolerating empagliflozin,
the dose may be increased to 25 mg. The FDA approval of
empagliflozin was based on a monotherapy study24 and in
a combination study with metformin, sulfonylurea, pio­
glitazone, and insulin.25,26
Clinical results. The safety and efficacy of em-
pagliflozin was shown to have linear pharmacokinetics
with dose increases with respect to time.24 Empagli-
flozin was associated with an increase in urine glucose
excretion compared with virtually no urine glucose
excretion in the placebo group. It also significantly
decreased blood glucose in the active drug group ver-
sus the placebo group. The amount of glucose in the
urine increased from baseline to day 1 by 74 g, 90 g,
and 81 g, with 10-mg, 25-mg, and 100-mg doses of
empagliflozin, respectively. The adverse events ob-
served with empagliflozin included excessive urina-
tion (10.3%), nasopharyngitis (9%), constipation
(9%), and headache (7.7%). The increase in urinary
glucose excretion remained elevated at similar levels
during the 28-day trial period.24
The efficacy and safety of empagliflozin in patients
with type 2 diabetes have been studied in conjunction
with metformin in a 12-week, double-blind, placebo-
controlled trial that compared the results with those
of placebo and open-label sitagliptin 100 mg daily.25
Empagliflozin’s dosing was 1 mg, 5 mg, 10 mg, 25 mg,
and 50 mg daily. The trial demonstrated a significant
reduction of HbA1c with empagliflozin (–0.09 to
–0.56%) compared with placebo (+0.15%). Further-
more, empagliflozin in conjunction with metformin
had significant reductions of blood glucose levels (–2
to –28 mg/dL) compared with placebo (+5 mg/dL;
P <.001), as well as significant benefits of body-weight
reductions (–2.3 to –2.9 kg) compared with placebo
(–1.2 kg; P <.01).
Empagliflozin had similar overall adverse event rates
(29.6%-48.6%) compared with placebo (36.6%) and
sitagliptin (35.2%). Empagliflozin had more urinary tract
infections than placebo (4% vs 2.8%, respectively) and
greater increase in urination (2.5% vs 1.4%, respective-
ly). Genital infections were only reported with empagli-
flozin, at a rate of 4.0%.
456 l American Health & Drug Benefits l www.AHDBonline.com
The once-daily dosing of empagliflozin was well-­
tolerated and was associated with significantly de-
creased levels in HbA1c, decreased fasting blood glu-
cose, and decreased body weight in poorly controlled
patients with type 2 diabetes who had been receiving
metformin monotherapy.25
Empagliflozin was also investigated as an add-on to
pioglitazone with or without metformin in patients with
type 2 diabetes in a 24-week trial.26 A significant reduc-
tion of HbA1c was seen with empagliflozin 10 mg and
25 mg (–0.6% and –0.7%, respectively) compared with
placebo (–0.1%; P <.001). In addition to reductions in
fasting blood glucose levels in this trial, empagliflozin
10 mg and 25 mg was associated with significant weight
loss (–1.62 kg and –1.47 kg, respectively) compared with
increased weight (+0.34 kg; P <.001) with placebo. Sig-
nificantly more patients with HbA1c levels of ≥7% had
their HbA1c level reduced to <7 by the end of the trial
with the 10-mg (23.8%) and 25-mg (30%) doses of em-
pagliflozin than with placebo (7.7%; P <.001). Finally,
similar proportions of patients reported adverse events
with empagliflozin (67.3%-71.4%) and with placebo
(72.7%). Confirmed hypoglycemia was reported by 1.2%
to 2.4% of patients receiving empagliflozin and by 1.8%
of patients receiving placebo.26
A special population trial was also conducted to de-
termine the efficacy and tolerability of empagliflozin
monotherapy in Japanese patients with type 2 diabetes
mellitus.27 A total of 547 patients were randomized to
empagliflozin 5 mg, 10 mg, 25 mg, 50 mg, or to placebo
for 12 weeks. Significant reductions in HbA1c levels (ap-
proximately –0.7% to –0.95%), FPG, and body weight
were reported in patients receiving empagliflozin com-
pared with those receiving placebo. More patients with
an HbA1c level of ≥7% at baseline reached an HbA1c
level of <7% with empagliflozin (19%-33%) than with
placebo (3%). Adverse events were reported by 33% to
38% of patients receiving empagliflozin and by 42% of
patients receiving placebo.27
Empagliflozin has been studied with other thera-
pies, such as for lipid control with simvastatin, in
healthy volunteers.28 No serious adverse reactions or
drug–drug interactions were observed when empagli-
flozin was combined with simvastatin. The pharmaco-
kinetic results suggest that no dose adjustments for
either drug are necessary when empagliflozin and
simvastatin are coadministered.28
Ipragliflozin
Ipragliflozin (Suglat) is an SGLT-2 inhibitor that
gained regulatory approval in Japan in January 2014 for
the treatment of patients with type 2 diabetes, but is not
yet approved by the FDA. It is the first SGLT-2 inhibitor
November 2014 l Vol 7, No 8
 New and Emerging Drugs and Targets for Type 2 Diabetes
on the Japanese market, and is currently available only
in Japan.29 Ipragliflozin is available in doses of 25-mg and
50-mg tablets, taken daily, and the dosing can be in-
creased to 100 mg daily if lower doses are inefficient. Ip-
ragliflozin has been studied in 6 phase 3 clinical trials in
Japan and has demonstrated significant reductions in
HbA1c, decreases in FPG, and decreases in total body
weight without many adverse events. All the clinical
trials were conducted in Japan, because the manufacturer
decided to focus on the Asian market for ipragliflozin.29
Because ipragliflozin is still not available in the United
States, and for lack of space, details of the trials are not
included in this review.
Tofogliflozin
Tofogliflozin (CSG452) is an investigational, potent,
and highly selective SGLT-2 inhibitor that is currently
in phase 3 clinical trials. It has the highest selectivity
toward SGLT-2 compared with the other SGLT-2 in-
hibitors (canagliflozin, ipragliflozin, empagliflozin, lu-
seogliflozin, and PF-04971729).30 The clinical data pub-
lished on tofogliflozin are currently limited; however,
early reports of tofogliflozin suggest that it is a true
SGLT-2 inhibitor. The SGLTs have several functions in
the body. The inhibition of SGLTs that are not involved
in renal glucose absorption would lead to undesirable
side effects. Therefore, the high selectivity of tofogliflo­
zin to SGLT-2s, if approved by the FDA, is expected to
play an important role in terms of safety.30
Glucagon-Like Peptide-1 Drugs
Incretins are hormones that are secreted by cells in
the small intestine during an oral nutrient load. Gluca-
gon-like peptide-1 (GLP-1) is an incretin that has po-
tent antihyperglycemic effects. In the presence of hyper-
glycemia, GLP-1 causes the release of insulin from the
pancreas, shuts down glucagon secretion, slows down
gastric emptying, and acts on the hypothalamus to in-
crease satiety.31 Currently, 4 GLP-1 agents are approved
by the FDA—exenatide (which also has an extended-­
release version), albiglutide, dulaglutide, and liraglutide.
The first 3 of these GLP-1 drugs recently had significant
marketing changes.
Exenatide Extended-Release Pen
The new exenatide extended-release for injectable
suspension pen (Bydureon) that was approved by the
FDA for the treatment of type 2 diabetes on March 3,
2014, is a prefilled, single-use, once-weekly pen injec-
tor.32 The pen contains the same formulation and dose of
exenatide as the original, single-dose tray that was ap-
proved by the FDA in 2012. It provides the same contin-
uous supply of the drug as the original formulation, but
Vol 7, No 8 l November 2014 www.AHDBonline.com
the new pen is designed to be more user-friendly. Pa-
tients attach the needle, twist the base of the pen to mix
the drug, then tap the pen firmly against the palm of
their hand for 80 times or more, while rotating the pen
until the solution is completely mixed.32 This new pro-
cess is a significant improvement from the manual mix-
ing of the drug in the 2012 version.
Each weekly dose in the pen is made up of micro-
spheres that house exenatide and slowly dissolve over
the span of a week. It requires no titration and can be
administered at any time of the day, with or without
meals. The exenatide extended-release pen improves
glycemic control by reducing fasting and postprandial
glucose concentrations in patients with type 2 diabetes.
The original single-dose tray version of Bydureon has
been shown to provide powerful HbA1c reduction and
weight loss.33 The exenatide extended-release pen aims
to provide an easier method of delivery for patients.
Albiglutide
Albiglutide (Tanzeum) subcutaneous injection is a
long-acting GLP-1 receptor agonist approved by the
FDA in April 2014 as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes
mellitus.34 The recommended dose is 30 mg once weekly
given as a subcutaneous injection in the abdomen, thigh,
or upper arm region. The dose may be increased to 50 mg
once weekly if the glycemic response is inadequate.26
Albiglutide may be administered at any time of day,
without regard to meals. As a once-weekly subcutaneous
injection, it requires fewer injections than short-acting
GLP-1 agonists.34
Clinical results. The clinical efficacy of albiglutide is
demonstrated in a series of phase 3 trials named the
HARMONY series.
HARMONY 2 demonstrated the efficacy of albiglu-
tide as monotherapy in a 52-week, randomized, double-­
blind, placebo-controlled multicenter trial.35 Patients
were randomized to 3 different groups, including (1)
placebo, (2) albiglutide 30 mg weekly, and (3) albiglu-
tide 30 mg weekly titrated to 50 mg weekly at week 12.
The mean patients’ age was 53 years, 55% of patients
were men, the mean duration of diabetes was 4 years, and
the mean baseline eGFR was 84 mL/min/1.73 m2. All 3
groups had approximately 100 patients, with a baseline
HbA1c of approximately 8%.
Albiglutide achieved –0.7% and –0.9% reductions in
HbA1c in the 30-mg and 50-mg groups, respectively,
whereas patients receiving placebo had a 0.2% increase
in HbA1c. A study extension to 3 years revealed a dura-
ble reduction in HbA1c.35
In the longest duration comparative study of albiglu-
tide to date, HARMONY 3 compared the efficacy and
l American Health & Drug Benefits l 457
 CLINICAL
safety of albiglutide versus sitagliptin, glimepiride, and
placebo in patients whose glycemic levels were inade-
quately controlled with metformin.36 At week 104, the
mean difference in HbA1c reduction when albiglutide
was added to metformin was significantly superior to the
comparator treatment: the reduction was –0.9% greater
than in the placebo group (P <.001); –0.4% greater than
in the sitagliptin group (P = .001); and 0.3% greater than
in the glimepiride group (P = .003).36 Weight loss was
also significantly greater (–2.4 kg) in the albiglutide
group than in the glimepiride group (P <.001), but it was
similar to the sitagliptin group (–0.4 kg) and the placebo
group (–0.2 kg).37
Gastrointestinal adverse events during 2 years of ob-
servation across the placebo, sitagliptin, glimepiride, and
albiglutide arms included nausea (11%, 7%, 6%, and
10%, respectively), vomiting (1%, 4%, 4%, and 6%, re-
spectively), and diarrhea (11%, 9%, 9%, and 13%, re-
spectively). There were no reports of severe hypoglyce-
mia in the albiglutide arm.37
The HARMONY 4 study compared the use of albi-
glutide and insulin therapy in patients with diabetes. In
a 52-week, randomized, open-label, noninferiority
study, HARMONY 4 compared albiglutide with insulin
glargine in patients receiving metformin with or with-
out a sulfonylurea.38 Both groups achieved a similar re-
duction in HbA1c (–0.7% in the albiglutide group and
–0.8% in the insulin glargine group), indicating the
noninferiority of albiglutide to insulin glargine. In addi-
tion, patients receiving albiglutide lost weight (–1.1
kg), whereas those receiving insulin glargine gained
weight (+1.6 kg), resulting in a treatment difference of
2.6 kg (P <.001) between the 2 groups.38
Similar results were seen when albiglutide was com-
pared with prandial lispro insulin 3 times daily in pa-
tients using background glargine ≥20 U in a 26-week,
randomized, noninferiority trial. The HbA1c levels
were reduced by –0.82% in the group using albiglutide
versus –0.66% in the group taking lispro insulin, meet-
ing the noninferiority end point of the trial.39 Further-
more, patients receiving albiglutide lost weight (–0.73
kg), whereas those using insulin lispro experienced
weight gain (+0.81 kg).39
Albiglutide has also been studied as an add-on thera-
py to other drugs, including pioglitazone. In HARMO-
NY 1, patients whose glycemic control was inadequate
with pioglitazone, with or without metformin, were
­administered either albiglutide 30 mg or placebo.40 At
the 52-week primary end point, albiglutide combined
with pioglitazone demonstrated a significant reduction
­in HbA1c levels from baseline compared with placebo
(for a difference of –0.8% between the 2 treatments;
­P <.001). Of the patients receiving albiglutide, 44%
458 l American Health & Drug Benefits l www.AHDBonline.com
achieved the HbA1c target of <7% compared with 15%
of patients receiving placebo. Weight changes were not
significantly different between the 2 groups. Adverse re-
actions of nausea and vomiting were comparable be-
tween the albiglutide and the placebo groups, but were
higher with albiglutide than with placebo in diarrhea
(11.3% vs 8.6%, respectively) and injection-site reac-
tions (11.3% vs 7.9%, respectively).40
Finally, as a new member of the GLP-1 drug class, it
is important to compare albiglutide with other drugs in
this class. HARMONY 7 was a 32-week, randomized,
open-label noninferiority phase 3 clinical trial compar-
ing albiglutide with liraglutide in patients with uncon-
trolled type 2 diabetes.41 The results revealed a lower
reduction of HbA1c levels with albiglutide than with li-
raglutide (–0.8% vs –1.0), which did not meet the non-
inferiority upper margin of 0.3% in this trial. In addition,
patients in the albiglutide group had more injection-site
reactions and fewer gastrointestinal events than patients
in the liraglutide group.41
Dulaglutide
The FDA approved dulaglutide (Trulicity) as a
once-weekly subcutaneous injection to improve glycemic
control, along with diet and exercise, in adults with type 2
diabetes on September 18, 2014.42 Dulaglutide is adminis-
tered once weekly, any time of day, independent of meals,
and should be injected subcutaneously in the abdomen,
thigh, or upper arm. The recommended starting dose is
0.75 mg, which can be increased to a 1.5-mg dose for
patients who need additional blood glucose control.42
­
­Dulaglutide has been studied in 6 clinical trials (AWARD
1-6) as a stand-alone therapy and in combination with
other type 2 diabetes therapies, including metformin,
­sulfonylurea, thiazolidinedione, and prandial insulin.42.43
Significant reductions in HbA1c were seen in patients re-
ceiving dulaglutide.43
In AWARD-6, a head-to-head, phase 3, randomized,
noninferiority trial of dulaglutide versus liraglutide in
patients with uncontrolled type 2 diabetes receiving
metformin, the least-squares mean reduction in HbA1c
was –1.42% in the dulaglutide group and –1.36% in the
liraglutide group.44 The mean treatment difference in
HbA1c was –0.06% between the groups, which met the
noninferiority criteria of the trial (margin, 0.4%).44 To
our knowledge, this is the first time a once-weekly GLP-1
agent has achieved a noninferiority status versus a
once-daily GLP-1 drug in a phase 3 clinical trial.
Dulaglutide has also been studied as a monotherapy
versus metformin in patients with uncontrolled type 2
diabetes.45 At 26 weeks, changes from baseline in HbA1c
levels were –0.78%, –0.71%, and –0.56% for dulaglutide
1.5 mg, dulaglutide 0.75 mg, and metformin, respective-
November 2014 l Vol 7, No 8
 New and Emerging Drugs and Targets for Type 2 Diabetes
ly. Nausea, diarrhea, and vomiting were the most com-
mon adverse events and occurred at similar rates in both
the dulaglutide and metformin treatment groups. No se-
vere hypoglycemia was reported.45
New Insulin Agents
Afrezza
Technosphere insulin human (Afrezza) is a recombi-
nant regular human insulin inhalation powder approved
by the FDA in June 2014 for the treatment of type 1 and
type 2 diabetes mellitus. When the insulin is inhaled
through the device, the powder is aerosolized and deliv-
ered to the lung. Afrezza should be administered at each
mealtime and is touted as an alternative to injectable
short-acting insulin.
Clinical results. The pharmacokinetics for the powder
was studied in 11 healthy nonsmokers who were random-
ized to either a dose of single inhalation consisting of 25
U, 50 U, or 100 U of inhaled human insulin or to a fixed
dose of 10 IU of regular human insulin. When comparing
the 2 groups, it was noted that the inhaled insulin
achieved peak concentration approximately 2 hours earli-
er than the regular human insulin. The pharmacokinetics
measured by the area under the curve was found to be
linear with the doses that were studied. No treatment-
related adverse events were reported with the inhaled
human insulin. It was concluded that this inhaled regular
insulin had a more rapid absorption than the subcutane-
ous regular human insulin with linear pharmacokinetics.46
The regular human insulin inhaled powder has been
studied in patients with type 1 and type 2 diabetes. Across
a broad spectrum of diabetes severity, inhaled human in-
sulin was noninferior to active comparators in 2 of 3 trials
and was superior to placebo in HbA1c reduction, as was
demonstrated in 24-week to 52-week clinical trials.47
A total of 334 patients receiving inhaled insulin with
a basal insulin dose of glargine were compared with 343
patients receiving biaspart insulin given twice daily in
patients with type 2 diabetes mellitus.48 The randomized,
multicenter, noninferiority trial compared the treatments
and their changes in HbA1c from baseline to the end of
the 52-week trial. At the end of 52 weeks, the change in
HbA1c with inhaled insulin plus insulin glargine was
–0.68% and was similar and noninferior to that with bi-
aspart insulin (–0.76%). The between-group difference
was 0.07% (the noninferiority margin was 0.4%).
The inhaled insulin group demonstrated fewer adverse
events of mild-to-moderate and severe hypoglycemic events
and significantly less weight gain. The safety profiles of the
drugs were similar, except the inhaled insulin demonstrated
an increase in forced expiratory volume in 1 second (FEV1)
and an increase in the occurrence of cough.48 Changes in
FEV1 do not progress over time with use, and they reverse
Vol 7, No 8 l November 2014 www.AHDBonline.com
with the cessation of the medication.49
The FDA has approved the medication with a box
warning that states that inhaled human insulin may
cause acute bronchospasm and is not recommended for
use by patients with asthma or chronic obstructive pul-
monary disease.50 The most common adverse events,
such as hypoglycemia, are similar to that of short-acting
subcutaneous insulin. Other common side effects include
throat pain or irritation (4.4%) and cough (25.6%).51
Miscellaneous Drugs with a Potential to Regulate
Glucose Dysregulation
Ranolazine
Ranolazine is a novel antiangina drug used in the
treatment of patients with chronic angina, and has also
been shown to lower HbA1c and FPG levels in clinical
trials. Ranolazine inhibits the cardiac late-phase sodium
current during cardiac repolarization, thus improving
sodium-calcium homeostasis and resulting in reduced
myocardial ischemia. In patients with coronary artery
disease and diabetes, ranolazine has been shown to de-
crease HbA1c levels in 2 clinical trials—the Combina-
tion Assessment of Ranolazine in Stable Angina (CARI-
SA) trial52 and the Metabolic Efficiency with Ranolazine
for Less Ischemia in Non-ST-Elevation Acute Coronary
Syndromes-Thrombolysis in Myocardial Infarction 36
(MERLIN-TIMI 36) trial.53
In the CARISA trial, ranolazine was associated with
a statistically significant decline in HbA1c in a dose-­
dependent manner.52 After 12 weeks of treatment with
ranolazine 750 mg or 1000 mg twice daily, the HbA1c
level was reduced by 0.48% (P = .008) and 0.7% (P =
.002) compared with placebo.52 This was further con-
firmed in the MERLIN-­TIMI 36 trial. The double-blind
study included 6560 patients with non–ST-segment el-
evation myocardial infarction acute coronary syndrome
and at least 1 indicator of moderate-to-high risk of a
recurrent ischemic event who were randomized in a 1:1
ratio to ranolazine or to placebo.53 The results showed a
significant reduction in HbA1c with ranolazine in addi-
tion to standard antidiabetic therapy. Ranolazine had a
placebo-adjusted reduction in HbA1c of 0.28% in pa-
tients with an HbA1c of 6% to 8% and by 0.59% in pa-
tients with an HbA1c of 8% to 10%. In addition, ranola-
zine also had a placebo-corrected reduction in FPG of
25.7 mg/dL in patients with an initial FPG of ≥150 to
400 mg/dL and no change in FPG in patients with an
initial FPG of <150 mg/dL.53
The exact mechanism of the reduction of HbA1c with
ranolazine is not known, but experimental models have
suggested that ranolazine increases glucose-stimulated
­insulin secretion in isolated pancreatic islet cells.54 In mice
with streptozotocin-induced diabetes that were treated
l American Health & Drug Benefits l 459
 CLINICAL
with ranolazine, the peak insulin levels were higher during
the oral glucose tolerance test (P <.05), the islet morpholo-
gy appeared healthier, there was higher beta-cell mass, and
there were significantly less apoptotic cells in the pancreas.54
Perhaps the most exciting aspects of these
novel developments in diabetes management
are that the new agents are either weight-
friendly or can induce weight loss, or they
have lower risks for hypoglycemia.
Sevelamer
Many patients with diabetes have concurrent ne-
phropathy. In patients with chronic kidney disease,
sevelamer is used in the management of hyperphos-
phatemia. In a single-center, randomized, crossover,
open-label, intention-to-treat study, sevelamer was
shown to lower HbA1c, total cholesterol, and tri-
glycerides compared with calcium carbonate (P <.05).55
The mechanism behind sevelamer’s effect on HbA1c is
unknown. Sevelamer is also a bile sequestrant in addi-
tion to being a phosphate binder. Thus, sevelamer’s
effect on HbA1c is possibly related to its bile acid–
binding ability.
Colesevelam is a bile sequestrant that is approved by
the FDA for the management of diabetes and has been
shown to lower HbA1c and FPG.56 Sevelamer enhances
the delivery of bile acids to the distal colon via its bile
sequestration capability, thereby promoting GLP-1 re-
lease and modulating HbA1c.57
Conclusions
The problem of diabetes in the United States will
continue to wreak heavy human and financial tolls.
The complications stemming from diabetes will contin-
ue to climb if they are not stemmed. The most common
obstacle a physician faces in clinical practice is patient
adherence. Aside from efficacy and safety, the common
themes seen with these new and emerging drugs are the
convenience of administration and the convenient
dosing frequency.
All the oral drugs discussed in this review article are
once-daily medications, with the exception of ranolazine.
All new injections for diabetes are coming out in a pen
format to improve patient adherence. A new inhaled in-
sulin was found to work more quickly than the injectable
version of the drug, and it has shown to be as effective as
other short-acting subcutaneous insulin agents.
Perhaps the most exciting aspects of these novel
460 l American Health & Drug Benefits l www.AHDBonline.com
developments in diabetes management are that the
new agents are either weight-friendly or can induce
weight loss, or they have lower risks for hypoglycemia.
At a mean total cost of $17,564 per hypoglycemic
episode requiring hospitalization,3 this is a meaningful
improvement to the healthcare system as a whole.
Weight gain in patients with diabetes is counter-
productive, because substances related to insulin resis-
tance are upregulated in obese patients. Weight loss
promotes HbA1c reduction, with a loss of 10% body
weight potentially reducing HbA1c by 0.81%.58 This,
in turn, improves insulin sensitivity potentiating
other therapies.
Postmarketing data are continuing to be collected for
these drugs to address safety concerns. No macrovascular
outcomes data are currently available for the antidiabe-
tes drugs that are mentioned in this review, although
each drug will have to conduct a dedicated CV safety
trial to meet the 2008 updated FDA guidance recom-
mendations. The risks and benefits of each drug should
be appropriately weighed when a diabetes regimen is
chosen for a particular patient. ■
Author Disclosure Statement
Dr Miller, Dr H. Nguyen, Dr Hu, and Dr Lin reported
no conflicts of interest. Dr Q.T. Nguyen is on the Speaker’s
Bureau for AstraZeneca.
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dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized con-
trolled trial (AWARD-3). Diabetes Care. 2014;37:2168-2176.
46. Rave K, Potocka E, Boss AH, et al. Pharmacokinetics and linear exposure of
Afresa compared with the subcutaneous injection of regular human insulin. Diabetes
Obes Metab. 2009;11:715-720. Erratum in: Diabetes Obes Metab. 2009;11:1175.
47. MannKind Corporation. Afrezza (insulin human [rDNA origin]) inhalation
powder: an ultra-rapid acting insulin treatment to improve glycemic control in adult
patients with diabetes mellitus. Briefing document. NDA 022472. April 1, 2014.
www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM390865.pdf. Accessed
September 29, 2014.
48. Rosenstock J, Lorber DL, Gnudi L, et al. Prandial inhaled insulin plus basal in-
sulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre
randomised trial. Lancet. 2010;375:2244-2253.
49. Santos Cavaiola T, Edelman S. Inhaled insulin: a breath of fresh air? A review of
inhaled insulin. Clin Ther. 2014;36:1275-1289.
50. US Food and Drug Administration. FDA approves Afrezza to treat diabetes. Press
release. June 27, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm403122.htm. Accessed September 29, 2014.
51. Afrezza (insulin human) inhalation powder [prescribing information]. Danbury,
CT: MannKind Corporation; June 2014
52. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance
and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42-48.
53. Chisholm JW, Goldfine AB, Dhalla AK, et al. Effect of ranolazine on A1C and
glucose levels in hyperglycemic patients with non-ST elevation acute coronary syn-
drome. Diabetes Care. 2010;33:1163-1168.
54. Ning Y, Zhen W, Fu Z, et al. Ranolazine increases β-cell survival and improves
glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol
Exp Ther. 2011;337:50-58.
55. Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflamma-
tion, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc
Nephrol. 2012;7:934-942.
56. Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride thera-
py in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid
effects. Arch Intern Med. 2008;168:1975-1983.
57. Brønden A, Hansen M, Sonne DP, et al. Sevelamer in a diabetologist’s perspec-
tive: a phosphate-binding resin with glucose-lowering potential. Diabetes Obes
Metab. 2014 Jul 9 [Epub ahead of print].
58. Shantha GP, Kumar AA, Kahan S, Cheskin LJ. Association between glyco-
sylated hemoglobin and intentional weight loss in overweight and obese patients
with type 2 diabetes mellitus: a retrospective cohort study. Diabetes Educ.
2012;38:417-426.
Stakeholder Perspective next page
l American Health & Drug Benefits l 461
 CLINICAL
STAKEHOLDER PERSPECTIVE
Addressing Adherence a Key Challenge in the Management of
Patients with Type 2 Diabetes
By Jeffrey A. Bourret, PharmD, MS, RPh, BCPS, FASHP
Senior Director, North America Medical Affairs, Pfizer Inc, Collegeville, PA
PAYERS: The passage of the Accountable Care Act in
2010 is driving improved accountability for quality through
the establishment of accountable care organizations
(ACOs). ACOs provide incentives for healthcare providers
to improve the quality of care delivered in physicians’ offic-
es, hospitals, and long-term care settings. Concerns about
the impact of diabetes on cost and quality of care are what
drove the development and triple weighting of the Centers
for Medicare & Medicaid Services 5-star quality rating
measures for diabetes,1 which is a top priority for every
health plan, ACO, hospital, and physician practice in the
United States that serves patients with diabetes.
Even with multiple efforts to improve diet and exercise,
pharmacologic treatments continue to be essential to im-
proving the quality of care and minimizing the costs asso-
ciated with the severe complications of type 2 diabetes in
the short term and the long term. In the past, when oral
agents failed in patients with diabetes, the only option was
the initiation of injectable insulin. But the introduction of
new medications that work through different mechanisms
of action, alone or in combination, to control hyperglyce-
mia has changed that approach. In their article, Miller and
colleagues describe some of these new and emerging drugs
and targets for treating type 2 diabetes.2
Clinically meaningful improvements in outcomes will
not be achieved, however, until patient adherence is im-
proved. Adherence is a major problem in patients with
type 2 diabetes. As Miller and colleagues point out, a 2011
study reported that 3.1 million (14.9%) patients with type
2 diabetes did not take their medications.3 Poor adherence
is multifactorial and is impacted by education, income,
location, complex drug regimens, medication side effects,
and patient support systems.
The adverse effects of antidiabetes drugs vary with each
class and include gastrointestinal side effects; weight gain
or loss; and the risk for hypoglycemia, which is one of the
most common causes of costly hospitalizations associated
with medication use in patients with diabetes. In their
article, Miller and colleagues report that the average cost
of a hospitalization episode for hypoglycemia is $17,564.2
Access to a broad choice of medications can aid in
improving adherence through individualized treatment
462 l American Health & Drug Benefits l www.AHDBonline.com
regimens; however, individualizing the treatment regi-
men for a patient with type 2 diabetes is complex. The
choice of medicines must take into account many vari-
ables and patient characteristics, such as comorbidities,
susceptibility to cardiac events, concomitant medica-
tions, the patient’s ability or willingness to self-inject,
the patient’s preference for mode of administration, and
the physician’s experience.
The number of medications available for the treatment
of type 2 diabetes has substantially increased as a result of
the pharmaceutical industry’s innovation and discovery of
new medicines that offer improved efficacy that address
tolerability and adverse effects of previously available
agents, enabling physicians to individualize treatment in
ways that they could not have in the past.
A paradigm shift has occurred in the treatment of
hyperglycemia in patients with diabetes with the intro-
duction of new medicines and an improved understand-
ing of the heterogeneity of diabetes. The current clinical
approach supports individualized treatment that takes
into account a patient’s age, the medication cost, the
medicine’s effect on weight gain or loss, the risk for hy-
poglycemia with individual drugs, and the drugs’ effec-
tiveness in achieving the target blood glucose or hemo-
globin A1c levels.4
The position statement of the American Diabetes Asso-
ciation and the European Association for the Study of Di-
abetes on the management of hyperglycemia in patients
with type 2 diabetes emphasizes that their recommenda-
tions should be considered within the context of the needs,
preferences, and drug tolerance of each patient; the indi-
vidualization of treatment is the cornerstone of success.5
Payers should seek input from experienced endocrinol-
ogists in their pharmacy benefit design to balance cost and
quality in a manner that allows physicians broad access to
medications that are aligned with national treatment
guidelines and include patient shared decision-making to
determine the optimal treatment regimen.
PROVIDERS: Patient-centered care is defined as an
approach to “providing care that is respectful of and re-
sponsive to individual patient preferences, needs, and val-
ues and ensuring that patient values guide all clinical deci-
November 2014 l Vol 7, No 8
 New and Emerging Drugs and Targets for Type 2 Diabetes
STAKEHOLDER PERSPECTIVE Continued
sions.” 6 During the clinical encounter, the patient’s
preferred level of involvement should be gauged and ther-
apeutic choices explored, potentially with the utilization of
decision aids.7 In a shared decision-making approach, clini-
cians and patients act as partners, mutually exchanging
information and deliberating on options to reach a consen-
sus on the therapeutic course of action.8 Strong evidence is
available to support the effectiveness of this approach.9
Most important, engaging patients in their healthcare
decisions may enhance adherence to therapy. It is critical
for healthcare providers to discuss options with patients
and to determine if patients will adhere to the treatments
that are being prescribed for them. For example, if a patient
prefers an oral medication to a self-injectable medicine and
will refuse to fill a prescription or to use a self-injectable
medication, this needs to be determined before the pre-
scription is written and before the patient leaves the office.
Primary nonadherence is defined as patients who do
not fill their first prescription. This has been a long-­
standing problem in medicine, and it is getting more
attention as data become more readily available through
the use of electronic medical records and electronic
prescribing, which can determine if prescriptions writ-
ten by physicians are actually filled.
Primary nonadherence can be reduced if a provider
knows that a patient is unwilling to take a certain medica-
tion at the time of prescribing. If there are managed care
restrictions on access to certain agents, the prior authori-
zation follow-up should reflect this provider–patient dis-
cussion, as well as the patient’s unwillingness to take a
preferred agent; this will assist the physician in gaining
access to a nonpreferred agent to avoid the patient not
Vol 7, No 8 l November 2014 www.AHDBonline.com
receiving treatment, which could lead to poor patient
outcomes and downstream cost implications to payers.
PATIENTS: Ultimately, patients’ own lifestyles and
preferences weigh into their personal decisions regarding
what medications they will take. A core principle of evi-
dence-based medicine is involving patients in decisions
about their treatment, together with their physicians’ as-
sessment of the best available evidence from the medical
literature, their clinical experience, and the patients’ de-
sires and behavioral inclinations.10 Patients have a respon-
sibility to ask about available treatment options and to
provide honest feedback to their healthcare providers re-
garding which treatment they are willing to adhere to. ■
1. Academy of Managed Care Pharmacy; American Pharmacy Association. Medicare
star ratings: stakeholder proceedings on community pharmacy and managed care
partnerships in quality. J Am Pharm Assoc (2003). 2014;54:228-240.
2. Miller BR, Nguyen H, Hu CJ, et al. New and emerging drugs and targets for type
2 diabetes: reviewing the evidence. Am Health Drug Benefits. 2014;7:451-462.
3. Centers for Disease Control and Prevention. Number (in millions) of adults with dia-
betes by diabetes medication status, United States, 1997-2011. Updated December 7,
2012. www.cdc.gov/diabetes/statistics/meduse/fig1.htm. Accessed September 22, 2014.
4. Weerarathna TP. Individualizing treatment of type 2 diabetes. Sri Lanka J Diabetes
Endocrinol Metab. 2014;4:56-58.
5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type
2 diabetes: a patient-centered approach. Position statement of the American Diabe-
tes Association (ADA) and the European Association for the Study of Diabetes
(EASD). Diabetes Care. 2012;35:1364-1379.
6. Committee on Quality of Health Care in America, Institute of Medicine. Crossing
the Quality Chasm: A New Health System for the 21st Century. Washington, DC:
National Academy Press; 2001.
7. Mullan RJ, Montori VM, Shah ND, et al. The diabetes mellitus medication choice
decision aid: a randomized trial. Arch Intern Med. 2009;169:1560-1568.
8. Tsapas A, Matthews DR. N of 1 trials in diabetes: making individual therapeutic
decisions. Diabetologia. 2008;51:921-925.
9. Shah ND, Mullan RJ, Breslin M, et al. Translating comparative effectiveness into
practice: the case of diabetes medications. Med Care. 2010;48(6 suppl):S153-S158.
10. Guyatt GH, Haynes RB, Jaeschke RZ, et al; for the Evidence-Based Medicine
Working Group. Users’ Guides to the Medical Literature: XXV. Evidence-based
medicine: principles for applying the Users’ Guides to patient care. JAMA.
2000;284:1290-1296.
VISIT OUR ENHANCED
USER-FRIENDLY WEBSITE
American Health & Drug Benefits is an
independent, peer-reviewed journal
founded in 2008
Examines drug and other healthcare
intervention value for payers, purchasers,
providers, patients, manufacturers, regulators,
distributors, and evaluators
Provides up-to-date information on new
drugs approved by the FDA
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l American Health & Drug Benefits l 463