Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Diabetes type 2 management: what are the

differences between DPP-4 inhibitors and how do
you choose?

Kashif M. Munir & Elizabeth M. Lamos

To cite this article: Kashif M. Munir & Elizabeth M. Lamos (2017) Diabetes type 2 management:
what are the differences between DPP-4 inhibitors and how do you choose?, Expert Opinion on
Pharmacotherapy, 18:9, 839-841, DOI: 10.1080/14656566.2017.1323878

To link to this article: https://doi.org/10.1080/14656566.2017.1323878

Accepted author version posted online: 28

Apr 2017.
Published online: 04 May 2017.

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EXPERT OPINION ON PHARMACOTHERAPY, 2017
VOL. 18, NO. 9, 839–841
https://doi.org/10.1080/14656566.2017.1323878

EDITORIAL

Diabetes type 2 management: what are the differences between DPP-4 inhibitors
and how do you choose?
Kashif M. Munir and Elizabeth M. Lamos
Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA

ARTICLE HISTORY Received 30 March 2017; Accepted 24 April 2017

KEYWORDS Alogliptin; dipeptidyl peptidase −4 inhibitor; linagliptin; saxagliptin; sitagliptin

1. Introduction monotherapy and ~0.6–1.1% when used in combination with

metformin, depending on agent, dose of therapy, and starting
Type 2 diabetes mellitus (T2DM) is characterized by progres-
HbA1c [4]. Gliptins are non-inferior to metformin and sulfony-
sive beta cell dysfunction and insulin resistance.
lurea monotherapy in glycemic control, but improve glycemic
Pharmacotherapy to treat dysregulated glucose metabolism
control when added to metformin, sulfonylurea, or insulin.
focuses on augmenting the insulin response to hyperglycemia,
There are no direct comparison trials of DPP-4 inhibitors. In
improving insulin sensitivity or altering glucose disposal
indirect comparison, sitagliptin was non-inferior to saxagliptin
through the gut or urine. Dipeptidyl-peptidase-4 (DPP-4) inhi-
in mean change in HbA1c when both were added on to
bitors or ‘gliptins’ block the inactivation of glucagon-like pep-
background metformin [5]. In a meta-analysis comparing vil-
tide-1 (GLP-1), which stimulates glucose-dependent insulin
dagliptin to sitagliptin, both demonstrated similar reductions
secretion and inhibits glucagon secretion. Additionally, gastric
in HbA1c, fasting plasma glucose and post-prandial glucose,
emptying is slowed, satiety is improved, and food intake is
but the magnitude of glycemic changes decreased more sig-
reduced [1]. These effects are more prominent with use of
nificantly with vildagliptin therapy [6].
GLP-1 receptor agonists.
Answering the question of which DPP-4 inhibitor to utilize
There are five DPP-4 inhibitors, including alogliptin, lina-
relies more on balancing patient characteristics and side-effect
gliptin, saxagliptin, and sitagliptin in the United States and
profile rather than significant differences in glycemic efficacy.
Europe and vildagliptin which is only available in Europe
DPP-4 inhibitors appear to produce more robust glycemic
(Table 1). This class of anti-hyperglycemic therapy is orally
control the higher the starting HbA1c; thus, initiation of ther-
administered once per day with the exception of vildagliptin
apy is likely to have a more significant effect on an individual
which is dosed twice per day. DPP-4 inhibitors can be taken
with a starting HbA1c of 10% rather than 8.0%. If the treat-
without regard to food.
ment goal is <7%, and the patient is uncontrolled on metfor-
DPP-4 inhibitors are not recommended for use as initial mono-
min with an HbA1c of 8.0%, it may be unlikely that the
therapy for T2DM treatment [3]. They are most commonly pre-
addition of a gliptin will achieve the target HbA1c <7%.
scribed in combination with lifestyle modification and metformin,
Thus, sometimes the decision is less about which gliptin to
sulfonylureas, thiazolidinediones, and/or basal insulin, but select
choose and rather whether to choose a gliptin at all.
patients intolerant to metformin have been successfully treated
There is minimal risk of hypoglycemia when DPP-4 inhibi-
with DPP-4 inhibitor monotherapy. There are a number of combi-
tors are used as monotherapy or in combination with metfor-
nation products available, including gliptin–metformin and glip-
min [7]. Hypoglycemia risk increases when gliptins are used in
tin–sodium glucose transporter-2 inhibitor products.
combination with sulfonylureas or insulin. Interestingly, in a
There is a paucity of direct head-to-head studies of DPP-4
study of vildagliptin added to insulin therapy, significantly
inhibitors. Most comparisons are indirect. Evaluation of singu-
lower rates of hypoglycemia, in the setting of superior glyce-
lar beneficial effects have been published, such as effects on
mic improvement, were observed in patients treated with
cholesterol, and attributed to one particular drug within the
vildagliptin compared to those receiving placebo [8].
class; however, it is reasonable to consider that these effects
may be applicable across the class of medications.
2.2. Cardiovascular parameters
2. Comparison between DPP-4 inhibitors Weight gain is generally neutral across the DPP-4 inhibitor
class [7]. There appears to be a modest/neutral effect on lipids,
2.1. Glycemic control
with a general trend toward improved triglyceride levels [9].
In general, the HbA1c reduction associated with this class of Systolic blood pressure reduction is very modest and compar-
therapy demonstrates a reduction ~0.5–1% when used as able within the class [9].

CONTACT Elizabeth M. Lamos elamos@som.umaryland.edu Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of
Maryland School of Medicine, 827 Linden Ave, 2nd Floor, Baltimore, MD 21201, USA
© 2017 Informa UK Limited, trading as Taylor & Francis Group
840 K. M. MUNIR AND E. M. LAMOS
An increased risk for hospitalization for heart failure was asso-
ciated with saxagliptin use [10], but this adverse signal was not
found in similarly designed trials of alogliptin, vildagliptin, linaglip-
tin, and sitagliptin. The significance of the increased risk for hospi-
talization for heart failure with saxagliptin is poorly understood. A
large meta-analysis demonstrated a small but significant increased
risk of hospitalization for heart failure in gliptin-treated versus
placebo-treated individuals, but this conclusion was tempered by
the short duration of the studies and low quality of evidence [11].
The United States Food and Drug Administration (FDA) actually
issued a formal safety warning regarding the association of heart
failure with DPP-4 inhibitors saxagliptin and alogliptin based on
their assessment of the cardiovascular trials in 2016. Risk for heart
failure hospitalization may be associated with factors such as pre-
existing cardiovascular disease, prior heart failure, and chronic
kidney disease (CKD).
2.3. Comorbid conditions
The gliptins are generally safe in renal dysfunction; however, alo-
gliptin, saxagliptin, and sitagliptin require dose adjustment for
renal impairment [2,3]. Linagliptin and saxagliptin do not require
dose adjustment for liver dysfunction. Alogliptin and sitagliptin
also do not require dose adjustment for mild or moderate liver
dysfunction but should be used with caution in severe liver
impairment.
2.4. Drug–drug interactions
With a few exceptions, there are no significant drug–drug inter-
actions when gliptins are co-administered with a variety of com-
monly prescribed medications, such as statins [12]. Because
CYPT3A4/5 metabolizes saxagliptin to its primary metabolite,
strong CYP3A4/5 inhibitors, such as diltiazem, ketoconazole,
and ritonavir, may increase saxagliptin exposure. One should
consider dose reduction. P-glycoprotein and CYP3A4 inducers,
such as rifampicin, may decrease the efficacy of linagliptin.
2.5. Adverse effects
Observational studies and case reports of adverse pancreatitis
outcomes with all DPP-4 inhibitors have driven the concerns
regarding a causal relationship between incretin therapy and
pancreatitis and pancreatic cancer. However, this relationship
remains controversial. In large cohort studies, current use of incre-
tin-based therapy was not associated with an increased risk of
hospitalization for acute pancreatitis [13] or pancreatic cancer [14].
The FDA and the European Medicines Agency continue to monitor
reporting of pancreatic adverse events, and patients with concern-
ing symptoms of pancreatitis, biochemical, or imaging evidence of
pancreatitis should stop DPP-4 therapy. A history of pancreatitis
should be considered a contraindication to incretin therapy.
The FDA released a safety announcement in 2015 which
alerted providers to report severe and persistent joint pain
with use of DPP-4 inhibitors. Sitagliptin was the most fre-
quently reported, followed by saxagliptin>linagliptin/vildaglip-
tin> alogliptin. The recommendation is to stop the DPP-4
inhibitor if there is any suspicion of causation and that
reintroducing the same agent or another in the class was
associated with recurrence of symptoms in some patients [15].
DPP-4 inhibitors have all been associated with hypersensitivity
reactions [16]. Saxagliptin and vildagliptin have both been asso-
ciated with significant skin reactions, but this reaction is considered
relatively rare.
3. Conclusion
DPP-4 inhibitors are one of many options to treat uncontrolled
T2DM. The long-term benefits and durability of glycemic effects
associated with this class of medications remain unclear. Hence,
they are not recommended as initial therapy for treatment of
T2DM. They do appear to be a reasonable second-line add-on
therapy to metformin, especially in situations requiring more
robust HbA1c reduction. DPP-4 inhibitors may be an ideal
choice in individuals at high risk for hypoglycemia (i.e. elderly)
or in whom a weight sparing or oral regimen is preferred.
However, the degree of HbA1c lowering desired must be
taken into account, and the relatively modest glycemic effects
at lower starting HbA1c may temper one’s enthusiasm for
prescribing this class of therapy. Additionally, in high cardiovas-
cular risk patients, the cardiac effects have not fully been eluci-
dated. The risk of hospitalization for heart failure remains poorly
understood, and risk factors such as prior heart failure and CKD
should be considered when prescribing this class of therapy.
4. Expert opinion
Within the DPP-4 inhibitor class of medications, the choice of
which medication to choose is really an assessment of patient
characteristics, comorbid conditions, preference, and insurance
or payer coverage. All of the gliptins are equally expensive com-
pared to metformin and more expensive when compared to other
oral second-line agents such as generic sulfonylureas or pioglita-
zone (Table 1). Reviewing a large medical database, individuals
who initiated saxagliptin had lower overall and diabetes-specific
related medical costs over 1 year of follow-up compared to those
who initiated sitagliptin; however, the mean predicted difference
in diabetes cost was approximately 660.00 USD [17]. However,
individuals who initiated saxagliptin demonstrated better adher-
ence and were less likely to discontinue therapy compared to
those that initiated linagliptin and sitagliptin [18]. In full disclosure,
each of these studies was supported by the manufacturer of
saxagliptin.
The potential for glycemic improvement is essentially uni-
form within the class. Cost and availability aside, linagliptin is
likely to be easily prescribed with one available dose, a once-
daily dosing regimen, and requires no dose adjustment for
renal dysfunction or liver dysfunction.
If interested in targeting the incretin system, one could really
argue that rather than pursue DPP-4 inhibition, utilization of GLP-
1 receptor agonism (GLP-1RA) could provide more robust glyce-
mic effects while maintaining favorable cardiovascular benefits.
In fact, liraglutide-treated patients with T2DM showed a 13%
reduction in death from cardiovascular disease, nonfatal myo-
cardial infarction, and nonfatal stroke compared to placebo [19].
GLP-1 RAs routinely provide more substantial glycemic lowering
effects compared to DPP-4 inhibitors with enhanced effects on
 EXPERT OPINION ON PHARMACOTHERAPY 841

Table 1. Comparison of currently marketed DPP-4 inhibitors.

Dose change in renal Dose change in hepatic 30-day cost of highest mg dose Available in
Drug Brand name ® Dosages dysfunction dysfunction (AWP in USD) [2] combination
Sitagliptin Januvia (Merck) 25 mg Yes Noa 457.20 With metformin
50 mg With simvastatin
100 mg
Saxagliptin Onglyza (AstraZeneca) 2.5 mg Yes Noa 462.17 With metformin
5 mg
Linagliptin Tradjenta (Boehringer 5 mg No No 357.20 With metformin
Ingelheim) With
empagliflozin
Alogliptin Nesina (Takeda 6.25 mg Yes Noa 374.33 With metformin
Pharmaceutical Limited) 12.5 mg With
25 mg pioglitazone
Vildagliptin Galvus (Novartis) 50 mg Yes Not recommended for N/A With metformin
use
AWP: average whole sale price; DPP-4: dipeptidyl-peptidase-4.
a
Mild–moderate dysfunction. Not recommended in severe dysfunction.

satiety and weight loss [3]. Although they do require subcuta-
neous injection, the injection itself is generally well tolerated and
can be provided in as few as a once-weekly injection for conve-
nience. GLP-1 RAs are associated with increased gastrointestinal
side effects compared to DPP-4 inhibitors. The cardiac profile is
reassuring, and durability of effects has been well documented.
Acknowledgment
The authors would like to acknowledge Jazmin Turner, PharmD, for her
assistance in obtaining cost analysis information.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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