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review article Diabetes, Obesity and Metabolism 18: 333–347, 2016.
© 2015 John Wiley & Sons Ltd

ARTICLE
REVIEW
Comparative review of dipeptidyl peptidase-4 inhibitors
and sulphonylureas
C. F. Deacon1 & H. E. Lebovitz2
1 Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark
2 State University of New York Health Science Center, Brooklyn, NY, USA

Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over
the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line
agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side
effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first
compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control
with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been
shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy
for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs
(DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages
and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each
individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.
Keywords: alogliptin, anagliptin, antidiabetic drug, diabetes mellitus, evogliptin, gemigliptin, glibenclamide, gliclazide, glipizide, glimepiride, GLP-1,
glyburide, glycaemic control, incretin, linagliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin, vildagliptin

Date submitted 8 September 2015; date of first decision 13 October 2015; date of final acceptance 18 November 2015

Introduction Since its introduction in the 1950s, metformin has become

the preferred choice for initial pharmacotherapy (together
It is 20 years since the idea of inhibiting dipeptidyl pepti-
with lifestyle intervention) for most patients. Sulphonylureas
dase (DPP)-4 was proposed as a potential new therapy for
(SUs) have traditionally been the next option, based partly
type 2 diabetes (T2DM) [1], and at least 11 DPP-4 inhibitors
on extensive clinical experience with these compounds (also
have now been approved. The rationale behind using DPP-4
stretching back over ∼60 years), and their low costs (like met-
inhibition to treat T2DM is that by inhibiting degradation
formin, generic drugs are widely available); however, DPP-4
of the incretin hormone, glucagon-like peptide-1 (GLP-1),
inhibitors are increasingly being positioned earlier in treatment
its beneficial effects on glucose homeostasis (which include
paradigms, either as monotherapy when metformin is unsuit-
both potentiation of glucose-induced insulin and suppression
able, or as second-line agents once glycaemic control is unsat-
of glucagon secretion [2,3]) will be enhanced [1,4]. This has
isfactory with metformin alone. This is driven partly by their
now been demonstrated in numerous studies, which show
lack of side effects; in particular, their glucose-dependent action
that DPP-4 inhibitors reduce glycated haemoglobin (HbA1c)
is advantageous for individuals where minimizing the risk of
levels with broadly similar efficacy to other oral antidia-
hypoglycaemia is important (e.g. because of their occupations),
betic drugs, but without the adverse effects (hypoglycaemia,
for elderly vulnerable patients or for those already at higher risk
weight gain, gastrointestinal side effects) typically associated
of hypoglycaemia (e.g. those with renal disease). Indeed, sev-
with other agents. DPP-4 inhibitors are now included in
eral guidelines, including consensus statements from the AACE
guidelines and treatment algorithms for controlling hyper-
[6,7] and the Latin American Diabetes Association [8], place
glycaemia in individuals with T2DM (e.g. the American
DPP-4 inhibitors ahead of SUs because of their lower hypogly-
Diabetes Association/European Association for the Study of
caemia risk and weight neutrality.
Diabetes (ADA/EASD) position statement [5], the American
Association of Clinical Endocrinologists/American College
of Endocrinology (AACE/ACE) diabetes algorithm [6,7] and Dipeptidyl Pepitidase-4 Inhibitors
numerous national guidelines). Dipeptidyl pepitidase-4 inhibitors were one of the first classes
of oral antidiabetic drugs to be prospectively designed as
anti-hyperglycaemic agents, in contrast to some of the more tra-
Correspondence to: Carolyn F. Deacon, Department of Biomedical Sciences, University of
Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. ditional agents, whose glucose-lowering effects were discovered
E-mail: deacon@sund.ku.dk serendipitously. The beneficial effects of GLP-1 on 𝛼- and 𝛽-cell
 14631326, 2016, 4, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.12610 by Egyptian National Sti. Network (Enstinet), Wiley Online Library on [06/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
review article DIABETES, OBESITY AND METABOLISM

secretion, 𝛽-cell function, gastric emptying and appetite were Table 1. In vitro selectivity of dipeptidyl peptidase (DPP)-4 inhibitors
well known, while the role of DPP-4 in metabolism of GLP-1 (expressed as fold selectivity relative to selectivity for DPP-4).
was understood, giving the rationale for inhibiting the enzyme
to enhance incretin hormones concentrations and improve glu- QPP/
cose tolerance [1,4]. Drug DPP II PEP FAP𝛼 DPP-8 DPP-9
The first DPP-4 inhibitor, sitagliptin, was launched in 2006, Alogliptin [34] >14 000 >14 000 >14 000 >14 000 >14 000
with new members continuing to be approved (anagliptin, Anagliptin [19] n.r. n.r. n.r. >16 000 >15 000
gemigliptin, teneligliptin in 2012; evogliptin, omarigliptin and Evogliptin [20] >20 000 n.r. >20 000 6 000 6 000
trelagliptin in 2015), and the class is now an established ther- Gemigliptin [21] >25 000 n.r. n.r. 10 560 2 940
apy; five inhibitors are globally available [alogliptin, linagliptin, Linagliptin [34] >100 000 >100 000 89 40 000 >10 000
saxagliptin, sitagliptin, vildagliptin (although vildagliptin Omarigliptin [23] >41 000 >41 000 >41 000 >41 000 >41 000
Saxagliptin [34] >50 000 n.r. >4 000 390 77
is not marketed in the USA/Canada)], while others have a
Sitagliptin [34] >5 550 >5 550 >5 550 >2 660 >5 550
more limited geographic distribution (anagliptin, evogliptin, Teneligliptin [25] n.r. n.r. >11 000 700 1 500
gemigliptin, omarigliptin, teneligliptin, trelagliptin, presently Vildagliptin [34] >100 000 60 000 285 270 32
only available in Japan and/or Korea).
QPP, quiescent cell proline dipeptidase; PEP, prolylendopeptidase; FAP𝛼,
fibroblast activation protein-𝛼; n.r., not reported.
Pharmacokinetics and Pharmacodynamics
Dipeptidyl pepitidase-4 was first described in 1966[9], and by as ‘dissociating slowly’ from the enzyme or having ‘tight
the early 1990s, much was known about its kinetic proper- binding kinetics’. In practice, this means that despite having
ties and substrate specificity [10]. This knowledge provided half-lives of <5 h, saxagliptin can still be used once daily,
the basis for the DPP-4 inhibitor concept [1], and was used while twice-daily administration is sufficient for anagliptin
in developing several DPP-4 inhibitors which were identi- and vildagliptin. Accordingly, despite different pharmacoki-
fied in drug discovery programmes based on structure-activity netic half-lives, direct comparison reveals that saxagliptin,
profiling (e.g. saxagliptin [11] and vildagliptin [12]). At the sitagliptin and vildagliptin give similar peak DPP-4 inhi-
turn of the century, the DPP-4 crystal structure was pub- bition [43]. Trough levels are similar with sitagliptin and
lished [13], and other novel, closely related, members of the vildagliptin, and greater than those of saxagliptin when the
DPP-4 enzyme family were discovered, notably DPP-8 [14] inhibitors are used at their therapeutic doses, but when
and DPP-9 [15]. Some prototype DPP-4 inhibitors had been vildagliptin is used once daily, as recommended when
associated with preclinical toxicities, and it was later sug- co-administered with SU, trough DPP-4 inhibition is markedly
gested that off-target inhibition of DPP-8 and/or -9 may have reduced [43].
been responsible [16]. Although this viewpoint has been ques- The DPP-4 inhibitors also differ in their elimination path-
tioned [17], further optimization resulted in compounds with ways (Table 2), which can influence their clinical usage.
improved selectivity for DPP-4 (alogliptin [18], anagliptin [19], Alogliptin, linagliptin, omarigliptin, sitagliptin and trelagliptin
evogliptin [20], gemigliptin [21], linagliptin [22], omarigliptin are not appreciably metabolized, and are eliminated pre-
[23], sitagliptin [24] and teneligliptin [25]); however, although dominantly unchanged [34,37,39]. Gemigliptin undergoes
differences in enzyme selectivity between DPP-4 inhibitors modest hepatic metabolism to form an active metabolite
clearly exist in in vitro studies (Table 1), there is currently no which makes up ∼10% of the circulating material but which
evidence for adverse effects related to off-target inhibition when is twice as potent as the parent inhibitor [36,44]. In contrast,
they are used therapeutically; numerous analyses of clinical trial the other inhibitors are metabolized more extensively. Hep-
and healthcare provider databases [26–30], and recent large atic metabolism of saxagliptin generates an active metabolite
prospective cardiovascular safety trials including thousands of (5-hydroxy saxagliptin) which is half as potent as the parent
patients [31–33] consistently indicate that DPP-4 inhibitors compound; after administration, ∼25% circulates as intact
have a benign adverse event profile resembling placebo. saxagliptin and ∼50% as the metabolite [34]. Evogliptin
The DPP-4 inhibitors differ widely in their chemistry [35] and teneligliptin [38] are also hepatically metabolized
and pharmacokinetic properties [34] (Table 2). Some have to form major metabolites which account for around half
intrinsically long-half-lives (alogliptin, evogliptin, gemigliptin, of the circulating material. It is not reported whether the
linagliptin, omarigliptin, sitagliptin, teneligliptin and tre- evogliptin metabolite retains any activity, but the teneligliptin
lagliptin) [34–39], giving sustained DPP-4 inhibition which metabolite is active, albeit less potent [45]. Both anagliptin and
allows once-daily or, for omarigliptin and trelagliptin, vildagliptin undergo cytochrome P450 (CYP)-independent
once-weekly dosing. Others have much shorter half-lives hydrolysis. For anagliptin, ∼45% circulates as the parent and
(anagliptin, saxagliptin and vildagliptin) [34,40]; however, <20% as the metabolite [40], but whether the metabolite pos-
whereas the aforementioned inhibitors interact non-covalently sesses inhibitory activity is not reported. Vildagliptin appears
with the enzyme, the cyanopyrrolide moiety in anagliptin, to be more sensitive to hydrolysis; one fifth circulates as the
saxagliptin and vildagliptin promotes covalent binding, result- parent inhibitor, with the resultant metabolite being pharma-
ing in these inhibitors remaining bound to the enzyme for cologically inactive [34]. Recent data indicate that DPP-4 itself
longer than predicted from their short half-lives [41,42]. Sub- accounts for ∼60% of this metabolism of vildagliptin [46]. The
sequent hydrolysis breaks the covalent bonds, releasing the kidneys are important in the final elimination of most of the
drug, and these inhibitors are therefore sometimes described inhibitors, with glomerular filtration and active secretion being

334 Deacon and Lebovitz Volume 18 No. 4 April 2016

 Table 2. Pharmacokinetics and pharmacodynamic characteristics of dipeptidyl peptidase-4 inhibitors.

DPP-4 inhibition
Drug Chemistry Metabolism Elimination route Half-life 24-h post-dose Dose*

Volume 18 No. 4 April 2016

Alogliptin [34,47] Modified Minimal Predominantly renal ∼21 h ∼75% 25 mg once daily
pyrimidinedione
Anagliptin [40] Cyanopyrrolidine Metabolite (hydrolysis) Metabolism (parent) ∼4.5 h (parent) ∼60% 100 mg twice daily
Renal (parent 10 h (metabolite) Can be increased to 200 mg
+ metabolite) twice daily
Evogliptin [20,35] Piperazine derivative Metabolite (hepatic via CYP3A4) Metabolism (parent) ∼33 h >80% 5 mg once daily
Renal (parent
DIABETES, OBESITY AND METABOLISM

+ metabolite)
Gemigliptin [36,44] 𝛽-amino acid based Active metabolite (2x potency of Metabolism (parent) ∼30 h ∼70% 50 mg once daily
(pyrimidinopiperidine parent) (hepatic via CYP 3A4) Renal (parent
derivative) + metabolite)
Linagliptin [34,49] Methyl xanthine Minimal Predominantly biliary ∼12 (effective) >80% 5 mg once daily
derivative (<6% renal) >100 h (terminal)
Omarigliptin [37,51] Tetrahydropyran Minimal Predominantly renal ∼63 h >95% 25 mg once weekly
analogue (steady-state
after 2–3 weeks)
Saxagliptin [34,50] Cyanopyrrolidine Active metabolite ( 1∕2 potency of Metabolism (parent) ∼2 1∕2 h (parent) ∼70% 5 mg once daily
parent) (hepatic via Renal (parent ∼3 h (metabolite)
CYP3A4/5) + metabolite)
Sitagliptin [34,52] 𝛽-amino acid based Minimal Predominantly renal ∼12 1∕2 h >80% 100 mg once daily
(triazolopiperazine
derivative)
Teneligliptin [38,45] L-prolylthiazolidine Active metabolite (hepatic via Metabolism (parent) ∼20 h (parent) >60% 20 mg once daily
CYP3A4 and FMO3) Renal (parent ∼10 h (metabolite) Can be increased to 40 mg
+ metabolite) once daily
Trelagliptin [39] Pyrimidinedione-based Minimal (hepatic, via CYP 2D6) Predominantly renal 54 h Average inhibition 100 mg once weekly
77%
Vildagliptin [34,55] Cyanopyrrolidine Inactive metabolite Metabolism (parent) ∼2 h <40% (∼80% 12 h 50 mg twice daily
(CYP-independent hydrolysis) Renal (parent post-dose)
+ metabolite)

CYP, cytochrome P450; DPP, dipeptidyl peptidase; FMO, flavine-containing mono-oxygenase.

*Dose may vary in some countries.

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review article
involved. Compounds such as alogliptin and sitagliptin rely
almost exclusively on the kidneys for clearance of the active
inhibitor molecules, whereas, as discussed above, metabolism
is involved for several of the other compounds, although
ultimately, both parent and metabolite are still predominantly
cleared renally [34–38,40]. In contrast, the main elimination
route for linagliptin is biliary excretion; at its therapeutic dose,
linagliptin is mostly protein-bound, which minimizes its renal
clearance (to <6%) [34].
These different clearance mechanisms influence, to some
extent, the way in which different DPP-4 inhibitors are used
therapeutically [35,47–55]. All can be used in subjects with
renal impairment, but declining renal function will increase
exposure to those drugs which are eliminated primarily by the
kidneys; thus, to maintain plasma inhibitor concentrations at
similar levels to those in subjects with normal renal function
requires larger dose reductions for alogliptin and sitagliptin
than for inhibitors, such as saxagliptin and vildagliptin, whose
clearance also involves metabolism (Table 3). For linagliptin,
whose clearance is largely independent of the kidney, expo-
sure is unaffected by changes in renal function and no dose
adjustment is necessary. Accordingly, prescribing information
for renally eliminated inhibitors recommends monitoring renal
function to allow appropriate dose selection, although this
should not be regarded as a distinguishing feature, because
renal function should be monitored routinely as a part of stan-
dard care for all patients [56]. It is worth mentioning that dose
reductions are not for safety reasons, but are based solely on
pharmacokinetics, with a lower clearance simply meaning that
less drug is needed to reach the same plasma concentration.
Nevertheless, it is doubtful that any accumulation would lead to
unfavourable outcomes if normal therapeutic doses were inad-
vertently used in subjects with impaired renal function because
of the wide therapeutic window. Moreover, adverse effects are
unlikely to occur based on the mechanism of action, since the
DPP-4 inhibitor itself has no direct effects on glucose home-
ostasis. Rather, effects are secondary to inhibition of DPP-4,
and because the enzyme is already maximally inhibited, any
increased exposure to the drug will have no further effect.
Indeed, a number of safety analyses and large clinical trials in
patients with T2DM and kidney disease, including end-stage
renal disease and those undergoing dialysis, all indicate that
DPP-4 inhibitors are well tolerated [57].
Most currently available DPP-4 inhibitors are suitable for
patients with mild/moderate liver insufficiency, although rec-
ommendations for their use in severe hepatic impairment vary
(Table 3), largely because of relatively limited clinical expe-
rience in such patients. Although saxagliptin is metabolized
by the liver, even severe hepatic impairment only modestly
increases exposure to the drug, most likely because of the kid-
neys’ role in the final elimination pathway [58]. Also notewor-
thy, given its biliary route of elimination, hepatic impairment
does not alter exposure to linagliptin in a clinically meaningful
way. It has been suggested that the biliary excretion pathway is
largely independent of the liver’s metabolizing function, mean-
ing that even patients with severe hepatic impairment probably
retain sufficient residual hepatic function to maintain elimi-
nation of linagliptin and prevent its accumulation [59]. Most
336 Deacon and Lebovitz
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DIABETES, OBESITY AND METABOLISM
DPP-4 inhibitors can therefore be used at the normal thera-
peutic dose in subjects with hepatic impairment. An associa-
tion between vildagliptin and elevated liver enzymes has been
reported, but despite this not appearing to be associated with
any increase in actual hepatic adverse effects [60], vildagliptin
is currently contraindicated in subjects with any degree of hep-
atic impairment, including those with pretreatment elevated
transaminase levels [55].
Drug–drug interactions between DPP-4 inhibitors and
other medications are minimal and, for most combinations,
do not necessitate dose adjustment of either agent; however,
because of its hepatic metabolism, exposure to saxagliptin can
be increased if used concomitantly with strong CYP3A4/5
inhibitors (Table 3), so that dose reduction of saxagliptin
is recommended [50]. Gemigliptin also undergoes hepatic
metabolism by CYP3A4, and dose adjustment may be neces-
sary when used with drugs which alter CYP3A4 activity [44].
Although linagliptin is only minimally metabolized, expo-
sure may be reduced to sub-therapeutic levels if linagliptin
is co-administered with CYP3A4 inducers (e.g. rifampicin),
which may reduce maximum efficacy [49].
Efficacy
The therapeutic effects of DPP-4 inhibitors are not attributable
to direct actions of the drugs themselves at target tissues,
but are mediated by enhanced levels of the substrates they
protect, with GLP-1 probably being the most important for
the anti-hyperglycaemic effects [3]; thus, it follows that if
DPP-4 activity is inhibited to a similar extent, the efficacy
of DPP-4 inhibitors should also be similar, and accordingly,
meta-analyses reveal no major differences between them with
regard to improvements in glycaemic control [61]. A few large
direct head-to-head comparisons (duration ≥18 weeks) have
shown non-inferiority for HbA1c -lowering for anagliptin [62],
gemigliptin [63] and saxagliptin [64] compared with sitagliptin
as add-on to metformin, although in the latter study, effects of
sitagliptin on fasting plasma glucose appeared to be modestly
greater than those of saxagliptin (95% confidence interval
excluded zero)[64]; whether this might be related to differ-
ences in the extent of DPP-4 inhibition seen 24 h post-dose
[43] requires further investigation. Sitagliptin and vildagliptin
had similar effects on glucose homeostasis in several small
12-week studies [65–67], with similar conclusions being drawn
from a larger 24-week study in subjects with T2DM and severe
renal impairment [68]. Non-inferiority for HbA1c-lowering
efficacy has also been shown in 24-week studies comparing
once-daily alogliptin with once-weekly trelagliptin [69], and
sitagliptin with the once-weekly compound omarigliptin [70].
It remains to be established whether once-weekly dosing may
help improve patient compliance and potentially give improved
glycaemic control in the ‘real-world’ setting.
Safety
In general, DPP-4 inhibitors have good tolerability, with
placebo-like adverse event profiles [30]. Thanks to their
glucose-dependent insulinotropic and glucagonostatic effects,
the frequency and severity of hypoglycaemia is low, particularly
Volume 18 No. 4 April 2016
 Table 3. Prescribing characteristics of commonly used dipeptidyl peptidase-4 inhibitors (data taken from prescribing information of the individual inhibitors; precise indications may vary by country).

Use in renal impairment Use in hepatic impairment

Renal Moderate
function Mild (CrCl ≥30- Severe/ESRD Liver function Use with

Volume 18 No. 4 April 2016

Drug monitoring (CrCl ≥50 ml/min) <50 ml/min) (CrCl <30 ml/min) monitoring Mild/moderate Severe§ other drugs†
Alogliptin [47] Yes Yes Yes, with dose adjustment Yes, with dose adjustment No Yes Not recom- —
(12.5 mg once daily) (6.25 mg once daily) mended
Anagliptin [48] (Yes) Yes Yes Yes, with dose reduction — Yes Yes —
(100 mg once daily)
Evogliptin [35] No Yes Yes Yes — — — —
Gemigliptin Yes Yes Yes, with caution Yes, with caution — Presently not Presently not May require dose
DIABETES, OBESITY AND METABOLISM

recom- recom- reduction when used

mended mended with drugs which alter
CYP3A4 activity
Linagliptin [49] No Yes Yes Yes No Yes Yes Efficacy may be reduced if
used with CYP3A4
inducer (e.g. rifampin)
Omarigliptin [50] (Yes) Yes Yes Yes, with care; dose No Yes Yes —
adjustment (12.5 mg once
weekly)
Saxagliptin [51] Yes Yes Yes, with dose adjustment Yes, with dose adjustment No Yes Yes Dose reduction (2.5 mg
(2.5 mg once daily) (2.5 mg once daily) once daily) when used
with strong CYP3A4/5
inhibitors (e.g.
ketoconazole,
ritonavir)
Sitagliptin [52] Yes Yes Yes, with dose adjustment Yes, with dose adjustment No Yes Not studied —
(50 mg once daily) (25 mg once daily)
Teneligliptin [53] No Yes Yes Yes — Yes Yes, with care —
Trelagliptin [54] Yes Yes Yes, with dose reduction No — Yes Yes —
(50 mg once weekly)
Vildagliptin [55] Yes Yes Yes, with dose adjustment Yes, with dose adjustment Yes No* No* Dose reduction (50 mg
(50 mg once daily) (50 mg once daily) once daily) when used
with sulphonylurea

CrCl, creatinine clearance; CYP, cytochrome P450; ESRD, end-stage renal disease; (Yes), not specifically recommended, but will be required to allow for appropriate dose selection.
*Including those with transaminase levels ≥3 times upper limit of normal.
†Dose reduction of sulphonylureas or insulin may be recommended when used together with a dipeptidyl peptidase-4 inhibitor.
§Studies in severe hepatic impairment are lacking.

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review article
when they are used in monotherapy or in combination with
other agents which are not known to provoke hypoglycaemia
(e.g. metformin and thiazolidinediones) [30]; however, when
used with SUs or insulin, the risk of hypoglycaemia may be
increased because of the inherent glucose-lowering properties
of these other agents, and accordingly, prescribing information
recommends reducing SU or insulin doses in this situation
[47–55]. When vildagliptin is used concomitantly with SU, the
vildagliptin dose should also be halved to 50 mg, administered
in the morning [55]. As with any drug, however, occasional
findings and isolated post-marketing observations occur. These
have focused primarily on pancreatic safety and, more recently,
on hospitalization for heart failure.
Regarding pancreatic safety, there has been much debate
concerning acute pancreatitis with incretin-based therapies,
including DPP-4 inhibitors, and although some conflicting
opinions remain, the balance of data does not appear to indicate
a significantly increased incidence [71]. Regulatory authorities
in the USA and the European Union have carried out inde-
pendent reviews of all data [72], finding no evidence to sup-
port a causal relationship between incretin therapies and pan-
creatitis, while major diabetes societies (the ADA, EASD and
International Diabetes Federation) have not modified current
treatment recommendations [73]. Pancreatitis and pancreatic
cancer were included as adjudicated events in the large cardio-
vascular safety trials with incretin therapies, which also had
longer follow-up than most phase III studies. Recent results
from the first three trials with DPP-4 inhibitors confirmed the
low incidence of acute pancreatitis; there were, however, small
non-statistically significant imbalances in the number of events,
being numerically higher with DPP-4 inhibitors than placebo
[31,33,74]. Event rates for pancreatic cancer were even lower,
and numerically lower in DPP-4 inhibitor recipients [31,33,74].
A pooled analysis of phase III studies and the first two of these
safety trials confirmed the low event rate for acute pancreatitis
(1.3 vs. 1.2 events per 1000 patient-years of exposure for DPP-4
inhibitors and comparators, respectively)[75]. It cannot, how-
ever, be fully excluded that a minor increase in the incidence of
acute pancreatitis may exist in susceptible patients, albeit that
the absolute risk is small, and should be evaluated for the indi-
vidual patient based on a risk–benefit judgement.
The incretin-based therapies are probably the first classes of
antihyperglycaemic therapies to undergo comprehensive inves-
tigation of their cardiovascular safety, with large safety outcome
trials underway or completed: the EXAMINE (NCT00968708;
alogliptin), CARMELINA (NCT01897532; linagliptin),
OMNEON (NCT01703208; omarigliptin), SAVOR-TIMI
(NCT01107886; saxagliptin) and TECOS (NCT00790205;
sitagliptin) trials compare DPP-4 inhibition against placebo
and CAROLINA (NCT01243424; linagliptin) with glimepiride
as the active comparator. There are no large cardiovascular
outcome trials with inhibitors, including vildagliptin, which
are not, or will not, be marketed in the USA. The outcome trials
were designed to examine cardiovascular safety, rather than
cardiovascular efficacy; in other words, they seek to show that
cardiovascular adverse events are not higher when compared
with the comparator (i.e. non-inferiority) in the absence of
any difference in glycaemic control, with both arms in the
338 Deacon and Lebovitz
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DIABETES, OBESITY AND METABOLISM
trials being treated to the same glycaemic targets. Reassuringly,
the first three to report their results [the EXAMINE (5400
patients with recent acute coronary syndrome, mean follow-up
1.5 years), SAVOR-TIMI (16 500 patients with pre-existing
cardiovascular disease or multiple risk factors, mean follow-up
2.1 years) and TECOS (14 600 patients with established cardio-
vascular disease, mean follow-up 3.0 years) trials] all met their
primary endpoints, showing conclusively that major adverse
cardiovascular events were not higher in number [31–33]. In
contrast to earlier pooled safety analyses and meta-analyses,
however, which suggested a potential risk reduction [76], there
was no indication of cardiovascular benefit associated with
DPP-4 inhibitors treatment in the EXAMINE, SAVOR-TIMI
or TECOS trials [31–33]. Differences in patient populations,
with phase III studies generally including younger subjects at
lower cardiovascular risk than those recruited to the cardiovas-
cular safety trials, together with the fact that subjects in both
arms of the cardiovascular safety trials were well treated with
respect to their comorbidities (75–90% on statins, aspirin and
antihypertensive medications) provide the most likely expla-
nations for this difference. Unexpectedly, however, saxagliptin
was associated with a small, but statistically significant increase
in hospitalization for heart failure (one component of the sec-
ondary endpoint) compared with placebo (absolute incidence,
3.5 vs 2.8%; relative risk 27%), although this was not associated
with any increase in mortality [32]. This increased risk of
hospitalization with saxagliptin was more evident during the
first 12 months of therapy, and was greater in those patients at
higher risk of heart failure; i.e. those with pre-existing heart
failure, elevated baseline B-type natriuretic peptide levels or
chronic kidney disease [77]. A retrospective post hoc analysis
of the EXAMINE data showed a similar, albeit non-significant,
trend (3.1 vs 2.9%), but alogliptin was not associated with
any increase in new hospital admissions for heart failure or
with poorer outcomes for patients with pre-existing heart
failure [78]. There was no indication of any increase in heart
failure-related hospitalizations in TECOS, with the incidence
being identical in both arms (3.1%; hazard ratio of 1.00) [33].
Currently, there are no plausible mechanistic explanations for
the increased incidence observed in the SAVOR-TIMI trial. It
seems unlikely to be causally related to inhibition of DPP-4 per
se, given the results of the EXAMINE and TECOS trials, both
of which used highly selective DPP-4 inhibitors (Table 1) and
may simply be a chance finding; however, the possibility cannot
be fully excluded that it could be related to differences in the
recruited patients between trials, or to some property of the
saxagliptin molecule. Further studies, also including patients
at high cardiovascular risk with a history of poor glycaemic
control, are required to explore these possibilities.
Sulphonylureas
Unlike DPP-4 inhibitors, which were rationally designed, the
SU effects on glucose homeostasis were discovered serendip-
itously, and it required >50 years to elucidate their mecha-
nism of action. Chance observations in the early 1940s, that
sulphonamide antibiotics caused symptoms typically associ-
ated with hypoglycaemia, initiated research into the effect
Volume 18 No. 4 April 2016

DIABETES, OBESITY AND METABOLISM
Table 4. Characteristics of commonly used sulphonylureas.
Elimination
Drug Half-life Metabolites route
Glibenclamide/ 8–10 h Active 50% bile, 50%
Glyburide [80,87] renal
Gliclazide [80,88] 10–12 h Inactive Predominantly
renal
Glimepiride [80,89] 5–8 h Active Predominantly
renal
Glipizide [80,90] 2–4 h Inactive Predominantly
renal
ESRD, end-stage renal disease.
of these compounds on glucose regulation [79], and ulti-
mately led to the development of SU drugs. First generation
SUs (e.g. tolbutamide and chlorpropamide), introduced dur-
ing the early 1960s, are now infrequently used in current clin-
ical practice [80]. They were followed by second generation
SUs [e.g. glibenclamide (glyburide in the USA), glipizide, gli-
clazide and glimepiride] in the late 1960s/1970s and 1980s [80].
Just as DPP-4 inhibitors are a heterogeneous group, so too
do SUs vary in their pharmacokinetic and pharmacodynamic
characteristics [80].
Sulphonylyreas work by binding to the sulphonylurea
receptor (SUR)-1 subunit of pancreatic 𝛽-cell ATP-sensitive
potassium (KATP ) channels, leading to their closure; the
resultant membrane depolarization opens voltage-dependent
calcium channels, causing intracellular calcium concentrations
to increase, with subsequent release of insulin [81,82]. KATP
channels are present in many other tissues, such as neurons,
myocardium and vascular smooth muscle cells [83]. They
are physiologically regulated by the ATP/ADP ratio through
nucleotide binding sites on the KATP channels [82]. SUR
subunits exist in different isoforms (SUR-1, SUR-2A and
SUR-2B) depending on the tissue, with different isoforms
having different binding affinities for SU drugs [83]; this affects
whether a particular SU will have any extra-pancreatic effects.
SUR-1, which is present in pancreatic 𝛽-cells and neurons,
has two unique binding sites, one of which recognizes the
SU moiety and another the meglitinide moiety [84]. Bind-
ing to either site will close the channel which, in pancreatic
𝛽-cells, increases insulin secretion. Some SUs bind to the SU
site (glipizide and gliclazide), some to the meglitinide site
(repaglinide), and some to both sites (glibenclamide/glyburide
and glimepiride)[85]. SUR-2A and SUR-2B have significantly
lower binding affinities for SU than SUR-1 [80]. The char-
acteristics of the SU structure and the affinity of the SUR
binding sites thus determine the activity and side effects of
each SU drug.
Pharmacokinetics and Pharmacodynamics
Sulphonylureas are absorbed rapidly, although this can be
slowed by formulations that delay their release (e.g. gli-
clazide modified-release). All SUs are metabolized by the
liver through oxidative pathways involving CYP450 enzymes
and glucuronidation. For some (glibenclamide/glyburide and
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review article
Duration Exposure in renal Use in renal Use in
of action impairment impairment ESRD + dialysis
Long (12 to >24 h) Increased Yes if GFR No
≥60 ml/min
Intermediate No change Yes with caution Yes with
(12–24 h) caution
Intermediate Increased Yes if GFR No
(12–24 h) ≥60 ml/min
Short (<12–24 h) No change Yes Yes
glimepiride), the metabolites retain hypoglycaemic activity,
while for others (glipizide and gliclazide) they have little or
no hypoglycaemic activity [86] (Table 4). The duration of SU
action therefore varies not only with the rapidity of absorption,
but also with the rate of hepatic metabolism and the hypogly-
caemic activity of the metabolites. Hypoglycaemic effects are
increased in significant hepatic impairment, and can be either
increased or decreased by drugs that modify CYP450 enzymes.
The kidney is important for final elimination of both parent
and metabolite molecules, and renal impairment increases the
hypoglycaemic effects of SUs, particularly those with active
metabolites [80,86]. Accordingly, SUs are contraindicated in
patients with severe hepatic insufficiency, and used with great
caution in patients with moderate to severe renal impairment
[80,87–90]. SUs are normally extensively protein-bound, so
the concomitant use of other drugs which displace them
from plasma proteins will also increase their hypoglycaemic
effects [80,86]. Moreover, co-administered medications which
themselves possess inherent effects on glucose homeostasis by,
for example, affecting gluconeogenesis, insulin secretion or
counter-regulatory mechanisms, will either enhance or reduce
SU efficacy [86]. Accordingly, the risk of hypoglycaemia can
be increased when SUs are used together with drugs such as
salicylates, warfarin, monoamine oxidase inhibitors and alco-
hol, while with glucocorticoids and 𝛽-2 adrenergic agonists,
hyperglycaemia may result [80].
Efficacy
The effect of SUs is the result of the timing and magnitude of
their insulin secretion and its independence on ambient glu-
cose concentrations. They do not correct the delay in first-phase
insulin secretion, but primarily increase second-phase insulin
secretion [80]. This, plus the independence of their stimulation
of insulin secretion on glucose concentrations, are the cause of
the frequently associated hypoglycaemia and weight gain. The
intrinsic activity of each SU differs depending on the binding
characteristics of each to the SUR-1 isoform [84,91]. Therapeu-
tically, this is compensated for by increasing the dose admin-
istered. Long-acting SUs with high binding affinities, such as
glibenclamide/glyburide and glimepiride, are administered 1
to 8–10 mg daily, while glipizide is usually given in doses of
10–25 mg daily and gliclazide modified release 30–120 mg daily
[80].
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Safety
Sulphonylureas are associated with significant risks of hypogly-
caemia and modest weight gain, both of which are attributable
to the non-physiological and unregulated release of insulin
[92]. Numerous studies comparing relative risks of hypo-
glycaemia between different SUs consistently show gliben-
clamide/glyburide to have the highest risk, an intermediate risk
with glimepiride and glipizide, and the least risk with gliclazide
[80,93–95]. The risk of SU-mediated hypoglycaemia is greatest
in patients with T2DM who are elderly, poorly nourished, or
who have cardiovascular or renal disease [80]. As discussed, the
risk of hypoglycaemia increases when SUs are used in combina-
tion with certain other drugs. SU-mediated hypoglycaemia is a
relatively frequent occurrence and has been shown to be a cause
of significant use of emergency services, emergency ward visits
and hospitalizations [96,97]. Severe hypoglycaemia tends to be
relatively resistant to acute glucose administration and may be
recurrent for 12–72 h. Such episodes generally require medical
treatment for several days [80].
Sulphonylureas are implicated with adverse effects related
to the increased risk of hypoglycaemia. Episodes of hypogly-
caemia correlate with periods of ventricular arrhythmias in
subjects with T2DM [98,99], and one or more episodes of
severe hypoglycaemia have been linked to an increased risk of
long-term adverse clinical outcomes and death [100]. Whether
SUs have direct effects to adversely affect cardiovascular out-
comes, however, is a matter of some controversy [101,102] and,
unlike for the newer diabetes therapies, there is no random-
ized, placebo-controlled cardiovascular safety trial with any
SU. Results from the UK Prospective Diabetes Study [103] have
been used to argue the case that SUs do not adversely affect
cardiovascular events, although it can be questioned whether
the newly diagnosed, treatment-naïve population, which was
poorly treated by today’s standards with respect to both gly-
caemic control and cardiovascular risk factors, is representative
of patients of the last two decades. Many retrospective or obser-
vational studies have shown that SU use is associated with a
higher risk of cardiovascular events compared with metformin
[104–106]. Similar conclusions were drawn from a small,
probably under-powered, prospective study comparing 3 years
treatment with metformin and glipizide over a follow-up period
of 5 years [107]. In all these studies, whether the difference is
attributable to an adverse effect of the SU, a beneficial effect of
metformin, or a combination of both, cannot be determined.
Attempts have been made to postulate an increase in adverse
cardiovascular outcomes of some SUs through their ability
to interact with the SUR isoforms present in myocardial
cells (SUR-2A) and/or coronary artery smooth muscle cells
(SUR-2B)[84]. SUs have higher affinity for SUR-1, but can
nevertheless, to varying extents, also interact with SUR-2
subunits. When used at their therapeutic doses, gliclazide
and glipizide appear to be selective for SUR-1 only, whereas
glibenclamide/glyburide and glimepiride which bind both
to the benzimido and SU binding sites, may be less selective
and bind to some degree to SUR-2 subunits [80]. It has been
suggested that these differences explain preclinical and clinical
data showing that glibenclamide/glyburide blocks ischaemic
preconditioning, whereas glimepiride and gliclazide have no
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DIABETES, OBESITY AND METABOLISM
effect [108]. Ischaemic preconditioning is a mechanism by
which a short episode of ischaemia reduces the detrimental
effects of a subsequent longer period of ischaemia [109], and
some evidence suggests that cardiomyocyte KATP channel
opening plays a role in this phenomenon. Some observational
studies indicate that not all SUs are associated with the same
cardiovascular risk [110–112], with several suggesting that
gliclazide may potentially pose less risk than other members of
the class, but whether any SU directly increases cardiovascular
adverse events remains an unanswered question.
DPP-4 Inhibitors versus Sulphonylureas
T2DM is a progressive disease and pharmacotherapy with a
single agent is unlikely to offer durable glycaemic control over
the long-term. SUs were the archetypal next choice to add
to metformin, but now DPP-4 inhibitors are a viable alterna-
tive. Second-line agents should provide efficacious – and ide-
ally, durable – glycaemic control without increasing the risk
of hypoglycaemia or weight gain. They should be safe, pos-
ing no undue risks regardless of patient comorbidities. Ide-
ally, they should have complementary mechanisms of action, be
‘user-friendly’ in order to improve adherence, and be cost effec-
tive. In many of these respects, DPP-4 inhibitors can match, or
even better, the traditional choice of SUs (Table 5).
Efficacy: HbA1c-Lowering vs Risk of Hypoglycaemia
There is a misconception that SUs are more efficacious in reduc-
ing HbA1c than DPP-4 inhibitors, with it commonly being
held that typical reductions of ∼1.5% can be obtained with
SUs whereas DPP-4 inhibitors ‘only’ lower levels by 0.5–0.9%
[113]. This belief persists, with the newest ADA/EASD posi-
tion statement still referring to SU efficacy as ‘high’ while
DPP-4 inhibitors efficacy is classified as ‘intermediate’ [5],
even though this is not supported by evidence. It has been
pointed out that comparisons based on ‘average reductions’
are misleading because they do not take into account differ-
ences in baseline HbA1c levels between studies [114]; patient
populations in many of the earlier SU trials (baseline HbA1c
often ≥9%) were very different from those enrolled in the
more modern trials with DPP-4 inhibitors (baseline HbA1c
∼7.5–8.5%), reflecting ongoing improvements in glycaemic
control. Indeed, when HbA1c reductions are expressed relative
to baseline levels, the apparent difference in efficacy between
DPP-4 inhibitors and SUs disappears [114]. Valid compar-
isons can only be made in head-to-head, randomized studies
comparing both drug classes in the same population. Such
studies uniformly show equivalent HbA1c-lowering by DPP-4
inhibitors and SUs, irrespective of which DPP-4 inhibitor or SU
is used (e.g. sitagliptin/glipizide [115], vildagliptin/gliclazide
[116], linagliptin/glimepiride [117], sitagliptin vs gliben-
clamide/glyburide [118]), with subgroup analyses showing
that this holds true across the entire range of baseline HbA1c
levels [119]. Moreover, while there may be a widely held belief
that the glucose-lowering effect of SUs is more immediate
than that of DPP-4 inhibitors, inspection of time courses for
HbA1c reductions generally shows this is not the case; indeed,
Volume 18 No. 4 April 2016

DIABETES, OBESITY AND METABOLISM
Table 5. Comparison of clinically relevant characteristics of sulphonlyureas and dipeptidyl peptidase-4 inhibitors.
Drug characteristics Sulphonylurea
Efficacy Yes
Durability Poor (secondary failure)
No hypoglycaemia No
No weight gain No
Few adverse events (including low cardiovascular risk) (No) (increased cardiovascular risk with some)
Address islet cell dysfunction
Insulin insufficiency Yes (glucose-independent)
Glucagon excess No
User friendly (compliance)
No injection Yes
No titration No
Administration independent of meals No
No glucose monitoring No (regular monitoring)
Cost Cheap
DPP, dipeptidyl peptidase.
Bold font indicates desirable attributes, italic font less desirable attributes, underlined font undesirable attributes.
a reduction in fasting plasma glucose is already evident within
3 days after initiation of a DPP-4 inhibitor [120].
It is notable, nevertheless, that even though HbA1c levels
are similarly improved, there are marked reductions in both
the incidence and severity of hypoglycaemia with the DPP-4
inhibitors, although, as expected, the absolute incidence with
SU varies according to which drug is used [115–118]. This is
seen across the full range of HbA1c levels, with the risk of hypo-
glycaemia being greater with SUs even in subjects with higher
HbA1c levels, and the difference becoming progressively larger
as HbA1c is brought closer to target level. In contrast, the risk of
hypoglycaemia with DPP-4 inhibitors is consistently low, even
in subjects with HbA1c levels of ≤7% [121–123]. The differ-
ence in risk between SU and DPP-4 inhibitors is not limited
to a comparison only with those patients on the higher SU
doses, but is seen consistently across all doses of SU [122,123].
These findings from randomized clinical trials have been con-
firmed in prospective registry studies, also showing that DPP-4
inhibitors provide similar glycaemic control to that of SUs, but
with a lower hypoglycaemia risk when used with metformin in
a more ‘real-world’ setting [124]. The ability to improve gly-
caemic control without increasing hypoglycaemia is particu-
larly relevant for those with a history of hypoglycaemic events,
and for elderly or frail patients, in whom the consequences of
hypoglycaemia can be more severe and occur with greater fre-
quency [125,126]. Indeed, the above observations in the general
population with T2DM have been reproduced in trials specifi-
cally recruiting elderly subjects [127,128]. Accordingly, DPP-4
inhibitors may be preferred to SUs when hypoglycaemia could
be particularly problematic, including not only in the elderly,
but also in those not necessarily with elevated hypoglycaemia
rates but who have high-risk professions. DPP-4 inhibitors may
also be preferable for others, such as ordinary driving licence
holders, where repeated episodes of severe hypoglycaemia can
result in licence withdrawal.
Durability
Therapy with SUs is associated with both a gradual loss of
glycaemic control over time, and a greater rate of failure
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review article
DPP-4 inhibitor
Yes
Too soon to tell
Yes
Yes
Yes (includes prospective
cardiovascular safety trials)
Yes (glucose-dependent)
Yes (glucose dependent)
Yes
Yes
Yes
Yes (less frequent monitoring)
Relatively expensive
than therapy with either metformin or thiazolidinediones
[129,130]. While it is currently too soon to know whether
DPP-4 inhibitors might affect the progressive deterioration
in glycaemic control, there are some encouraging data from
short- to mid-term studies. In the SAVOR-TIMI trial (median
follow-up 2.1 years), 𝛽-cell function was improved and the
times to initiation of insulin or increases in antihypergly-
caemic medications were reduced with saxagliptin compared
with placebo [131]. Similarly, in TECOS (median follow-up
3.0 years), fewer sitagliptin-treated patients required additional
antihyperglycaemic agents or initiated long-term insulin ther-
apy [33]. In a ‘real-world’ setting, the ODYSSEE observational
study suggested that treatment maintenance of dual therapy
with metformin plus sitagliptin was longer than with met-
formin plus SU (43.2 vs 20.2 months) [132]. Similarly, in a
retrospective cohort study of electronic medical records, fewer
sitagliptin users initiated insulin therapy compared with SU
users over 6 years (26.6 vs 34.1%), when both drugs were used
as add-on therapy to metformin [133].
Cardiovascular Safety
As already discussed, the cardiovascular safety of DPP-4
inhibitors has been demonstrated in purpose-designed safety
studies [31–33], whereas the question of whether SUs adversely
affect cardiovascular outcomes remains unresolved [102].
Nevertheless, both retrospective meta-analyses and obser-
vational registry studies uniformly suggest that SUs might
be associated with greater all-cause mortality and increased
cardiovascular risk and mortality than DPP-4 inhibitors
[134–137]. For example, a recent large (n = 346476) retro-
spective cohort study from Korea indicated that the incidence
of total cardiovascular disease, myocardial infarction and
ischaemic stroke events were significantly higher in subjects
treated with SU plus metformin than in those treated with
DPP-4 inhibitors plus metformin (hazard ratios of 1.20, 1.14
and 1.51, respectively) [137]. The CAROLINA study, a large
prospective cardiovascular safety trial comparing linagliptin
with glimepiride [138], may be expected to shed further light
on this issue; results are expected in 2018.
doi:10.1111/dom.12610 341

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Impact on Disease Pathology
Whereas metformin acts as an insulin sensitizer, both DPP-4
inhibitors and SUs target the inadequate 𝛽-cell secretion of
insulin that characterizes T2DM; together, therefore, the com-
bination of metformin with either a DPP-4 inhibitor or an
SU addresses two of the key pathological defects of T2DM;
however, whereas the effect of DPP-4 inhibitors is strictly
glucose-dependent, SUs stimulate insulin secretion even when
plasma glucose levels are low, and as discussed, this difference
confers a lower hypoglycaemia risk to the DPP-4 inhibitors.
Given that SUs and DPP-4 inhibitors release insulin through
different mechanisms, however, in some instances SUs can be
cautiously added to DPP-4 inhibitors to increase insulin secre-
tion [139]. Another major effect of DPP-4 inhibitors is to tar-
get the 𝛼-cell defects, by reducing the hyperglucagonaemia of
T2DM in a glucose-dependent manner, leading to reductions
in the exaggerated endogenous glucose production character-
istic of T2DM [140,141]. KATP channels are present on 𝛼-cells,
but SUs are generally reported to have little effect on glucagon
levels in subjects with T2DM [142]. However, in patients with
T1DM and no residual 𝛽-cell function, where the restraining
effect of insulin on the 𝛼-cell is lost, SUs may be associated
with increased glucagon secretion [143]; whether this is also
the case in subjects with T2DM and treatment failure to SU is
presently unknown. Also of interest is the observation that the
combination of DPP-4 inhibitors with metformin may interact
favourably on the incretin system. Metformin is associated with
increased total GLP-1 levels which, in the presence of a DPP-4
inhibitor, results in further enhancement of active GLP-1 con-
centrations [144]. Indeed, the combination of metformin plus
DPP-4 inhibitors has been shown to have additive effects to
improve HbA1c levels [145]. Finally, modest weight gain is typ-
ically associated with SUs, whereas DPP-4 inhibitors are usually
considered to be weight-neutral in effect, although small reduc-
tions of 1–2 kg have been seen in some studies [146].
Unique Aspects of Sulphonylurea Action
Sulphonylurea treatment is unique in that it will stimulate
insulin secretion when glucose metabolism, and hence ATP
production, within the 𝛽-cell is impaired or there is a defect
in the ability of ATP to close the KATP channel. Although not
common, such abnormalities are seen in genetic mutations of
the glucose metabolism pathway or of the SUR-1 or Kir 6.2 sub-
units of the KATP channel [147], and in either instance, insulin
secretion is blunted or blocked. In these disease states, such
as the various forms of neonatal diabetes, MODY-3 (HNF-1𝛼)
mutations [148], or some polymorphisms of Transcription Fac-
tor 7-like 2 [149], SUs are the therapeutic agents of choice.
Moreover, some patients with T2DM have mutations in the
genes coding for the Kir 6.2 or SUR1 subunit, which provide
an increase in SU responsiveness [150,151], while, because of
their different mechanisms of action, SUs may be useful for
those patients who have primary treatment failure to DPP-4
inhibitors (and vice versa).
Clinical Utility/Ease of Use
Dipeptidyl peptidase-4 inhibitors are relatively easy to use and,
with few exceptions, can be used in all patients, including
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DIABETES, OBESITY AND METABOLISM
elderly, frail or vulnerable patients, and those with reduced
renal function, including those on dialysis, or with hepatic
impairment. Because they do not cause hypoglycaemia, they
do not require dose titration and can be taken at any time
of day, independently of meal times. They are also generally
free of drug–drug interactions and can mostly be used with
other medications without the need for dose adjustment of
either agent. Neither the pharmacokinetic profiles of nor expo-
sure to other commonly used medications, including drugs
which alter the activity of the CYP system [e.g. ketocona-
zole, rifampicin (rifampin) and ritonavir] or the P-glycoprotein
transporter (e.g. cyclosporine) are affected in a clinically rele-
vant manner by DPP-4 inhibitors [152]. DPP-4 inhibitors may,
therefore, be useful in conditions such as tuberculosis or HIV,
which often present with diabetes as a side effect of the disease
itself or its treatment. Likewise, the pharmacokinetics of DPP-4
inhibitors are also generally unaffected by concomitantly used
medications [152]; however, as discussed, because of their
route of metabolism, exposure to gemigliptin and saxagliptin
is increased if used with strong CYP 3A4/5 inhibitors, such
as ketoconazole or ritonavir, but if the dose is inadvertently
not reduced, hypoglycaemia is unlikely to occur because of the
glucose-dependent mechanism of action of DPP-4 inhibitors.
When DPP-4 inhibitors are used with an SU or insulin, a lower
SU/insulin dose is usually recommended.
By contrast, SUs require more factors to be taken into
account. Because of their inherent hypoglycaemic action, which
is largely independent of prevailing blood glucose levels, both
dose titration and dose timing (with meals) are important. They
are not suitable for all patients, particularly those in whom
the risk of hypoglycaemia is already increased or when it is
especially important to minimize that risk. SUs are specifi-
cally contraindicated in severe renal or hepatic insufficiency
since, unlike DPP-4 inhibitors, any increase in exposure will
be associated with increased glucose-lowering, irrespective of
concurrent blood glucose concentrations. Moreover, as dis-
cussed above, the hypoglycaemic effects of SUs can be influ-
enced by a number of other drugs. Thus, while only a few
combinations may be absolutely contraindicated or inadvis-
able, precautions are required if SUs are used concomitantly
with a considerable number of other medications, including
some which may be commonly co-prescribed. For example,
angiotensin-converting enzyme inhibitors and salicylates may
potentiate the glucose-lowering effects, while corticosteroids
and sympathomimetics have the opposite effect, and 𝛽-blockers
may mask some of the symptoms of hypoglycaemia. The addi-
tion or withdrawal of some of these other medications may,
therefore, result in either hypo- or hyperglycaemia if blood glu-
cose levels are not monitored to allow appropriate SU dose
adjustment.
Conclusions
Dipeptidyl peptidase-4 inhibitors and SUs each belong to drug
classes in which members of the class can be differentiated from
one another on the basis of their pharmacokinetic and pharma-
codynamics characteristics; these in turn have implications for
the way in which individual drugs are used in clinical practice.
Volume 18 No. 4 April 2016

DIABETES, OBESITY AND METABOLISM
Both classes are widely used as second-line agents, and clinical
experience has shown that their effects on HbA1c are similar.
Whether there are differences in long-term durability remains
unknown, but may be answered in due course by the Glycemia
Reduction Approaches in Diabetes: a comparative Effectiveness
(GRADE) study [153]. DPP-4 inhibitors are generally associ-
ated with fewer side effects than SUs; they do not inherently
cause hypoglycaemia, they are weight-neutral and they have
been shown not to increase cardiovascular risk. They are prefer-
able to SUs in certain patients, including vulnerable individuals
or those with occupational/social activities where avoidance of
hypoglycaemia is important, although for others, where abnor-
mal pancreatic KATP channel activity results in deficient insulin
secretion, an SU is still the preferred drug. Nevertheless, the
favourable features of DPP-4 inhibitors (Table 5) may increas-
ingly result in them being seen as a better option than SUs when
patients require additional antidiabetic medication. Medication
costs clearly influence drug choice in some geographic regions
(due to economics and/or healthcare provider systems), but this
may become less relevant in the future, when generic DPP-4
inhibitors may be readily available. Ultimately, the decision of
which drug to use should take into account differences, both
within and between drug classes, and be made according to the
individual patient needs.
Conflict of Interest
No writing assistance or financial support was used in the
preparation of this article. C. F. D. has received consul-
tancy/lecture fees from companies with an interest in devel-
oping and marketing incretin-based therapies for treatment
of T2DM (Boehringer Ingelheim, Lilly, Merck/MSD, Novo
Nordisk). Her spouse is employed by MSD and holds stock
options in Merck. H. E. L. serves on scientific advisory boards
for several companies (Biocon Pharma, Intarcia, Metacure
Ltd and Poxel Pharma) which are engaged in developing new
products and devices for the treatment of metabolic diseases.
H. E. L. owns stock shares in Abbott, Abbivie and MSD).
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