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The efficacy and safety of Dipeptyl Peptidase-4 inhibitors compared to other Oral glucose-lowering medications in the treatment of type 2 diabetes
Anca Pantea Stoian, Alexandros Sachinidis, Roxana Adriana Stoica, Dragana Nikolic, Angelo Maria Patti, Ali A. Rizvi
PII: S0026-0495(20)30159-1
DOI: https://doi.org/10.1016/j.metabol.2020.154295
Reference: YMETA 154295
To appear in: Metabolism
Received date: 4 January 2020
Revised date: 7 June 2020
Accepted date: 11 June 2020
Please cite this article as: A.P. Stoian, A. Sachinidis, R.A. Stoica, et al., The efficacy and safety of Dipeptyl Peptidase-4 inhibitors compared to other Oral glucose-lowering medications in the treatment of type 2 diabetes, Metabolism (2020), https://doi.org/ 10.1016/j.metabol.2020.154295
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier.
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The Efficacy and Safety of Dipeptyl Peptidase-4 Inhibitors Compared to other
Oral Glucose-lowering Medications in the Treatment of Type 2 Diabetes
Anca Pantea Stoian 1 , Alexandros Sachinidis
2 , Roxana Adriana Stoica
1 ,
Dragana Nikolic 2 , Angelo Maria Patti
2 , Ali A. Rizvi
3
1 Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University
of Medicine and Pharmacy, Bucharest, Romania;
2 PROMISE Department, School of Medicine, University of Palermo, Italy;
3 Division of Endocrinology, Metabolism, and Lipids, Emory University School of
Medicine, Atlanta, Georgia, USA
Corresponding author:
Prof. Ali A. Rizvi, MD
Division of Endocrinology, Metabolism, and Lipids
Emory University School of Medicine,
Atlanta, Georgia, USA
Tel.: 404-778-2064 (USA)
Fax: (404) 251-1260
E-mail: [email protected]
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SUMMARY
Introduction: The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong
to the class of incretin-based medications, are recommended as second or third-line
therapies in guidelines for the management of type 2 diabetes mellitus. They have a
favorable drug tolerability and safety profile compared to other glucose-lowering
agents.
Objective: This review discusses data concerning the use of DPP-4is and their
cardiovascular profile, and gives an updated comparison with the other oral glucose-
lowering medications with regards to safety and efficacy. Currently available original
studies, abstracts, reviews articles, systematic reviews and meta-analyses were
included in the review.
Discussion: DPP4is are moderately efficient in decreasing the HbA1c by an
average of 0.5% as monotherapy, and 1.0% in combinationtherapy with other drugs.
They have a good tolerability and safety profile compared to other glucose-lowering
drugs. However, there are possible risks pertaining to acute pancreatitis and
pancreatic cancer.
Conclusion: Cardiovascular outcome trials thus far have proven the
cardiovascular safety for ischemic events in patients treated with sitagliptin,
saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of
hospitalisation in the case of saxagliptin did not seem to be a class effect.
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1. Introduction
Inhibitors of dipeptidyl peptidase-4 (DPP-4is), also known as “gliptins”,
belong to the group of incretin-based medications that act by stimulating the insulin
secretion and inhibiting glucagon secretion in a glucose-dependent manner [1]. They
improve glycaemic control in monotherapy or combined therapy with other
medications without having a large number of adverse effects [2, 3]. Glucagon-like
peptide-1 (GLP-1) is a gut hormone which is released from L cells in the small
intestine in response to digestion and absorption of food, leading to postprandial
insulin release. This incretinic effect is reduced in patients with type 2 diabetes
mellitus (T2DM), resulting in reduced glucose tolerance [4]. The second incretin
hormone, the glucose-dependent insulinotropic polypeptide (GIP), is also degraded by
DPP-4 [3, 5]. Several clinical studies in the literature demonstrate that DPP-4is could
increase the circulating concentrations of intact endogenous GLP-1 and GIP-1 by
about 2- to 4- fold [6, 7].
DPP-4is are currently recommended as second or third-line therapies in
guidelines for the management of T2DM [8-11]. In some cases where DPP-4is may
be used as first-line medications, especially when there is metformin intolerance
orcontra-indication, and a number of metformin/DPP-4i fixed-dose combinations are
available [12]. DPP-4is are also recommended as triple therapy with metformin and
sodium-glucose co-transporter type 2 (SGLT-2) inhibitors or with metformin and
insulin. The current 2020 ADA guidelines on T2DM management strongly support
the use of GLP-1 RA or SGLT2i, both with demonstrated CVD benefit, for patients
with established ASCVD or indicators of high ASCVD risk (such asthose≥55years
of age with left ventricular hypertrophy or coronary, carotid, or lower-extremity artery
stenosis >50%), established heart failure or kidney disease, independently of A1C and
considering patient-specific factors [13].
The DPP-4is have good tolerability, few adverse events and an excellent
safety profile compared to other glucose-lowering drugs, including the SGLT2
inhibitors [14-19]. There are, however, concerns about the adverse effects of DPP-
4isespecially regarding acute pancreatitis (AP) and pancreatic cancer [20-22]. In the
important area of cardiovascular (CV) safety and efficacy, saxagliptin showed a raised
risk of hospitalisation for heart failure (hHF) in people with diabetes with established
cardiovascular disease (CVD) [23]. Last but not least, DPP-4is are associated
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potentially with arthralgias, and this is very important for diabetic patients in clinical
practice [24].
This review aims at discussing the latest data concerning the use of DPP-4is
and to make an updated comparison with the other oral glucose-lowering medications,
both for safety and efficacy. Currently available original studies, abstracts, reviews
articles including systematic reviews and meta-analyses were examined.
2. Effectiveness of DPP-4is on glucose control
Intensive glucose control has been shown to reduce the risk of microvascular
and macrovascular complications.[25]. It is imperativ to achieve the target glycated
haemoglobin (HbA1c) from the very beginning of the disease, since the reduction in
CV complications has been observed after many years of the primary intervention
[26-28]. It was demostrated that a reduction of 1% in HbA1c was associated with a
21% reduction in death and a 37% reduction in microvascular complications [25].
The target for glucose control is individualised since it depends on various
parameters, such as age, the presence of CVD, the duration of the disease, risk for
hypoglycemia and socioeconomic factors. Glucose targets are stricter in young
patients with the newly diagnosed disease and higher in old-aged subjects with long-
standing T2DM, CV complications and potentially shorter life expectancy [29].
DPP-4is have demonstrated moderate glycemic efficacy and reduce HbA1c on
average by about 0.6-0.8% [30]. There is little risk of hypoglycemia, since the
magnitude of action of DPP-4is depends on the glucose level [31]. Another significant
feature of DPP-4is use is the lack of weight gain. Most important classes of
antidiabetic drugs, such as sulfonylureas, thiazolidinediones and insulin are associated
with weight gain. However, the impact of DPP-4is on weight is not as strong as with
GLP-1 receptor agonists (GLP-1RA) (which are associated with weight loss) [32] and
the SGLT2 inhibitors [33]. Therefore, the DPP4is stand in the middle between older
and newer anti-diabetic agents in their glucose profile: glycemic reduction, with few
hypoglycemic episodes and a weight neutral effect [34].
In addition to the HbA1c target, the durability of glycemic control is also an
important parameter. Alogliptin is one of the drugs that had a sustained efficacy over
a 2-year period when compared to glipizide in patients treated only with metformin
[35]. When Saxagliptin was compared with dapagliflozin, dapagliflozin demonstrated
greater durability of glucose control, both short-term and long-term analyses [36].
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In the trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)
study, treatment with sitagliptin was associated with improved glycaemic control and
a delayed use of insulin in subjects receiving metformin monotherapy or combination
therapy metformin with SU. The subjects treated with sitagliptin achieved lower
HbA1c throughout follow‐up without an increased risk for severe hypoglycemia,
irrespective of baseline therapy. A down‐titration of concomitant medications was
encouraged in case of severe hypoglycemia, rather than discontinuation of the study
drug [37]. Similarly, linagliptin as monotherapy or as add-on to other oral glucose-
lowering agents resulted in sustained long-term glycemic control for up to 102 weeks
[38]. However, in the CAROLINA (Cardiovascular Outcome Study of Linagliptin
Versus Glimepiride in Patients With Type 2 Diabetes) CVOT study, there was hardly
any difference in HbA1c reduction between glimepiride and linagliptin, indicating
that glimepiride's effect was also as sustainable as that of linagliptin. However,
subjects on glimepiride experienced significantly more hypoglycemia compared to
those on linagliptin, associated with weight gain [39].
3. Safety of DPP-4is
3.1. Hypoglycemia
A significant advantage of DPP-4is is the decreased risk of hypoglycemia. It
seems that DPP-4is reduce the risk of hypoglycemia about tenfold when compared to
sulphonylureas [40, 41] in both randomised clinical trials and observational studies [2,
41]. Two specific observational studies performed in Taiwan and Sweden had
demonstrated a low risk of severe hypoglycemia and a lower risk of a major CV event
and all-cause mortality when they were compared to sulphonylureas [42, 43].
Reduced the risk of hypoglycemia is important for all diabetic patients, but more in
specific population groups, such as elderly, frail patients and patients with high-risk
professions. Another significant meta-analysis of randomized controlled trials (RCTs)
with DPP-4is and other oral glucose-lowering medications showed better glycemic
control by DPP-4is compared to α-glucosidase inhibitors, including lower risks of
gastrointestinal adverse effects [44]. About 39 placebo-controlled trials assessed and
provided information on hypoglycemia. Some heterogeneity and increased risk ratios
for hypoglycemia were noticed in the linagliptin and sitagliptin subgroups with
concomitant use of insulin or a sulphonylurea. However, without concomitant use of
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insulin or a sulphonylurea, no elevated risk of hypoglycemia was observed for any
agent [45].
When the same authors compared sitagliptin with vildagliptin in patients
with T2DM and severe renal insufficiency, either without or in combination with a
sulphonylurea, thiazolidinediones, or insulin, no difference could be detected [45].
Moreover, DPP-4is combined with metformin or pioglitazone is not correlated with a
significant risk of hypoglycemic episodes. Contrariwise, when they are combined
with sulphonylureas, there were increased episodes of hypoglycemia compared to
sulphonylurea in monotherapy, especially in those T2DM subjects with a slightly
increased HbA1c at baseline [46]. In another meta-analysis of randomized controlled
trials (RCTs), the combination of DPP-4is with insulin ameliorated the glycemic
profile significantly, without an increased risk of weight gain or severe hypoglycemia
compared with insulin monotherapy. Nevertheless, when it was compared with the
combination alpha-glucosidase inhibitor/insulin, thiazolidinediones/insulin and GLP-1
RAs/insulin treatments, DPP-4is/insulin treatment had equivalent placebo-corrected
effects on HbA1c and both fasting and postprandial plasma glucose (FPG and PPG)
[47]. Combining DPP-4is with GLP-1RA is not recommended because they have a
similar mechanism of action and the effect on HbA1c was not superior [48]; however
longer-term studies are needed for confirmation. Finally, when DPP-4 is are
combined with SLGT-2 inhibitors, they have beneficial effects on glucose control,
possibly due to their complementary mechanisms of action [49, 50].
3.2 Gastrointestinal and pancreatic safety
A significant advantage of DPP-4is compared to the other class of incretin-
based medications is that they do not cause gastrointestinal adverse effects like nausea
and vomiting, possibly since they do not slow gastric emptying [51]. In a recent
network meta-analysis and systematic review which included 165 RCTs (122,072
T2DM patients), the DPP-4is - alogliptin, linagliptin, sitagliptin and vildagliptin did
not increase the rate of gastrointestinal adverse events when compared with placebo,
GLP-1RA, metformin and alpha-glucosidase inhibitors (acarbose, voglibose) [52].
Another concern about incretin-based medications is represented by
pancreatic events [20, 21, 52]. The US Food and Drug Administration (FDA) and the
European Medicines Agency (EMA), in 2014, could not establish a clear relationship
between DPP-4is and pancreatitis or pancreatic cancer. Subesquently, further studies
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were designed in order to resolve this controversy [53]. Firstly, two systematic
reviews of phase 2 and 3 RCTs, with 19,241 and 20,526 patients, respectively, have
shown that DPP-4is were not associated with an increased risk of AP. A meta-analysis
of 3 cohort studies, including 1,324,515 subjects demonstrated no significant
relationship between DPP-4is use and increased risk of AP [54-56]. On the contrary,
the results of a meta-analysis including the three CV outcome trials (CVOT) for
saxagliptin (SAVOR TIMI 53), alogliptin (EXAMINE) and sitagliptin (TECOS),
demonstrated that the incidence of AP was significantly increased in the gliptin-
treated group compared with the placebo group in an average follow-up of 2-3 years;
however, the difference in the absolute risk was relatively small (0.13%) [57].
In another recent meta-analysis including 36 double-blind RCTs and 54,664
subjects, there was no significant difference in pancreatic cancer (RR=0.54, 95%
CI=0.28-1.04) with the use of DPP-4is. However, their use was associated with an
increased risk of HF (RR=1.13, 95% CI=1.01-1.26) and AP (RR=1.57, 95% CI=1.03-
2.39) [58]. In an additional analysis in the TECOS study, all suspected cases of AP
and pancreatic cancer were studied prospectively for 14,671 participants during the
follow-up time of 3 years and were adjudicated blindly. The rates for these events
were uncommon and were not significantly different between the sitagliptin and
placebo groups, although numerically more sitagliptin-treated participants developed
pancreatitis and fewer developed pancreatic cancer. Meta-analysis suggests a small
but absolute increased risk for pancreatitis associated with the DPP-4is use [59].
Several observational studies were done in order to clarify the association
between DPP-4is and increased risk of AP. In a case-control study using Taiwan's
National Health Insurance Research Database, the risk of AP was similar among
current and past users of DPP-4is (adjusted odds ratio (aOR) for current users: 1.04;
95% CI [0.89-1.21]; past users: aOR 1.61 [0.93-2.77]) compared with non-users [60].
Similar results were reported in sensitivity analyses when various definitions of
"current users" of DPP-4is were used. On the contrary, the adjusted risk of AP was
found to be raised significantly in subjects with alcohol-related disease (aOR 5.36
[4.05-7.08]), gallstone disease (aOR 5.89 [4.71-7.35]), dyslipidemia with
hypertriglyceridemia (aOR 1.80 [1.26-2.56]), pancreatic disease (a OR 17.29 [10.60-
28.19]), and a higher Diabetes Complications Severity Index (DCSI) score (DCSI 3-4:
a OR 1.49 [1.21-1.84]; DCSI ≥5:aOR1.32[1.01-1.73]) [60]. Therefore, it seems that
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underlying diseases and as well as the severity of T2DM, but not DPP-4is use, were
associated with AP [60].
In another analysis of 114,141 subjects, the risk of AP was not significantly
higher in T2DM subjects treated with DPP-4is than in those not treated. Greater
interaction effects were seen between gender and age (HR 0.80, 95% confidence
interval [CI] 0.64-0.99) and age and DCSI score (HR 0.83, 95% CI: 0.71-0.97) [61].
In subgroup analyses, significant risks of AP were noted in elderly DPP-4is users
(aged 65 years and over) with HR 2.39 (95% CI: 1.11-5.15). Among women, the risk
of AP was significantly higher among DPP-4is users compared with non-users (HR
2.27, 95% CI: 1.30-3.97) [61].
Other observational studies provide reassuring results for the use of DPP-4is.
One of them is a retrospective study in Japan of an extensive medical claims database
that compared the incidence of AP among those receiving DPP-4is and those
receiving other oral antidiabetic agents. The incidence of AP and hospitalisations for
AP were similar between the two groups [62]. Another nationwide population-based
case-control study using medical databases in Denmark evaluated 12,868 patients
with a first-time hospitalisation for AP between 2005 and 2012 with a population of
128,680 matched control subjects. The findings suggested that the use of incretin-
based therapy appeared not to be associated with an increased OR of AP [63]. Finally,
another large, international, multicenter, population-based cohort study was reported
using combined health records from 7 participating sites in Canada, the United States,
and the UK, with an overall cohort of 1,532,513 T2DM subjects initiating the use of
antidiabetic drugs. The use of incretin-based drugs was not associated with an
increased risk of AP compared with other oral antidiabetic drugs [64].
3.3 Cardiovascular safety
CVD is the leading cause of morbidity and mortality in patients with T2DM
[65]. The improvement of blood glucose haemostasis results in amelioration of other
CV risk factors. DPP-4is may have positive effects, either by effective glucose control
or via direct effects on the CV system. DPP-4 enzyme is widely expressed in the
blood vessels, myocardium and myeloid cells.
There are preclinical studies that have demonstrated at a molecular basis that
DPP-4is have a clear positive association with CV abnormalities, improving vascular
endothelial function and blood pressure. Moreover, DPP-4is, through GLP-1R
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activation, inhibit the development of atherosclerosis, which is associated with a
reduction in intestinal lipoprotein secretion and inflammation [66-69].
However, the direct effects of DPP-4is on the vascular function in patients
are controversial. Since the first reports from preclinical studies were promising and
alongwith the high importance of the CV safety of antidiabetic drugs, large
prospective CVOT were designed to evaluate the CV safety and effectiveness of DPP-
4is in subjects with T2DM and CVD [70]. The first two large published clinical trials
were EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus
Standard of Care) with alogliptin, and SAVOR-TIMI 53 (Saxagliptin Assessment of
Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in
Myocardial Infarction) with saxagliptin that has demonstrated that these two DPP-4is
are non-inferior to placebo for CVD, but they do not have a CV benefit [23, 71]. The
CVOT trial for sitagliptin (TECOS), has shown similar findings concerning the
primary CV outcome [72]. It is noteworth that the overall CV safety of DPP-4is is
proved even for T2DM subjects with moderate chronic kidney disease (CKD) for
saxagliptin and sitagliptin [73, 74]. A systematic review and meta-analysis of phase 2-
3 trials, including T2DM subjects at a low CV risk and treated with DPP-4is
medication, have demonstrated a significantly reduced the incidence of MACE (major
adverse cardiac events) [75, 76]. In RCTs that evaluated alogliptin, saxagliptin, and
sitagliptin, there was no overall increased risk for MACE compared to placebo in
T2DM patients at high CV risk or with known CVD, although an increased rate of
hHF was associated with saxagliptin treatment [76]. The same findings have been
emerged for the risk of stroke, while pooled analysis of smaller phase 2-3 RCTs
demonstrated a trend toward benefit against stroke associated with the use of DPP-4is,
although non-significant (OR 0.639, 95% CI 0.336-1.212) [77].
The three above mentioned large clinical trials compared the safety of DPP-
4is with placebo in T2DM subjects with established CVD. There is a need to compare
DPP-4is with other oral antidiabetic agents in patients with lower CV risk in clinical
practice. There are meta-analyses in the literature comparing DPP-4is and placebo or
another glucose-lowering agent.
Regarding the comparison of DPP-4is with placebo, three meta-analyses
evaluated CV outcomes in patients with T2DM and demonstrated a neutral CV effect
[58, 78, 79]. In another meta-analysis, saxagliptin was associated with an increased
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risk of HF, while sitagliptin was associated with an important decreased risk of all-
cause death compared to active controls [80].
Regarding the potential mechanism of CV protection, sitagliptin has been
shown to significantly increase the flow-mediated dilation in association with an
increase in the circulating CD34+ cells, which is a marker of endothelial progenitor
cells, in patients with T2DM, thus implying a potentially positive effect [81]. A
similar protective effect of sitagliptin is seen in diabetic patients with coronary artery
disease since it improves the endothelial function by reducing the high-sensitivity C-
reactive protein levels [67]. In addition to these basic and pathophysiological effects
of sitagliptin, another cohort study of a total of 104,756 new diabetic subjects from
the Taiwan National Health Insurance Research Database has shown a favourable
outcome of sitagliptin on lowering CVD incidence in T2DM subjects [82].
Several studies compared DPP-4is with sulphonylureas. The latter are used
commony in clinical practice but have an uncertain CV safety profile [83]. A meta-
analysis of 12 head-to-head comparison clinical studies of DPP-4is and
sulphonylureas have shown beneficial effects of DPP-4is, concerning CV events[40].
Another meta-analysis that included both RCTs and cohort studies compared the
combination of metformin with DPP-4is versus metformin and sulphonylurea
combination. Combination therapy with metformin and DPP-4i significantly
decreased the relative risk of nonfatal CV events, CVD mortality, and all-cause
mortality, compared with the combination therapy of metformin and sulfonylurea.
However, the number of fatal CV events (e.g. HF) was not significantly different
between the two groups [84].
A large study including 40,028 Danish diabetic patients without prior
myocardial infarction or stroke, demonstrated that the combination of metformin with
DPP-4i was statistically associated with an RR of 0.65 (0.54-0.80) for mortality, an
RR of 0.57 (0.40-0.80) for CV mortality and an RR of 0.70 (0.57-0.85) for the mixed
endpoint (myocardial infarction, stroke and CV death). In other words, the
combination of metformin plus DPP-4i was associated with a lower incidence of all-
cause mortality, CV mortality, and the 3-point MACE, in comparison with metformin
plus sulphonylurea [85]. Similar findings have emerged from the UK Clinical Practice
Research Datalink (CPRD), which demonstrated a reduction in MACE and all-cause
mortality for subjects under treatment with metformin and DPP-4i versus the use of
metformin with sulphonylurea [86, 87]. The Korean Health Insurance Database Study
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showed that DPP-4is combined with metformin decreased CVD risk compared to
sulphonylureas added to metformin in T2DM patients [88]. The findings mentioned
above are confirmed in a nationwide large study using Taiwan's National Health
Insurance Research Database since DPP-4is led to lower risks for MACEs, ischemic
stroke, and all-cause death (HR 0.63; 95% CI 0.55–0.72) compared the
sulphonylureas and metformin combination, but the risk for myocardial infarction did
not change significantly [42]. A nationwide observational study (20,422 patients with
T2DM) showed that second-line treatment with DPP-4is as an add-on to metformin
was associated with significantly lower risks of mortality and CV events compared
with sulphonylureas, whereas basal insulin was associated with a higher risk of
mortality [89]. Another cohort study in the UK examined the same combination
therapy showing an HR for metformin plus DPP4i of 0.78 (95% CI 0.55; 1.11) for a
major adverse cardiac event in comparison with the metformin-sulphonylurea
regimen [90]. In multivariate-adjusted analyses of the UK Clinical Practice Research
Datalink database, total event rates for MACE for this dual therapy were significantly
lower than with sulphonylurea added to metformin, while the most important
difference between the two groups of patients was the rate of myocardial infarction
[91].
Finally, several studies have evaluated individual DPP-4is. A prospective
study examining saxagliptin did not find a higher acute myocardial infarction risk for
this treatment compared with patients who use other selected glucose-lowering drugs
during the first 5 years after U.S. FDA approval of the drug [92]. Additionally,
subjects who initiated therapy with saxagliptin had no increased risk of a major
adverse cardiac effect in their clinical follow-up; it is noteworthy that in this study the
risk of HF was not included in the primary or secondary endpoints [93]. Similar,
another research for saxagliptin has shown that this drug did not increase change the
rate of the ischemic events, despite a rise in the hHF [23].
3.4 Heart failure
An important point for the CV efficacy and safety of DPP-4is is their
association with HF since their class effect remains controversial. In the SAVOR-
TIMI 53 trial, more subjects in the saxagliptin group were hospitalised for HF
compared to placebo. This difference was present after 12 months but lost its
significance with time (time-varying interaction p=0.017) [23]. However, in the
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EXAMINE study a non-significant trend towards a higher rate of hHF in alogliptin
group compared to the placebo group was observed, in diabetic patients at high CV
risk with recent acute coronary syndrome [71]. In contrast to these two clinical
studies, TECOS did not show a difference between sitagliptin and placebo group
concerning hHF in diabetic patients with CVD [72]. Post-hoc analyses of these
studies showed positive results for DPP-4is [92, 93]. In SAVOR-TIMI, 53 the patients
who were at increased risk for hHF already had established HF, estimated glomerular
filtration rate(eGFR)≤60mL/minand/orelevatedlevelsofNT-proBNP at baseline
[94]. In a post hoc analysis of the EXAMINE study, alogliptin had no significant
association with composite events, such as CV death and hHF [95]. A subgroup
analysis of sitagliptin in TECOS did not reveal increased risk for hHF [96].
Since the association between saxagliptin and increased risk of HF has
provoked considerable controversy, an alternative measure to evaluate the risk of hHF
was examined [94-96]. When another method for HR evaluation was used in all three
extensive clinical studies, no differences in the risk of hHF between alogliptin,
saxagliptin or sitagliptin and placebo were reported [97].
An extensive systematic review and meta-analysis of 43 RCTs and 12
observational studies evaluated the possible connection between the use of DPP-4is
and the risk of HF or hHF in T2DM subjects. The overall conclusion was that DPP-
4is might raise the hHF risk in diabetic subjects, with either established CVD or those
with multiple vascular risk factors compared to placebo [98]. Another large meta-
analysis including 54 studies with 74,737 T2DM participants, DPP-4is was associated
with a non-significant trend for an increased risk of HF compared both to placebo or
other anti-diabetic drugs (RR 1.106; 95% CI 0.995–1.228; p = 0.062). However, in
this meta-analysis and subgroup analysis, only saxagliptin was associated with a
significantly increased risk of HF (RR 1.215; 95% CI, 1.028–1.437; p = 0.022) [99].
A third meta-analysis of 100 randomized control trials, including EXAMINE,
SAVOR-TIMI 53 and TECOS, demonstrated a 13% increase in hHF in the group of
DPP-4is-treated subjects compared to control subjects. However, there is no clear
correlation between DPP-4is and increased risk of HF [100]. Although the effect of
DPP-4is on HF remains controversial, it is suggested that they be used with prudence
in T2DM subjects who are at high risk of HF.
The three main large clinical trials included diabetic subjects largely without
recognized HF at baseline. More specifically, in SAVOR-TIMI, 53 saxagliptin-treated
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diabetic subjects with prior HF and/or increased NT-proBNP levels at baseline, were
at higher risk for hHF [94]. When compared to placebo, saxagliptin was associated
with an increased rate of HF of 1.5% in subjects with previous HF compared with
0.6% in those without prior HF (p for interaction = 0.67). However, in a post hoc
analysis of EXAMINE, neither new-onset not worsening HF in subjects with a history
of HF were seen after alogliptin use [101].
The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial, a small
randomised controlled study evaluated the safety of vildagliptin in T2DM patients
with established HF [102]. The primary endpoint, which was the mean increase in the
ejection fraction at 52 weeks, confirmed noninferiority in the vildagliptin-treated
group compared to placebo (4.1 vs 3.5, p=0.670). The vildagliptin-treated subjects
showed significant elevations in left ventricular end-diastolic volume (LVEDV,
p=0.007), end-systolic volume (LVESV, p=0.06) and stroke volume (p=0.002).
Although improvements in LVEDV and LVESV are usually considered to be
unfavourable, reflecting decreased systolic function, the primary endpoint
demonstrated that vildagliptin did not have an unfavourable effect on left ventricular
ejection fraction (LVEF) [102]. More studies are needed concerning the safety of
DPP-4is in subjects with HF and left ventricular systolic dysfunction as well as those
with HF and preserved LVEF.
3.5 Other safety concerns- Bone metabolism, Rracture, and Arthralgia
Two large meta-analyses evaluated the association between DPP-4is and
fracture events. The first included 51 RCTs (36,402 patients) and the second looked at
62 RCTs with 62,206 patients. There was no significant difference in the risk of
fracture between diabetic patients who used DPP-4is and controls (RR 0.95; 95% CI
0.83–1.10) [102, 103].
An emerging issues with the use of DPP-4is is the induction of joint pain
[104]. A large meta-analysis of 69 studies and 28,006 patients, has demonstrated that
vildagliptin had an association with an increased incidence of arthralgia compared
with other antidiabetic drugs [105], whereas a more recent systematic review and
meta-analysis of a total of 67 RCTs, that included 79,110 subjects showed that DPP-
4is, in general, had a clear and statistical significant connection with a slightly raised
risk of overall arthralgias (RR 1.13; 95% CI: 1.04–1.22; p = 0.003), but a
nonsignificant with an increased risk of severe arthralgias (RR 1.44; 95% CI: 0.83–
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2.51; p = 0.20) [106]. However, other cohort studiesdo not support these findings, as
mentioned above [107, 108].
4. Special populations
4.1 Patients with CKD
DPP-4is are a desirable option for the treatment of T2DM due to their low
risk of hypoglycemia. This issue is even more pertinent in diabetic patients with
CKD. An important meta-analysis demonstrated that DPP-4is afforded glucose
control similar to other anti-diabetic drugs in T2DM subjects with renal insufficiency,
without an increased risk of hypoglycemia [109]. However, in another meta-analysis
of 12 RCTs and 4,403 patients with CKD and 239 on dialysis, DPP-4is were inferior
in glucose control compared with the other antidiabetic drugs, but with a lower risk of
hypoglycemia [110].
When linagliptin was added to standard care in subjects with T2DM at high
risk of CV events (with advanced coronary artery disease or a history of MI) and
albuminuria, or they had impaired kidney function, the incidence of these events did
not increase over of 2 years. Specifically, linagliptin was not inferior to placebo for
both the primary (MACE) and secondary (composite renal) outcomes. It should be
highlighted that the study population included older patients and those with severe
CKD, and linagliptin demonstrated a reassuring long-term CV and safety profile, with
a reduction in the progression of albuminuria, no increase in hypoglycemia, and no
dose adjustment. These data are of particular importance for clinical practice as they
support the CV and kidney safety of this drug in T2DM subjects at high CV risk and
with kidney disease [111].
4.2 Patients with Non-Alcoholic Fatty Liver Disease (NAFLD)
Clinical studies with sitagliptin at a dose of 100 mg/day showed no
significant reduction in hepatic steatosis or fibrosis in diabetic subjects after 12 or 24
weeks of therapy [112-114]. DPP-4i (sitagliptin) provided glucose control
comparable to sulphonylurea (glimepiride) but had a beneficial effect on intrahepatic
lipid content, in overweight Japanese patients with diabetes [115]. Last but not least,
vildagliptin 50 mg twice a day demonstrated positive effects on NAFLD progression
in subjects with diabetes by decreasing hepatic triglyceride and transaminases levels
[116].
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4.3 Elderly
In the TECOS study [117], 14% of patients were older than 75 years.
Sitagliptin treatment did not significantly impact the risk of death (1.05 [0.83-1.32]),
severe hypoglycemia (1.03 [0.62-1.71]), and hHF (0.99 [0.65-1.49]).The authors
concluded that this treatment was safe for use and could have a positive effect on
sarcopenia in this specific age group [118]. Sitagliptin significantly ameliorated
glycemic control and was well tolerated in T2DM subjects aged >/= 65 years [119].
4.4. Brief critical discussion
The results of recent meta-analysis showed that addition of DPP4i to insulin
was associated with significantly improved glycemic control, no further weight gain
and no hypoglycemia in T2DM patients [120]. These benefits of DPP4i were
independent of study design, duration, specific drug used, and type and dose of
insulin, supporting the use of these drugs as an add-on therapy to insulin in daily
clinical practice. As mentioned above, guideline updates based on recent CVOTs,
support the use of GLP-1 RA or SGLT2i as add-on to metformin therapy in T2DM
patients with established CVD. However, additional treatment options and therapy
intensification is required, especially in T2DM patients without established CVD,
included both DPP-4i and sulfonylureas [121]. The results of the CAROLINA trial
providing important information on the comparative CV safety of a commonly
prescribed sulfonylurea and a DPP-4i should be highlighted, since few head-to-head
trials have compared the effects of different oral glucose-lowering agents on CV
outcomes in T2DM. In addition, guidelines suggest the use of DPP-4i in metformin
failure in patients who do not require antidiabetic therapy with proven CV benefit and
have increasingly replaced sulfonylureas as second line therapy. Additionally, in later
stages of T2DM, DPP-4i are recommended in triple therapy regimens with metformin
and SGLT-2i or with metformin and insulin. On the other hand, treatment with DPP-
4i should be discontinued when GLP-1RA therapy is initiated. DPP-4i can be used as
monotherapy when metformin is not tolerated or is contraindicated. Some studies
indicate the importance of initial metformin-DPP-4i combination use in subjects with
renal impairment and the elderly [12].
Further, it should be highlighted that the linagliptin study (CARMELINA)
included subjects with renal disease as well as prior CV events and confirms its
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overall CV safety, without any associated HF risk. However, the findings from the
studies using sitagliptin and saxagliptin as well as the three DPP4i CVOTs (SAVOR,
TECOS, CARMELINA) have highlighted a safety signal regarding risk of
pancreatitis.
The long-term safety findings are important because of the initial a concern
that DPP-4 inhibition might lead to adverse events. This concern was based on the
action of DPP-4 in cleaving biologically active peptides with alanine or proline as the
second amino acid from the N-terminal end apart from GLP-1 and GIP, such as
neuropeptide Y, substance P, gastrin-releasing peptide, and chemokines [122].
However, as these bioactive peptides are also inactivated by other pathways, the DPP-
4 action is not as important for their inactivation as it is for GLP-1 and GIP, which
could explain why the risk for adverse events with DPP-4i was not different from the
risk with placebo [123]. In addition, potential serious acute safety concerns have been
raised regarding AP, respiratory tract infections, and acute kidney injury. However,
recent studies have not shown that initiation of a DPP4i is associated with such risks
compared to sulfonylureas or other glucose-lowering therapies [124]. Furthermore,
the overall risk of infections was not increased compared with placebo, metformin,
sulfonylureas, thiazolidinedione and alpha glucosidase inhibitor treatment [125].
Longer follow-up observation is required to confirm their safety. The combination
between DPP-4i and SGLT2i has been suggested as a potential early glucose-
lowering treatment in T2DM due to their complementary mechanism of action [126].
Clinical studies have also demonstrated good glycemic control in association with low
risk for hypoglycemia with this combination [127, 128]. Therefore, it appears that
DPP4is are a safe choice when used in the the glucose-lowering stepped-up algorithm
[129]. It should be noted that progression of T2DM is inexorable, and further research
is needed to understand its predictors so that personalized diabetes management can
be instituted [37].
Conclusion
DPP4is are moderately efficacious in decreasing HbA1c by an average of
0.5% as monotherapy, and by 1.0% in combination therapy. The main advantages of
this class are a low risk of hypoglycemia, ease of administration, and good
tolerability, making it a suitable for treating older patients or those who have
moderate to advanced CKD. Most of the DPP4is have been proven to be safe from the
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CV standpoint in large CVOTs. Data regarding the increased rate for hHF did not
seem to be a class effect, although caution should be exercised in the case of
saxagliptin. The association between DPP4is and AP/pancreatic cancer is
controversial; the risk for these adverse events appears to be increased significantly in
patients with alcohol-related disease, gallstone disease, and hypertriglyceridemia.
Funding
This review was written independently. The authors did not receive any
financial or professional help in the preparation of the manuscript.
Conflict of interest
The authors have given talks, attended conferences and participated in several
advisory boards and trials sponsored by various pharmaceutical companies. Prof. APS
is currently Vice President of Romanian National Diabetes Committee. The authors
declare no conflict of interest, financial or otherwise.
Author contribution statement
APS, AS, RAS, DN, AMP, AAR all contributed equally to this paper.
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Highlights
1. The dipeptidyl peptidase-4 inhibitors (DPP-4is) are recommended as second or
third-line therapies for type 2 diabetes mellitus.
2. DPP4is have a moderate efficiency in decreasing the glycated haemoglobin
depending on the associated drug.
3. Cardiovascular outcome trials proved the cardiovascular safety for ischemic events
after sitagliptin, saxagliptin, alogliptin and vildagliptin use.
4. The increased rate for heart rate hospitalisation did not seem to be a class effect.
5. There are concerns about the link between DPP4is use and acute
pancreatitis/pancreatic cancer.
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