486165

2013
TAE432042018813486165Therapeutic Advances in Endocrinology and MetabolismB Gallwitz

Therapeutic Advances in Endocrinology and Metabolism Review

Safety and efficacy of linagliptin in type Ther Adv Endocrinol

Metab

2 diabetes patients with common renal

(2013) 4(3) 95­–105

DOI: 10.1177/
2042018813486165

and cardiovascular risk factors © The Author(s), 2013.

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Baptist Gallwitz

Abstract:  Dipeptidyl-peptidase-IV (DPP-4) inhibitors have become an important orally active

drug class for the treatment of type 2 diabetes as second-line therapy after metformin failure
or as monotherapy or combination therapy with other drugs when metformin is not tolerated
or contraindicated. DPP-4 inhibitors act mainly by increasing endogenous incretin hormone
concentrations. They stimulate insulin secretion and inhibit glucagon secretion in a glucose-
dependent manner with a significantly lower risk for hypoglycaemia than sulfonylureas.
Furthermore, DPP-4 inhibitors are weight neutral. Linagliptin is a DPP-4 inhibitor that is
eliminated by a hepatobiliary route, whereas the other DPP-4 inhibitors available today show a
renal elimination. Therefore, it can be used in normal kidney function as well as in all stages of
chronic kidney disease to stage 5 (glomerular filtration rate <15 ml/min/1.73 m2) without dose
adjustments. Linagliptin was noninferior to metformin and sulfonylureas in clinical studies.
In recent studies, it showed a superior safety profile over sulfonylurea treatment regarding
hypoglycaemia and weight gain. More patients reached an HbA1c <7% without hypoglycaemia
and weight gain with linagliptin compared with glimepiride. The safety profile with respect to a
composite cardiovascular endpoint and stroke was also favourable for linagliptin, most likely
due to a higher incidence of hypoglycaemia associated with glimepiride therapy and titration.
This review gives an overview on the efficacy and safety of linagliptin in comparison with other
antidiabetic drugs in type 2 diabetes patients with renal and cardiovascular risk factors as well
as an outlook on the perspective for linagliptin in this patient population in the future.

Keywords:  cardiovascular risk, DPPP-4 inhibitors, incretin-based therapies, linagliptin, oral

antidiabetic drugs, renal impairment, type 2 diabetes

Introduction present. The phenomenon that orally ingested Correspondence to:

Prof. Baptist Gallwitz, MD
Dipeptidyl-peptidase-IV (DPP-4) inhibitors have glucose leads to a higher insulin response than an Department of Medicine
become important oral antidiabetic agents as sec- isoglycaemic intravenous glucose administration IV, Eberhard-Karls-
University Tübingen,
ond line therapy when patients do not reach their has been termed the incretin effect. GLP-1 and Otfried-Müller Strasse 10,
glycaemic targets with metformin alone or as first GIP are hormones responsible for this effect 72076 Tübingen, Germany
baptist.gallwitz@med.
line therapy when metformin is not tolerated or [Drucker and Nauck, 2006]. In type 2 diabetes, uni-tuebingen.de
contraindicated. Sitagliptin was the first sub- the incretin effect is diminished [Nauck et  al.
stance to be approved in 2006, followed by vilda­­ 1993], however supraphysiological concentra-
gliptin, saxagliptin, linagliptin and alogliptin tions of GLP-1still exert the typical insulinotropic
[Gallwitz, 2007, 2013]. DPP-4 inhibitors belong and glucagonostatic actions in a glucose depend-
to the incretin-based therapies. The incretin hor- ent manner, while GIP has lost its insulinotropic
mones glucagon-like peptide-1 (GLP-1) and gas- action [Drucker and Nauck, 2006; Nauck et al.
tric inhibitory polypeptide (GIP) are secreted 1993]. Both incretin hormones possess a bio-
from the intestinal L- and K-cells after a meal, logical half-life of only 1–2 minutes due to rapid
respectively. Insulin secretion is stimulated via enzymatic degradation by DPP-4. GLP-1 is the
these incretin hormones when hyperglycaemia is substrate with the highest affinity for DPP-4

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Therapeutic Advances in Endocrinology and Metabolism 4 (3)

[Deacon et  al. 1998; Mentlein et  al. 1993; 2013]. A distinct pathophysiological mechanism
Mentlein, 1999]. DPP-4 inhibition leads to an explaining these elevated risks for incretin-based
approximately threefold elevation of endogenous therapies has not been identified. However, large
GLP-1 plasma concentrations that contribute sig- controlled retrospective studies that were under-
nificantly to the glucose-dependent stimulation of taken to investigate this hypothesis further have
insulin secretion and inhibition of glucagon secre- not so far shown a difference in the pancreatitis
tion [Ahren et  al. 2002; Deacon et  al. 1998; risk or pancreatic cancer risk for the incretin-based
Drucker and Nauck, 2006]. In recent years, addi- therapies [Dore et al. 2009; Engel et al. 2010; Garg
tional, nonglycaemic effects of GLP-1 have been et al. 2010; Williams-Herman et al. 2010].
described that may be advantageous with respect
to the pathophysiology of type 2 diabetes: GLP-1 For most DPP-4 inhibitors, fixed dose combina-
has been shown to have cardiovascular effects tions with metformin are already available that
(e.g. improving left ventricular function, reducing have shown a good patient adherence. DPP-4
myocardial infarct sizes in artificial ischaemia inhibitors have been perceived as an important
models and lowering systolic blood pressure in addition to the treatment algorithm in type 2 dia-
hypertension in clinical studies) and to have neu- betes and have been placed as second and third
roprotective effects in animal models [Meier, line therapy among other agents in the recent
2012; Ussher and Drucker, 2012]. joint position statement of the American Diabetes
Association (ADA) and the European Association
Effective and safe medications for type 2 diabetes for the Study of Diabetes (EASD) [Inzucchi et al.
therapy are needed that are easy to use and to dis- 2012]. In this review article, the efficacy and
tribute because the number of patients affected by safety of linagliptin in patients with type 2 diabe-
this disease is rising dramatically on a global basis tes and common renal and cardiovascular risk
[IDF, 2011], especially in countries adopting life- factors is discussed, since linagliptin is a DPP-4
styles with less physical activity and high caloric inhibitor that is eliminated by a hepatobiliary
intake. Safe medications are needed with respect route, whereas the other DPP-4 inhibitors availa-
to a low risk for hypoglycaemias, because addi- ble today show a renal elimination. Furthermore,
tional counselling regarding frequent self control novel study outcomes have shown better out-
and monitoring may not be feasible. Further than comes with linagliptin compared with a conven-
that, the diabetes incidence increases both in a tional treatment with a sulfonylurea. An outlook
geriatric population, where self-management is on the perspective for potential linagliptin use in
difficult and in younger patients that drive vehicles this patient population in the future is also given.
or with occupations with the need for continu-
ously high attentiveness. Furthermore, frequent
glucose monitoring necessitated by diabetes ther- Chemistry and pharmacology of linagliptin
apy with an intrinsic hypoglycaemia risk or man- Linagliptin is a xanthine-based DPP-4 inhibitor
datory monitoring of organ functions with and was developed by Boehringer Ingelheim
additional laboratory tests (e.g. for renal or hepatic Pharmaceuticals (Ingelheim, Germany). DPP-4
function) would be associated with additional inhibition by linagliptin is competitive and revers-
costs on healthcare systems. DPP-4 inhibitors ible with a slow rate of dissociation from the active
seem to fulfil most of these requirements since center of DPP-4 [Thomas et al. 2008]. The selec-
they have shown noninferiority to sulfonylureas tivity of linagliptin towards DPP-4 is approxi-
regarding efficacy together with a low risk of hypo- mately 40,000-fold higher towards DPP-4
glycaemia, body weight neutrality and their mostly compared with other enzymes of this peptidase
once daily dosing in a standard dose without a family. Linagliptin does not inhibit the cytochrome
necessary titration. Beyond that, DPP-4 inhibitors P450 (CYP450) enzymes (IC50 >50 μM)
have demonstrated a low rate of adverse events [Eckhardt et al. 2008; Gallwitz, 2011].
and a good tolerability. The translation of the ben-
eficial nonglycaemic cardiovascular effects of Linagliptin is excreted by approximately 90% in
GLP-1 is also debated as a potential pharmaco- unmetabolized form via the faeces by a hepatobil-
logical advantage of the DPP-4 inhibitors iary route, while only 1–6% is eliminated via the
[Gallwitz, 2013]. Some concerns have been raised kidney and urine [Fuchs et al. 2009; Heise et al.
connecting incretin-based therapies with an ele- 2009; Huttner et  al. 2008]. At therapeutic con-
vated risk for developing acute pancreatitis or even centrations, linagliptin is almost completely
pancreatic cancer [Elashoff et al. 2011; Singh et al. bound to plasma proteins [Fuchs et  al. 2009].

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 B Gallwitz

Steady state concentrations are reached within increased risk of hypoglycaemia and weight gain,
2–5 days after once daily administration of lina- glimepiride treatment might be associated with a
gliptin. In once-daily dosing, linagliptin led to a higher risk for negative cardiovascular outcomes
maximal DPP-4 inhibition of 90% with doses of compared with linagliptin [Gallwitz et al. 2012].
5 mg at steady state with approximately 85% inhi- Besides being an important study for the phase III
bition still remaining after 24 hours post dose programme of linagliptin, this study prospectively
[Heise et al. 2009]. No relevant drug–drug inter- assessed cardiovascular safety. A masked inde-
actions between linagliptin and metformin, other pendent clinical event committee evaluated the
widely used antidiabetic medications or drugs for prespecified criteria for adjudication endpoints
other indications were detected [Graefe-Mody (cardiovascular death, stroke, myocardial infarc-
et al. 2010]. tion and admission to hospital for unstable
angina). In this head-to-head study, the addition
Pooled study data investigated the peak and trough of linagliptin achieved basically similar glycaemic
concentrations in patients with varying degrees of reductions compared with glimepiride in patients
chronic kidney disease (CKD). Data were inadequately controlled by metformin monother-
obtained from phase III studies from 969 patients apy, but was associated with much less hypogly-
who were determined by estimated glomerular fil- caemia and weight reduction. Prospectively
tration rate (eGFR) to have normal renal function captured and adjudicated major cardiovascular
(n = 438), CKD stage 2 renal impairment (RI) events occurred in 12 (2%) of 776 patients treated
(n = 429), CKD stage 3 RI (n = 44), or stage 4 RI with linagliptin and 26 (3%) of 775 patients
(n = 58). In patients with normal renal function, treated with glimepiride, resulting in a relative risk
the geometric mean linagliptin trough concentra- (RR) reduction of 0.46 [95% confidence interval
tion (coefficient of variation) was 5.93 nmol/l (CI) 0.23–0.91; p = 0.0213] compared with glime-
(56.3%); in patients with stage 2, 3, or 4 of CKD, piride, corresponding to a number needed to treat
geometric mean concentrations were 6.07 nmol/l (NNT) of 55.3 patients. This finding was mainly
(62.9%), 7.34 nmol/l (58.6%) and 8.13 nmol/l attributable to a significantly lower number of
(49.8%), respectively. In patients with type 2 dia- nonfatal strokes in patients on linagliptin com-
betes, CKD had a minor effect on linagliptin pared with glimepiride (RR 0.27, 95% CI 0.08–
exposure. Therefore, neither dose-adjustment nor 0.97; p = 0.0315) without any relation to a
drug-related monitoring of eGFR is necessary for hypoglycaemic event. Whether these findings are
patients with RI [Friedrich et al. 2013]. explained by a lower cardiovascular risk related to
the mode of action of the DPP-4 inhibitor lina-
gliptin and GLP-1 related effects [Frederich et al.
Linagliptin, cardiovascular safety and risk 2010; Schweizer et  al. 2010; Williams-Herman
factors et al. 2010] or by an increased cardiovascular risk
GLP-1 receptors are not only expressed on pan- associated with the use of sulfonylureas that has
creatic β-cells, but also on cardiomyocytes and in also been shown in some (but not all retrospective
the vasculature [Ban et  al. 2008; Ussher and analyses of sulfonylurea safety studies [Tzoulaki
Drucker, 2012]. In patients with myocardial et al. 2009] is not clear. In the context of the over-
infarction, an intravenous infusion of human all clinical benefit of glucose-lowering medications
GLP-1 significantly improved parameters of left for type 2 diabetes, hypoglycaemia may worsen
ventricular function [Nikolaidis et al. 2004; Sokos patients’ morbidity and mortality, and clearly
et al. 2006]. An artificial myocardial ischemia in affects their adherence to therapy and quality of
rats was used to investigate potential cardiovascu- life [Amiel et  al. 2008]. Weight gain is another
lar effects of linagliptin. A significant reduction of undesirable effect that may potentially increase
infarcted tissue and infarction size was observed patients’ already elevated risk for cardiovascular
with linagliptin administration that was followed disease [Eeg-Olofsson et al. 2009]. Achieving gly-
by a significant elevation of endogenous GLP-1 caemic control without hypoglycaemia or weight
plasma concentrations [Hocher et al. 2012]. gain, therefore, is increasingly considered impor-
tant for individualising therapies and may improve
In a comparative clinical phase III study, patients long-term clinical outcomes [Gallwitz et al. 2013;
with type 2 diabetes not optimally controlled on Inzucchi et al. 2012].
metformin alone received either linagliptin or
glimepiride as add on therapy. The rationale and In order to further determine the cardiovascu-
hypothesis in this 2-year trial was that, due to an lar safety of linagliptin, a meta-analysis of the

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Therapeutic Advances in Endocrinology and Metabolism 4 (3)

cardiovascular risk associated with linagliptin ver- on the Modification of Diet in Renal Disease
sus placebo or active comparators in patients with (MDRD) equation] in this study was comparable
type 2 diabetes participating in the linagliptin with that from previous studies including the
phase III study programme was performed. This National Health And Nutrition Examination
was a prespecified meta-analysis in which sus- Survey (NHANES) population from the United
pected cardiovascular events were prospectively States in 2009 [ US Renal Data System (USRDS),
captured and adjudicated in a blinded fashion by 2009; Williams et al. 2002]. In general, the study
an independent cardiovascular expert committee population characteristics were comparable with
[Johansen et al. 2012]. In total, 8 studies with >12 those of previous studies. The incidence rates (per
weeks’ duration were included in this meta- 1000 patient-years) for the primary cardiovascu-
analysis. A prespecified list of trigger events (the lar endpoint were 5.3 for linagliptin versus 16.8
Standard MedDRA Queries for ischaemic heart for total comparators [Johansen et al. 2012].
disease and cerebrovascular disorders) and all
fatal events were identified for adjudication and Other cardiovascular meta-analyses reported
collected for the full or interim analyses. The pri- incidence rates for custom MACE ranging from
mary endpoint was a composite of cardiovascu- 5.8 to 14.6 with sitagliptin, saxagliptin or vilda-
lar death (including fatal stroke and fatal gliptin, and 9.0 to 14.1 with comparators
myocardial infarction), nonfatal stroke, nonfatal [Frederich et  al. 2010; Schweizer et  al. 2010;
myocardial infarction and hospitalization for Williams-Herman et  al. 2010]. All these meta-
unstable angina pectoris. The three secondary analyses reported relative risks for cardiovascular
endpoints were different cardiovascular compos- outcomes with DPP-4 inhibitors versus compara-
ites of cardiovascular death, nonfatal stroke, tors that were below 1.0, but not statistically rel-
nonfatal myocardial infarction, unstable angina evant throughout all studies. The reductions in
with or without hospitalization, stable angina risk were significant in the meta-analysis of lina-
pectoris and transient ischaemic attacks (TIAs). gliptin (HR 0.34, 95% CI 0.16–0.70) and in the
Risk estimates were calculated using several sta- analysis of saxagliptin 2.5–10 mg (HR 0.43, 95%
tistical methods including Cox regression analy- CI 0.23–0.80) [Frederich et  al. 2010; Johansen
sis. The main results show that of 5239 treated et al. 2012].
patients [mean ± standard deviation (SD)
HbA1c 8.0 ± 0.9%, age 58 ± 10 years, body Various mechanisms could explain the potential
mass index (BMI) 29 ± 5 kg/m2], 3319 received cardiovascular benefits for linagliptin. First, lina-
linagliptin once daily (5 mg 3159 patients; gliptin may confer the beneficial effects of
10 mg 160 patients) and 1920 received compar- improved glycaemic control, including the lower-
ators (placebo 977 patients; glimepiride 1–4 mg ing of postprandial glucose, without the poten-
781 patients; voglibose 0.6 mg 162 patients). tially harmful effects of weight gain or increased
The cumulative exposure (patient-years) was hypoglycaemia [Ansar et al. 2011; Dicker, 2011;
2060 for linagliptin and 1372 for comparator Gallwitz et al. 2012, 2013]. Second, the increased
drugs. Primary cardiovascular events occurred endogenous GLP-1 levels attained by linagliptin
in 11 (0.3%) patients receiving linagliptin and action may provide beneficial cardioprotection as
23 (1.2%) receiving the comparator therapies. data from mechanistic-, animal-and clinical stud-
The hazard ratio (HR) for the primary endpoint ies suggest that increased GLP-1 concentrations
showed significantly lower risk with linagliptin can improve lipid metabolism and profiles,
than comparators (HR 0.34, 95% CI 0.16–0.70) reduce infarct size and improve cardiac function
as did estimates for all secondary endpoints (HR [Ansar et al. 2011; Ban et al. 2009]. Third, DPP-4
ranging from 0.34 to 0.55, all upper 95% CIs acts not only on incretins as substrates but also
<1.0) [Johansen et al. 2012]. on vasoactive peptides involved in inflammation,
immunity and cardiovascular function. Some
This cardiovascular meta-analysis also indicates studies, mostly in a preclinical setting, show that
that linagliptin may have a beneficial or neutral reduced DPP-4 activity can diminish inflamma-
impact on cardiovascular outcomes in a large tion, stimulate endothelial repair and decrease
population of type 2 diabetes patients compared ischaemic injury [Fadini and Avogaro, 2011].
to therapy with a sulfonylurea or a α-glucosidase Lastly, linagliptin holds inherent anti-oxidative
inhibitor. The incidence rates of previous myocar- properties, most likely due to its xanthine-based
dial infarction, previous strokes and RI [based molecular structure with further positive effects

98 http://tae.sagepub.com
 B Gallwitz

on the vasculature [Brownlee, 2005; Johansen requiring dialysis [Eckhardt et al. 2008; Kothny
et al. 2012; Kroller-Schon et al. 2012]. et al. 2012; National Kidney Foundation, 2012;
Nowicki et al. 2011a; Taskinen et al. 2011].
The meta-analysis with linagliptin, however, has
a couple of limitations. Despite a large total A recently published study investigated the long-
patient exposure of 3432 years, the duration of term efficacy, safety and tolerability of linagliptin
individual patient exposure was only 1.7 years. compared with placebo when administered in
Furthermore, the low incidence of cardiovascu- combination with existing glucose-lowering
lar events, low rates of triple oral therapy and background therapy in patients with type 2 dia-
lack of insulin treatment all suggest that a large betes and severe RI over 52 weeks [McGill et al.
proportion of patients had less progressed type 2 2013]. In this 1-year, double-blind study, 133
diabetes with a lower cardiovascular risk than patients with type 2 diabetes and severe RI
those with more advanced type 2 diabetes. (eGFR <30 ml/min/1.73 m2) and an HbA1c
However, approximately 30% of patients had a between 7.0 to 10.0% at screening were rand-
baseline Framingham 10-year cardiovascular omized to linagliptin 5 mg (n = 68) or placebo
risk score of >15% and more than a 50% also (n = 65) once daily, added to existing background
had >5 years’ known disease duration, which therapy. The primary efficacy endpoint was
indicates a proportion of the population were at HbA1c change from baseline to week 12. The
increased cardiovascular risk. Finally, the efficacy and safety endpoints were assessed after
observed cardiovascular risk reductions for the 1 year. At week 12, the adjusted mean HbA1c
primary and secondary endpoints were influ- significantly decreased by –0.76% with linaglip-
enced by the differences in cardiovascular events tin compared with –0.15% with placebo (treat-
in the head-to-head study with linagliptin versus ment difference, –0.60%; 95% CI –0.89 to –0.31;
glimepiride as add on to metformin [Gallwitz p < 0.0001). The HbA1c improvements were sus-
et al. 2012; Johansen et al. 2012]. Despite this, it tained with linagliptin (–0.71%) over placebo
is important to note that glimepiride is an estab- (–0.01%) at 1 year (treatment difference –0.72%,
lished and recommended second line therapy 95% CI –1.03 to –0.41; p < 0.0001). The mean
with a well-characterized safety profile, which insulin doses decreased by –6.2 units with lina-
has not been directly linked to increased cardio- gliptin and -0.3 units with placebo. The overall
vascular risk either as part of intensive treatment adverse event incidence was similar over 1 year
regimens or when compared with other conven- (94.1% versus 92.3%) while the incidence of
tional treatments [Johansen et  al. 2012; Selvin severe hypoglycaemia with linagliptin and pla-
et  al. 2008]. Moreover, analysis of the pooled cebo was comparably low (3 patients per group).
placebo studies alone confirmed that linagliptin Linagliptin and placebo had little effect on renal
did not increase cardiovascular risk compared to function (median change in eGFR, –0.8 versus
placebo [Johansen et al. 2012]. –2.2 ml/min/1.73 m2) and no drug-related renal
failure occurred. The incidence of adjudicated
cardiovascular events was similar in both groups
Linagliptin in patients with type 2 diabetes [McGill et al. 2013].
and CKD
Table 1 summarizes the pivotal trials with lina- In this study, adding linagliptin to glucose-
gliptin [Gallwitz, 2013]. Linagliptin is the first lowering background therapy provided a clini-
DPP-4 inhibitor available that is mainly elimi- cally significant placebo corrected reduction of
nated via a hepatobiliary route and only approxi- 0.7% in HbA1c after 52 weeks in patients with
mately 5% of linagliptin are excreted with the type 2 diabetes and severe RI. This finding is in
urine in unmetabolized form [Blech et al. 2010; line with previous 24-week studies that reported
Heise et al. 2009]. Therefore, there is no need for that linagliptin (5 mg once daily) used either
a dose adjustment of linagliptin in patients with alone or in combination with oral diabetes med-
CKD [Deacon and Holst, 2010; Graefe-Mody ications was associated with placebo-corrected
et al. 2011]. Dose adjustments are recommended HbA1c reductions ranging from 0.5% to 0.9%
for the other DPP-4 inhibitors sitagliptin, saxa- in patients with uncontrolled type 2 diabetes
gliptin and vildagliptin in patients with a creati- and normal renal function or mild to moderate
nine clearance of less than 50 ml/min, including RI [Del Prato et  al. 2011; Gomis et  al. 2011;
patients with end stage renal disease (ESRD) Kawamori et  al. 2012; Taskinen et  al. 2011].

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 Table 1.  Important clinical studies in the phase III programme with linagliptin (studies with ≥24 weeks duration).

Reference Background Comparator(s) [n randomized] / Baseline HbA1c HbA1c change from baseline Placebo/ comparator Duration [weeks]
therapy treatment arms [%] (±SD) [%](±SD or 95% CI) corrected HbA1c
reduction [%]
Del Prato Therapy naïve/ Placebo [n = 167]   8.0 ± 0.91 –0.46 ± 0.73 (12 weeks) n.r. (12 weeks)  12
et al. washout 1 Linagliptin 5 mg [n = 333] –0.44 ± 0.91 (24 weeks) –0.69 + 0.08 (24  24
[2011] previous OAD weeks)
Kawamori Therapy naïve/ Placebo [n = 80]   7.95 ± 0.67   0.63 (0.08)(SE) 12 versus placebo
et al. washout 1–2 Linagliptin 5 mg [n = 159]   8.07 ± 0.66 –0.24 (0.06)(SE) versus PBO –0.87 (–1.04, –0.70) 26 versus VO
[2012] previous OAD Linagliptin 10 mg [n = 160]   7.98 ± 0.68 –0.25 (0.06)(SE) versus PBO –0.88 (–1.05, –0.71)
Voglibose [0.2 mg tid]   8.02 ± 0.71   0.19 (0.07) –0.32 (–0.49, –0.15)
Linagliptin 5 mg [n = 159] s.a. –0.13 (0.07)(SE) versus VO –0.39 (–0.56, –0.21)
Linagliptin 10 mg [n = 160] s.a. –0.19 (0.07)(SE) versus VO
Taskinen Add on to Placebo [n = 177]   8.02 ± 0.07   0.15 ± 0.06 –0.64 (–0.78, –0.50)
Therapeutic Advances in Endocrinology and Metabolism 4 (3)

et al. metformin Linagliptin 5 mg [n = 524]   8.09 ± 0.04 –0.49 ± 0.04 24

[2011]
Owens Add on to Placebo [n = 265]   8.14 (0.05)(SE) –0.62 (–0.73, –0.50)
et al. metformin plus Linagliptin 5 mg [n = 793]   8.15 (0.03)(SE) n.r. 24
[2011] sulfonylurea
Gallwitz Add on to Linagliptin 5 mg [n = 776]   7.17 (0.04)(SE) –0.56 (0.03)(SE)   0.08 (0.04)(SE)
et al. metformin Glimepiride mean dose 3 mg (week   7.31 (0.04)(SE) –0.63 (0.03)(SE) (Completers cohort) 104
[2012] 28–104) [n = 775]
Haak et al. Initial combination Placebo [n = 72]   8.7 ± 1.0   0.1 ± 0.1
[2012] with metformin Linagliptin 5 mg [n = 142]   8.7 ± 1.0 –0.5 ± 0.1 –0.6 ± 0.1
Metformin 500 mg bid [n = 144]   8.7 ± 0.90 –0.6 ± 0.1 –0.8 ± 0.1 24
Metformin 1000 mg bid [n = 147]   8.5 ± 0.90 –1.1 ± 0.1 –1.2 ± 0.1
LINA 2.5 mg + MET 500 mg bid [n = 143]   8.7 ± 1.0 –1.2 ± 0.1 –1.3 ± 0.1
LINA 2.5 mg + MET 1000 mg bid [n = 143]   8.7 ± 1.0 –1.6 ± 0.1 –1.7 ± 0.1
Open label LINA + MET [n = 66] 11.8 ± 1.4 –3.7 n.r.
Gomis Initial combination Placebo + pioglitazone [n = 130]   8.58 (0.08)(SE) –0.56 (0.09)(SE)
et al. with pioglitazone Linagliptin 5 mg + pioglitazone [n = 259]   8.60 (0.05)(SE) –1.06 (0.06) –0.51 (0.10)(SE) 24
[2011] (30 mg)
CI, confidence interval; LINA, linagliptin; MET, metformin; n.r., not reported, OAD, oral antidiabetic drug; PBO, placebo; SD, standard deviation; SE, standard error; tid, three times a
day; VO, voglibose; s.a., see above.

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 B Gallwitz

These studies have shown the efficacy of lina- Perspectives for linagliptin concerning
gliptin to improve HbA1c in patients with renal cardiovascular outcomes
function ranging from normal to severe CKD Although the results of the different meta-analyses
[McGill et al. 2013]. of DPP-4 inhibitors are not entirely comparable
(due to differences in primary composite end-
The studies on the efficacy and safety of the other points and cardiovascular adjudication methods),
DPP-4 inhibitors (saxagliptin, sitagliptin and vilda­ all are supportive of the hypothesis that, in gen-
gliptin) are difficult to compare with this study eral, DPP-4 inhibitor treatment does not have a
due to different study designs and patient popula- deleterious impact on the incidence of cardiovas-
tions [McGill et al. 2013]. The HbA1c reductions cular events. The present analysis shows that lina-
in patients with type 2 diabetes and moderate or gliptin treatment does not increase cardiovascular
severe RI with linagliptin were similar, or greater, risk and may even yield cardiovascular benefits in
than those seen with other DPP-4 inhibitors patients with type 2 diabetes mellitus. Meta-
[Kothny et al. 2012; Nowicki et al. 2011a, 2011b]. analyses of other DPP-4 inhibitors were frequently
In contrast to other DPP-4 inhibitors, linagliptin retrospective in nature. However, the prespecified
does not require dose adjustment in patients with design of the present meta-analysis involved pro-
severe CKD, whereas a recent study reported that spective and blinded adjudication of cardiovascu-
sitagliptin was frequently used at inappropriate lar events, which should strengthen the validity of
doses in patients with type 2 diabetes and RI, and the current findings. In addition, this meta-analy-
only 15% of patients with moderate to end stage sis was based on individual patient data from a
RI received recommended doses [Meyers et  al. consistently designed, large clinical development
2011]. The fasting plasma glucose reductions programme; this allows consistent derivation of
observed with linagliptin over placebo do not seem endpoints and extensive subgroup analyses and
to fully account for the HbA1c change, suggesting minimizes between study heterogeneity that can
that postprandial glucose reductions, which can confound analyses of unrelated studies.
occur with incretin-based therapies, must have
made more substantial contributions than fasting In summary, this pre-specified cardiovascular
plasma glucose reductions. This contention is sup- meta-analysis of a large phase III programme that
ported by previous observations of linagliptin’s involved prospective and independent adjudica-
positive effects on postprandial glucose [Del Prato tion of cardiovascular events provides valuable
et  al. 2011; Monnier et  al. 2003; Taskinen et  al. new insights on the cardiovascular safety profile of
2011]. Long-term improvements in glycaemic linagliptin. Although a meta-analysis, with distinct
control with linagliptin were associated with a limitations, the data indicate that linagliptin does
trend toward decreases in background insulin not increase cardiovascular risk and, moreover,
therapy in the current study [McGill et al. 2013]. support a potential reduction of cardiovascular
This may help to improve diabetes management events with linagliptin compared with pooled
and to lower the hypoglycaemia risk, but warrants comparators. These results suggest that linagliptin
further studies to determine the extent of this may be a valuable new therapeutic option for
effect. Along with a previous finding that linaglip- improving glycaemic control in patients with type
tin exposure did not vary in patients with normal, 2 diabetes mellitus. The hypothesis that linagliptin
mild or moderate CKD, the pharmacokinetic data may have cardiovascular benefits is currently being
from this study confirm that linagliptin is not tested prospectively in the CAROLINA study
expected to accumulate at any degree of impaired (NCT01243424), the first large outcomes study
renal function [McGill et al. 2013]. In progressive to directly compare a DPP-4 inhibitor versus a sul-
renal failure and advanced cardiovascular disease, fonylurea (glimepiride), predominantly as second
glycaemic control is more difficult to achieve with- line therapy (i.e. on a background of metformin).
out adverse effects because of the increased risk of
hypoglycaemia due to reduced renal gluconeogen- Glycaemic control is fundamental to diabetes
esis on the one hand and the retarded clearance of management. Several large clinical trials have
insulin as well as of some antihyperglycaemic demonstrated an association between hypergly-
agents and their metabolites on the other hand caemia and the progression of microvascular
[Ritz, 2011]. This study showed that symptomatic complications, such as cardiovascular disease, in
hypoglycaemic events and severe hypoglycaemic patients with type 2 diabetes [UKPDS Group
episodes occurred at similar rates in the linagliptin 1998a, 1998b; Ohkubo et  al. 1995]. However,
and placebo groups [McGill et al. 2013]. antihyperglycaemic treatment options are limited

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Therapeutic Advances in Endocrinology and Metabolism 4 (3)

in patients with type 2 diabetes and cardiovascu- and Takeda. He has also received honoraria from
lar disease because many oral glucose-lowering these companies for giving lectures.
agents are cleared by the kidney. Therefore, in
patients with severe RI, most of these therapies are
either not recommended or contraindicated (e.g.
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