REVIEW ARTICLE Pharmacokinetics and Clinical Use of Incretin-Based Therapies in Patients with Chronic Kidney Disease and Type 2 Diabetes Andre ´ J. Scheen Ó Springer International Publishing Switzerland 2014 Abstract The prevalence of chronic kidney disease (CKD) of stages 3–5 (glomerular filtration rate [GFR] \ 60 mL/min) is about 25–30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin- based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vil- dagliptin, saxagliptin, alogliptin) are predominantly excre- ted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in pro- portion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmaco- kinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP- 1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population. A. J. Scheen Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Lie `ge, Lie `ge, Belgium A. J. Scheen (&) Division of Diabetes Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman (B35), University of Lie `ge, 4000 Lie `ge, Belgium e-mail: [email protected]Clin Pharmacokinet DOI 10.1007/s40262-014-0198-2
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REVIEW ARTICLE
Pharmacokinetics and Clinical Use of Incretin-Based Therapiesin Patients with Chronic Kidney Disease and Type 2 Diabetes
Andre J. Scheen
! Springer International Publishing Switzerland 2014
Abstract The prevalence of chronic kidney disease(CKD) of stages 3–5 (glomerular filtration rate [GFR]
\60 mL/min) is about 25–30 % in patients with type 2
diabetes mellitus (T2DM). While most oral antidiabeticagents have limitations in patients with CKD, incretin-
based therapies are increasingly used for the management of
T2DM. This review analyses (1) the influence of CKD onthe pharmacokinetics of dipeptidyl peptidase-4 (DPP-4)
inhibitors and glucagon-like peptide-1 (GLP-1) receptor
agonists; and (2) the efficacy/safety profile of these agentsin clinical practice when prescribed in patients with both
T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vil-
dagliptin, saxagliptin, alogliptin) are predominantly excre-ted by the kidneys. Thereby, pharmacokinetic studies
showed that total exposure to the drug is increased in pro-
portion to the decline of GFR, leading to recommendationsfor appropriate dose reductions according to the severity of
CKD. In these conditions, clinical studies reported a good
efficacy and safety profile in patients with CKD. In contrast,linagliptin is eliminated by a predominantly hepatobiliary
route. As a pharmacokinetic study showed only minimal
influence of decreased GFR on total exposure, no doseadjustment of linagliptin is required in the case of CKD.
The experience with GLP-1 receptor agonists in patients
with CKD is more limited. Exenatide is eliminated by renalmechanisms and should not be given in patients with severe
CKD. Liraglutide is not eliminated by the kidney, but
it should be used with caution because of the limitedexperience in patients with CKD. Only limited pharmaco-
kinetic data are also available for lixisenatide, exenatide
long-acting release (LAR) and other once-weekly GLP-1receptor agonists in current development. Several case
reports of acute renal failure have been described with GLP-
1 receptor agonists, probably triggered by dehydrationresulting from gastrointestinal adverse events. However,
increasing GLP-1 may also exert favourable renal effects
that could contribute to reducing the risk of diabeticnephropathy. In conclusion, the already large reassuring
experience with DPP-4 inhibitors in patients with CKD
offers new opportunities to the clinician, whereas morecaution is required with GLP-1 receptor agonists because of
the limited experience in this population.
A. J. ScheenDivision of Clinical Pharmacology, Centre for InterdisciplinaryResearch on Medicines (CIRM), University of Liege, Liege,Belgium
A. J. Scheen (&)Division of Diabetes Nutrition and Metabolic Disorders,Department of Medicine, CHU Sart Tilman (B35),University of Liege, 4000 Liege, Belgiume-mail: [email protected]
Clin Pharmacokinet
DOI 10.1007/s40262-014-0198-2
Key Points
An increasing number of patients with type 2
diabetes mellitus have impaired renal function,especially in the elderly population, but the use of
glucose-lowering agents is challenging in these
patients who require a dosing adjustment or havecontraindications for safety reasons.
Although more recently available, dipeptidylpeptidase-4 inhibitors have been more carefully
saxagliptin–metformin [110], linaglipin–metformin [111]and alogliptin–metformin. Such FDCs may only be pre-
scribed when both compounds are not contraindicated
because of the presence of CKD and appropriate adjust-ments of individual doses may be required. There is some
controversy about the use of metformin in T2DM patients
with CKD, especially the level of eGFR beyond whichmetformin is contraindicated [5, 112]. The recent scientific
literature suggests that reconsidering the contraindications
of metformin is urgently needed in order to avoid physi-cians prescribing the most popular glucose-lowering
therapy in daily clinical practice outside the official rec-
ommendations [113]. Nevertheless, caution should berecommended when using a gliptin–metformin FDC in
patients with CKD [114].
GLP-1 receptor agonists may represent an alternative toinsulin therapy for patients not successfully treated with
oral antidiabetic agents [5, 115]. In the case of CKD,
insulin may be used without restriction. Because the hor-mone is largely clearly by the kidneys, caution is recom-
mended to the clinician as a reduction of daily insulin dose
may be necessary to avoid hypoglycaemia. However, theclinical experience of using insulin in CKD patients is
considerable, especially because basic oral glucose-lower-
ing agents such as metformin and many sulphonylureas areclassically contraindicated in presence of moderate to
severe CKD [18]. Concerning GLP-1 receptor agonists, the
pharmacokinetic data appear reassuring (Fig. 2), but theclinical experience in patients with CKD is still limited
[20]. No dosage adjustment of exenatide is required for
patients with mild to moderate CKD [90]. Indeed, therecommended starting dose of 5 lg twice daily was well
A. J. Scheen
Table 3 Clinical practice recommendations regarding the use ofdipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists in patients with type 2 diabetes mellitus
with various degrees of chronic kidney disease (CKD) according tothe glomerular filtration rate (GFR)
Incretin-basedtherapies
Exposure (AUC) in patients withCKD
Use according to GFR (mL/min)
Use in patients with ESRD andhaemodialysis
DPP-4 inhibitors
Sitagliptin Increased C50: yes Caution
30–50: half dose
\30: quarter dose
Vildagliptin Increased C50: yes Caution
\50: half dose
Saxagliptin Increased (? active metabolite) C50: yes No
\50: half dose
\30: caution
Alogliptin Increased C50: yes Caution
\50: reduced dose
Linagliptin No change Yes (without dose adjustment) Possibly yes (no data)
Gemigliptina Slightly increased Probably yes Possibly yes (no data)
GLP-1 receptor agonists
Exenatide Increased C60: yes No
30–60: caution
\30: no
Exenatide LAR Increased C60: yes No
30–60: caution
\30: no
Liraglutide No change (or slightly decreased) C50: yes No
\50: no
Lixisenatide Slightly increased C50: yes No
30–50: caution
\30: no
AUC area under concentration–time curve, ESRD end-stage renal disease, LAR long-acting releasea Limited experience because not available in Europe or in the USA
Table 4 Dose adjustments recommended when using incretin-based therapies in patients with various stages of chronic kidney disease (CKD)based on previous pharmacokinetic studies
CLCR creatinine clearance, ESRD end-stage renal disease, LAR long-acting release, NR not recommendeda Limited experience because not available in Europe or in the USA
Incretin-Based Therapy and Kidney Disease
tolerated in this population and any subsequent increase in
dosage would be based on the patient’s individual tolerance
and glycaemic response. However, as mean exenatideclearance was significantly reduced by about 70 % and a
single 5 lg dose of exenatide was not well tolerated in
patients with ESRD, exenatide may not be suitable for usein patients with severe CKD (CLCR \30 mL/min) or
ESRD, at least at the current therapeutic dose [92]. As far
as liraglutide is concerned, the available data indicated that
the pharmacokinetics of liraglutide are essentially inde-pendent of renal function [95]. However, lower exposure
with CKD cannot be excluded based on the available data
[95]. No safety concerns were raised in the availablepharmacokinetic and clinical studies. In particular, the
Fig. 1 Comparison ofgeometric mean ratios (with90 % confidence intervals whenavailable) of areas under plasmaconcentration–time curves (totalexposure) for sitagliptin,vildagliptin, saxagliptin and itsactive metabolite 5-hydroxy(OH)-saxagliptin, alogliptin,linagliptin and gemigliptin inpatients with mild (creatinineclearance [CLCR] 51–80 mL/min), moderate (CLCR
31–50 mL/min), severe (CLCR
B30 mL/min) chronic kidneydisease (CKD) and end-stagerenal disease treated byhaemodialysis compared withpatients with normal kidneyfunction (no CKD; CLCR
[80 mL/min). Grey barscorrespond to data after a singledose while hatched barscorrespond to data after multipledoses. Black bars correspond to5-OH-saxagliptin
A. J. Scheen
degree of CKD of subjects did not appear to be associatedwith an increased risk of adverse events, except perhaps a
trend for higher incidence of nausea [96]. Therefore, one
can expect that T2DM patients with CKD will be able touse standard treatment regiments for liraglutide without
dose adjustments [91]. Nevertheless, there is currentlylimited experience with liraglutide in patients beyond mild-
stage CKD and thus caution is required (Tables 2, 3) [95].
Published case reports have documented the relationshipbetween exenatide [116–121] or liraglutide [121–123] use
and acute kidney injury in patients with T2DM. Both acute
interstitial nephritis and acute tubular necrosis may accountfor GLP-1 receptor agonist-related acute renal failure
[121]. One of the proposed explanations was the occur-
rence of gastrointestinal side effects with recurrent vomit-ing leading to dehydration and secondary acute kidney
disease. Although prerenal acute kidney injury appears tobe exceptional with the use of GLP-1 receptor agonists,
physicians should be aware of this adverse event and
patients should also be educated about the need to quicklyreport unusual or prolonged gastrointestinal symptoms.
However, a retrospective cohort study of a large medical
Fig. 2 Comparison of geometric mean ratios (with 90 % confidenceintervals) of areas under plasma concentration–time curves forexenatide, liraglutide, lixisenatide and albiglutide in patients withmild (creatinine clearance [CLCR] 51–80 mL/min), moderate (CLCR
31–50 mL/min), severe (CLCR B30 mL/min) chronic kidney disease(CKD) and end-stage renal disease treated by haemodialysiscompared with patients with normal kidney function (no CKD; CLCR
[80 mL/min)
Incretin-Based Therapy and Kidney Disease
and pharmacy claims database revealed an increased inci-
dence of acute renal failure in diabetic versus nondiabeticpatients but no association between use of exenatide and
acute renal failure [124].
Finally, some experimental data suggested that incretin-based therapies may exert positive renal effects which
could exert some protection against the development or
worsening of diabetic nephropathy [24–26]. Clinical stud-ies supporting GLP-1-mediated renal protection exist, but
they are few and with limitations [97]. In the large pro-spective SAVOR-TIMI 53 cardiovascular outcomes trial,
microalbuminuria was positively influenced by saxagliptin
as compared with placebo. However, hard renal end pointswere similar in the saxagliptin group and placebo group,
possibly because of a too short follow-up period [68].
Therefore, the renoprotective potential of GLP-1 therapyneeds to be thoroughly investigated in humans.
7 Conclusion
The increasing prevalence of T2DM and CKD, especiallyamong elderly people, requires regular monitoring of renal
function and appropriate selection and dosing of glucose-
lowering agents according to GFR. A careful benefit/riskbalance assessment should be performed in these more
fragile diabetic patients. While carefully conducted phar-
macokinetic studies are lacking with most of the ancientcommonly prescribed oral glucose-lowering agents, nice
pharmacokinetic studies have been recently published with
almost all incretin-based medications. The pharmacoki-netics of DPP-4 inhibitors (except linagliptin) and GLP-1
receptor agonists (especially exenatide) are modified by
CKD, which may require appropriate dose reductions. Theclinical experience with DPP-4 inhibitors in T2DM
patients with CKD is already quite substantial and the
efficacy–safety profile has been demonstrated in manycontrolled studies using appropriate dose adjustment
according to GFR decline when requested. Of interest,
patients with CKD represent a specific subpopulation thatmay take advantage of using a DPP-4 inhibitor instead of a
sulphonylurea in order to reduce the potential risk of
hypoglycaemia. The clinical experience with GLP-1receptor agonists is more limited and so the use of exe-
natide, liraglutide or lixisenatide should be cautious in
patients with CKD until further studies are availabledemonstrating the efficacy and safety of these medications
in patients with moderate to severe CKD.
Funding and conflict of interest No sources of funding were usedto assist in the preparation of this manuscript. No conflicts of interestare directly relevant to the content of this manuscript.
A. J. Scheen has received lecture/advisor/clinical investigator feesfrom AstraZeneca/BMS, Boehringer Ingelheim, Eli Lilly,
GlaxoSmithKline, Janssen, Merck Sharp and Dohme, Novartis,NovoNordisk, Sanofi-Aventis and Takeda.
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