Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor

Bergman, Arthur; Côté, Josée; Yi, Bingming; Marbury, Thomas; Swan, Suzanne K.; Smith, William B.; Gottesdiener, Keith; Wagner, John A.; Herman, Gary

doi:10.2337/dc06-2545

Cited by 183 publications

(136 citation statements)

References 5 publications

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“…The effects of CKD on fu have been reported for some drugs with medium to high protein binding capacities such as cefazolin, pemetrexed, and sitagliptin. 20,25,66 There were no differences between the fu values measured in healthy volunteers and patients with CKD for pemetrexed (fu = 0.23) and sitagliptin (fu = 0.64). 20,66 The values of fu of cefazolin increased from 0.16 to 0.28 in patients with CKD Stage 4.…”

Section: Clinical Evidence Supporting the Role Of Uremic Solutes In Mmentioning

confidence: 88%

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

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One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

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Section: Clinical Evidence Supporting the Role Of Uremic Solutes In Mmentioning

confidence: 88%

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

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“…Exposure to sitagliptin and saxagliptin increases proportionately with reducing renal function but has not been associated with an increased incidence of adverse effects. 13,14 Use of doses outwith the product licence also has potential medicolegal implications for prescribers. In a patient population where renal function tends to decline, prescribers should be aware of the potential risks involved in failing to adjust the dose.…”

Section: Dose Adjustment In Renal Impairmentmentioning

confidence: 99%

Dipeptidyl peptidase 4 inhibitors in routine clinical practice: experiences from a Scottish teaching hospital

et al. 2014

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Aims: This study aimed to assess the effect of dipeptidyl peptidase 4 inhibitors (DPP4i) on glycaemia and weight control and review adherence to renal dosing guidance in routine clinical practice. Methods: A retrospective review of type 2 diabetes patients prescribed a DPP4i was undertaken in a general hospital. Date, type and dose of DPP4i, HbA1c, weight and renal function were recorded at initiation of DPP4i therapy and at the first follow-up appointment at least 3 months later.

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“…Because sitagliptin is essentially excreted via the kidney, a study evaluated the PK of single doses of sitagliptin in patients with various degrees of renal insufficiency (RI) [37]. According to the results of this study, the recommended sitagliptin dosage adjustments are as follows: no adjustment for patients with mild RI (creatinine clearance 50-80 ml/min), a twofold decrease in the clinical dose of 100 mg q.d.…”

Section: Sitagliptinmentioning

confidence: 99%

“…Because of the PK characteristics of sitagliptin [37], to achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate RI should receive sitagliptin 50 mg once daily and patients with severe RI 25 mg once daily. When using such dose adjustment, sitagliptin was generally well tolerated and provided effective glycemic control in patients with T2DM and moderate to severe RI [75].…”

Section: Atorvastatin-sitagliptin Coadministrationmentioning

confidence: 99%

Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes

Scheen

2012

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Patients with type 2 diabetes (T2DM) are exposed to a high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing CVD events in T2DM patients. Dipeptidylpeptidase-4 inhibitors (gliptins), which are increasingly used to target hyperglycemia, also offer promising preliminary results regarding a possible reduction in CVD events. As most patients with T2DM may be treated with both a statin and a gliptin, dual pharmacological therapy, possibly as a fixed-dose combination (FDC), deserves further consideration. Areas covered: The reader is provided with an update of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin and sitagliptin. The article provides an analysis of the potential PK/PD interactions between the two compounds and puts into perspective the potential cardiovascular protection that such a dual therapy may offer in patients with T2DM. Expert opinion: Atorvastatin and sitagliptin are not prone to PK drug-drug interactions. Their coadministration, either separately or in an FDC, improves both blood glucose levels and cholesterol concentrations, without clinically relevant adverse events. The atorvastatin plus sitagliptin combination may be used to reduce LDL cholesterol and hyperglycemia in patients with T2DM, with the aim to improve CVD prognosis and adherence to therapy.Keywords : atorvastatin ; cardiovascular disease ; DPP-4 inhibitor ; pharmacokinetics ; sitagliptin ; type 2 diabetes mellitus Box 1. Drug summary.Published in: Expert Opinion on Drug Metabolism & Toxicology (2012), vol. 8, iss. 6, pp. 745-758. Status: Postprint (Author's version) Article highlights • Patients with type 2 diabetes mellitus (T2DM) are exposed to a high risk of cardiovascular disease (CVD) and most of them should receive a statin irrespective of their lipid profile.• In CARDS, but not in ASPEN, atorvastatin has proven its remarkable efficacy in improving lipid profile and reducing CVD events in patients with T2DM. Nevertheless, some recent data suggested that atorvastatin, like other statins, may slightly deteriorate glucose control and increase new-onset diabetes.• DPP-4 inhibitors (gliptins) are new incretin-based oral glucose-lowering agents that improve fasting and postprandial glucose levels (thus resulting in significant reduction in HbA1c), without promoting hypoglycemia or weight gain (two adverse events that may increase the CVD risk).• Sitagliptin, the first in class among DPP-4 inhibitors, slightly improves lipid profile (especially postprandially), besides its glucose-lowering activity, and may also exert other positive effects on cardiovascular system via increased GLP-1 levels.• The encouraging results obtained in Phase III program with less CVD events with sitagliptin than with comparators (placebo or active) triggers the large prospective cardiovascular outcome trial TECOS, in which numerous T2DM patients will probably be treated simultaneously with sitagliptin and atorvastatin (o...

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Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor

Cited by 183 publications

References 5 publications

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Dipeptidyl peptidase 4 inhibitors in routine clinical practice: experiences from a Scottish teaching hospital

Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes

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