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Is There Evidence of Any Safety Differences Among DPP-4 Inhibitors in the Treatment of People with Type 2 Diabetes Mellitus and Reduced GFR Due to Chronic Kidney Disease?

Evans M, Dejager S, Schweizer A, Foley JE - Diabetes Ther (2015)

View Article: PubMed Central - PubMed

Affiliation: University Hospital Llandough, Cardiff, UK, marcevans4@sky.com.

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Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD) globally... Unlike linagliptin, with other DPP-4 inhibitors the drug exposure increases with decreasing renal function (Fig.  1)... Thus, doses or dose frequencies are recommended to be reduced according to standard renal thresholds... The dose adjustments thus require regular monitoring of renal function, which is also good clinical practice because in these patients it is important to closely monitor renal disease progression... In a recent review article on linagliptin, the authors state that “other widely available DPP-4 inhibitors are excreted predominantly via the kidneys and require consideration/adjustment of dose or are not recommended in patients with moderate or severe RI or ESRD requiring dialysis”... Such statements may cast doubt over the suitability of DPP-4 inhibitors other than linagliptin in treating patients with RI, implying that failure to adequately adjust the dose of these DPP-4 inhibitors may be associated with an increased risk of adverse effects and even nephrotoxicity... A key issue, therefore, is whether this failure in appropriate DPP-4 inhibitor dose adjustment in line with renal function translates into clinically meaningful consequences? Such concerns are further compounded by the fact that many other commonly prescribed drugs are associated with potential renal toxicity particularly when there is an increase in pharmacological exposure due to reduced clearance or catabolism... Finally, with regard to the risk of hypoglycemia with DPP-4 inhibitors, if the dose is not adjusted according to the label in patients with moderate/severe RI, it should be appreciated that DPP-4 inhibitors do not enhance hypoglycemia risk per se because elevations in glucagon-like peptide-1 and glucose insulinotropic polypeptide modulate insulin and glucagon secretion in a glucose-sensitive manner... Thus, recommendations to reduce the dose or dose frequency of DPP-4 inhibitors in patients with RI are not based on a risk of adverse effects or renal toxicity, but are aimed towards achieving drug exposure that yields the maximum efficacy... In conclusion, DPP-4 inhibitors represent an appealing treatment option for the management of blood glucose control in people with T2DM and CKD... It is important to remember that there is a continuum of renal function in patients with diabetes, with declining renal function associated with increasing age... The routine monitoring of renal function thus represents good clinical care of people with diabetes, beyond an appropriate dose adjustment of DPP-4 inhibitor... While there may be differences in the pharmacological profiles of the individual DPP-4 inhibitors in relation to renal function, there is no evidence that these translate into differences in terms of efficacy, safety, and nephrotoxic potential.

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Related in: MedlinePlus

Renal function threshold and recommended dose of DPP-4 inhibitors in renal impairment patients. b.i.d. twice daily, DPP-4 dipeptidyl peptidase-4, GFR glomerular filtration rate, o.d. once daily, Rl renal impairment
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Fig1: Renal function threshold and recommended dose of DPP-4 inhibitors in renal impairment patients. b.i.d. twice daily, DPP-4 dipeptidyl peptidase-4, GFR glomerular filtration rate, o.d. once daily, Rl renal impairment

Mentions: Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD) globally. Multiple risk factor management is essential in such patients to delay the disease progression [1]; however, the management of blood glucose presents a particular challenge, with limited treatment options available beyond exogenous insulin therapy [2–5]. Patients with T2DM and CKD are at particular risk of hypoglycemia and its adverse consequences. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide a simple, oral, glucose-sensitive treatment option that does not increase the risk of hypoglycemia and does not confound the comorbidities that afflict many of the other drugs used to treat T2DM [2]. In addition, DPP-4 inhibitors have been shown to be associated with no further decline in estimated glomerular filtration rate (eGFR) when treating patients with CKD [2]. In recent years, several DPP-4 inhibitors have become available and have been extensively evaluated in patients with T2DM and varying degrees of renal impairment (RI). These studies have demonstrated good efficacy and tolerability of the DPP-4 inhibitor class in these patients, and have subsequently led to regulatory approval for the use in patients with T2DM and reduced eGFR due to CKD. Indeed, only exogenous insulin and DPP-4 inhibitors are indicated and now utilized widely across all thresholds of renal function, including end-stage renal disease (ESRD; Fig. 1) [2, 6–11].Fig. 1


Is There Evidence of Any Safety Differences Among DPP-4 Inhibitors in the Treatment of People with Type 2 Diabetes Mellitus and Reduced GFR Due to Chronic Kidney Disease?

Evans M, Dejager S, Schweizer A, Foley JE - Diabetes Ther (2015)

Renal function threshold and recommended dose of DPP-4 inhibitors in renal impairment patients. b.i.d. twice daily, DPP-4 dipeptidyl peptidase-4, GFR glomerular filtration rate, o.d. once daily, Rl renal impairment
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4374076&req=5

Fig1: Renal function threshold and recommended dose of DPP-4 inhibitors in renal impairment patients. b.i.d. twice daily, DPP-4 dipeptidyl peptidase-4, GFR glomerular filtration rate, o.d. once daily, Rl renal impairment
Mentions: Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD) globally. Multiple risk factor management is essential in such patients to delay the disease progression [1]; however, the management of blood glucose presents a particular challenge, with limited treatment options available beyond exogenous insulin therapy [2–5]. Patients with T2DM and CKD are at particular risk of hypoglycemia and its adverse consequences. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide a simple, oral, glucose-sensitive treatment option that does not increase the risk of hypoglycemia and does not confound the comorbidities that afflict many of the other drugs used to treat T2DM [2]. In addition, DPP-4 inhibitors have been shown to be associated with no further decline in estimated glomerular filtration rate (eGFR) when treating patients with CKD [2]. In recent years, several DPP-4 inhibitors have become available and have been extensively evaluated in patients with T2DM and varying degrees of renal impairment (RI). These studies have demonstrated good efficacy and tolerability of the DPP-4 inhibitor class in these patients, and have subsequently led to regulatory approval for the use in patients with T2DM and reduced eGFR due to CKD. Indeed, only exogenous insulin and DPP-4 inhibitors are indicated and now utilized widely across all thresholds of renal function, including end-stage renal disease (ESRD; Fig. 1) [2, 6–11].Fig. 1

View Article: PubMed Central - PubMed

Affiliation: University Hospital Llandough, Cardiff, UK, marcevans4@sky.com.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD) globally... Unlike linagliptin, with other DPP-4 inhibitors the drug exposure increases with decreasing renal function (Fig.  1)... Thus, doses or dose frequencies are recommended to be reduced according to standard renal thresholds... The dose adjustments thus require regular monitoring of renal function, which is also good clinical practice because in these patients it is important to closely monitor renal disease progression... In a recent review article on linagliptin, the authors state that “other widely available DPP-4 inhibitors are excreted predominantly via the kidneys and require consideration/adjustment of dose or are not recommended in patients with moderate or severe RI or ESRD requiring dialysis”... Such statements may cast doubt over the suitability of DPP-4 inhibitors other than linagliptin in treating patients with RI, implying that failure to adequately adjust the dose of these DPP-4 inhibitors may be associated with an increased risk of adverse effects and even nephrotoxicity... A key issue, therefore, is whether this failure in appropriate DPP-4 inhibitor dose adjustment in line with renal function translates into clinically meaningful consequences? Such concerns are further compounded by the fact that many other commonly prescribed drugs are associated with potential renal toxicity particularly when there is an increase in pharmacological exposure due to reduced clearance or catabolism... Finally, with regard to the risk of hypoglycemia with DPP-4 inhibitors, if the dose is not adjusted according to the label in patients with moderate/severe RI, it should be appreciated that DPP-4 inhibitors do not enhance hypoglycemia risk per se because elevations in glucagon-like peptide-1 and glucose insulinotropic polypeptide modulate insulin and glucagon secretion in a glucose-sensitive manner... Thus, recommendations to reduce the dose or dose frequency of DPP-4 inhibitors in patients with RI are not based on a risk of adverse effects or renal toxicity, but are aimed towards achieving drug exposure that yields the maximum efficacy... In conclusion, DPP-4 inhibitors represent an appealing treatment option for the management of blood glucose control in people with T2DM and CKD... It is important to remember that there is a continuum of renal function in patients with diabetes, with declining renal function associated with increasing age... The routine monitoring of renal function thus represents good clinical care of people with diabetes, beyond an appropriate dose adjustment of DPP-4 inhibitor... While there may be differences in the pharmacological profiles of the individual DPP-4 inhibitors in relation to renal function, there is no evidence that these translate into differences in terms of efficacy, safety, and nephrotoxic potential.

No MeSH data available.


Related in: MedlinePlus