Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from <scp>TECOS</scp>

Engel, Samuel S.; Suryawanshi, Shailaja; Stevens, Susanna R.; Josse, Robert G.; Cornel, Jan H.; Jakubonienė, Neli; Riefflin, Axel; Tankova, Tsvetalina; Wainstein, Julio; Peterson, Eric D.; Holman, Rury R.

doi:10.1111/dom.12983

Cited by 25 publications

(21 citation statements)

References 11 publications

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“…Moreover, there was no impact of sitagliptin or vildagliptin on GFR, even when renal function was already moderately/severely impaired. Likewise, in the longer duration CV safety outcome studies, neither alogliptin nor saxagliptin had any effect on GFR compared to placebo, while in TECOS, although GFR was modestly lower in the sitagliptin arm, the rate of decline was similar in both arms of the trial as a whole (but interestingly, a sub‐group analysis revealed no decline in GFR in the sitagliptin cohort with CKD in TECOS). Of note, a recent mechanistic study has reported that, compared with placebo, acute and chronic (1 month) DPP‐4 inhibition with sitagliptin in patients with T2DM stimulated natriuresis in the distal, rather than the proximal, tubule, via a mechanism said to involve enhancement of levels of SDF‐1α, in line with some of the animal data mentioned above .…”

Section: Renal Safetysupporting

confidence: 73%

“…The large CV safety outcome studies also included large numbers of patients with impaired renal function, and analyses of the cohorts with chronic kidney disease (CKD) in TECOS and SAVOR-TIMI clearly showed a correlation between poorer renal function and increasing numbers of CV, renal and hypoglycaemic events, as expected. [48][49][50] However, with the exception of hospitalization for heart failure in SAVOR-TIMI (which was higher in the saxagliptin arm), overall event rates in the CKD cohort, although greater in number, were generally not different between the DPP-4 inhibitor and the placebo arms of the trials, 48,50 reflecting the findings in the trial populations as a whole, 9,11 and indicating that the presence of kidney disease per se did not differentially influence outcomes in the 2 arms of the trials. Moreover, a specific analysis of renal events in SAVOR-TIMI revealed no adverse effects of DPP-4 inhibition with saxagliptin on renal safety outcomes.…”

Section: Heart Failurementioning

confidence: 99%

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A review of dipeptidyl peptidase‐4 inhibitors. Hot topics from randomized controlled trials

Deacon

2018

Diabetes Obesity Metabolism

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The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have investigated DPP-4 inhibitors in patient groups which are often under-represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP-4 inhibitors are not associated with any additional CV risk in these already-at-high-risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP-4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP-4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP-4 inhibitors in other circumstances, including for in-hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP-4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.

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Section: Renal Safetysupporting

confidence: 73%

Section: Heart Failurementioning

confidence: 99%

A review of dipeptidyl peptidase‐4 inhibitors. Hot topics from randomized controlled trials

Deacon

2018

Diabetes Obesity Metabolism

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“…Sitagliptin, predominantly (in up to 90%) excreted with urine as an active drug, accumulates in CKD. Despite precautions suggested by the manufacturer for CKD patients, the drug was generally well tolerated and effective in improving metabolic control of T2D also in this patient group [36]. Vildagliptine is also safe and effective in CKD patients, despite the fact that the drug is metabolised by the kidneys and excreted with urine.…”

Section: Dpp4 Inhibitorsmentioning

confidence: 78%

Diagnosis and treatment of type 2 diabetes mellitus in patients with chronic kidney disease and eGFR < 60 mL/min — a position statement of the Polish Society of Nephrology Working Group on Metabolic and Endocrine Disorders in Kidney Diseases

Stompór

Adamczak

Masajtis-Zagajewska

et al. 2020

Endokrynologia Polska

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Diabetes mellitus is one the most frequent co-morbid conditions in patients with chronic kidney disease (CKD), frequently leading to chronic kidney failure. Progression of CKD accelerates several metabolic disorders, predominantly those related to abnormalities of carbohydrate metabolism. Patients with CKD are usually characterised by an insulin resistance additionally aggravated by several co-morbid conditions (for example chronic low-grade inflammation). Treatment with anti-diabetic medications in patients with CKD remains a challenge because, along with the disease progression, the dosing of several drugs needs to be adjusted to the reduced kidney function (especially those that are excreted intact with urine or as active metabolites). Progression of CKD also increases the risk of hypoglycaemia in patients treated with anti-diabetic drugs, and other adverse drug reactions may occur more frequently. Usefulness of the new generation drugs has not yet been verified in patients with advanced kidney disease (although some of them act through kidney-related mechanisms). The current position statement of the Polish Society of Nephrology Working Group provides practical recommendations for the diagnosis and treatment of type 2 diabetes mellitus in patients with CKD and reduced kidney function.

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“…It has been suggested that inhibiting these additional pathways may lead to beneficial outcomes, such as improved diabetic wound healing via SDF-1 inhibition [14]. Prior to CARMELINA, CVOTs had been reported for three DPP-4 inhibitors approved for clinical use in the European Union: saxagliptin [15], alogliptin [16,17] and sitagliptin [18][19][20]. Safety was uniformly demonstrated across the class for atherosclerotic CV outcomes, with a neutral effect on major adverse CV event (MACE) outcomes for all three agents [1] ( Table 1).…”

Section: 2mentioning

confidence: 99%

“…2B). A limitation of these CVOTs has been that only a minority of patients in the study cohorts had reduced renal function at baseline [1,19] (Fig. 3A), while renal outcomes were usually only assessed as exploratory or post hoc analyses [15][16][17][18][19][20].…”

Section: 2mentioning

confidence: 99%

CARMELINA: An important piece of the DPP-4 inhibitor CVOT puzzle

Schernthaner

Wanner

Jurišić‐Eržen

et al. 2019

Diabetes Research and Clinical Practice

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Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of glucose-lowering agent for type 2 diabetes (T2D) that are commonly used in clinical practice. With the recent disclosure of data from the CARMELINA cardiovascular outcomes trial (CVOT), which investigated linagliptin, CV and renal outcomes data are now available for four agents in the DPP-4 inhibitor class that are approved in most markets. To consider how the CARMELINA study may be interpreted, and the relevance for our clinical practice, we convened as an expert group of diabetes specialists from the Central and Eastern Europe region to discuss the new disclosures. Our discussions revealed a general confidence in safety across the class that is further supported by CARMELINA. However, we also concluded that there are important differences in the available evidence level between agents in the setting of heart failure and data on renal outcomes. Here, we noted the clinical relevance to our practice of the study population in CARMELINA, which is unique among CVOTs in including a majority of patients with chronic kidney disease (CKD). Given the risk for future development of

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Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS

Cited by 25 publications

References 11 publications

A review of dipeptidyl peptidase‐4 inhibitors. Hot topics from randomized controlled trials

A review of dipeptidyl peptidase‐4 inhibitors. Hot topics from randomized controlled trials

Diagnosis and treatment of type 2 diabetes mellitus in patients with chronic kidney disease and eGFR < 60 mL/min — a position statement of the Polish Society of Nephrology Working Group on Metabolic and Endocrine Disorders in Kidney Diseases

CARMELINA: An important piece of the DPP-4 inhibitor CVOT puzzle

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