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Renal Effects of DPP-4 Inhibitor Sitagliptin Or GLP-1 Receptor

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Renal Effects of DPP-4 Inhibitor Sitagliptin Or GLP-1 Receptor Diabetes Care 1 Lennart Tonneijck,1 Mark M. Smits,1 Renal Effects of DPP-4 Inhibitor Marcel H.A. Muskiet,1 Trynke Hoekstra,2,3 Mark H.H. Kramer,1 A.H. Jan Danser,4 Sitagliptin or GLP-1 Receptor Piet M. ter Wee,5 Michaela Diamant,1† Agonist Liraglutide in Overweight Jaap A. Joles,6 and Daniel¨ H. van Raalte1 Patients With Type 2 Diabetes: a 12-Week, Randomized, Double- Blind, Placebo-Controlled Trial DOI: 10.2337/dc16-1371 OBJECTIVE To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal 1Diabetes Center, Department of Internal Medi- hemodynamics, tubular functions, and markers of renal damage in overweight cine, VU University Medical Center, Amsterdam, patients with type 2 diabetes without chronic kidney disease (CKD). the Netherlands 2Department of Health Sciences and the EMGO RESEARCH DESIGN AND METHODS Institute for Health and Care Research, VU PATHOPHYSIOLOGY/COMPLICATIONS University Amsterdam, Amsterdam, the In this 12-week, randomized, double-blind trial, 55 insulin-na¨ıve patients with Netherlands type 2 diabetes (mean 6 SEM: age 63 6 7years,BMI31.86 4.1 kg/m2,glomerular 3Department of Epidemiology and Biostatistics, filtration rate [GFR] 83 6 16 mL/min/1.73 m2; median [interquartile range]: VU University Medical Center, Amsterdam, the Netherlands albumin-to-creatinine ratio (ACR) 1.09 mg/mmol [0.47–3.31]) received sitagliptin 4Division of Pharmacology and Vascular Medi- (100 mg/day), liraglutide (1.8 mg/day), or matching placebos. GFR (primary end cine, Department of Internal Medicine, Erasmus point) and effective renal plasma flow (ERPF) were determined by inulin and para- University Medical Center, Rotterdam, the aminohippuric acid clearance, respectively. Intrarenal hemodynamic variables Netherlands. 5Department of Nephrology, VU University Med- were estimated. Absolute and fractional excretions of sodium (FENa), potassium, ical Center, Amsterdam, the Netherlands 6 and urea (FEU) and renal damage markers (ACR, neutrophil gelatinase–associated Department of Nephrology and Hypertension, Uni- lipocalin [NGAL], and kidney injury molecule-1 [KIM-1]) were measured. Plasma versity Medical Center, Utrecht, the Netherlands Corresponding author: Lennart Tonneijck, renin concentration (PRC) and glycated hemoglobin (HbA1c) were assessed. At weeks 2 and 6, estimated GFR and fractional electrolyte excretions were determined. [email protected]. Received 27 June 2016 and accepted 10 August RESULTS 2016. At week 12, GFR was not affected by sitagliptin (26 mL/min/1.73 m2 [95% CI 214 Clinical trial reg. no. NCT01744236, clinicaltrials .gov. to 3], P = 0.17) or liraglutide (+3 mL/min/1.73 m2 [25 to 11], P = 0.46), compared This article contains Supplementary Data online with placebo. Sitagliptin modestly reduced estimated glomerular hydraulic pres- at http://care.diabetesjournals.org/lookup/ sure (PGLO; P = 0.043). ERPF, other intrarenal hemodynamic variables, renal dam- suppl/doi:10.2337/dc16-1371/-/DC1. age markers, and PRC did not change for both treatments. Both agents reduced †Deceased. In memory of Michaela Diamant, HbA1c. Only at week 2, sitagliptin increased FENa and FEU (P =0.005). whoseexperienceandexpertisewerecrucial for the design of this study. CONCLUSIONS © 2016 by the American Diabetes Association. Twelve-week treatment with sitagliptin or liraglutide does not affect measured Readers may use this article as long as the work renal hemodynamics. No sustained changes in tubular functions or alteration in is properly cited, the use is educational and not for profit, and the work is not altered. More infor- renal damage markers were observed. The validity and clinical relevance of the mation is available at http://www.diabetesjournals slight sitagliptin-induced PGLO reduction remains speculative. .org/content/license. Diabetes Care Publish Ahead of Print, published online September 1, 2016 2 Renal Effects of GLP-1–Based Therapies Diabetes Care Driven by the relentless global obesity in type 2 diabetes may be explained by treated with a stable dose of metformin and diabetes pandemic, diabetic kidney their actions on several renal risk factors and/or sulfonylurea for $3 months be- disease (DKD) has become the leading (1). As such, in patients with type 2 diabe- fore enrollment. Key exclusion criteria cause of chronic kidney disease (CKD), tes, DPP-4Is and GLP-1RAs decrease blood included history of malignancy, pancre- resulting in end-stage kidney disease, pressure (1) and improve lipid profiles, atic or active liver disease, estimated cardiovascular events, and premature whereas GLP-1RA treatment reduces GFR (eGFR) ,60 mL/min/1.73 m2, cur- death (1). Prevention and treatment of body weight (1). GLP-1 peptide infusion rent urinary tract infection, active ne- DKD in type 2 diabetes focuses on early in obese hyperfiltrating males (25% of phritis, urinary retention (completeness detection of albuminuria and decline whom were diagnosed with type 2 diabe- of bladder emptying was assessed by of glomerular filtration rate (GFR) and tes) resulted in a reduction of creatinine bladder ultrasonography at screening control of renal risk factors, including clearance–measured glomerular hyperfil- visit), or use of diuretics that could not hyperglycemia, obesity, systemic hyper- tration (17), which is closely associated be stopped 3 months prior to and during tension, glomerular hyperfiltration, al- with glomerular hydraulic pressure (PGLO) the intervention period. All patients pro- buminuria, and dislipidemia (1). As (1). Moreover, the reduction in albumin- vided written informed consent before renin-angiotensin system (RAS) inhibi- uria at 7 weeks (18) and 1 year (13) of trial-related activities. tors exhibit blood pressure–independent liraglutide treatment was paralleled by a benefits on renal outcome, these drugs decrease in GFR in an uncontrolled open- Intervention and Randomization are widely recommended for hyperten- label study in patients with type 2 diabe- Patients were randomized 1:1:1, with a sion management in type 2 diabetes tes. However, other acute studies using block size of six, by an independent trial (1). However, despite intensified control GLP-1RA in healthy males and patients pharmacist using computer-generated of multiple risk factors, 25% of the pa- with type 2 diabetes did not observe favor- numbers (25). Patients and investiga- tients with type 2 diabetes in the Steno-2 able responses on renal hemodynamics tors remained blinded to treatment sta- trial developed or progressed in their re- (19–24). Thus, the effects of DPP-4I or tus until the last patient completed the nal disease, and the rate of GFR decline GLP-1RA treatment on renal hemodynam- last study visit and database lock. Pa- was similar to conventional therapy ics remain incompletely understood. tients received prefilled pens for subcu- (2). Interestingly, in Steno-2 and daily In the current study, we determined taneous injection containing visually clinical practice (2,3), recommended tar- the effects of prolonged (12-week) identical liraglutide or placebo (Novo gets are often not achieved, and as treatment with the DPP-4I sitagliptin Nordisk A/S, Bagsværd, Denmark), in ad- such, a single drug that targets various or GLP-1RA liraglutide on GFR, effective dition to visually identical encapsulated risk factors involved in the pathogenesis renal plasma flow (ERPF), tubular func- oral capsules (ACE Pharmaceutical, Zee- of DKD may lead to more salutary long- tions, markers of renal damage, and re- wolde, the Netherlands) containing term renal outcomes. nal risk factors in patients with type 2 sitagliptin (Merck, Kenilworth, NJ) or Glucagon-like peptide 1 (GLP-1)–based diabetes without CKD. We hypothesized placebo, both to be taken once daily in therapies, i.e., dipeptidyl peptidase-4 that GLP-1–based therapies reduce gold the evening. A dose increment schedule inhibitors (DPP-4Is) and GLP-1 re- standard–measured GFR and estimated was used for the subcutaneous injec- ceptor agonists (GLP-1RAs), are widely PGLO in type 2 diabetes. tions (week 1, 0.6 mg; week 2, 1.2 mg; used antihyperglycemic drugs in type 2 weeks 3–12, 1.8 mg daily), and depend- diabetes. Both drug classes improve RESEARCH DESIGN AND METHODS ing on drug tolerance, time between pancreatic islet cell function by increasing Trial Design dose increments could be extended or insulin and reducing glucagon secretion This was a phase 4, monocenter, ran- the dose could be decreased at the in- but also display various extrapancreatic domized, double-blind, placebo-controlled, vestigator’s discretion. actions (1). Interestingly, in experimen- double-dummy, parallel-group, mecha- tal models of diabetes and hypertension, nistic intervention trial, as described Study End Points GLP-1–based therapies prevented the previously (25). The study was approved The primary end point was treatment- – onset and progression of renal disease by the ethics review board of the VU induced change in inulin clearance as well as renal morphological abnormal- University Medical Center and local measured GFR from baseline to week ities of DKD (4). In clinical trials, DPP-4Is authorities. The study was registered 12, compared with placebo (25). All (5–9) and GLP-1RAs (10–14) decrease at clinicaltrials.gov (NCT01744236) and other (intra)renal hemodynamic vari- the surrogate renal end point albuminuria complied with the Declaration of Helsinki ables, tubular functions (i.e., tubular han- in patients with type 2 diabetes, while the
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