Pathophysiology/Complications Open Access Original research BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2017-000391 on 7 July 2017. Downloaded from Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose- lowering-independent manner Munehiro Kitada,1,2 Shin-ichi Tsuda,1 Kazunori Konishi,1 Ai Takeda-Watanabe,1 Mizue Fujii,1 Keizo Kanasaki,1,2 Makoto Nishizawa,1 Atsushi Nakagawa,1 Daisuke Koya1,2 To cite: Kitada M, Tsuda S, ABSTRACT Konishi K, et al. Anagliptin Objective The objective of this study is to elucidate Significance of the study ameliorates albuminuria and the effect of anagliptin on glucose/lipid metabolism urinary liver-type fatty acid- and renoprotection in patients with type 2 diabetic What is already known about this subject? binding protein excretion in nephropathy. ► Previous clinical reports already exhibit that patients with type 2 diabetes dipeptidyl peptidase-4 (DPP-4) inhibitors ameliorate with nephropathy in a glucose- Methods Twenty-five patients with type 2 diabetic nephropathy received anagliptin 200 mg/day for diabetic nephropathy, such as albuminuria, in a lowering-independent manner. glucose-lowering effect. BMJ Open Diab Res Care 24 weeks, and 20 patients who were switched to 2017;5:e000391. doi:10.1136/ anagliptin from other dipeptidyl peptidase-4 (DPP- What are the new findings? bmjdrc-2017-000391 4) inhibitors were analyzed regarding primary and ► Our current study demonstrates that administration secondary endpoints. The primary endpoint was of anagliptin, which is switched from other DPP-4 change in hemoglobin A1c (HbA1c) during treatment ► Additional material is inhibitors, in patients with type 2 diabetes with with anagliptin. Additionally, we evaluated changes in nephropathy showed that the levels of urinary published online only. To view lipid data (low-density lipoprotein-cholesterol, high- please visit the journal online albumin to creatinine ratio were significantly reduced density lipoprotein-cholesterol and triglyceride), blood (http:// dx. doi. org/ 10. 1136/ after 24 weeks. However, the levels of hemoglobin pressure (BP), urinary albumin to creatinine ratio (UACR), bmjdrc- 2017- 000391). A1c in patients showed no significant change during liver-type fatty acid-binding protein to creatinine ratio the treatment. (ULFABP) and renal function (estimated glomerular We also found that treatment with anagliptin http://drc.bmj.com/ Received 14 January 2017 filtration rate and serum cystatin C) as secondary ► significantly decreased urinary liver-type fatty acid- Revised 21 April 2017 endpoints. binding protein excretion after 24 weeks. Accepted 15 May 2017 Results After switching to anagliptin from other DPP- 4 inhibitors, the levels of HbA1c in the 20 participants How might these results change the focus of showed no significant change, 7.5%±1.2% at 24 weeks research or clinical practice? compared with 7.3%±0.9% at baseline. The levels ► Anagliptin may exert beneficial effects for of the log10-transformed UACR were significantly renoprotection in patients with type 2 diabetes with on October 2, 2021 by guest. Protected copyright. reduced from 1.95±0.51 mg/g creatinine (Cr) at baseline nephropathy in a glucose-lowering-independent to 1.76±0.53 mg/g Cr at 24 weeks after anagliptin manner. treatment (p<0.01). The percentage change in the UACR (Δ%UACR) from baseline to 24 weeks was also significantly lower by −10.6% (p<0.001). Lipid data, systolic BP and renal function were not changed during 1Department of Diabetology INTRODUCTION and Endocrinology, Kanazawa anagliptin treatment. Additionally, ULFABP in eight The prevalence of diabetes mellitus has Medical University, Ishikawa, participants, who had ≥5 µg/g Cr at baseline, was been increasing worldwide in recent years. significantly decreased from baseline (8.5±2.8 µg/g Cr) Japan Long-term diabetes results in vascular 2 to 24 weeks (3.1±1.7 µg/g Cr, p<0.01) after anagliptin Division of Anticipatory changes and dysfunction, and its compli- Molecular Food Science treatment, and the percentage change in the ULFABP and Technology, Medical during anagliptin treatment was −58.1% (p<0.001). cations are the major causes of morbidity Research Institute, Kanazawa Conclusions Anagliptin induced no significant change and mortality in patients. Among diabetic Medical University, Uchinada, in HbA1c, lipid data, systolic BP and renal function. vascular complications, nephropathy is Ishikawa, Japan However, anagliptin reduced the UACR and ULFABP, recognized as a leading cause of end-stage although without a corresponding change in HbA1c, Correspondence to renal disease (ESRD) and an indepen- indicating direct action of anagliptin on renoprotection in Dr Munehiro Kitada; dent risk factor for cardiovascular diseases patients with type 2 diabetic nephropathy. 1 kitta@ kanazawa- med. ac. jp (CVD). The early clinical sign of diabetic BMJ Open Diab Res Care 2017;5:e000391. doi:10.1136/bmjdrc-2017-000391 1 Pathophysiology/Complications BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2017-000391 on 7 July 2017. Downloaded from nephropathy is elevated urinary albumin excretion, function, including albuminuria, in patients with type referred to as microalbuminuria, which progresses to 2 diabetes with nephropathy. overt proteinuria. Microalbuminuria in patients with diabetes has been recognized as a useful biomarker for diagnosing diabetic nephropathy and as a predic- RESEARCH DESIGN AND METHOD tive factor for progression to ESRD.2 Additionally, Subjects microalbuminuria has been shown to be closely A total of 48 participants with type 2 diabetes (30 associated with an increased risk of cardiovascular men and 18 women) were selected for the present morbidity and mortality.3–5 Therefore, microalbu- study from outpatients who visited the Department of minuria is a biomarker for the diagnosis of diabetic Endocrinology and Metabolism at Kanazawa Medical nephropathy and an important therapeutic target for University Hospital. The entry criteria included (1) improving the prognosis of renal and cardiovascular age ≥20 years old, (2) type 2 diabetes with hemoglobin risk in patients with diabetes.6 Previous clinical data A1c (HbA1c) ≥6.0%, (3) urinary albumin to creati- also showed that urinary liver-type free fatty acid- nine (Cr) ratio (UACR) ≥30 mg/g Cr in spot urine for binding protein (L-FABP), which is associated with screening of diabetic nephropathy, and (4) treatment renal tubulointerstitial damage and oxidative stress, with diet, exercise therapy and oral antidiabetic agents may be a predictive marker for renal and cardiovas- (glimepiride ≤2 mg/day or gliclazide ≤40 mg/day or glib- cular prognosis in patients with type 2 diabetes.7 8 enclamide ≤1.25 mg/day). The exclusion criteria were Multifactorial management, including diet therapy (1) type 1 diabetes, (2) treatment with insulin therapy, and glycemic, blood pressure (BP) and lipid control, is (3) severe diabetic metabolic complications such as keto- recommended for diabetic nephropathy.2 9 10 Among acidosis, (4) severe liver dysfunction, (5) hemodialysis, the multifactorial treatments, intensive glycemic (6) severe chronic heart failure, (7) pregnant or nursing control in type 2 diabetes significantly reduced women and those who might be pregnant, and (8) any diabetes-induced microvascular events, mainly as a patient whom the investigator judged to be inappropriate consequence of a reduction in nephropathy.2 However, for this study. Patients were given detailed explanations of intensive glycemic control, accompanied by hypogly- the study protocol. Informed consent was obtained from cemia, is closely related to increased mortality, which each patient. The study protocol was approved by the is associated with increased incidence of CVD.11 12 Ethical Committee of Kanazawa Medical University. The Therefore, avoiding hypoglycemia is important in the trial was registered with the University Hospital Medical treatment of patients with diabetes, in particular those Information Network (UMIN No 000012802). who have diabetic nephropathy, because they are a high-risk group for CVD. Treatment with dipeptidyl Study protocol peptidase-4 (DPP-4) inhibitors, which are oral anti- The present study was an open-label, prospective study. diabetic agents, results in improvements in the blood At the start of the study, anagliptin 200 mg/day was added glucose levels in patients with diabetes following to other oral antidiabetic agents such as sulfonylurea stimulation of endogenous insulin secretion, inhi- (SU), metformin, an α-glucosidase inhibitor (α-GI), http://drc.bmj.com/ bition of glucagon release and reduction of gastric pioglitazone and a sodium-glucose cotransporter 2 emptying via the enhanced production of incretin (SGLT2) inhibitor or, when participants received other hormones. DPP-4 inhibitors enhance active levels DPP-4 inhibitors, the DPP-4 inhibitor was switched to of glucagon-like peptide-1 (GLP-1) and gastric inhib- anagliptin 200 mg/day. In addition, in some cases, the itory polypeptide (GIP) via inhibition of cleaving and anagliptin dose was increased to up to 400 mg/day after inactivating these incretins by DPP-4 enzyme. DPP-4 12 weeks, if the physician judged glucose control in the on October 2, 2021 by guest. Protected copyright. inhibitors have become widely accepted in clinical patients to be insufficient. Participants were assessed for practice because of their low risk of hypoglycemia.