Abbreviations

Introduction

Diabetes Mellitus (DM) is recognized as a global health concern, imposing a considerable impact on human life and a burden on socio-economic development [1]. International Diabetes Federation (IDF, 2021) estimated that nearly 537 million adults have diabetes at present and this number is expected to increase to 783 million (12%) by 2045 [2].Diabetes, together with its host of micro- and macro-vascular complications, is the 10^th leading cause of death [3]. Chronic kidney disease (CKD) or diabetic kidney disease (DKD), is characterized by persistently low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² and/or elevated urinary albumin (albumin-to-creatinine ratio [ACR] ≥ 30 mg/g), and is one of the major macro-vascular complications of DM. According to the previous studies, T2DM was the second leading cause of CKD and CKD-related deaths and the third leading cause of CKD-related disability-adjusted life years (DALYs) [4,5].

According to the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) 2022 executive summary, the choice of therapy for T2DM depends on the patient’s cardiac, cerebrovascular, and renal status [6].According to the Kidney Disease Outcomes Quality Initiative (KDOQI) guideline, only a few of several oral hypoglycemic agents can be administered in CKD patients, including sulfonylurea (Glipizide and Gliclazide), Meglitinide (Repaglinide), Thiazolidinediones (TZD), and Dipeptidylpeptidase IV (DPP-4) inhibitors [7,8].

Teneligliptin, a novel 3rd generation DPP4 inhibitor, is a competitive reversible inhibitor of the enzyme DPP4. DPP4 inhibitors exert antihyperglycemic effects by inhibiting the DPP4 enzyme and thereby enhancing levels of endogenous glucagonlike peptide 1 (GLP1) and other incretin hormones. This action stimulates glucose-dependent insulin synthesis and secretion and suppresses glucagon secretion. Teneligliptin has a unique structure exhibiting five consecutive rings (J-shaped) and has an exceptional potency and long-lasting effect [9,10]. Studies on the pharmacokinetics of Teneligliptin suggest no dose adjustment is required, irrespective of renal impairment [11]. Approximately 34% of the administered dose of Teneligliptin is excreted unchanged via the renal route, while 66% is metabolized and eliminated via the hepatic and renal routes [12].

Several evidence of the efficacy and safety of Teneligliptin in Indian T2DM patients are available but there is no robust data available on the safety and effectiveness of Teneligliptin in Indian T2DM patients with CKD. Hence, this real- world, multicenter, retrospective, observational study that aimed to evaluate the effect of Teneligliptin on renal parameters in T2DM patients with CKD was conducted.

Methodology

TOP RENAL study was six months real- world, retrospective, observational, multicenter study on Indian T2DM patients with CKD treated with Teneligliptin orally once daily. The study data collection were done between August 2022 to

October 2022.The protocol of TOP RENAL was approved by the Excel endocrine center Institutional Ethics committee and was in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP).

The TOP RENAL study enrolled adult (>18 years of age) T2DM patients with eGFR ≥ 15 ml/min/1.73 m² to ≤ 60 ml/ min/1.73 m² at the time of treatment initiation with Teneligliptin; patients who were initiated on Teneligliptin and had no change in their prescription of anti-diabetic medication or other concomitant medications for the consecutive six months; and patients for whom complete data of the six months were available according to the study endpoints. Type 1 diabetes patients, pregnant or breastfeeding females; those with known liver or kidney dysfunction (eGFR < 15 ml/min/1.73m² ) or with any Cardiovascular Disease (CVD) event at the time of initiation of treatment with Teneligliptin; patients with renal impairment requiring dialysis; and patients who were diagnosed with or suffering from COVID-19 infection were excluded from the study.

The study investigators and site personnel identified the patient data as per the enrollment criteria from the available patient medical records at the study site. Prescriptions and laboratory investigations of individual patients were uploaded from each site into a web-based database by study investigators. Qualified data entry personnel entered data from prescriptions into electronic data collection form.

The primary endpoint of the study was change in eGFR, serum creatinine (Sr. Creatinine) and blood urea nitrogen (BUN) from baseline to 3 and 6 months. Secondary endpoints were changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), and body weight at 3 and 6 months as compared to baseline, and percentage of patients achieving HbA1c ≤7 % at 6 month. Safety of Teneligliptin was assessed throughout the study.

Statistical Analysis

Demographic characteristics, continuous data like age, weight etc. were summarized with n, mean, Standard Deviation (SD), range and Confidence Intervals (CI). Effectiveness parameters such as HbA1c, FPG, and PPG were presented using descriptive statistics and changes from baseline were evaluated. Number of patients achieving the HbA1c level of <7% were summarized with count (%). Paired t-test was applied to assess the statistical significance and p value<0.05 was considered statistically significant. Incidences of adverse events were summarized with count (%).

Results

Data of 377 patients were collected across 4 centers from India during August 2022 to October 2022 and were analyzed. Of the 377 subjects, 179 (47.5 %) were females. Themean age(±SD) of the study population was 59.9 (±9.58) years. The baseline demographic and clinical characteristics such as duration of the diabetes were presented in Table 1. Concomitant anti-diabetic medications of the study population are presented in Table 2.The dose of Teneligliptin used was 20 mg once daily in the study population (n=271), there were a few patients (n=106)  who were either initiated or up-titrated to Teneligliptin 40 mg once daily.

Table 1: Demographics and clinical characteristics of the study population.

Effect of Teneligliptin on Renal Parameters:

Patients were classified based on the captured eGFR values. Of the 377 patients, 102 patients had eGFR between 45-59 mL/ min/1.73m² (G3a), 124 patients had eGFR 30-44 mL/min/1.73m² (G3b) and 151 had eGFR 15-29 mL/min/1.73m² (G4). Overall, the mean eGFR (mL/min/1.73m²) at baseline, 3 months and 6 months were 36.4±12.3, 36.4±12.4, and36.8±12.5, respectively. The overall differences in eGFR in the follow up visits were not statistically significant (P> 0.05) (Figure 1). In the G3a, G3b, and G4 groups, the baseline eGFR values were 51.7±3.6, 40±3.6 and 23.2±3.4, respectively. After 6 months, these values were 52.1±4.5, 40.5±4.5 and 23.4±3.2 respectively. There was no significant change in serum creatinine and BUN levels from baseline (1.86±0.53 and 21.42±9.69, respectively) to six months (1.85±0.54 and 21.08±10.82, respectively) (Table 2).

Figure 1: Change in eGFR (ml/min/1.73m²).

Table 2: Concomitant Anti-Diabetic Medications (eGFR Class wise) of the study population.

Effect of Teneligliptin on Glycemic Parameters

The mean HbA1C (% ± SD) at baseline, 3 months and 6 months were 8.05±0.67, 7.62 ±0.81 and7.23±0.79, respectively. The mean change in HbA1c from baseline across both time intervals was found to be statistically significant (P < 0.001). In the G3a, G3b, and G4 groups, the mean reductions in HbA1c values were 0.73, 1.08, and 0.67, respectively.

The proportion of patients that achieved HbA1c levels ≤ 7 % at 6 months was 48.81% (Figure 2). The overall mean baseline FPG significantly decreased from baseline 142.9± 32.9to 128.1±35.4at 6 months (P <0.0001). Similarly, significant (P <0.0001) reduction was seen in overall PPG from baseline200.75±32.29to174.9±35.94at 6 months (Table 3).There was no significant change in body weight was observed throughout the study duration.

Figure 2: Change in HbA1c (%).

Table 3: Changes in Renal Parameters (Sr. Creatinine and BUN) and Glycemic Parameters (FPG and PPG).