Teneligliptin as an add on Therapy to Oral Anti diabetic agents in type 2 Diabetes Mellitus

 

Leena Varghese¹, K. Murthi², K. Pandey³

¹KMCH College of Pharmacy, Coimbatore

²Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur-844102, India

³Rajendra Memorial Research Institute (RMRI), Patna

 

ABSTRACT:

A study was conducted on a novel dipeptidyl peptidase-4 inhibitor, Teneligliptin when given as an add on therapy with oral anti diabetic agents in patients with type 2 diabetes mellitus. Previously diagnosed subjects with type 2 diabetes (T2DM) were assigned 20 mg/day teneligliptin along with other anti-diabetic drugs. At 3 months, levels of glycemic parameters like HbA1C, fasting blood glucose levels, Post Prandial levels as well as non-glycemic parameters like lipid profile (Total cholesterol, LDL, HDL, Triglycerides), hsCRP level, serum creatinine, Blood urea, BMI were compared with those at baseline. Teneligliptin as an add on therapy led to significant reduction in glycemic parameters like HbA1c (1.6±0.97mg/dl),fasting blood glucose (45.86±62.85), and post prandial levels (72.73±47.97) from the baseline values (p <0.000). Significant co relation was observed between change in HbA1c level and baseline HbA1C levels. Significant reduction in the total cholesterol levels were observed (p < 0.000) but other lipid profile parameters like HDL, LDL, and triglycerides were not shown to be statistically significant after treatment. No change in hsCRP level and BMI was observed. Addition of teneligliptin to oral anti diabetic agents led to a significant improvement in glycemic control in subjects with type 2 diabetes mellitus without causing any weight change.

 

 

INTRODUCTION:

Diabetes mellitus is a non-communicable disease which is one of the most challenging health problems of 21^st century. Type 2 diabetes mellitus (T2DM) is becoming a pandemic propotions, which is due to significant increase in incidence of obesity and insulin resistance.^[1] According to International Diabetes Federation 2015 report India has second place with 69.2 million people with diabetes, which is predicted to rise to 123.5 million patients by 2040 which is an alarming increase if the current trend continues.

 

According to American Diabetes Association (ADA) 2016 and American Association of clinical Endocrinology 2016 and American Association of Endocrinology 2016, DPP4 inhibitor is considered to be a new class of anti-hyperglycemic agent which is now recommended as 2^nd/1^st line in the treatment^[2]. DPP4 is a highly specific serine protease involved in the regulation and cleavage of two incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)which are released from enteroendocrine cells and enhance insulin secretion.^[3] Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), and have a very short half-life (t_1/2). DPP-4 inhibitors prolong the action of endogenous incretins which inhibit glucagon release and in turn increase insulin. Hence DPP-4 inhibitors can be considered as a promising class of anti-diabetic for its management.^[4]

 

Life style modifications are cornerstone of management of Diabetes Mellitus and include the prescription of a healthy diet, regular exercise and management of stress. However, optimal control of glucose levels is not achieved sometimes which necessitates drug therapy.^[5] Since years sulfonyl ureas, metformin and thiazolidinediones remain the main stay of therapy as first line agents^[6]. Based on the mechanism of action they are categorized into agents like sulfonyl urea, meglitinides, alpha glucosidase inhibitors, thiazolidinediones, incretin mimetics, DPP4 inhibitors, sodium glucose co transporter inhibitor and amylin receptor agonists. To produce an effective glycemic control and to avoid unwanted effects, drugs with different mode of action can be combined to provide additional effects on cardio vascular risk factors^[7]

 

 Due to the progressive beta cell failure nature of diabetes mellitus, monotherapy often causes inadequate glycemic control which necessitates the usage of multiple drugs. Sulfonyl ureas can be employed for concomitant use with metformin, thiazolidinedione, insulin and alpha-glucosidase inhibitors for treatment of type 2 (noninsulin dependent) diabetes mellitus^[8]. Hence to improve drug adherence fixed dose combinations can be used.

 

This study aims to evaluate teneligliptin as add on therapy to oral antidiabetic agents and its effect on glycemic parameters like HbA1c, Fasting Blood Glucose level, Post Prandial Blood Glucose and non-glycemic parameters like Lipid Profile (Total cholesterol, HDL, LDL, Triglycerides), hsCRP, BMI, Serum creatinine, and Blood urea. The rationale behind this study expanding prevalence of Diabetes Mellitus, which is a worldwide epidemic leading to a major concern to health management systems. Weight gain and hypoglycemia’s represent a serious problem to most oral anti-diabetics. Dyslipidemia andHypertension in type 2 diabetes mellitus (DM) leads to a sharp increase in coronary artery disease which is more in men compared women^[9] Decreasing triglycerides and increasing HDL cholesterol with a fibrate is associated with a depletion in cardiovascular events in subject with,low HDL and near-normal levels of LDL^[10].

 

Micro vascular complications of diabetic mellitus includesdiabetic retinopathy were found to have association with duration of diabetes mellitus, presence of hypertension, presence of hyperlipidemia, and also glycated haemoglobin level and serious peripheral neuropathy alongwith impairments in immune function had increased rate of lower extremity amputations and main cause of end stage renal disease isdiabetic nephropathy^[11] Even in diabetics without renal disordershigher incidence of anaemia was observed.^[12]. Hence effective steps should be taken inorder to give grounds for drug therapy. Drug utilization research should be employed effectively.^[13] Educational intervention would produce a reduction in the BMI in patients with type 2 diabetes mellitus and t the need for patients empowerment in the self-management should be put forward for consideration.^[14] The effectiveness of Structured Teaching Programme on knowledge concerned with management of type 2 diabetes mellitus was also proven to be effective^[15]

 

One of the novel oral DPP4 inhibitor Teneligliptin which is recently available in Japan, South Korea, Argentina, and India is approved for treatment of type 2 diabetes mellitus^[16]. Its efficacy for use in Korean and Japanese populations has been studied in different clinical trials^[17]. It was introduced in India by May 2015 which is available to one fifth of cost of other DPP4 inhibitors and can be considered cost effective. Hence the availability of an affordable medication is welcomed and teneligliptin can be viewed as a beneficial step for achieving the goal^[18]. As its clearance is by both hepatic (35%) and renal (65%) route, dose modification is not required. It has a half-life of ~ 24 hours and can be administered with 20–40 mg once daily. It can be administered at a dose of 20-40 mg at a time daily since its half-life is about 24 hours^[19]. The present study was conducted to assess the efficacy of teneligliptin with type 2 diabetes in India. Hence it has its therapeutic importance to find out its non-glycemic and glycemic efficacy in Indian population too.

 

MATERIALS AND METHODS:

The present study was a prospective observational study conducted at the Rajendra Memorial Research Institute, Bihar, India evaluating efficacy of teneligliptin 20mg as an add on drug to oral anti diabetic agents. The study was conducted after obtaining approval from the institutional ethical committee at Rajendra Memorial Research Institute (reference: 09/RMRI/EC/2017) for a period of 1 year. Previously diagnosed type 2 diabetes mellitus patients on oral anti-diabetic agents for at least 2 years, and hba1c> 7% who attended the outpatient department were included. The patients were given an additional drug of teneligliptin 20mg whose glycemic status was not controlled with other oral anti diabetic drugs. Patients with a history of type 1 diabetes, HIV, Hepatitis, TB like comorbid conditions were excluded. This study recruited 60 diabetic patients with uncontrolled blood glucose levels who were on different fixed drug combinations of glimeperide, metformin, voglibose and pioglitazone.

 

Baseline HbA1C, Fasting Blood Sugar, Post Prandial Glucose, serum creatinine, blood urea and lipid profile and CRP level were obtained after 12 hours overnight fasting. Patients were asked to report back after 15 days who has taken the drug and followed for subsequent months up to 3 months for follow up result. Fasting Blood Sugar, and Post Prandial Blood Sugar was estimated by glucose –oxidase peroxidase method. Blood urea was analyzed by Urease-GLDH method and serum creatinine by Jafee-kinetic method. HbA1C, lipid profile (total cholesterol, LDL, HDL, Triglycerides, Non-HDL), were estimated by AS 100 Analyzer which reports values directly. hsCRP was done by ELISA technique. HbA1C and lipid profile values were recorded at baseline and after a follow up of 3 months.

 

STATISTICAL ANALYSIS:

The results were tabulated as mean ± standard deviation. Changes in each parameter was analyzed by paired student’s t test. Multiple regression analysis was done for determining the factors that affect the change in HbA1C level. Difference was calculated as post therapy minus pre therapy. The level of significance was determined as its ‘p’ value with p> 0.05 taken as not significant, p < 0.05 taken as significant at 5% significance level, p < 0.01 taken as significant at 1% significance level and p < 0.001 taken as highly significant.

 

RESULTS AND DISCUSSIONS:

60 patients who completed the study were analyzed consisting of 27 females and 33 males. The mean age of the patients was 52 years.  53% of patients were above the age of 55 and 47% were below the age of  years. 60% of patients had a history of illness below 4 years. Most of the patients were overweight (42%), 37% were normal, 13% were obese. (table 1)

 

Table 1: Baseline Demographic Details And Clinical Characteristics of Patients

Patient details	No.of patients
Total patients	60
Age      >52 <52	28 (47%) 32(53%)
Gender  Male Female	27 (45%) 33 (55%)
Bmi Underweight Normal Overweight Obese	8% 37% 42% 13%
History of illness <4 >4	60% 40%
Comorbid condition Hypertension	33%
Anti diabetic drug combinations Met- glim Met-glim-vogli Others	15% 28% 15%

 

Efficacy of Teneligliptin on glycemic parameters:

HbA1c Fasting Blood sugar and Post Prandial Blood sugar levels showed a significant reduction in blood glucose levels over a period of 3 months. HbA1C, FBG, PPG levels were reduced by 1.6±0.97, 45.86±62.85 , 72.73±47.97 respectively (table 2). Sub group analysis had shown that when it given as add on therapy to Glimiperide –metformin combination HbA1C, FBG, PPG shown a reduction in blood glucose level to 1.58±0.87, 42.40±61.00, 70.76±39.96 respectively, add on glimepiride-metformin–voglibose combinations it reduced to 1.57±0.99, 49.45±66.97, 72.73±47.29 respectively and with other combinations it reduced to 1.72±1.15, 46.86±64.36, 67.60±60.25 respectively (table3). To found out the glycemic efficacy of teneligliptin by considering different predictive parameters, multiple regression analysis was performed between the changes of (Δ)HbA1c levels (as dependable variable) and the baseline levels of metabolic parameters including age, gender, history of illness, HbA1c, FBG, BMI (as independent variables). Among these factors, the baseline HbA1c level was selected as the significant contributing factor for ΔHbA1c (table 4).

 

Table 2: Glycemic Parameters Before and After The Administration of Teneligliptin

	Mean ± SD Baseline	Mean ± SD Follow up	P value
HbA1C (%)	8.53  ± 0.96	6.95  ± 0.96	0.000
FBG (mg/dl)	202.98 ± 53.32	151.11±42.27	0.000
PP (mg/dl)	310.66 ± 45.87	237.93±44.60	0.000

 

Table 3: Mean Reduction Of Glycaemic Parameters After Administration Of Teneligliptin

	Hba1c	Fbg	Pp
Over all (mg/dl)	1.6 ± 0.97	45.86±62.85	72.73±47.97
Gly-met (mg/dl)	1.58±0.87	42.40±61.00	70.76±39.96
Gly-met-vog (mg/dl)	1.57±0.99	49.45±66.97	72.73±47.29
Others (mg/dl)	1.72±1.15	46.86±64.36	67.60±60.25

 

Table 4: Multiple Regression Analysis:

Multiple regression analysis with factors associated with change of HbA1C with teneligliptin.

	Β	Std.error	t	P value	R²
(Constant)	2.055	1.519	-1.353	0.182
Age	-0.04	0.014	-0.282	0.779	0.000
Gender	0.280	0.251	-1.115	0.270	0.054
Bmi	0.010	0.026	0.392	0.697	0.002
History	0.023	0.036	0.640	0.525	0.001
HbA1C	0.513	0.130	3.984	0.000	0.242
Fasting	-0.02	002	-1.074	0.288	0.000

 

Efficacy of teneligliptin on non-glycemic parameters:

There was a significant reduction in total cholesterol levels (p<0.001) but no effect was found on LDL, HDL, Triglyceride values. No change in BMI was observed which shows that it is weight neutral like other DPP4 inhibitors. No significant change in hsCRP was observed. No significant  change in serum urea and serum creatinine was observed. (Table 5)

 

Table 5: Non-Glycemic parameters Before And After The administration of Teneligliptin

	Mean ± sd Baseline	Mean ± sd Follow up	P value
Urea (mg/dl)	35.65 ± 15.69	34.43 ± 9.33	0.619
Creatinine(mg/dl)	1.11 ± 0.53	1.12 ± 0.52	0.956
T.chol(mg/dl)	195.85 ± 32.12	174.63 ± 35.47	0.000
Ldl(mg/dl)	105.41 ±  28.48	106.17 ± 31.14	0.896
Hdl(mg/dl)	47 ± 9.79	45.60 ± 8.15	0.399
Triglycerides(mg/dl)	153.50± 121.14	150.83 ± 96.11	0.899
Hscrp(mg/dl)	5.63 ± 13.32	5.43 ± 13.35	0.139
Bmi(cm/m2)	25.54 ± 4.73	25.41 ±  4.84	0.106

 

Teneligliptin is a novel DPP4 inhibitor approved as an add on therapy along with other anti-diabetic agents^[20]. Since 75% of people with diabetes live in low and middle income settings reported evidences suggests that cost of medicine causes a direct and strong economic impact in them^[21]. Cost effectiveness of teneligliptin  when compared to any other class of gliptins can be considered as a positive goal in the management of diabetics.

 

In the Indian scenario, this data shows that there is a higher prevalence of uncontrolled glycemic status in India. Most of them have a history of illness below 4 years but blood glucose level remains uncontrolled. The average age of patients was 52 years. Fixed drug combination [FDC] is one of the method for improved patient adherence^[22]. Most of the patients included in this studied were mostly prescribed on different fixed drug anti diabetic combinations consisting of glimepiride (1mg)-metformin (500 mg) and voglibose (0. 3 mg).

 

Glycemic efficacy of teneligliptin:

In the present study, when teneligliptin 20 mg/day was given as an add on therapy to different anti diabetic drug combinations. Ghosh s et al conducted a study to find out the glycemic efficacy of teneligliptin when given as monotherapy as well as add-on treatment which significantly improved glycemic control with type 2 diabetes ^[23]Ryuichi Monistat et al concluded that teneligliptin effectively reduces the blood glucose level which are beneficial in the development of diabetes complications^[24]. The results obtained with teneligliptin are in agreement with previous studies. The reduction in glycemic parameters stongly co related with the baseline values (P value < 0.000) It lowered both the fasting as well as post prandial blood glucose level with in a short period of time.

 

Non glycemic efficacy of teneligliptin:

EijiKutoh et al suggested that the association between lipid levels and DPP4 inhibitors was found to be controversial ^[25]. But in some studies, it was found that DPP4 inhibitors improved total cholesterol levels, which is beneficial in reduction of cardio vascular risk            factors^[26]. Teneligliptin produced a significant reduction in the total cholesterol level (p <0.05) but no effect was found on other non-glycemic parameters like HDL, LDL, Triglyceride]. Seiichi Tanaka, et al suggested that there is no significant improvement in hsCRP level when given as add on along with insulin^[27]. A previous conducted by Satoh-Asahara et al demonstrated that sitagliptin, another DPP-4 inhibitor, decreased serum hsCRP levels in patients with type 2 diabetes. But in our study teneligliptin showed no significant change in the hsCRP level was found out which shows there is lack of anti-inflammatory effect. No significant change in BMI was monitored. So it can be considered to be weight neutral like other DPP4 inhibitors^[28].

 

LIMITATIONS AND STRENGTH OF STUDY:

The study was conducted for a short duration of time subjects involved was lessin number. But the number of studies conducted on this new DPP4 inhibitor, teneligliptin in Indian subjects is very few and till now no studies were done on to find out its efficacy on parameters like lipid profile and hsCRP. A large-scale clinical trial is to be performed to know the shortcomings of the present study.

 

Results obtained from this study showed that there is a significant improvement in glycemic parameters after the administration of teneligliptin in Indian subjects with uncontrolled hyperglycemia when prescribed as add on therapy with different oral anti diabetic drug combinations.

 

ACKNOWLEDGEMENTS:

The authors thank all the staffs of our biochemistry department and pathology department of RMRI for their timely help and co-operation while doing the lab work.

 

REFERENCES:

1.      Mohsen, Hussien and Shaden, H and Faiza, A.Q. and Taghrid, H. (2013). Correlation of serum leptin levels with insulin resistance in Syrian obese patients with type 2 diabetes mellitus. Research Journal of Pharmacy and Technology. 6. 1149-1151.

2.      Giugliano D, Maiorino MI, Bellastella G, Esposito K. Comment on American Diabetes Association. Approaches to Glycemic Treatment. Sec. 7. In Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(Suppl. 1):S52-S59. Diabetes Care. 2016;39(6):e86-7.

3.      Janardhan S, Sastry GN. Dipeptidyl peptidase IV inhibitors: a new paradigm in type 2 diabetes treatment. Curr Drug Targets. 2014;15(6):600-21.

4.      Sharma SK, Panneerselvam A, Singh KP, Parmar G, Gadge P, Swami OC. Teneligliptin in management of type 2 diabetes mellitus. Diabetes Metab Syndr Obes. 2016;9:251-60.

5.      Sharma HL and Sharma KK, Principles of Pharmacology, 3^rd edition, 2017: page 639

6.      Thompson AM, Trujillo JM. Advances in the treatment of type 2 diabetes: impact of dulaglutide. Diabetes Metab Syndr Obes. 2016;9:125-36.page;6

7.      Amita J et al. Efficacy and safety of voglibose as an add-on triple drug in patients of type two diabetes mellitus uncontrolled with glimepiride and metformin in Punjabi population. Indian Journal of Basic and Applied Medical Research. 2014:3;3:111-116.

8.      Shobha Rani G, Lohita M, Jaya Preethi P, Madhavi R, Sunisitha B, Mounika D. Glimepiride: A Review of Analytical Methods. Asian J. Pharm. Ana. 4(4): Oct. - Dec. 2014; Page 178-182

9.      Acharya L, Rau N, Udupa N, Rajan M, Vijayanarayana K. Trends in Prescribing Antihypertensive Medications and Lipid Lowering Therapy in type-2 Diabetic Patients in South Indian Tertiary Care Hospital. Research Journal of Pharmacy and Technology. 2016;9(7):857

10.   Geetha P, Shanmugasundaram P. A Prospective Observational Study on assessment of risk factor associated with diabetic retinopathy in patients diagnosed with type 2 Diabetes Mellitus in south Indian population. Research Journal of Pharmacy and Technology. 2019;12(2):595

11.   Fadheel Q. A Comparative Study of the effect of Metformin and Metformin plus Garlic on Blood Glucose Level in patients with Type 2 Diabetes Mellitus in Iraq. Research Journal of Pharmacy and Technology. 2019;12(4):1806.

12.   Mounika V, Sarumathy S, Ebens J, Shanmugarajan T. A prospective study on incidence of Anaemia in type 2 Diabetes Mellitus Patients. Research Journal of Pharmacy and Technology. 2017;10(1):11

13.   Raphael M, Vijayanarayana K, Thunga G, Rao N, Sreedharan N. Utilization Pattern of Anti-Diabetic Drugs in Type 2 Diabetes Mellitus in Tertiary Care Hospital. Research Journal of Pharmacy and Technology. 2017;10(7):2063

14.   Sindhu L, Kumar B. Effectiveness of Educational Intervention on Body Mass Index (BMI) of Patients with Type 2 Diabetes Mellitus in South Indian Population. Asian Journal of Nursing Education and Research. 2018;8(3):434.

15.   Vasudevan N. J., Sara B. A Study to Assess the Effectiveness of Structured Teaching Programme on Knowledge regarding Management of Type 2 Diabetes Mellitus among Patients with Type 2 Diabetes Mellitus attending Diabetic OPD, RMMCH, Annamalai University. Int. J. Nur. Edu. and Research 2(2): April- June 2014; Page 113-116..

16.   Kishimoto M. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes. Diabetes Metab Syndr Obes. 2013;6:187-95.

17.   Eto T, Inoue S, Kadowaki T. Effects of once-daily teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2012;14(11):1040-6.

18.   Sharma SK, Panneerselvam A, Singh KP, Parmar G, Gadge P, Swami OC. Teneligliptin in management of type 2 diabetes mellitus. Diabetes Metab Syndr Obes. 2016;9:251-60.

19.   19.Yoshida T, Akahoshi F, Sakashita H, Kitajima H, Nakamura M, Sonda S, et al. Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem. 2012;20(19):5705-19.

20.   Manish Maladkar et al. Teneligliptin: Heralding Change in Type 2 Diabetes, Journal of Diabetes Mellitus. 2016, 6, 113-131.

21.   21.American Diabetes Association ADA 2016 Standards of Medical Care in Diabetes—2016. Diabetes Care. 2016 Jan; VOL 1(Suppl 1): S13

22.   Tanaka S, Suzuki K, Aoki C, Niitani M, Kato K, Tomotsune T, et al. Add-on treatment with teneligliptin ameliorates glucose fluctuations and improves glycemic control index in Japanese patients with type 2 diabetes on insulin therapy. Diabetes technology and therapeutics. 2014;16(12):840-5

23.   Ghosh S, Trivedi S, Sanyal D, Modi KD, Kharb S. Teneligliptin real-world efficacy assessment of type 2 diabetes mellitus patients in India (TREAT-INDIA study). Diabetes Metab Syndr Obes. 2016;9:347-53

24.   Morishita R, Nakagami H. Teneligliptin : expectations for its pleiotropic action. Expert Opin Pharmacother. 2015;16(3):417-26

25.   Kutoh E et al. Teneligliptin as an initial therapy for newly diagnosed, drug naive subjects with type 2 diabetes. J Clin Med Res. 2014;6(4):287-94

26.   Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, et al. A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metabolism. 2013;62(3):347-51

27.   Tanaka S, Suzuki K, Aoki C, Niitani M, Kato K, Tomotsune T, et al. Add-on treatment with teneligliptin ameliorates glucose fluctuations and improves glycemic control index in Japanese patients with type 2 diabetes on insulin therapy. Diabetes Technology and Therapeutics. 2014;16(12):840-5

28.   Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vascular Health and Risk Management. 2010;6:541-8

 

Accepted on 15.11.2019         © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(5): 2310-2314.