Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

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On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



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Professor and Head
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Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
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Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
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Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : November | Volume : 16 | Issue : 11 | Page : FC01 - FC06 Full Version

Effect of Teneligliptin versus Glimepiride on Tumour Necrosis Factor Alpha and High Sensitivity C-Reactive Protein in Type 2 Diabetes Mellitus Patients Treated with Metformin: A Randomised Double-blind Parallel Group Study


Published: November 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/57237.16981
Maleha Butul, Pingali Usharani, MVS Subbalaxmi

1. Assistant Professor, Department of Pharmacology, Shadan Institute of Medical Sciences, Hyderabad, Telangana, India. 2. Professor and Head and Guide, Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India. 3. Additional Professor and Co-Guide, Department of General Medicine, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India.

Correspondence Address :
Dr. Maleha Butul,
6-3-1086/3, Somajiguda, Hyderabad, Telangana, India.
E-mail: butulmaleha67@gmail.com

Abstract

Introduction: Inflammatory markers like Tumour Necrosis Factor-α (TNF-α), C-Reactive Protein (CRP), and Interleukin-6 (IL-6) play intermediary role in insulin resistance, pathogenesis of Type 2 Diabetes Mellitus (T2DM) and its complications. Hence, antidiabetic drugs having anti-inflammatory effects may play an important role in management of T2DM and prevention of its complications.

Aim: To study the effect of glimepiride versus teneligliptin on TNF-α, high sensitivity C-reactive Protein (hsCRP) and Diabetic Peripheral Neuropathy (DPN) in T2DM patients on metformin.

Materials and Methods: The randomised, double-blind, parallel group study was conducted in Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India, from April 2018 to October 2019. Total 44 participants were screened and 40 participants of either gender, age range of 35-65 years, Body Mass Index (BMI) ≥25-≤35 kg/m2 and Fasting Blood Sugar ≥126 to ≤200 mg/dL, and glycosylated-haemoglobin (HbA1c) 7.0 to ≤10.0% were included into the study. The T2DM patients (N=40) on metformin (1500-2500 mg/day) were randomised to receive glimepiride (2 mg/day) and teneligliptin (20 mg/day) in group A and group B for 12 weeks, respectively. TNF-α, hsCRP and Vibration-Perception Threshold (VPT) at baseline, 4 weeks and 12 weeks were evaluated for all participants. FBS, HbA1c, Adverse Drug Reactions (ADRs) were also recorded. Unpaired t-test and repeated-measures Analysis of Variance (ANOVA) for normally-distributed variables using Shapiro-Wilk’s test was done. Mann-Whitney and Friedman’s test for non normally distributed variables; for between-group and within-group analysis, respectively were done.


Results: Forty T2DM patients (17 males and 23 females) with mean age of 49.45±6.8 and 50.3±7.9 years, were studied. The mean TNF-α level reduced significantly, in group B (159.25±58.58 to 83.15±26.18 pg/mL; p-value<0.001) from baseline to 12 weeks. Similar significant reduction was seen in the group A (175.2±66.13 to 116.15±63.32 pg/mL; p-value<0.05). There was significant reduction observed in mean VPT-scores (25±6 to 18.0±5.22 V; p-value<0.001) and (26±12.11 to 25±12 V; p-value<0.05) in group B and group A, at 12 weeks, respectively. However, both study groups showed non significant decrease in mean hsCRP levels at 12 weeks. There was a non significant reduction in all study parameters at four weeks. Mean percentage reduction of 34% and 44% in TNF-α, 13% and 11% in hsCRP and 7% and 27% in VPT-scores was observed in group A and group B, respectively at 12 weeks. Improvement in FBS and HbA1c levels (p-value<0.001) was observed in both study groups. Both treatments were tolerated well and no serious adverse drug reactions were observed.

Conclusion: Teneligliptin by reducing TNF-α level, demonstrated modest anti-inflammatory activity along with metformin, by 12 weeks. It also improved VPT-scores. Glimepiride showed lesser degree of anti-inflammatory activity compared to teneligliptin. Both study drugs did not affect hsCRP levels.

Keywords

Antidiabetic drugs, Diabetic peripheral neuropathy, Inflammatory markers, Vibration-perception threshold

Type 2 Diabetes Mellitus (T2DM) is characterised by hyperglycaemia due to insulin-deficiency and peripheral insulin resistance. It is estimated that, 77 million Indian individuals had diabetes in 2019, and this figure is expected to rise to over 134 million by 2045 in India (1).

Inflammatory marker like Tumour Necrosis Factor-α (TNF-α), C-Reactive Protein (CRP), and Interleukin-6 (IL-6) play intermediary-role in insulin resistance, pathogenesis of T2DM and its complications (2). TNF-α biomarker influence intermediary metabolism and act as a link between inflammation and insulin resistance. Due to underlying inflammation, there is increased release of cytokines like TNF-α in skeletal muscles as well as liberation of CRP from the liver resulting in insulin resistance in T2DM (3). The TNF-α bind to TNF receptor-1 thus, activating sphingomyelinase and cascade of events resulting in decrease in Glucose Transporter-4 (GLUT-4) translocation and glucose uptake (4). Role of TNF-α in reducing insulin production from β-cell, was also reported (5).

The CRP is an independent risk determinant for newly diagnosed T2DM (6). Clinically, high sensitivity C-Reactive Protein (hsCRP) is more stable and integrated measure of low-grade inflammation. Chronic low-grade underlying inflammation due to elevated CRP might be a cause for aetiology and manifestation of T2DM. A prospective study reported significantly higher baseline CRP levels in people, who later developed T2DM and its complications providing link between inflammation and development of micro and macrovascular-complications, respectively (7). In addition, subjects with high CRP levels had 2.2 and 8.1 times elevated-risk of pre-diabetes and T2DM, respectively even after adjusting for confounders like age, gender, and Body Mass Index (BMI) (8). It has been reported that, elevated CRP concentrations increase with increasing HbA1c levels (9). During disease progression, both TNF-α and CRP level increase in uncontrolled diabetes. Raised serum TNF-α level in T2DM patients were found to be associated with increased BMI, fasting insulin levels and insulin resistance (10). TNF-α has also shown strong and positive correlation with duration of disease. Increased levels of TNF-α (13.5 pg/mL) levels after adjusting for confounders, were also associated with severity of diabetic complication (11).

The underlying enhanced inflammatory responses due to increase in TNF-α and CRP production during diabetes progression may be responsible for Diabetic Peripheral Neuropathy (DPN). Vibration Perception Threshold (VPT) test, a gold standard, cost-effective bedside screening procedure helps in diagnosis of DPN (12). Hence, pharmacological strategies utilising anti-inflammatory effects of anti-diabetic drugs in treatment of T2DM is important to achieve a comparable quality of life near to those of healthy people. Near normal HbA1c significantly decreases risk of macro and microvascular complications.

The beneficial anti-inflammatory effects of metformin, pioglitazone in T2DM are also well-established (13). Sulfonylureas (SUs) showed anti-inflammatory properties by blocking potassium ion (K+) channels and suppressing TNF-α production from activated macrophages (14). Glibenclamide and gliclazide demonstrated improvement in DPN in diabetic animals by inhibiting the TNF-α production (15). Anti-inflammatory activity of Dipeptidyl Peptidase-4 Inhibitor (DPP-4I) in T2DM patients and improvement in DPN in animals was also reported (13),(16),(17).

Teneligliptin, is a DPP-4I approved for commercial use in India in 2015 for treatment of T2DM (18). It has similar antidiabetic efficacy and safety profile compared to other drugs of its class (19). But currently, limited information on effect of teneligliptin and glimepiride on inflammatory cytokines and their role in DPN is available in T2DM patients. Even though these inflammatory markers are thought to be well understood, they have limited acceptance as clinical markers in regulation of T2DM. It could be due to variation in their levels among various ethnic groups (20),(21),(22). Therefore, studies are required to show their anti-inflammatory action in T2DM. And if, these drugs demonstrate anti-inflammatory effects, these may reduce the burden on healthcare cost in Indian population.

Hence, the present study was undertaken to study effect of teneligliptin versus glimepiride in T2DM patients on metformin. Primary-endpoints were change in serum concentrations of TNF-α and hsCRP at 12 weeks and secondary endpoints were change in VPT scores, FBS, HbA1c and incidence of adverse effects at 12 weeks.

Material and Methods

A randomised, double-blind, parallel group study was conducted from April 2018 to October 2019 at Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India (tertiary care hospital). The Institutional Ethics Committee (IEC) had approved the study (ESGS No. 672/2018, dated 06-03-2018). Written informed consent was taken from all the subjects prior to participation in the study. The study is registered with the Clinical Trials Registry-India (CTRI number= CTRI/2018/03/012603). Uncomplicated T2DM patients (n=44), for past 1-3 years and on stable oral dose of metformin 1500-2500 mg/day and naïve to glimepiride and teneligliptin before enrollment were recruited for screening. They were on a stable dose of antihypertensives for maintenance of blood pressure ≤160/90 mmHg.

Inclusion criteria: Participants of either gender and age between 35-65 years, BMI ≥25 kg/m2 to ≤35 kg/m2 and fasting blood sugar ≥126 mg/dL to ≤200 mg/dL, and glycosylated-haemoglobin (HbA1c) 7 to≤10% were included in the study.

Exclusion criteria: Participants with blood pressure >160/90 mmHg, HbA1c>10%, hsCRP >3 mg/L, impaired renal, liver-function test ≥3ULN, abnormal lipid-profile, pregnancy, lactation, other concomitant-medications, hypersensitivity to drugs and participation in other clinical trials in past three months were excluded from the study.

Sample size calculation: To detect 20±20 pg/mL fall in TNF-α level (16) about 32 participants were found sufficient at α-value=0.05 and 80% power. Considering screen-failure (15%) and dropout rate (15%), 44 participants were screened to enroll 40 participants in the study (Table/Fig 1).

Randomisation was done according to a computer-generated randomisation-sequence, using 10’ random permuted-blocks of four patients each, to enroll 40 participants in the study.

Group A: Glimepiride (2 mg/day) (AMARYL, Sanofi-India,Ltd) with metformin (1500-2500 mg/day) for 12 weeks.

Group B: Teneligliptin (20 mg/day) (ZITEN, Glenmark-Pharmaceuticals) with metformin (1500-2500 mg/day) for 12 weeks.

Study Procedure

Both investigator and participants were blinded; dispense of study medications were performed by a third-person not related to study.Tablets were provided in identical sequentially-numbered containers. The study medications were dispensed to participants at each visit according to their randomisation. They were instructed to take medicine at the same time of the day. Unblinding of randomisation was done 24 hours after last visit of the participant.

Evaluation of TNF-α, hs-CRP levels and VPT scores were done at baseline, 4 weeks and 12 weeks. FBS was recorded at baseline, 4 weeks, 8 weeks and 12 weeks. HbA1c was done at baseline and 12 weeks. Physical examination, vitals, safety and tolerability assessments were done at every review visit. Concomitant medications taken and Adverse Drug Reactions (ADRs) reported were recorded in Case Record Forms (CRF). Medication compliance was monitored by pill-count method. At the end of treatment, participants were asked to report to the clinician for their standard clinical care.

Evaluation Methods

B#BTNF-α:B?B Detection-limit-7.8-500 pg/mL (human serum) evaluated by Boster’s human TNF-alpha symbol, Enzyme Linked Immunosorbent Assay (ELISA) Kit (Boster-Biological-Technology Co).

hsCRP: Levels estimated by immunoturbidimetry method (Beckman-Coulter AU640) (Assay range: 0.2–155.86 mg/L).

VPT: It was measured by Vibrometer-VPT® (Diabetic foot care, Madras Engineering Service, India) by single observer. A probe was kept at great-toe, base of 1st, 3rd and 5th metatarsal, in-step, and heel in right and left feet. Voltage was increased from 0 to 50 V and mean-VPT recorded. Grading of VPT score 15 V (normal), 16-25 V (Grade-I) and >25 V (Grade-II) as per manufacturer manual was followed.

FBS: It was measured by glucose-hexokinase method on Siemens-RXI-analyser

HbA1c: It was estimated using HPLC on Bio-Rad-D10.

Statistical Analysis

Data was presented as Mean±Standard Deviation (SD). Unpaired t-test and repeated-measure Analysis of Variance (ANOVA) for normally-distributed variables using Shapiro-Wilk’s test was done. Mann-Whitney and Friedman’s test for non normally distributed variables; for between-group and within-group analysis respectively were done. A p≤0.05 was considered statistically significant. Incidence of adverse effects was presented as proportions. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS, Armonk, NY:IBM-Corp) version 20.0.

Results

Total 40 T2DM patients (17 males and 23 females) with mean age 49.88±7.26 years and BMI 27.81±2.43 kg/m2 were randomised to receive the study medications. Demographic and clinical characteristics for both study groups are shown in (Table/Fig 2). Both study groups were homogenous at baseline (p-value>0.05).

1. Tumour Necrosis Factor-α level (TNF-α) pg/mL:

Within group analysis: There was a significant reduction in mean TNF-α level in group A and group B from baseline to 12 weeks. Both groups showed non significant reduction from baseline to four weeks. However, the mean TNF-α level reduced significantly from 4 to 12 weeks in group B, but not in group A (Table/Fig 3).

Between group analysis: There was significant reduction observed in mean TNF-α level, when group A vs group B comparisons were done at 12 weeks using unpaired t test. But non significant change was observed at four weeks and at baseline (Table/Fig 3). Mean absolute change (-59.05±52.13 pg/mL) vs (-76.1±54.19 pg/mL) in TNF-α levels in group A vs group B, respectively, was observed at 12 weeks.

2. High sensitivity C-Reactive Protein levels (mg/L):

Within group analysis: There was a significant reduction observed in mean hsCRP level in group A and group B from baseline to 12 weeks. Further analysis showed non significant reduction in mean hsCRP level from baseline to four weeks and from four week to 12 weeks in both study groups (Table/Fig 3).

Between group analysis: Non significant reduction in mean hsCRP level in group A vs group B was observed at 4 and 12 weeks. Both groups were homogenous and comparable at baseline (Table/Fig 3). Mean absolute change in hsCRP level was observed at 12 weeks, respectively (-0.42±0.61 mg/L vs -0.37±0.49 mg/L).

3. Vibration-perception threshold (V):

Within group analysis: VPT scores improved significantly in both groups from baseline to four weeks and 12 weeks. Significant improvement in the VPT scores were noticed from week four weeks to 12 week in group B, but not in group A (Table/Fig 3).

Between group analysis: There was significant improvement in VPT scores in both study groups at 12 weeks. Similar change was not observed at four weeks. Both groups were comparable at baseline (Table/Fig 3).

Mean absolute change of in VPT scores was observed in group A vs group B, respectively at 12 weeks (-1.7±1.13 V and -6.8±2.8 V).

Differences in percentage reduction in TNF-α, hsCRP levels and VPT scores were observed between the groups (Table/Fig 4).

4. Glycaemic control, body weight and BMI

Within group analysis: There was a significant reduction in mean FBS levels from baseline to 4, 8 and 12 weeks and median HbA1c levels from baseline to 12 weeks in both groups (p-value<0.001) (Table/Fig 5), (Table/Fig 6). There were non significant changes in body weight and BMI from baseline to four weeks, eight weeks and 12 weeks in group A and group B (p-value<0.001).

Between group analysis: Non significant difference in mean FBS levels at four weeks, eight weeks and 12 weeks and median HbA1c levels at 12 weeks was noticed in both study groups (Table/Fig 5), (Table/Fig 6).

Safety analysis: There were no serious untoward events or adverse drug reactions observed during the study. Nausea (n=2) in group A and constipation (n=3) and abdominal pain (n=1) in group B were self-limited. Medication compliance (>90%) in all participants was verified by pill-count method. All subjects tolerated the therapy well. None of the participants reported hypoglycaemia or discontinued the study or withdrew from the study.

Discussion

Diabetes being a progressive disease, most of the uncontrolled T2DM patients, may require antidiabetic drugs having additional anti-inflammatory effects. These drugs can be combined as add-on drugs to metformin in order to control symptoms and complications of T2DM. Hence, in the present study, an effort was made to evaluate the anti-inflammatory role of teneligliptin 20 mg/day in comparison to glimepiride 2 mg/day in T2DM patients not adequately controlled by metformin therapy. Teneligliptin may be added to metformin as it has similar beneficial properties as other gliptins i.e. reduction in HbA1c (0.8%-0.9%) low incidence of hypoglycaemia and benefits of weight neutral effects, less seen with glimepiride (23).

Teneligliptin is reported to be a potent DPP-4I with enhanced potency and selectivity; and having fivefold higher activity than sitagliptin (24). It inactivates DPP4 activity at a lower IC50 (0.34 nmol/L) than other DPP-4I (24). Rise in new β-cells, inhibition of β-cell apoptosis, effectiveness in obesity, metabolic syndrome and improvement in vascular endothelial function are few additional effects of teneligliptin (23). Therefore, looking at the beneficial effects of teneligliptin, it could be understood that addition of teneligliptin to metformin at the earliest may result in better control of both glycaemic and inflammatory status in T2DM as compared to glimepiride.

The present study evaluated the effects of teneligliptin versus glimepiride on TNF-α and hsCRP levels in T2DM patients treated with metformin. Effect on DPN was also assessed by analysing VPT-scores. The results of the study, demonstrated significant decrease in TNF-α level and an improving trend in VPT scores in group B compared to group A at 12 weeks. However, similar change was not observed in hsCRP levels in both study groups. All participants showed improvement in FBS and HbA1c at 12 weeks which was almost similar in both study groups. Treatment goal of 130 mg/dL FBS and ≤7.5% HbA1c was achieved, which is in accordance with standards of medical care and thus, up-titration was not required for glimepiride and teneligliptin doses in treatment groups during the study duration. There was no significant change observed in body weight and BMI during study period.

Effect of teneligliptin on TNF-α and hsCRP level: A study by Vinendra MP and Sunita SG, showed statistically significant (p-value<0.05) reduction in TNF-α in teneligliptin 20 mg/day treated group (15.348±1.69 to 14.597±1.65 pg/mL) from baseline to 24 weeks respectively (25).

The present study results, support the previous clinical study where in teneligliptin demonstrated modest but statistically significant anti-inflammatory effects, better than glimepirideat 12 weeks. Appreciable effect on hsCRP level could not be demonstrated by both drugs probably due to short duration of study. Even though TNF-α is the hall mark of inflammation in T2DM, reduction in CRP would also be requiredfor a meaningful reduction in inflammation. As CRP is an established biomarker for coronary risk associated with diabetes, it would have been of great importance, if present study could have demonstrated reduction in hsCRP levels. Longer study duration may probably be required to highlight reduction in hsCRP levels.

Effect of glimepiride on TNF-α and hsCRP level: Sulfonylureas (SUs) produce anti-inflammatory effects either by preventing the inflammatory responses by MAPKs/NF-κb-dependent pathway or suppressing production of cytokines like TNF-α and CRP (26). Study by Koshiba K et al., reported significant reduction in TNF-α and hsCRP levels in T2DM patients in glimepiride group compared to glibenclamide and insulin groups (27). A decrease in TNF-α (2.67 to 1.45 pg/mL) and hsCRP (0.048 to 0.022 mg/L) level in T2DM patients at 28 weeks was reported. There was 45% reduction in TNF-α level at 28 weeks. Simó R et al., reported an absolute decrease in hsCRP level (-0.2 mg/L) at 36 months in glimepiride group. Glimepiride with rosiglitazone, empagliflozin and exenatide added to metformin, reduced hsCRP serum concentrations (28).

The present study results showed a decrease in TNF-α, but not in hsCRP level with glimepiride administration and moreover, decrease in TNF-α level with glimepiride was less compared to teneligliptin treatment. In addition, TNF-α and hsCRP levels did not decrease at four weeks in both study groups. It could be possible that, patients at onset of study were only on treatment with metformin and naïve to glimepiride and teneligliptin. Antidiabetic agents may perhaps require adequate time of 2-4 weeks to decrease inflammatory markers and to affect IRS-1 and translocation of GLUT4 in order to improve insulin resistance.

Effect of Teneligliptin and Glimepiride on VPT: Because of insidious nature of diabetes, chronic diabetic complications are often unavoidable in T2DM patients. In addition to hyperglycaemia and dyslipidaemia, underlying inflammatory markers could be responsible for development and progression of DPN (29). TNF-α regulated CRP, might result in neuronal ischaemia or necrosis resulting in nerve conduction block leading to nerve damaging symptoms and diabetic foot ulcers (29).

Administration of TNF-α to diabetic rats, decreased Motor Nerve Conduction Velocity (MNCV) of sciatic nerve compared to non diabetic rats (17). Inhibitory effects of certain drugs on TNF-α production and as a result amelioration of experimental diabetes neuropathy was reported. Studies reported suppression of TNF-α and CRP production in diabetes animals by sitagliptin or glipizide reduced the severity of DPN, either by increase in myelinated fiber density in diabetic rats or improvement in nerve conduction velocity (17).

In the present study, presence of grade II mean VPT scores, uncontrolled hyperglycaemia (HbA1c ≥7.5%) and higher TNF-α and hsCRP levels at baseline were observed in both study groups when treated with metformin alone. Add-on intervention with teneligliptin showed significant improving trend in VPT scores, when, between and within group comparisons were done at 12 weeks. Negligible improvement was also observed in glimepiride group at 12 weeks. Improvement in VPT scores from grade II to grade I, by teneligliptin was achieved within 12 weeks. Reduction in TNF-α level by teneligliptin treatment, perhaps contributed to this improvement. Teneligliptin may, thus, help in correction of both hyperglycaemia and underlying inflammation of neurons. It may also improve diabetic neuropathy by inhibiting infiltration of macrophages responsible for nerve damage.

Prolonged administration of teneligliptin along with metformin may probably delay development of diabetic foot ulcers resulting due to underlying inflammatory pathology. Hence, anti-diabetic drugs that reduce inflammation and prevent diabetes complications, in addition to improving glycaemic status are required for better outcomes in T2DM.

Anti-inflammatory effect of anti-diabetic agents resulting in improvement in DPN symptoms has not been thoroughly investigated in Indian population. The present study is first of its kind, to evaluate action of teneligliptin verses glimepiride on inflammatory markers and on clinical improvement in in symptoms of DPN. Appropriate anti-inflammatory serum markers like TNF-α and hsCRP were used to observe their involvement in T2DM and complications. Both inflammatory markers selected were sensitive and robust (30). They provide closer associations and better prediction of risk outcomes, than other markers of inflammation.

Limitation(s)

The short duration of study is a major limitation. Other nerve function test like touch and temperature perception could have also been evaluated. In addition, adverse drug reactions on long-term use of glimepiride with metformin and teneligliptin with metformin could not be assessed.

Conclusion

Teneligliptin may thus help in correction of both hyperglycaemia and underlying inflammation of neurons. It may also improve diabetes neuropathy by inhibiting infiltration of macrophages responsible for nerve damage. Moreover, it may be an effective substitute for 1st and 2nd generation gliptins and sulfonylureas, when added to metformin at earliest; without waiting for maximum dose of metformin to be achieved. Hence, teneligliptin by virtue of its anti-inflammatory and hypoglycaemic effects and availability at affordable price range in India, may be chosen as an add on drug for effective management of hyperglycaemia and associated neurological complications. It may improve symptoms of diabetic neuropathy. However, long term studies with a larger sample-size along with objective assessment of DPN could help in strengthening this objective further; as amelioration of DPN may require longer duration to translate into clinical improvement.

Acknowledgement

The authors would like to thank and acknowledge the support of PhD students of the Institution, for helping in estimation of TNF-α and hsCRP biomarkers. Authors would also thank the other residents and staff members for their support and help. The authors sincerely thank all the participants in the study.

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DOI and Others

DOI: 10.7860/JCDR/2022/57237.16981

Date of Submission: Apr 21, 2022
Date of Peer Review: Jun 06, 2022
Date of Acceptance: Jul 11, 2022
Date of Publishing: Nov 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

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