Incretin-based therapies (IBT) including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been the cornerstone of therapy for type 2 diabetes mellitus (T2DM) since the evolution of incretin science. DPP-4Is are particularly popular in the treatment of T2DM as they are oral drugs, less costlier than GLP-RAs, with modest to moderate glucose lowering similar to sulfonylureas (SU) depending on the baseline glycemic load. DPP-4Is carries novel mechanism of action and also have additional potential to protect from hypoglycemia, through unique glucagon dynamics.[1] Indeed, consensus statements from the American College of Endocrinology/American Association of Clinical Endocrinologist and the Latin American Diabetes Association consider DPP-4I ahead of SU, mainly driven by their lower risk of hypoglycemia as well as weight neutrality.[2 3] Moreover, Asians (mainly East Asians) have also been found to respond comparatively better to IBT, compared to Caucasian. However, incretin response in South Asians (including Indians) appears to be different from East Asians and thus currently there is no clear consensus whether Indians also exhibit exaggerated response to IBT, like East Asians.[4] Consequently, at least 11 different compounds of DPP-4Is have been made available worldwide, of which mostly available in Japan.[5] In India, 4 DPP-4Is are already available and marketed that includes sitagliptin, vildagliptin, saxagliptin, and linagliptin. Recently, two newer molecule teneligliptin and gemigliptin have been added to this segment. Importantly, teneligliptin has been already approved and marketed product in Japan since 2012 and in Korea since 2014. However, teneligliptin is neither approved in the USA or in Europe although it was registered in the US Food and Drug Administration (FDA) for Phase 1 clinical development in 2007 and Phase 2 clinical developments in European Medicines Agency in 2009, without any further progress.[6] Recently an Indian study by Suryawanshi et al, reported the results of a 16-week, multicentric, double-blind, placebo-controlled, Phase 3 studies of teneligliptin 20 mg daily in drug naive T2DM patients. This study (N = 237) reported a significant −0.55% glycated hemoglobin (HbA1c) reduction (placebo-subtracted) in teneligliptin arm (P = 0.0043) compared to control. While a significant reduction in 2 h postprandial glucose (PPG) (−25.8 mg/dl, P = 0.0070) versus placebo was observed, an insignificant reduction in fasting plasma glucose (FPG) was seen (−8.8 mg/dl, P = 0.18) in teneligliptin 20 mg arm. Similarly, higher percentage of patient achieved the target HbA1c of 10,000 times greater than that for DPP-4.[9 15] The most important pharmacodynamic parameter for any DPP-4Is that translates to clinical efficacy is the extent of percentile DPP-4 inhibition. While percentage of DPP-4 inhibition was 81.3 and 89.7% within 2 h after teneligliptin 10 and 20 mg, respectively, percentage inhibition of plasma DPP-4 activity at 24 h after administration was 53.1 and 61.8% in the teneligliptin 10 and 20 mg group, respectively, in a 4-week study conducted by Eto et al.[9] Another study by Nabeno et al. demonstrated that the percentage inhibition of plasma DPP-4 activity 24 h after administration of 20 and 40 mg dose of teneligliptin was varying somewhere between 53.9–66.9% and 59.8%, respectively.[15] Besides, only 80 mg doses of teneligliptin exhibited >80% (72–85%) plasma DPP-4 inhibition at 24h after administration.[15] Table 1 summarizes the extent of DPP-4 inhibition at various time point with different dosage of teneligliptin. Interestingly, both 10 and 20 mg teneligliptin demonstrated higher concentrations of plasma active GLP-1, compared to placebo even at 24 h after administration. Moreover, the differences in AUC0–2h for plasma active GLP-1 concentration between both teneligliptin treated groups and placebo were statistically significant (P 7.3%.[19 20] Table 2 summarizes the results from all these studies including the Indian data. Table 2 Efficacy of teneligliptin 20 mg daily in type 2 diabetes in phase 2 or 3, randomized, double-blind, placebo-controlled multicenter trials The efficacy and safety when teneligliptin dose is increased to 40 mg in patients with insufficient response to 20 mg are also available from one of the integrated analyses of the Japanese long-term treatment study as a review file by Japan Pharmaceuticals and Medical Devices Agency (PMDA).[22] This integrated analysis reported the pooled data of three studies including two published studies[19 20] and one unpublished study. In this analysis, the teneligliptin dose was to be increased to 40 mg, if HbA1c target met the criteria for dose increase as per the protocol. Interestingly, results from the pooled data found that the dose was required to be increased to 40 mg in 45.9% (290 of 632 patients) of patients. Of 275 patients (275 of 290 patients) whose HbA1c data were available at 12 weeks after the dose increase, 30.9% (85 of 275 patients) showed a ≥0.3% decrease in HbA1c when switched to teneligliptin 40 mg. Overall, HbA1c level decreased to 8.0% at baseline. In a very small (n = 43), short-term (28 weeks), observational, Japanese study, Otsuki et al. evaluated the efficacy and safety of teneligliptin (n = 14) to controls (n = 29) on existing antidiabetic therapy, in adults with T2DM, who had end-stage renal disease. The study found no significant difference (P = 0.057) between the teneligliptin and control group for changes in HbA1c levels at 24 weeks although significant drop in HbA1c was noticed in 7 patients on teneligliptin who switched from other antidiabetic therapy. Currently, no randomized controlled trial in renal-compromised patients has been published with teneligliptin.[24] Two studies that have studied the teneligliptin effect on glucose variation also merit special mention although they are too short in duration and too small in a number of patient included and therefore may not be very conclusive. In one Japanese study in T2DM patients receiving insulin therapy (n = 26), with or without other antidiabetes drugs, teneligliptin was found to improve indices of glucose fluctuations (the SD of 24 h glucose levels and mean amplitude of glycemic excursions [MAGE]) using continuous glucose monitoring without inducing hypoglycemia.[25] In another very small (n = 10) report from Japanese T2DM patients, 3 days of teneligliptin on ongoing insulin therapy found to improve 24 h glucose levels, SD of 24 h glucose levels, and MAGE.[26] Collectively, these results suggest improvement in glucose fluctuations with teneligliptin. Safety and tolerability of teneligliptin Teneligliptin as a monotherapy or add-on therapy to other agents such as glimepiride, metformin, and pioglitazone, was generally well tolerated in patients with T2DM participating in clinical trials. In monotherapy study, adverse drug reactions (ADRs) and AEs occurred in ≥5% of patients in any group were nasopharyngitis, positive urine ketone body, urine glucose, and urinary protein.[17] The incidence of ADRs was not significantly different among the four groups although the adverse rate tended to be higher in the teneligliptin 40 mg group. All ADRs were categorized as mild in intensity by the investigator. In Phase 3 add-on to glimepiride study, the incidence rates of serious AEs were similar in both groups at week 12.[19] In Phase 3 add-on to pioglitazone, specific AEs occurred in >5% and included nasopharyngitis and peripheral edema.[20] Hypoglycemia was reported in two patients (1.9%) in the teneligliptin group at week 12. In the pooled 52 weeks safety analysis, treatment-related hypoglycemia occurred with an overall incidence of 3.4% in teneligliptin recipients, with all episodes of mild intensity. The incidence of hypoglycemia was numerically higher in the teneligliptin plus SU (10.1%) and teneligliptin plus glinide (5.0%) groups than in the teneligliptin monotherapy (2.5%), teneligliptin plus biguanide (1.1%), or teneligliptin plus α-glucosidase inhibitor (1.3%) groups.[23] Thyroid cancer was observed in one patient in the teneligliptin monotherapy group. Cardiac safety of teneligliptin Overall, in all published randomized controlled trial, no serious cardiac events have been attributable to teneligliptin. Interestingly, a thorough QT/QTc evaluation study of teneligliptin 40 and 160 mg actively compared to moxifloxacin found a significant increase in latter dose. Teneligliptin 40 mg/day which is currently the maximal recommended dose prolonged the placebo-corrected QTcF (QTc corrected for heart rate) by 4.9 ms after 3 h. The 160 mg/day of teneligliptin significantly increased the QTcF by 11.2 ms after 1.5 h of the drug was administered, almost similar to 12.1 ms of QTcF prolongation as observed 2 h after moxifloxacin. The Japanese PMDA also concluded “In the Phase III studies of teneligliptin, patients being treated for arrhythmia, patients with a history of ventricular tachycardia, and patients with abnormality in resting standard 12-lead electrocardiography (ECG) at the start and end of the run-in period were excluded. Therefore, the risks of QTc interval prolongation and arrhythmia in these patients have not been investigated. Furthermore, since the timing for ECG measurement was not specified in the Phase III studies, the possibility cannot be excluded that the effect of teneligliptin on QTc interval prolongation was not thoroughly investigated. In addition, taking into account that there are diabetic patients who have concurrent diseases such as arrhythmia and ischemia, and that teneligliptin may be administered to such patients for a long period of time, it is deemed necessary to raise caution in administering teneligliptin to these patients and to collect information on proarrhythmic risk via postmarketing surveillance.”[22] Table 3 summarizes the QTc prolongation with various dosages of teneligliptin. Table 3 QTc prolongation with various dosage teneligliptin (adapted from Japan Pharmaceuticals and Medical Devices Agency dossier) This may also suggest that a great caution may be required in patients who are prone to QT prolongation such as those with episodes of bradycardia, ischemic heart diseases, heart failure, and hypokalemia. In addition, the coadministration of teneligliptin with drugs known to cause QT prolongation such as Class IA or Class III antiarrhythmic drugs must be performed with great caution.[22] Extraglycemic effect of teneligliptin Experimental studies conducted with teneligliptin found notable improvement in metabolic features in rat and mice.[27 28] Teneligliptin 20 mg also appeared to improve vascular endothelial function at 2 weeks in a study of 11 elderly T2DM patients.[29] Hashikata et al. in a 3-month study of 29 Japanese T2DM patients evaluated the effect of teneligliptin 20/40 mg daily on left ventricular (LV) function using echocardiography at baseline and at the end of the study. A significant improvement in both LV systolic and diastolic function was observed at the end of 3 months. LV ejection fraction improved from 62.0 ± 6.5% to 64.5 ± 5.0%, P = 0.01 and peak early diastolic velocity/basal septal diastolic velocity (E/e′) ratio improved from 13.3 ± 4.1 to 11.9 ± 3.3, P = 0.01. In addition, a significant improvement in endothelial function was also observed, as measured by reactive hyperemia peripheral arterial tonometry (RHPAT) index (RHPAT index improved from 1.58 ± 0.47 to 2.01 ± 0.72, P 70% at 24 h. This outcome is perhaps, somewhat lower as seen in head-to-head study of sitagliptin, vildagliptin, and saxagliptin.[34] Whether that translates into any lower glycemic efficacy with teneligliptin compared to other DPP-4Is is yet to be seen, as no head-to-head trial is being currently done or undergoing. Teneligliptin 20 or 40 mg once daily studied for 12–16 weeks, in placebo-controlled trials, as a monotherapy or in combination with metformin, glimepiride, or pioglitazone, was found to improve glycemic control. Moreover, teneligliptin 40 mg daily was found to lower HbA1c to 40%, with expected completion in June 2019.[42] This study appears to be similar in line to vildagliptin in VIVIDD trial and may give some solace to practicing clinician. From cardiac safety point of view, prolongation of QTc is a unique issue with teneligliptin not observed with any other available DPP-4Is. Current threshold set by US FDA for cardiac safety of any drugs in Phase 1 trial is a drug should not prolong QTc by 5 ms or the upper bound 90% confidential interval (CI) of QTc studies should not cross the threshold of 10 ms.[43] While teneligliptin 160 mg (although not recommended for clinical use) is clearly associated with a prolonged QTc, even teneligliptin 40 mg also appears to approach that critical threshold of 5 ms or upper bound 90% CI of 10 ms. This threshold perhaps becomes even more important when teneligliptin will be prescribed with several other drugs which tend to prolong QTc including antibiotics (azithromycin), antihistaminics (astemizole, terfenadine), diuretics (thiazide), selective serotonin uptake inhibitors, haloperidol, and obviously antiarrhythmic drugs (amiodarone and sotalol). Moreover, hypoglycemia being one of the strong QTc prolongators, combination with other hypoglycemic drug may need strict pharmacovigilance. Overall, the present study will be a valuable addition to the accumulating data on teneligliptin. Particularly, the Indian evidence has been lacking and is therefore welcome. However, several questions remain, on the efficacy and “in particular” safety of teneligliptin as discussed earlier. A robust pharmacovigilance program to watch out for safety signals is important as are mechanized and clinical studies on CVOT, especially a dedicated CVOT given the QT prolongation. Till then, health-care providers must keep in mind, the limitation of the data with teneligliptin and discuss the same with their patients.
