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BRIEF COMMUNICATION
Year : 2016  |  Volume : 20  |  Issue : 4  |  Page : 568-572

Alternate-day dosing of linagliptin in type 2 diabetes patients controlled on once daily dose: A case series


Endocrinology Unit, Excel Centre (Initiative of Excel Care Hospitals Pvt. Ltd.), Guwahati, Assam, India

Date of Web Publication3-Jun-2016

Correspondence Address:
Manash P Baruah
Excel Centre (Initiative of Excel Care Hospitals Pvt. Ltd.), Barthakur Mill Road, Ulubari, Guwahati, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.183468

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   Abstract 


Linagliptin, a dipeptidyl peptidase 4 (DPP 4) inhibitor with a long terminal half life, significantly inhibits the DPP 4 enzyme at a steady state up to 48 h after the last dose. The present case series examined the hypothesis that linagliptin retains its efficacy during alternate day dosing in type 2 diabetes patients when switched over from once daily (OD) dosing. Eight type 2 diabetes patients maintaining stable glycosylated hemoglobin (HbA1c) with acceptable fasting plasma glucose and postprandial glucose levels and receiving linagliptin 5 mg OD for at least 6 weeks, with a stable dose of concomitant antidiabetic medications were given linagliptin 5 mg every alternate day. The median HbA1c while on the OD regimen was 6.1% (43 mmol/mol) (range: 5.8–6.9% [40–52 mmol/mol]) and median duration of diabetes was 7 years (range: 0.75–16 years). After a median follow-up period of 21weeks,the glycemic control was maintained in all patients similar to their baseline values (median HbA1c: 6.0% [42 mmol/mol], range: 5.1–7.1% [32–54 mmol/mol]). The body weight, fasting, and random glucose levels at baseline were also well maintained at the end of treatment. Optimal glycemic status maintained in our study population favors our hypothesis that linagliptin used alternate daily after switching from initial OD dose of the drug in patients on a stable background antidiabetic medications retains its efficacy. Paradoxically, alternate day dosing may affect compliance if the patient forgets when they took the last dose. Further studies including larger cohorts are needed to validate this finding and identify patients who can benefit from the alternate day regimen.

Keywords: Diabetes mellitus, dipeptidyl peptidase 4 inhibitors, hyperglycemia, linagliptin


How to cite this article:
Baruah MP, Bhuyan SB, Deka J, Bora J, Bora S, Barkakati M. Alternate-day dosing of linagliptin in type 2 diabetes patients controlled on once daily dose: A case series. Indian J Endocr Metab 2016;20:568-72

How to cite this URL:
Baruah MP, Bhuyan SB, Deka J, Bora J, Bora S, Barkakati M. Alternate-day dosing of linagliptin in type 2 diabetes patients controlled on once daily dose: A case series. Indian J Endocr Metab [serial online] 2016 [cited 2021 Feb 27];20:568-72. Available from: https://www.ijem.in/text.asp?2016/20/4/568/183468




   Introduction Top


Dipeptidyl peptidase-4 (DPP-4) inhibitors are a promising therapeutic class of glucose-lowering medications and include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. These inhibitors stimulate and increase the secretions of endogenous glucagon such as peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are hormones released in response to food intake. The enhancement of GLP-1 and GIP leads to insulin secretion by pancreatic β-cells, reduction in glucagon secretion, and reduction in liver glucose production.[1],[2] According to the recommendations from the American Association of Clinical Endocrinologists, DPP-4 inhibitors are recommended an option for first-line therapy in patients with an intolerance or contraindication to metformin such as renal or hepatic disease, gastrointestinal intolerance, or risk of lactic acidosis.[3],[4] DPP-4 inhibitors have also been recommended as part of combination therapy with two or three agents in patients with uncontrolled hyperglycemia.

Linagliptin is a competitive reversible DPP-4 inhibitor with a long terminal half-life. It has a high volume of distribution that leads to potent and long-lasting DPP-4 inhibitory effect in vivo.[5] It has an elimination half-life of 131 h, and achieves steady-state concentrations after three doses of 5 mg once daily (OD).[6] Daily doses of linagliptin 5 mg showed >80% inhibition of DPP-4 even after 24 h of administration. It has been demonstrated earlier that >80% DPP-4 inhibition did not result in additional glycemic efficacy [7] and therefore, the trough DPP-4 inhibition of at least 80% is considered as a biomarker for the maximal glucose lowering capacity of these drugs. In a dose ranging study on Asian patients, inhibition of plasma DPP 4 at 24 h after 4 weeks therapy with linagliptin 0.5, 2.5, and 10 mg was 46%, 78%, and 90%, respectively.[8] Both in vitro and ex vivo human and preclinical studies showed that linagliptin has higher potency and long duration of DPP-4 inhibition compared to other DPP-4 inhibitors.[8],[9] In fact, the maximum DPP-4 inhibition within one dosing interval at steady state was 92.3 and 93.7%, respectively for the 5 and 10 mg dose.[6] A comparative study on the enzyme binding kinetics of the available gliptins indicates that linagliptin had a high affinity toward DPP-4 enzyme and had the slowest dissociation rate from the enzyme among the class. This is also the reason linagliptin can continue to inhibit the DPP-4 even after the free drug has been cleared from circulation.[9],[10] Pharmacokinetic (PK)-pharmacodynamic modeling and simulation studies with linagliptin assessed the impact of missing a dose and found that missing a dose could not adversely affect the DPP-4 inhibition, and it was maintained well above the required 80% inhibitory action,[10],[11] suggesting that linagliptin may be given on alternate days to achieve similar glycemic control as OD dosing. However, clinical evidence to support the hypothesis is lacking. With this background, we hypothesized that linagliptin retains its efficacy during alternate day dosing in type 2 diabetes patients when switched from OD dosing. This case series examined the hypothesis in a cohort of patients well controlled with 5 mg OD dosing of linagliptin, who were switched over to receive linagliptin 5 mg on alternate days.


   Materials and Methods Top


Study participants

Eight cases of type 2 diabetes patients are described in this series. The patients were aged more than 18 years, well controlled on linagliptin for at least 6 weeks and with acceptable fasting plasma glucose (FPG), and postprandial glucose (PPG) levels, glycosylated hemoglobin (HbA1c) <7.0% (53 mmol/mol), and on stable antidiabetic treatment. No patient had any comorbid systemic ailment. All patients had documented stable hepatic and renal status. No patient received any concomitant medication which could have influenced linagliptin action.[12]

Method

This hypothesis-generating study with cross-over design was conducted in compliance with good clinical practice and with ethical standards for human experimentation established by Declaration of Helsinki and in accordance with the applicable regulatory requirements. All subjects gave verbal informed consent before participation in the study. All the eligible patients receiving linagliptin 5 mg OD for at least 6 weeks along with other concomitant antidiabetic medication were switched over to the alternate day regimen, i.e. to receive linagliptin 5 mg alternate day, and were followed up for a median period of 21 weeks (range: 12–27 weeks). Subjects were followed up through telephonic calls at least twice a week and were reviewed in the outpatient clinic at least once in 6 weeks of therapy. During the last visit, they were evaluated for the efficacy and safety of linagliptin. Blood samples were collected for evaluation of FPG, PPG, and HbA1c at baseline and again on the last day of the follow-up period. Physical examinations, vital signs, 12-lead electrocardiographic, and safety laboratory measurements comprising hematology, clinical chemistry, and urinalysis were performed before and at the end of the study. Adverse events (AEs) were monitored throughout the study. Compliance was assessed by pill count method.

Statistical analysis

As the present study is a case series, descriptive statistics have been used to summarize the demographics.


   Results Top


A total of 8 patients (7 male and 1 female) were enrolled and completed the study. The mean age, height, weight, and body mass index were 56.13 ± 15.78 years, 164.93 ± 7.41 cm, 73.25 ± 13.79 kg, and 26.57 ± 4 kg/mr 2 respectively. The median duration of diabetes was 7 years (range: 0.75–16 years) [Table 1].
Table 1: Baseline characteristics of the patients

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Before enrollment, all the patients were taking linagliptin 5 mg OD in combination with other antidiabetic medications (metformin in five patients, metformin and glimepiride, neutral protamine hagedorn (NPH) insulin, and premix insulin in one patient each) as part of the stable ongoing therapy for at least 6 weeks (range: 6–88 weeks). In one patient, NPH insulin was replaced with metformin 500 mg OD during alternate day therapy. The dose and frequency of concomitant medications in other patients were not altered.

At the end of 12 weeks or more of alternate dosing, the change in HbA1c compared to baseline was maintained [Table 2]. A further reduction in FPG was observed compared to baseline [Table 2]. However, a slight rise in PPG compared to baseline was observed [Table 2]. The HbA1c, FPG, and PPG change in the individual cases are depicted in [Figure 1] and [Figure 2], respectively.
Table 2: Changes in glycemic parameters from baseline (on linagliptin 5 mg once daily) to the end of follow-up on alternate daily therapy (12 or more weeks)

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Figure 1: Change in glycosylated hemoglobin while on alternate day dosing – patient level data (*linagliptin daily dosing; **linagliptin alternate day dosing)

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Figure 2: Change in fasting plasma glucose and postprandial plasma glucose (PPPG) while on alternate day dosing – patient level data (*linagliptin daily dosing; **linagliptin alternate day dosing)

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In one patient, variations in 24 h blood glucose levels were measured for 6 consecutive days during the linagliptin alternate day therapy using continuous glucose monitoring system device (CGMS iPro2; Medtronic Minimed, Northridge, CA, USA). No significant changes were observed in the 24-h blood glucose level profile during both day and night on the days of linagliptin administration and on days without linagliptin therapy, which suggested that linagliptin alternate day dosing was associated with stable and sustained glycemic control at all-time points [Figure 3]. Modest reduction in body weight was observed after minimum 6 weeks of therapy compared to baseline {70.50 kg (59–101) versus 67.25 kg (52–104.5)}. Linagliptin was well- tolerated in all the patients with no hypoglycemia reported during the study. All the patients showed good compliance with the medication regimen. No patient required alteration of dose of linagliptin or any other concomitant antidiabetic drug except in one where NPH insulin was replaced with metformin 500 mg OD during alternate day therapy.
Figure 3: 24 h blood glucose levels obtained by continuous glucose monitoring system over 6 days period with linagliptin alternate day treatment in one patient

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   Discussion Top


The DPP-4 inhibitors are widely used in the treatment of type 2 diabetes mellitus. These include compounds, that efficiently lower fasting, and postprandial hyperglycemia and reduce HbA1c levels by 0.5–0.9%.[11],[13] However, these compounds differ in terms of their potency to inhibit the DPP-4 enzyme, their duration of action, and their metabolism and elimination. The PKs of linagliptin, notably its long elimination half-life, suggests that alternate-day dosing may be appropriate compared to the daily dosing. It also induces highly selective, potent, dose-dependent inhibition of DPP-4, with ≥ 80% inhibition of DPP-4 throughout the 24-h dosing interval. To our knowledge based on the available literature, the present case series is the first to investigate the effects of linagliptin 5 mg alternate day dosing on blood glucose levels in type 2 diabetes mellitus patients maintained on OD treatment. We are also not aware of any study using alternate daily dosing of any other DPP-4 inhibitor.

Several clinical trials have demonstrated that linagliptin causes significant reductions in HbA1c, FPG, and PPG, when administered as monotherapy,[12],[13],[14],[15] initial combination therapy (with metformin or pioglitazone),[14],[15],[16],[17] or add-on therapy to other oral antihyperglycemic agents (metformin and/or sulfonylurea)[17],[18],[19],[20] or basal insulin (with or without metformin and/or pioglitazone)[19],[21] in type 2 diabetes patients with AEs generally being mild or moderate in intensity. The present case series showed that efficacy of linagliptin 5 mg administered every other day for a median period of 21 weeks is similar to that of daily dosing in reducing glucose parameters in patients with diabetes mellitus. Linagliptin continued to inhibit the DPP-4 activity beyond 24 h after the last dose. Such prolonged DPP-4 inhibition may be sufficient to exert a meaningful clinical efficacy beyond 24 h. Based on the information, one can speculate, that linagliptin 5 mg alternate dosing would provide an equivalent effect to linagliptin 5 mg administered on a daily basis, however, further randomized studies in a large population are required to confirm this postulate. It is worth remembering that noncompliance is the major concern with alternate day dosing, which may affect the clinical outcome adversely. A major limitation of the study was a lack of randomized controlled arm although the crossover design (from OD dosing to alternate daily dosing) provided a template for comparison. We also could not perform serum linagliptin level estimation, or objective documentation of DPP-4 enzyme activity before and after the crossover, both of which could have been quite ideal for such a study.


   Conclusions Top


Linagliptin 5 mg used alternate daily in patients who are well controlled with linagliptin 5 mg OD along with a stable background antidiabetic medication can maintain optimal glycemic control. Paradoxically, alternate-day dosing may affect compliance if the patient forgot when they took the last dose. Larger randomized clinical trials are warranted before the alternate-day administration is recommended for type 2 diabetes mellitus patients.

Acknowledgments

The authors would like to thank Makrocare Clinical Research Limited, Hyderabad for the preparation of the manuscript and for analyzing the statistical data. We gratefully acknowledge the cooperation and support given by the patients, who made this work possible.

Financial support and sponsorship

Nil.

Conflicts of interest

Manash P Baruah has received travel grants and speaker honoraria from Borheinger Ingelhem, Astra Zeneca, MSD, Novartis and USV in the past.

 
   References Top

1.
Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: A comparative review. Diabetes Obes Metab 2011;13:7-18.  Back to cited text no. 1
    
2.
Palalau AI, Tahrani AA, Piya MK, Barnett AH. DPP-4 inhibitors in clinical practice. Postgrad Med 2009;121:70-100.  Back to cited text no. 2
    
3.
Handelsman Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA, et al. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan: Executive summary. Endocr Pract 2011;17:287-302.  Back to cited text no. 3
[PUBMED]    
4.
Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: An algorithm for glycemic control. Endocr Pract 2009;15:540-59.  Back to cited text no. 4
[PUBMED]    
5.
Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem 2007;50:6450-3.  Back to cited text no. 5
    
6.
Heise T, Graefe-Mody EU, Hüttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab 2009;11:786-94.  Back to cited text no. 6
    
7.
Roy RS, Wu J, Eiermann G, Lyons K, He H, Weber A, et al. Plasma DPP-4 inhibition by sitagliptin and other DPP-4 inhibitors correlates with and predicts glucose lowering efficacy. Poster session presented at 69th Scientific Sessions of American Diabetes Association; 2009 June 5–9, New Orleans, Louisiana. 2373- PO.  Back to cited text no. 7
    
8.
Horie Y, Kanada S, Watada H, Sarashina A, Taniguchi A, Hayashi H, et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor linagliptin: A 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients. Clin Ther 2011;33:973-89.  Back to cited text no. 8
    
9.
Thomas L, Eckhardt M. Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), A novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 2008;325:175-82.  Back to cited text no. 9
    
10.
Schnapp G, Klein T, Mark M, Fuchs H, Bakker RA, Nar H. Comparative Enzyme Kinetic Analysis of the Launched Dipeptidyl Peptidase-4 Inhibitors. Poster Session Presented at 74th Scientific Sessions of American Diabetes Association; 2014 June 13-17, San Francisco, California. p1048.  Back to cited text no. 10
    
11.
Wright S, Singh RP, Retlich S, Graefe-Mody U, Derendorf H. The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety. Int J Clin Pharmacol Ther 2012;50:323-30.  Back to cited text no. 11
    
12.
Scott LJ. Linagliptin: In type 2 diabetes mellitus. Drugs 2011 26;71:611-24.  Back to cited text no. 12
    
13.
Sena CM, Bento CF, Pereira P, Seiça R. Diabetes mellitus: New challenges and innovative therapies. EPMA J 2010;1:138-63.  Back to cited text no. 13
    
14.
Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of ß-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab 2011;13:258-67.  Back to cited text no. 14
    
15.
Horie Y, Kanada S, Watada H, Sarashina A, Taniguchi A, Hayashi N, et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor linagliptin: A 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients. Clin Ther 2011;33:973-89.  Back to cited text no. 15
    
16.
Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:65-74.  Back to cited text no. 16
    
17.
Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet Med 2010;27:1409-19.  Back to cited text no. 17
    
18.
Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:653-61.  Back to cited text no. 18
    
19.
Lewin AJ, Arvay L, Liu D, Patel S, von Eynatten M, Woerle HJ. Efficacy and tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus: An 18-week, multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther 2012;34:1909-19.e15.  Back to cited text no. 19
    
20.
Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: A 24-week randomized study. Diabet Med 2011;28:1352-61.  Back to cited text no. 20
    
21.
Yki-Järvinen H, Rosenstock J, Durán-Garcia S, Pinnetti S, Bhattacharya S, Thiemann S, et al. Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: A≥52-week randomized, double-blind study. Diabetes Care 2013;36:3875-81.  Back to cited text no. 21
    


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