Sponsored Symposium Highlights LinagLiptin in Combination with other anti-hypergLyCaemiCs Frequently, type 2 diabetes mellitus (T2DM) treatment may require combining several anti-hyperglycaemic drugs to achieve optimal glycaemic control and to prevent cardiovascular complications.1 However, these combinations may often trigger adverse events that affect patient compliance, and ultimately, compromise glycaemic control. Among the new anti-hyperglycaemics, dipeptidyl peptidase (DPP)-4 inhibitors have provided good outcomes and fewer adverse effects when used in combination therapy. Only about 30% of patients with T2DM receiving insulin difference between HbA1c levels of -0.7% favouring linagliptin (-7.1 mmol/mol) [95%, CI -0.74, -0.55; P<0.0001] (Figure 1)2. Hypoglycaemia and other adverse events were similar between groups, and mean body weight remained unchanged.2 alone or in combination with oral anti-hyperglycaemic drugs (OADs) achieve target HbA1c levels.3,4 Oftentimes, weight gain.5,6 hba1c (%) regimens becomes necessary but may lead to a higher risk of adverse outcomes, such as hypoglycaemia or 8.4 Difference: 0.7% 95% CI -0.74,-0.55 P<0.0001 8.2 Baseline HbA1c: 8.3% 8.6 addition of other oral agents or more complex insulin 8.4 Linagliptin 5 mg once daily may be a viable treatment option in patients with inadequately controlled T2DM on basal insulin as single therapy or in combination with other OADs. Addition of linagliptin to basal insulin was associated with a low frequency of hypoglycaemia. 8 7.8 7.7 7.6 In this light, Yki-Järvinen et al investigated the efficacy and 7.4 safety of linagliptin 5 mg once daily, as add-on therapy to 7.2 basal insulin alone or in combination with metformin in Linagliptin Placebo patients with T2DM and inadequate glycaemic control.2 mmol/mol to 86 mmol/mol) on basal insulin monotherapy or combined with metformin were randomised to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥ 52 weeks.2 There was a significant An Adherence Intervention: Metformin and DPP4-inhibitor Fixed-dose Combination Therapy Professor Merlin Thomas Baker IDI Heart and Diabetes Institute Melbourne, Australia Adherence to treatment interventions has far greater impact on patient health than the science involved in the improvement of specific medications. In patients with T2DM, the common reasons for non-compliance are the side effects, lack of confidence in immediate or future benefits of treatment, duration of disease, pill burden, and complexity of drug regimen.7,8 Consequently, increasing treatment complexity and poor adherence equals poor glycaemic control.9 Because of these issues, fixed-dose combination therapies or “polypills” become necessary.10 Studies have shown that patients on fixed-dose combination therapy had better adherence10,11 (Figure 2) and achieved target HbA1c levels compared to those on free combination therapy.12 Combination products were also observed to be significantly less expensive than when the same drugs were taken separately.11 Figure 1: Comparison of Baseline HbA1c and After Treatment with Linagliptin versus Placebo2 This is the first study to evaluate the efficacy and safety of a DPP-4 inhibitor in basal insulin treated patients to include both a period of stable insulin dosing, allowing adherence rate (%) A total of 1,261 patients with HbA1c values of 7.0 to 10.0% (53 100 90 80 70 60 50 40 30 20 10 0 P<0.001 P<0.001 87 77 71 Fixed dose combination Free combination Previously on monotherapy The study results are consistent with current knowledge and recommendations on the use of linagliptin in that glycaemic control can be improved without increasing hypoglycemia or inducing weight gain in a broad range of patients and in combination with OADs. An additional advantage is that the dose does not need to be altered in the elderly or in those with impaired renal function. there is an observed increase of GLP-1 levels due to the synergism between these drugs.13 The fixed-dose combination of linagliptin and metformin has comparable glucose lowering efficacy as free combination.14 It has also been found to be bioequivalent to that of single pill combinations; hence, its efficacy and safety are equivalent.15 54 Free combination an assessment of the efficacy and safety of add-on linagliptin, and an extension period during which adjustment of insulin dose were permitted; this reflects a “real world” scenario. This study also demonstrated that the efficacy and tolerability of linagliptin is not affected by the choice of basal insulin, concomitant OAD use, age, or degree of renal impairment. Fixed dose combination Previously on combination therapy, then switched Figure 2: Comparison of Adjusted Adherence Rates between Patients Transitioned from Monotherapy (left) to Either Free Combination or Fixed Dose Combination Therapy and Adjusted Adherence Rates Before and After the Switch from Free Combination Therapy (right) to Fixed Dose Combination Therapy10 Metformin has been shown to improve glycaemic control when administered concurrently with DPP-4 inhibitors. Metformin enhances glucagon-like peptide-1 (GLP1) secretion and upregulates the expression of GLP-1 receptors in the β-cells of the pancreas. On the other hand, DPP-4 inhibitors reduce GLP-1 degradation and maintain endogenous GLP-1 activity. When combined, Physicians now have more options for treatment of poorly controlled T2DM. The issue of adherence often hounding poorly-controlled diabetic patients may be addressed by using oral fixed-dose combination therapy. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Derosa G, et al. Vasc Health Risk Manag 2007;3:665-71. Yki-Järvinen H, et al. Diabetes Care 2013;36:3875-81. Hoerger TJ, et al. Diabetes Care 2008;31:81-6. Willey CJ, et al. The American Journal of Managed Care 2006;12:43540. Inzucchi SE, et al. Diabetes care 2012;35:1364-79. Ilag LL, et al. Clinical Therapeutics 2007;29:1254-70. Grant RW, et al. Diabetes Care 2003;26:1408-12. Mateo JF, et al. Int J Clin Pract 2006;60:422-8. Pollack M, et al. J Clin Outcomes Manage 2010;17:257-65. Melikian C, et al. Clin Ther 2002;24:460-7. Cheong C, et al.Clin Ther 2008;30:1893-907. Han S, et al. Curr Med Res Opin 2012;28:969-77. Liu Y, et al. Diabetes Obes Metab 2013;Epub ahead of print. Ross SA, et al. Curr Med Res Opin 2012;28:1465-74. Graefe-Mody EU, et al. Curr Med Res Opin 2009;25:1963-72. Sponsored as a service to the medical profession by Boehringer-Ingelheim and Eli Lilly Editorial development by MIMS MedComms. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever arising is hereby disclaimed. ©2014 MIMS Pte Ltd. All rights reserved. No part of this publication may be reproduced by any process in any language without the written permission of the publisher. MIMS Pte Ltd 6 Shenton Way, OUE Downtown 2, #15-08 Singapore 068809 Tel: +65-6290 7400 Fax: +65-6290 7401 Email: [email protected] Website: www.mims.com TRAJ/41-2014 Linagliptin plus basal insulin improves glycaemic control without hypoglycaemia or weight gain2