Efficacy and Safety of Linagliptin for Type 2 Diabetes Mellitus: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 LIUYing , ZHAOYu-mei , ZHANGXu-xiang ,  SONGDian-ping

The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China;

Corresponding author：

SONGDian-ping, Email: drsongdp@sina.com

Keywords：

Linagliptin; Type 2 diabetes; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20150177

Video：

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Objective To systematically review the efficacy and safety of linagliptin in the treatment of type 2 diabetes. Methods We searched The Cochrane Library, EMbase, PubMed, CNKI, CBM, VIP and WanFang data to collect randomized controlled trials (RCTs) on linagliptin versus placebo for type 2 diabetes from inception to January 2015. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed using RevMan 5.3 software. Results A total of 16 RCTs were included. The results of meta-analysis showed:The linagliptin monotherapy group was superior to the placebo group in reducing HbA1c (MD=-0.76, 95%CI -0.85 to -0.66) and FPG (MD=-1.12, 95%CI -1.28 to -0.95), and there were no statistical differences in the incidence of overall adverse events (OR=0.86, 95%CI 0.70 to 1.06) and hypoglycemic (OR=1.19, 95%CI 0.36 to 4.01) between the two groups. The linagliptin combination treatment group (combined with other oral antihyperglycemic drugs) was superior to the placebo combination treatment group in reducing HbA1c (MD=-0.61, 95%CI -0.67 to -0.56) and FPG (MD=-0.79, 95%CI -0.96 to -0.63), and there was no statistical difference in the incidence of overall adverse events between the two groups (OR=1.07, 95%CI 0.92 to 1.24), however, the incidence of hypoglycaemic in the linagliptin combination treatment group was higher than that in the placebo combination treatment group (OR=1.55, 95%CI 1.19 to 2.02). Conclusion Linagliptin is effective and safe in the treatment of type 2 diabetes. Due to the limited quantity and quality of included studies, more high quality studies are needed to verify the above conclusion.

Citation： LIUYing, ZHAOYu-mei, ZHANGXu-xiang, SONGDian-ping. Efficacy and Safety of Linagliptin for Type 2 Diabetes Mellitus: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2015, 15(9): 1068-1077. doi: 10.7507/1672-2531.20150177 Copy

1.	葛均波, 徐永健. 内科学. 第8版. 北京:人民卫生出版社, 2013:733-756.
2.	Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in china. N Engl J Med, 2010, 362(12):1090-1101.
3.	Higgins Jpt, Green S. Cochrane handbook for systematic re views of interventions version 5.1.0[updated march 2011]. The cochrane collaboration, 2011. Available at:www.cochrane-handbook.org.2012-11-27/2012-12-10.
4.	Bajaj M, Gilman R, Patel S, et al. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone:a 24-week randomized, double-blind study. Diabet Med, 2014, 31(12):1505-1514.
5.	Barnett AH, Patel S, Harper R, et al. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate:an 18-week randomized, double-blind, placebo-controlled phase iii trial with a 34-week active-controlled extension. Diabetes Obes Metab, 2012, 14(12):1145-1154.
6.	Barnett AH, Huisman H, Jones R, et al. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments:a randomised, double-blind, placebo-controlled trial. Lancet, 2013, 382(9902):1413-1423.
7.	Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes:a randomized controlled trial.Diabetes Obes Metab, 2011, 13(3):258-267.
8.	Forst T, Uhlig-Laske B, Ring A, 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(12):1409-1419.
9.	Gomis R, Espadero RM, Jones R, et al. 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(7):653-661.
10.	Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes:a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab, 2012, 14(6):565-574.
11.	Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in japanese patients with type 2 diabetes:a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab, 2012, 14(4):348-357.
12.	Lajara R, Aguilar R, Hehnke U, et al. Efficacy and safety of linagliptin in subjects with long-standing type 2 diabetes mellitus (> 10 years):evidence from pooled data of randomized, double-blind, placebo-controlled, phase Ⅲ trials. Clin Ther, 2014, 36(11):1595-1605.
13.	Lewin AJ, Arvay L, Liu D, et al. 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(9):1909-1919.
14.	Owens DR, Swallow R, Dugi KA, et al. 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. Clin Ther, 2011, 28(11):1352-1361.
15.	Ross SA, Rafeiro E, Meinicke T, et al. Efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin:a randomised, double-blind, placebo-controlled trial. Curr Med Res Opin, 2012, 28(9):1465-1474.
16.	Taskinen MR, Rosenstock J, Tamminen I, 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(1):65-74.
17.	Thrasher J, Daniels K, Patel S, et al. Efficacy and safety of linagliptin in black/african american patients with type 2 diabetes:a 6-month, randomized, double-blind, placebo-controlled study. Endocr Pract, 2014, 20(5):412-420.
18.	Wang W, Yang J, Yang G, et al. Efficacy and safety of linagliptin in asian patients with type 2 diabetes mellitus inadequately controlled by metformin:a multinational 24-week, randomized clinical trial. J Diabetes, 2015, doi:10.1111/1753-0407.
19.	Zeng Z, Yang JK, Tong N, et al. Efficacy and safety of linagliptin added to metformin and sulphonylurea in chinese patients with type 2 diabetes:a sub-analysis of data from a randomised clinical trial. Curr Med Res Opin, 2013, 29(8):921-929.
20.	Aletti R, Cheng LA. Linagliptin:the newest dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus. Cardiol Rev, 2012, 20(1):45-51.
21.	Blech S, Ludwig SE, Graefe ME, et al. The metabolism and disposition of the dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos, 2010, 38(4):667-678.
22.	Graefe MU, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab, 2011, 13(10):939-946.
23.	Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med, 2013, 369(14):1317-1326.

1. 葛均波, 徐永健. 内科学. 第8版. 北京:人民卫生出版社, 2013:733-756.
2. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in china. N Engl J Med, 2010, 362(12):1090-1101.
3. Higgins Jpt, Green S. Cochrane handbook for systematic re views of interventions version 5.1.0[updated march 2011]. The cochrane collaboration, 2011. Available at:www.cochrane-handbook.org.2012-11-27/2012-12-10.
4. Bajaj M, Gilman R, Patel S, et al. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone:a 24-week randomized, double-blind study. Diabet Med, 2014, 31(12):1505-1514.
5. Barnett AH, Patel S, Harper R, et al. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate:an 18-week randomized, double-blind, placebo-controlled phase iii trial with a 34-week active-controlled extension. Diabetes Obes Metab, 2012, 14(12):1145-1154.
6. Barnett AH, Huisman H, Jones R, et al. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments:a randomised, double-blind, placebo-controlled trial. Lancet, 2013, 382(9902):1413-1423.
7. Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes:a randomized controlled trial.Diabetes Obes Metab, 2011, 13(3):258-267.
8. Forst T, Uhlig-Laske B, Ring A, 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(12):1409-1419.
9. Gomis R, Espadero RM, Jones R, et al. 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(7):653-661.
10. Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes:a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab, 2012, 14(6):565-574.
11. Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in japanese patients with type 2 diabetes:a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab, 2012, 14(4):348-357.
12. Lajara R, Aguilar R, Hehnke U, et al. Efficacy and safety of linagliptin in subjects with long-standing type 2 diabetes mellitus (> 10 years):evidence from pooled data of randomized, double-blind, placebo-controlled, phase Ⅲ trials. Clin Ther, 2014, 36(11):1595-1605.
13. Lewin AJ, Arvay L, Liu D, et al. 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(9):1909-1919.
14. Owens DR, Swallow R, Dugi KA, et al. 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. Clin Ther, 2011, 28(11):1352-1361.
15. Ross SA, Rafeiro E, Meinicke T, et al. Efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin:a randomised, double-blind, placebo-controlled trial. Curr Med Res Opin, 2012, 28(9):1465-1474.
16. Taskinen MR, Rosenstock J, Tamminen I, 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(1):65-74.
17. Thrasher J, Daniels K, Patel S, et al. Efficacy and safety of linagliptin in black/african american patients with type 2 diabetes:a 6-month, randomized, double-blind, placebo-controlled study. Endocr Pract, 2014, 20(5):412-420.
18. Wang W, Yang J, Yang G, et al. Efficacy and safety of linagliptin in asian patients with type 2 diabetes mellitus inadequately controlled by metformin:a multinational 24-week, randomized clinical trial. J Diabetes, 2015, doi:10.1111/1753-0407.
19. Zeng Z, Yang JK, Tong N, et al. Efficacy and safety of linagliptin added to metformin and sulphonylurea in chinese patients with type 2 diabetes:a sub-analysis of data from a randomised clinical trial. Curr Med Res Opin, 2013, 29(8):921-929.
20. Aletti R, Cheng LA. Linagliptin:the newest dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus. Cardiol Rev, 2012, 20(1):45-51.
21. Blech S, Ludwig SE, Graefe ME, et al. The metabolism and disposition of the dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos, 2010, 38(4):667-678.
22. Graefe MU, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab, 2011, 13(10):939-946.
23. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med, 2013, 369(14):1317-1326.

Chinese Journal of Evidence-Based Medicine

Efficacy and Safety of Linagliptin for Type 2 Diabetes Mellitus: A Meta-analysis

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