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Original research

Safety and tolerability of empagliflozin and linagliptin combination therapy in patients with type 2 diabetes mellitus: a pooled analysis of data from five randomized, controlled clinical trials

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Pages 1193-1202 | Received 09 May 2020, Accepted 11 Jun 2020, Published online: 02 Jul 2020

References

  • International Diabetes Federation. IDF Diabetes Atlas. Brussels, Belgium: International Diabetes Federation; 2019. Available from https://www.diabetesatlas.org/en/resources/
  • Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487–493.
  • Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669–2701.
  • Haneda M, Noda M, Origasa H, et al. Japanese clinical practice guideline for diabetes 2016. J Diabetes Investig. 2018 May;9(3):657–697.
  • Haneda M, Noda M, Origasa H, et al. Japanese clinical practice guideline for diabetes 2016. Diabetol Int. 2018 Feb;9(1):1–45.
  • Cahn A, Cernea S, Raz I. An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opin Emerg Drugs. 2016 Dec;21(4):409–419.
  • Ahren B. DPP-4 inhibition and the path to clinical proof. Front Endocrinol (Lausanne). 2019;10:376.
  • Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019 Jan 1;321(1):69–79.
  • Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA. 2019 Sep 19;322(12):1155–1166.
  • Inagaki N, Yang W, Watada H, et al. Linagliptin and cardiorenal outcomes in Asians with type 2 diabetes mellitus and established cardiovascular and/or kidney disease: subgroup analysis of the randomized CARMELINA((R)) trial. Diabetol Int. 2020 Apr;11(2):129–141.
  • Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol. 2015 Dec 1;309(11):F889–900.
  • Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015 Mar;12(2):78–89.
  • Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117–2128.
  • Kaku K, Lee J, Mattheus M, et al. Empagliflozin and cardiovascular outcomes in Asian patients with type 2 diabetes and established cardiovascular disease - results from EMPA-REG OUTCOME((R)). Circ J. 2017 Jan 25;81(2):227–234.
  • Singh-Franco D. Potential for dipeptidyl peptidase-4 inhibitor and sodium glucose cotransporter 2 inhibitor single-pill combinations. Expert Rev Endocrinol Metab. 2015 May;10(3):305–317.
  • Sharma MD. Potential for combination of dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors for the treatment of type 2 diabetes. Diabetes Obes Metab. 2015 Jul;17(7):616–621.
  • Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016 Dec;12(12):1407–1417.
  • DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015 Mar;38(3):384–393.
  • Lewin A, DeFronzo RA, Patel S, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015 Mar;38(3):394–402.
  • Tinahones FJ, Gallwitz B, Nordaby M, et al. Linagliptin as add-on to empagliflozin and metformin in patients with type 2 diabetes: two 24-week randomized, double-blind, double-dummy, parallel-group trials. Diabetes Obes Metab. 2017 Feb;19(2):266–274.
  • Softeland E, Meier JJ, Vangen B, et al. Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin: a 24-week randomized, double-blind, parallel-group trial. Diabetes Care. 2017 Feb;40(2):201–209.
  • Kaku K, Haneda M, Tanaka Y, et al. Linagliptin as add-on to empagliflozin in a fixed-dose combination in Japanese patients with type 2 diabetes: glycaemic efficacy and safety profile in a two-part, randomized, placebo-controlled trial. Diabetes Obes Metab. 2019 Jan;21(1):136–145.
  • Kawamori R, Haneda M, Suzaki K, et al. Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: glycaemic efficacy and safety profile in a 52-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2018 Sep;20(9):2200–2209.
  • DeFronzo RA, Lee C, Kohler S. Safety and tolerability of combinations of empagliflozin and linagliptin in patients with type 2 diabetes: pooled data from two randomized controlled trials. Adv Ther. 2018 Jul;35(7):1009–1022.
  • Vijayakumar TM, Jayram J, Meghana Cheekireddy V, et al. Safety, efficacy, and bioavailability of fixed-dose combinations in type 2 diabetes mellitus: a systematic updated review. Curr Ther Res Clin Exp. 2017;84:4–9.
  • Blonde L, San Juan ZT. Fixed-dose combinations for treatment of type 2 diabetes mellitus. Adv Ther. 2012 Jan;29(1):1–13.
  • Hutchins V, Zhang B, Fleurence RL, et al. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011 Jun;27(6):1157–1168.
  • Hendrieckx C, Ivory N, Singh H, et al. Impact of severe hypoglycaemia on psychological outcomes in adults with Type 2 diabetes: a systematic review. Diabet Med. 2019 Sep;36(9):1082–1091.
  • International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol. 2019 May;7(5):385–396.
  • Johnson-Rabbett B, Seaquist ER. Hypoglycemia in diabetes: the dark side of diabetes treatment. A patient-centered review. J Diabetes. 2019 Sep;11(9):711–718.
  • Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014 Dec;10(12):711–722.
  • Ahren B. Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. Vasc Health Risk Manag. 2013;9:155–163.
  • Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and Diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013 May;36(5):1384–1395.
  • Marrett E, Stargardt T, Mavros P, et al. Patient-reported outcomes in a survey of patients treated with oral antihyperglycaemic medications: associations with hypoglycaemia and weight gain. Diabetes Obes Metab. 2009 Dec;11(12):1138–1144.
  • Kohler S, Zeller C, Iliev H, et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017 Jul;34(7):1707–1726.
  • Yabe D, Yasui A, Ji L, et al. Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. J Diabetes Investig. 2019 Mar;10(2):418–428.
  • Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Saf. 2019 Apr;18(4):295–311.
  • Lehrke M, Marx N, Patel S, et al. Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled studies. Clin Ther. 2014 Aug 1;36(8):1130–1146.
  • Heise T, Jordan J, Wanner C, et al. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016 Oct;38(10):2265–2276.
  • Yasui A, Lee G, Hirase T, et al. Empagliflozin induces transient diuresis without changing long-term overall fluid balance in Japanese patients with type 2 diabetes. Diabetes Ther. 2018 Apr;9(2):863–871.
  • Boehringer Ingelheim Pharmaceuticals, Inc. JARDIANCE (empagliflozin) prescribing information; 2020 Jan. [cited 2020 Mar 27]. Available from: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf.
  • Boehringer Ingelheim International GmbH. Jardiance (empagliflozin) summary of product characteristics; 2020 Jan 10. [cited 2020 Mar 27]. Available from: https://www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_en.pdf.
  • Nippon Boehringer Ingelheim. Jardiance (empagliflozin) Japanese package insert. [cited 2020 Mar 27]. Available from: https://www.info.pmda.go.jp/go/pack/3969023F1023_1_10/.
  • Boehringer Ingelheim Pharmaceuticals, Inc. GLYXAMBI (empagliflozin and linagliptin) prescribing information; 2020 Jan. [cited 2020 Mar 27]. Available from: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Glyxambi/Glyxambi.pdf.
  • Boehringer Ingelheim International GmbH. Glyxambi (empagliflozin and linagliptin) summary of product characteristics; 2019 Dec 10. [cited 2020 Mar 27]. Available from: https://www.ema.europa.eu/en/documents/product-information/glyxambi-epar-product-information_en.pdf.
  • Nippon Boehringer Ingelheim. Tradians (empagliflozin and linagliptin) Japanese package insert. [cited 2020 Mar 27]. Available from: https://www.info.pmda.go.jp/go/pack/3969108F1027_1_02/.
  • Winocour PH. Diabetes and chronic kidney disease: an increasingly common multi-morbid disease in need of a paradigm shift in care. Diabet Med. 2018 Mar;35(3):300–305.
  • Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2016 Feb;12(2):73–81.
  • Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):610–621.
  • Wanner C, Heerspink HJL, Zinman B, et al. Empagliflozin and kidney function decline in patients with type 2 diabetes: a slope analysis from the EMPA-REG OUTCOME trial. J Am Soc Nephrol. 2018 Nov;29(11):2755–2769.
  • Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):323–334.
  • Thomson SC, Vallon V. Renal effects of sodium-glucose co-transporter inhibitors. Am J Cardiol. 2019 Dec 15;124(Suppl 1):S28S35.
  • Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug 17;377(7):644–657.
  • Matthews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019 Jun;62(6):926–938.
  • Janssen Pharmaceuticals, Inc. INVOKANA (canagliflozin) prescribing information; 2020 Jan. [cited 2020 Mar 27]. Available from: http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf.
  • Inzucchi SE, Iliev H, Pfarr E, et al. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care. 2018 Jan;41(1):e4–e5.
  • Merck Serono Limited. Glucophage (metformin) summary of product characteristics; 2019 August. [cited 2020 Mar 27]. Available from https://hcp.merckgroup.com/content/dam/web/healthcare/diabetes/glucophage-ir/MRP%20SPC%20LAB%20PL%20Glucophage%20500mg%20fct%20Type%20IAIN%20122%202017Jan10%20en%20app.pdf.
  • Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018 Feb;41(2):356–363.

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