Safety of Ipragliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Phase II/III/IV Clinical Trials

Atsunori Kashiwagi, Marina V Shestakova, Yuichiro Ito, Masahiro Noguchi, Wim Wilpshaar, Satoshi Yoshida, John P H Wilding, Atsunori Kashiwagi, Marina V Shestakova, Yuichiro Ito, Masahiro Noguchi, Wim Wilpshaar, Satoshi Yoshida, John P H Wilding

Abstract

Introduction: Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials.

Methods: Safety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements.

Results: The overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier's gangrene in ipragliflozin-treated patients across the 12 studies.

Conclusion: In randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed.

Trial registration numbers: NCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094.

Funding: Astellas Pharma Inc.

Keywords: Ipragliflozin; Pooled analysis; Safety; Sodium-glucose cotransporter 2 inhibitor; Type 2 diabetes mellitus.

References

    1. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27:136–142. doi: 10.1111/j.1464-5491.2009.02894.x.
    1. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427–3434. doi: 10.2337/diabetes.54.12.3427.
    1. Rieg T, Masuda T, Gerasimova M, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014;306:F188–F193. doi: 10.1152/ajprenal.00518.2013.
    1. Mosley JF, Smith L, Everton E, Fellner C, Fellner C. Sodium-glucose linked transporter 2 (SGLT2) inhibitors in the management of type-2 diabetes: a drug class overview. Pharm Ther. 2015;40:451–462.
    1. Fonseca VA, Ferrannini E, Wilding JP, et al. Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J Diabetes Complic. 2013;27:268–273. doi: 10.1016/j.jdiacomp.2012.11.005.
    1. Kashiwagi A, Kazuta K, Yoshida S, Nagase I. Randomized, placebo-controlled, double-blind glycemic control trial of novel sodium-dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2014;5:382–391. doi: 10.1111/jdi.12156.
    1. Shestakova MV, Wilding JPH, Wilpshaar W, Tretter R, Orlova VL, Verbovoy AF. A phase 3 randomized placebo-controlled trial to assess the efficacy and safety of ipragliflozin as an add-on therapy to metformin in Russian patients with inadequately controlled type 2 diabetes mellitus. Diabetes Res Clin Pract. 2018;146:240–250. doi: 10.1016/j.diabres.2018.10.018.
    1. Kashiwagi A, Takahashi H, Ishikawa H, et al. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the Long-Term ASP1941 Safety Evaluation in Patients with Type 2 Diabetes. Diabetes Obes Metab. 2015;17:152–160. doi: 10.1111/dom.12403.
    1. Kashiwagi A, Kazuta K, Takinami Y, Yoshida S, Utsuno A, Nagase I. Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: the BRIGHTEN study. Diabetol Int. 2015;6:8–18. doi: 10.1007/s13340-014-0164-0.
    1. Wilding JPH, Ferrannini E, Fonseca VA, Wilpshaar W, Dhanjal P, Houzer A. Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study. Diabetes Obes Metab. 2013;15:403–409. doi: 10.1111/dom.12038.
    1. Kashiwagi A, Kazuta K, Goto K, Yoshida S, Ueyama E, Utsuno A. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2015;17:304–308. doi: 10.1111/dom.12331.
    1. Kashiwagi A, Akiyama N, Shiga T, et al. Efficacy and safety of ipragliflozin as an add-on to a sulfonylurea in Japanese patients with inadequately controlled type 2 diabetes: results of the randomized, placebo-controlled, double-blind, phase III EMIT study. Diabetol Int. 2015;6:125–138. doi: 10.1007/s13340-014-0184-9.
    1. Kashiwagi A, Shiga T, Akiyama N, et al. Efficacy and safety of ipragliflozin as an add-on to pioglitazone in Japanese patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study (the SPOTLIGHT study) Diabetol Int. 2015;6:104–116. doi: 10.1007/s13340-014-0182-y.
    1. Ishihara H, Yamaguchi S, Nakao I, Asahina S, Sakatani T. Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a 36-week, open-label extension of a 16-week, randomized, placebo-controlled, double-blind study. Diabetol Int. 2018;2018:1–14.
    1. Lu C-H, Min KW, Chuang L-M, Kokubo S, Yoshida S, Cha B-S. Efficacy, safety, and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin: results of a phase 3 randomized, placebo-controlled, double-blind, multicenter trial. J Diabetes Investig. 2016;7:366–373. doi: 10.1111/jdi.12422.
    1. Han K-A, Chon S, Chung CH, et al. Efficacy and safety of ipragliflozin as an add-on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: a randomized controlled trial. Diabetes Obes Metab. 2018;20:2408–2415. doi: 10.1111/dom.13394.
    1. Storgaard H, Gluud LL, Bennett C, et al. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2016;11:e0166125. doi: 10.1371/journal.pone.0166125.
    1. Kashiwagi A, Yoshida S, Kawamuki K, et al. Effects of ipragliflozin, a selective sodium–glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials. Diabetol Int. 2017;8:76–86. doi: 10.1007/s13340-016-0283-x.
    1. Min K-W, Ku BJ, Lee J-H, et al. Addition of ipragliflozin to metformin treatment in Korean patients with type 2 diabetes mellitus: subgroup analysis of a phase 3 trial. Diabetes Metab J. 2017;41:135. doi: 10.4093/dmj.2017.41.2.135.
    1. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8:330–339. doi: 10.1016/j.jash.2014.02.003.
    1. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–428. doi: 10.2337/dc14-1096.
    1. Kashiwagi A, Sakatani T, Nakamura I, et al. Improved cardiometabolic risk factors in Japanese patients with type 2 diabetes treated with ipragliflozin: a pooled analysis of six randomized, placebo-controlled trials. Endocr J. 2018;65:693–705. doi: 10.1507/endocrj.EJ17-0491.
    1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.
    1. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925.
    1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;2019:NEJMoa1811744. doi: 10.1056/nejmoa1811744.
    1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389.
    1. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–39. doi: 10.1016/S0140-6736(18)32590-X.
    1. Kaku K, Isaka H, Toyoshima J, Sakatani T. Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: a phase 2, randomized, placebo-controlled trial. Diabetes Obes Metab. 2019;21:1445–1454. doi: 10.1111/dom.13679.
    1. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:864–876. doi: 10.1016/S2213-8587(17)30308-X.
    1. Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41:2560–2569. doi: 10.2337/dc18-1749.
    1. Kaku K, Isaka H, Sakatani T, Toyoshima J. Efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: a randomized, double-blind, phase 3 trial. Diabetes Obes Metab. 2019;2019:dom.13807. doi: 10.1111/dom.13807.
    1. Filippas-Ntekouan S, Filippatos TD, Elisaf MS. SGLT2 inhibitors: are they safe? Postgrad Med. 2018;130:72–82. doi: 10.1080/00325481.2018.1394152.
    1. Rådholm K, Wu JH, Wong MG, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes—a systematic review. Diabetes Res Clin Pract. 2018;140:118–128. doi: 10.1016/j.diabres.2018.03.027.
    1. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia. 2017;60:1385–1389. doi: 10.1007/s00125-017-4301-8.
    1. Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60:1862–1872. doi: 10.1007/s00125-017-4370-8.
    1. Food and Drug Administration. FDA briefing document, NDA 202293 Dapagliflozin tablets, 5 and 10 mg. Advisory Committee Meeting. 2013.
    1. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101:157–166. doi: 10.1210/jc.2015-3167.
    1. Food and Drug Administration. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Safety Announcement 2018. . Accessed 14 Jan 2019.
    1. Yabe D, Nishikino R, Kaneko M, Iwasaki M, Seino Y. Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events. Expert Opin Drug Saf. 2015;14:795–800. doi: 10.1517/14740338.2015.1034105.
    1. Vasapollo P, Cione E, Luciani F, Gallelli L. Generalized intense pruritus during canagliflozin treatment: is it an adverse drug reaction? Curr Drug Saf. 2018;13:38–40. doi: 10.2174/1574886311666160405110515.
    1. Sakaeda T, Kobuchi S, Yoshioka R, et al. Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors. Int J Med Sci. 2018;15:937–943. doi: 10.7150/ijms.22224.
    1. Mellander A, Billger M, Johnsson E, Träff AK, Yoshida S, Johnsson K. Hypersensitivity events, including potentially hypersensitivity-related skin events, with dapagliflozin in patients with type 2 diabetes mellitus: a pooled analysis. Clin Drug Investig. 2016;36:925–933. doi: 10.1007/s40261-016-0438-3.
    1. Poole RM, Dungo RT. Ipragliflozin: first global approval. Drugs. 2014;74:611–617. doi: 10.1007/s40265-014-0204-x.
    1. Yokote K, Terauchi Y, Nakamura I, Sugamori H. Real-world evidence for the safety of ipragliflozin in elderly Japanese patients with type 2 diabetes mellitus (STELLA-ELDER): final results of a post-marketing surveillance study. Expert Opin Pharmacother. 2016;17:1995–2003. doi: 10.1080/14656566.2016.1219341.
    1. Nakamura I, Maegawa H, Tobe K, Tabuchi H, Uno S. Safety and efficacy of ipragliflozin in Japanese patients with type 2 diabetes in real-world clinical practice: interim results of the STELLA-LONG TERM post-marketing surveillance study. Expert Opin Pharmacother. 2018;19:189–201. doi: 10.1080/14656566.2017.1408792.
    1. Nakamura I, Maegawa H, Tobe K, Uno S. Safety and effectiveness of ipragliflozin for type 2 diabetes in japan: 12-month interim results of the STELLA-LONG TERM post-marketing surveillance study. Adv Ther. 2019 doi: 10.1007/s12325-019-0895-1.
    1. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes. Ann Intern Med. 2013;159:262. doi: 10.7326/0003-4819-159-4-201308200-00007.
    1. Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I–III clinical trials. Adv Ther. 2017;34:1707–1726. doi: 10.1007/s12325-017-0573-0.
    1. Jabbour S, Seufert J, Scheen A, Bailey CJ, Karup C, Langkilde AM. Dapagliflozin in patients with type 2 diabetes mellitus: a pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20:620–628. doi: 10.1111/dom.13124.
    1. Qiu R, Balis D, Xie J, Davies MJ, Desai M, Meininger G. Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis. Curr Med Res Opin. 2017;33:553–562. doi: 10.1080/03007995.2016.1271780.
    1. Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7:2824. doi: 10.1038/s41598-017-02733-w.
    1. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2015. . Accessed 14 Jan 2019.
    1. European Medicines Agency. SGLT2 Inhibitors. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes 2016. . Accessed 14 Jan 14 2019.
    1. Reed JW. Impact of sodium-glucose cotransporter 2 inhibitors on blood pressure. Vasc Health Risk Manag. 2016;12:393–405. doi: 10.2147/VHRM.S111991.
    1. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71:2628–2639. doi: 10.1016/j.jacc.2018.03.009.
    1. Wu JHY, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4:411–419. doi: 10.1016/S2213-8587(16)00052-8.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa