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PO429 SKIN COMPLICATIONS OF SGLT2 INHIBITOR TREATMENT IN JAPANESE
Posters / Diabetes Research and Clinical Practice 106S1 (2014) S47–S267
Result: The PK and PD were similar between treatments, with the 90% CI for the ratios of geometric least squares means completely contained in the prespecified bioequivalence limit of 0.80-1.25 (Table). Adverse events were similar for LY IGlar and IGlar. No safety concerns were noted in clinical laboratory, vital signs, or ECG data. Conclusion: These studies demonstrate similarity in the PK and PD properties of LY IGlar and IGlar. PO429 SKIN COMPLICATIONS OF SGLT2 INHIBITOR TREATMENT IN JAPANESE Y. Suzuki1 . 1 HDC Atlas Clinic, Tokyo, Japan Background: In Japan, recent report of ipragliflozin: one of sodium-glucose cotransporter-2 (SGLT2) inhibitors, indicates the highest number of adverse effect is with skin complication. Japan Diabetes Society published warning recommendation in June 2014 [1]. However, the incidence of skin complication has not been reported at any institute. Method: 142 patients of type 2 diabetes [male 112, female 30, aged 61.8±10.0 y/o (Mean±SD)] were subjected. They had taken ipragliflozin for more than 6 weeks and switched to luseogliflozin, otherwise they had dropped out because of adverse effects. With them, the adverse effects were retrospectively examined. Result: In result, 22 patients dropped out, and 120 patients remained and switched ipragliflozin to luseogliflozin. As shown in Table 1, skin complication occurred in 19 patients (13.4%). Three patients experienced severe eruption. Regarding mild complication of skin, it had two different patterns. One is eruption with itching and the other is only itching. In result, 14 patients first noticed mild skin complication after ipragliflozin. 5 cases showed eruption only in ipragliflozin and dropped out. 7 cases showed itching only in ipragliflozin. The itching relieved after switching. 2 cases showed itching both in two drugs similarly. Hence, these two drugs seem to have cross-sensitization. Other 2 patients noticed only after luseogliflozin but not after ipragliflozin. They switched back to ipragliflozin. Table 1. Summary among a total of 142 subjects Skin complication, n = 19 (13.4%) Ipragliflozin Eruption & itching Itching
Luseogliflozin Eruption & itching
Itching
Severe eruption 3 (→ all dropped out) 5a 7b 2c
2c 2d
a
All patients stopped to take ipragliflozin. All patients relieved itching after switching to luseogliflozin. Same two patients. Their symptoms were the same even after switching from ipragliflozin to luseogliflozin, and they finally dropped out. d These two patients switched back from luseogliflozin to ipragliflozin. b c
Conclusion: The true reason why skin complication is so highly found in patients with ipragliflozin after the release has not been clarified. One reason might be that the itching is so mild as has been unnoticed in pre-launched clinical trials. And the other reason might be explained by that intra-tissue concentration ratio after 24 hours of medication (in plasma vs. in skin) is almost 6.5 times higher in rat with ipragliflozin than that with luseogliflozin (ipragliflozin: plasma 6 ng eq/mL, skin 15 ng eq/mL, ratio 2.5; vs. luseogliflozin: plasma 6.92 ng eq/mL, skin 2.72 ng eq/mL, ratio 0.39) [2,3]. This high intra-skin concentration ratio could lead to high occurence of skin complication.
S265
Environmental air change by Asian dust has been emerging problem recently in Japanese [4]. Therefore, it might have become a latent trigger to immune disturbance, leading to skin complication. It could explain why the same trouble was not occurred during the phase III trial period of ipragliflozin when the problem of Asian dust was not serious in Japan [5]. To confirm these, more long time safety study should be needed. Reference(s) [1] Japan Diabetes Society: Recommendation from “Committee on the proper use of SGLT2 inhibitors”. [2] Interview Form of ipragliflozin. 2014. p. 73. [3] Interview Form of luseogliflozin. 2014. p. 61. [4] Otani S, et al. The relationship between skin symptoms and allergic reactions to Asian dust. Int J Environ Res Public Health. 2012; 9: 4606–14. [5] Kashiwagi A, et al. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomised, double-blind, placebocontrolled study. Diabetes Obes Metab. 2014; 12. doi: 10.1111/ dom.12331.
PO430 CHANGE OF GRIP STRENGTH AND BACK STRENGTH AFTER SGLT2 INHIBITORS TREATMENT IN DIABETES Y. Suzuki1 . 1 HDC Atlas Clinic, Tokyo, Japan Background: SGLT2 inhibitor (SGLT2i) has an effect to reduce lean tissue mass as well as fat mass (1). Weakness and/or sarcopenia are the concerns when SGLT2i is prescribed onto the thin patients. Therefore, we examined the change of grip strength (GS) and back strength (BS) before and after the SGLT2i treatment. Method: 112 diabetes patients of Japanese were subjected. Male 91, Female 21. They were all treated with ipragliflozin, luseogliflozin, dapagliflozin, or tofogliflozin for over at least 4 weeks and more. GS and BS were measured before and after the months of SGLT2i treatment. Result: In male, 30% showed increase of GS and BS. 41% showed increase of GS and decrease of BS. Hence, 71% showed increase of GS. 5% showed decrease of GS and increase of BS. 24% showed decrease of both GS and BS. Hence, 65% showed decrease of BS. In female, 62% showed increase of GS and BS. 14% showed increase of GS and decrease of BS. Hence, 76% showed increase of GS. 14% showed decrease of GS and increase of BS. 10 % showed decrease of both GS and BS. Hence, 24% showed decrease of BS. In total, both male and female patients are likely to increase GS. About 71–76 % patients showed increase of GS, indicating no sexual difference. In contrast, more percentage of patients showed decrease of BS in male than in female. It seems that male patients are likely to lose BS, while female patients are resistant to lose BS. Conclusion: In general, BS is a parameter of total muscle power in healthy Japanese. Therefore, the muscle power loss is reflected by the decease of BS. This study confirmed that the loss of muscle power could occur in diabetes patients under SGLT2i treatment. However, although SGLT2i reduces lean tissue mass and BS, it increased GS in majority of diabetes patients. It seems as if increase of GS compensates decrease of BS, making the muscle power balance homeostatic. Tendency was clearly observed more in male than in female. Several explanations are possible. In diabetes, GS is decreased under hyperglycemia with diabetes (2). Therefore, improvement of hyperglycemia itself could make the GS stronger. Second, nerve conduction velocity recovers rapidly after the improvement of hyperglycemia. Because GS depends on nerve conduction function, the improvement of velocity by SGLT2i therapy might make the grip power stronger. Third, BS is dependent on musculi trunci and GS is dependent on musculi thoracici. Triglyceride accumulation (TGA) in
Result: The PK and PD were similar between treatments, with the 90% CI for the ratios of geometric least squares means completely contained in the prespecified bioequivalence limit of 0.80-1.25 (Table). Adverse events were similar for LY IGlar and IGlar. No safety concerns were noted in clinical laboratory, vital signs, or ECG data. Conclusion: These studies demonstrate similarity in the PK and PD properties of LY IGlar and IGlar. PO429 SKIN COMPLICATIONS OF SGLT2 INHIBITOR TREATMENT IN JAPANESE Y. Suzuki1 . 1 HDC Atlas Clinic, Tokyo, Japan Background: In Japan, recent report of ipragliflozin: one of sodium-glucose cotransporter-2 (SGLT2) inhibitors, indicates the highest number of adverse effect is with skin complication. Japan Diabetes Society published warning recommendation in June 2014 [1]. However, the incidence of skin complication has not been reported at any institute. Method: 142 patients of type 2 diabetes [male 112, female 30, aged 61.8±10.0 y/o (Mean±SD)] were subjected. They had taken ipragliflozin for more than 6 weeks and switched to luseogliflozin, otherwise they had dropped out because of adverse effects. With them, the adverse effects were retrospectively examined. Result: In result, 22 patients dropped out, and 120 patients remained and switched ipragliflozin to luseogliflozin. As shown in Table 1, skin complication occurred in 19 patients (13.4%). Three patients experienced severe eruption. Regarding mild complication of skin, it had two different patterns. One is eruption with itching and the other is only itching. In result, 14 patients first noticed mild skin complication after ipragliflozin. 5 cases showed eruption only in ipragliflozin and dropped out. 7 cases showed itching only in ipragliflozin. The itching relieved after switching. 2 cases showed itching both in two drugs similarly. Hence, these two drugs seem to have cross-sensitization. Other 2 patients noticed only after luseogliflozin but not after ipragliflozin. They switched back to ipragliflozin. Table 1. Summary among a total of 142 subjects Skin complication, n = 19 (13.4%) Ipragliflozin Eruption & itching Itching
Luseogliflozin Eruption & itching
Itching
Severe eruption 3 (→ all dropped out) 5a 7b 2c
2c 2d
a
All patients stopped to take ipragliflozin. All patients relieved itching after switching to luseogliflozin. Same two patients. Their symptoms were the same even after switching from ipragliflozin to luseogliflozin, and they finally dropped out. d These two patients switched back from luseogliflozin to ipragliflozin. b c
Conclusion: The true reason why skin complication is so highly found in patients with ipragliflozin after the release has not been clarified. One reason might be that the itching is so mild as has been unnoticed in pre-launched clinical trials. And the other reason might be explained by that intra-tissue concentration ratio after 24 hours of medication (in plasma vs. in skin) is almost 6.5 times higher in rat with ipragliflozin than that with luseogliflozin (ipragliflozin: plasma 6 ng eq/mL, skin 15 ng eq/mL, ratio 2.5; vs. luseogliflozin: plasma 6.92 ng eq/mL, skin 2.72 ng eq/mL, ratio 0.39) [2,3]. This high intra-skin concentration ratio could lead to high occurence of skin complication.
S265
Environmental air change by Asian dust has been emerging problem recently in Japanese [4]. Therefore, it might have become a latent trigger to immune disturbance, leading to skin complication. It could explain why the same trouble was not occurred during the phase III trial period of ipragliflozin when the problem of Asian dust was not serious in Japan [5]. To confirm these, more long time safety study should be needed. Reference(s) [1] Japan Diabetes Society: Recommendation from “Committee on the proper use of SGLT2 inhibitors”. [2] Interview Form of ipragliflozin. 2014. p. 73. [3] Interview Form of luseogliflozin. 2014. p. 61. [4] Otani S, et al. The relationship between skin symptoms and allergic reactions to Asian dust. Int J Environ Res Public Health. 2012; 9: 4606–14. [5] Kashiwagi A, et al. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomised, double-blind, placebocontrolled study. Diabetes Obes Metab. 2014; 12. doi: 10.1111/ dom.12331.
PO430 CHANGE OF GRIP STRENGTH AND BACK STRENGTH AFTER SGLT2 INHIBITORS TREATMENT IN DIABETES Y. Suzuki1 . 1 HDC Atlas Clinic, Tokyo, Japan Background: SGLT2 inhibitor (SGLT2i) has an effect to reduce lean tissue mass as well as fat mass (1). Weakness and/or sarcopenia are the concerns when SGLT2i is prescribed onto the thin patients. Therefore, we examined the change of grip strength (GS) and back strength (BS) before and after the SGLT2i treatment. Method: 112 diabetes patients of Japanese were subjected. Male 91, Female 21. They were all treated with ipragliflozin, luseogliflozin, dapagliflozin, or tofogliflozin for over at least 4 weeks and more. GS and BS were measured before and after the months of SGLT2i treatment. Result: In male, 30% showed increase of GS and BS. 41% showed increase of GS and decrease of BS. Hence, 71% showed increase of GS. 5% showed decrease of GS and increase of BS. 24% showed decrease of both GS and BS. Hence, 65% showed decrease of BS. In female, 62% showed increase of GS and BS. 14% showed increase of GS and decrease of BS. Hence, 76% showed increase of GS. 14% showed decrease of GS and increase of BS. 10 % showed decrease of both GS and BS. Hence, 24% showed decrease of BS. In total, both male and female patients are likely to increase GS. About 71–76 % patients showed increase of GS, indicating no sexual difference. In contrast, more percentage of patients showed decrease of BS in male than in female. It seems that male patients are likely to lose BS, while female patients are resistant to lose BS. Conclusion: In general, BS is a parameter of total muscle power in healthy Japanese. Therefore, the muscle power loss is reflected by the decease of BS. This study confirmed that the loss of muscle power could occur in diabetes patients under SGLT2i treatment. However, although SGLT2i reduces lean tissue mass and BS, it increased GS in majority of diabetes patients. It seems as if increase of GS compensates decrease of BS, making the muscle power balance homeostatic. Tendency was clearly observed more in male than in female. Several explanations are possible. In diabetes, GS is decreased under hyperglycemia with diabetes (2). Therefore, improvement of hyperglycemia itself could make the GS stronger. Second, nerve conduction velocity recovers rapidly after the improvement of hyperglycemia. Because GS depends on nerve conduction function, the improvement of velocity by SGLT2i therapy might make the grip power stronger. Third, BS is dependent on musculi trunci and GS is dependent on musculi thoracici. Triglyceride accumulation (TGA) in