ルセオグリフロジンの薬疹がダパグリフロリジンへ切り替え後、改善した糖尿病の一症例
A case of Diabetes who experienced improvement of Skin Complication after the change from Luseogliflozin to Dapagliflozin
ＳＧＬＴ２阻害剤がＳＣを起こしやすい薬剤である事実は海外では注目されていなかった。日本で行われた治験段階においてもＳＣが起こりやすい頻度は、0.8から2.9％の間であり、重篤例が多いことは発売前には予測されていなかった１，２，3, 4）。治験を元にしたＳＧＬＴ２阻害剤、4製剤のSC頻度を比較すると、イプラフロリジンが2.9％、トホグリフロジンが1.5％、ダパグリフロリジンが1.2％、ルセオグリフロジンが0.8％の順だった。そのため、本症例はアトピー性皮膚炎を有していた事から、SCが最も発症しにくいと考えられたルセオフロリジンから処方を開始した。しかし、当初の予測とは反対に、ルセオフロリジンで薬疹を発症し、ダパグリフロジンに切り替える事で、その事象が消えた。
ルセオフロリジンとダパグリフロジンは構造体として似ているが、一部の構造の違いがSC発症の引き金の違いになっている可能性は否定できない。本症例はカナグリフロジンを1年間、治験の薬剤として服用していた既往もある事から、ダパグリフロジンやカナグリフロジンには反応せず、ルセオフロリジンあるいはその代謝産物だけに反応するアレルギー反応がSCの原因であったと考えるのが自然である。患者さんの背景には、基礎にアトピー性皮膚炎があるため、なにかしらの特定物質だけにアレルギー反応を惹起しうる体質を有しやすい背景があることは不思議ではない。
興味深いのは、発汗が多い部位に薬疹が発現しやすかった事象である。腹部、両側前腕外側部など、サウナに入ると汗が貯まりやすい部位に、薬疹が起こり掻痒感も一致して起こっていた。これは、ルセオフロリジンのほうが、発汗によって皮膚表面にルセオフロリジン自体か、その代謝産物が流出し皮膚表面に停滞しやすく、ダパグリフロジンやカナグリフロジンは、そうした性質に乏しい製剤間の違いを有している可能性がある。我々が経験したイプラフロリジンやダパグリフロジン、トホグリフロジンなどによっておこった糖尿病患者におけるSCには同様の傾向は認められていない（unpublished data）。一方、コリン作動性蕁麻疹の体質を持つ患者では、発汗などに反応しやすく、未知の血清因子などに反応しやすい事も知られている5)。よってSGLT2阻害剤の製剤間差を議論する研究において、こうした「発汗と薬疹」との関係は、今後、興味あるテーマになりうる。
本患者さんでは薬疹がでた段階で、薬疹の悪化が心配になり飲酒を止めていた。飲酒は炎症部位を悪化させるため、禁酒した事がSCの改善に繋がった可能性は高い6)。元々の過飲酒傾向が、既往にもあるように中性脂肪を高め、急性膵炎を起こし、糖尿病の原因にもなり、アトピーの原因にもなっていた7）。ルセオフロリジンからダパグリフロジンに切り替えた時期に禁酒をした事と合致し、危険因子が消えて、ダパグリフロジンに切り替えた時に発疹が回復してきた現象に見えた可能性も否定できない。よって今後、SGLT2阻害剤の切り替えを行う場合、飲酒傾向がどう変化したかなどの注意深い観察も必要である。
結論：SGLT2阻害剤は日本人ではSCを起こしやすい薬剤である。その中でも治験結果が提示された段階では、ルセオフロリジンが最もSCの発生頻度が少ないと考えられる。しかし、本症例のように、ルセオフロリジンでSCが現れ、ダパグリフロジンやカナグリフロジンでは現れないという症例もいることは、これまでに報告がない。したがって製薬メーカーが自主的に行った治験報告に全てを依存する事なく、医師らが共同で市販後調査を行い、原因追及していく方策をとるべき事が肝要であると考えた。
考察
1)大正富山医薬品株式会社、ノバルティスファーマ株式会社: 医薬品インタビューフォーム,ルセフィ2.5mg, ルセフィ5mg（2014年８月改訂、第３版）
２）アストラゼネカ株式会社，小野薬品工業株式会社：医薬品インタビューフォーム，フォシーガ5mg，10mg（2014年改訂、第2版）
３）アステラス製薬株式会社、寿製薬株式会社、 MSD株式会社：医薬品インタビューフォーム,スーグラ25mg スーグラ50mg（２１０４年４月改訂）
４）サノフィ株式会社、興和創薬株式会社: 医薬品インタビューフォーム,アプルウェイ錠20mg,デベルザ錠20mg（２01４年５月改訂、第２版）
５）Kim JE1, Jung KH, Cho HH, Kang H, Park YM, Park HJ, Lee JY.The significance of hypersensitivity to autologous sweat and serum in cholinergic urticaria: cholinergic urticaria may have different subtypes. Int J Dermatol. 29. 2014 doi: 10.1111/ijd.12549. [Epub ahead of print]
６）Sugino M, Todo H, Sugibayashi K. Skin permeation and transdermal delivery systems of drugs: history to overcome barrier function in the stratum corneum. Yakugaku Zasshi. 129:1453-8, 2009
７）Linneberg A1, Hertzum I, Husemoen LL, Johansen N, Jørgensen T.Association between alcohol consumption and aeroallergen sensitization in Danish adults. Clin Exp Allergy. 36:714-21, 2006
（Abstract)
Skin complication (hereinafter referred to as SC) has been controversial issue for treatment of SGLT2i (sodium-glucose co-transporter 2 inhibitor). Among the out-patients of HDC Atlas clinic, we experienced a patient who suffered from SC 10 days after taking luseogliflozin. He had an unique history which might give a hint to solve why SC is so often accompanied among certain individuals.
36 y/o. male. SC appeared on the skin around belly and forearm. It gets worsened onto the skin-surface where he sweats in sauna. Because the patient strongly wished to continue SGLT2 medication, luseogliflozin was switched to dapagliflozin. And he stopped to drink alcohol. Soon after the switch and temperance, the eruption relieved surprisingly. Although the true mechanism is unknown, association of cholinergic urticaria with sweat is recently reported. In addition, association between alcohol consumption and allergy sensitization is also reported. Therefore, we speculate that not only the different characteristics of SGLT2 inhibitors but also other environmental factors such as temperance and change of sweating condition could be synergistically causative factors.
In conclusion, this is the first report in literature, in terms of that switching of SGLT2 inhibitor from luseogliflozin to depagliflozin happens to be beneficial.
スーグラとフォシーガに、皮膚障害において交差反応を示した症例。
A Case of Diabetes who experienced Cross-sensitization of Skin complication between Ipragliflozin and Dapagliflozin
Skin complications, like eruption and/or itching, has become controversial for treating diabetes in Japanese, because summary report of adverse effect due to ipragliflozin, one of SGLT2i (sodium-glucose transporter 2 inhibitors), presented unexpectedly high number of patients who experienced various skin complications. Accordingly, Japan Diabetes Society published recommendation in June 2014 [1]. When the documentations of various SGLT2i’s records are compared, the incidence regarding skin complication is the most high in studies of ipragliflozine. According to pre-release drug informations of ipragliflozin and depagliflozin, the frequency of skin complication with ipragliflozin is 2.9% (n=48, among 1669 subjects), verses, that with dapagliflozin is 1.2% (n=12, among 1012 subjects). Ipragliflozin can be calculated over two-fold higher than dapagliflozin, as having a characteristic prone to skin disorders [2].
We encountered a patient who suffered from eruption after taking ipragliflozin and thereafter also with dapagliflozin. 47 y/o. male. During the ages from 44 to 45 y/o, he first experienced to take tohogliflozin as a subject of clinical trial. He did not notice any adverse effect during the clinical trial period.
Recently, his social circumstances have changed. He began to drink alcohol socially. Since April of 2014, he started to receive SGLT2i therapy, first taking ipragliflozin. He had beneficial effect on HbA1c and weigh loss. However, after 35 days of taking ipragliflozin, eruption appeared on skin of various parts of the body, such as leg, crotch, forearm and face. Therefore, he changed SGLT2i from ipragliflozin to dapagliflozin, based on expectation that dapagliflozin is more safe than ipragliflozin.
As expected, most of the eruptions disappeared within two weeks. However, one week after the recovery, that is, three weeks after the switching from ipragliflozin to dapagliflozin, he noticed the recurrence of eruption on face accompanied by strong itching (Fig.1-a). Eruption around cheek impaired his quality of life. He had no choice but to abandon SGLT2i treatment. It has become unforeseen circumstances. After the withdrawal, the eruption disappeared completely and itching was gone (Fig.1-b).
The pathogenesis of SGLT2i on skin has not been clarified. However, ipragliflozin and dapagliflozin have molecular mimicry. Therefore, the similarity might contribute to allergic sensitization. In this case, we speculate that a cross-sensitization between ipragliflozin and depagliflozin must be a complicating factor. On the barrier of fragile skin surface, built by ipragliflozin, dapagliflozin might have made the condition worse, which leads to the recurrence of complications. In addition, life style change, especially drinking alcohol, might have been another complicating factor, because there is an association between alcohol consumption and allergy sensitization and because alcohol consumption weakens the barrier of skin surface [3,4]. Further investigations are needed to gain a more complete understanding of this important topic.
In conclusion, this is the first report, in the sense that it demonstrate that dapagliflozin could trigger the recurrence of skin complication caused by ipragliflozin. Physicians need to know in advance, that such cross-sensitization might occur in SGLT2i therapy.
(/479 words)
References
[1] Japan Diabetes Society: Recommendation from "Committee on the proper use of SGLT2 inhibitors" (in Japanese) http://www.jds.or.jp/modules/important/index.php?page=article&storyid=48
[2] Interview Form of ipragliflozin . http://www.info.pmda.go.jp/go/interview/1/800126_3969018F1022_1_1F
2014. p73 (in Japanese)
[3]Linneberg A1, Hertzum I, Husemoen LL, Johansen N, Jørgensen T.Association between alcohol consumption and aeroallergen sensitization in Danish adults. Clin Exp Allergy. 2006; 36:714-21.
[4] Sugino M, Todo H, Sugibayashi K. Skin permeation and transdermal delivery systems of drugs: history to overcome barrier function in the stratum corneum.Yakugaku Zasshi. 2009;129:1453-8.
A Case of Diabetes who Experienced Cross-Sensitization of Skin Complication between lpragliflozin and Dapagliflozin
Y.Suzuki, Diabetes Department, HDC Atlas Clinic , Tokyo, Japan
A Case of Diabetes who Experienced Cross-Sensitization of Skin Complication between Ipragliflozin and Dapagliflozin
Yoshihiko Suzuki Diabetes Department, HDC Atlas Clinic, Japan
Skin complications have become controversial for treating diabetes in Japanese, because summary report of adverse effect due to ipragliflozin, one of SGLT2i (sodium-glucose transporter 2 inhibitors), presented unexpectedly high number of patients who experienced various skin complications. We encountered a patient who suffered from eruption after taking ipragliflozin and thereafter also with dapagliflozin. 47 y/o. male. Since April of 2014, he started to receive SGLT2i therapy, first taking ipragliflozin. He had beneficial effect on HbA1c and weigh loss. However, after 35 days of taking ipragliflozin, eruption appeared. Therefore, he changed SGLT2i from ipragliflozin to dapagliflozin.
Then, the eruption disappeared within two weeks. However, one week after the recovery, that is, three weeks after the switching from ipragliflozin to dapagliflozin, he noticed the recurrence of eruption on face accompanied by strong itching. He had no choice but to abandon SGLT2i treatment. After the withdrawal, the eruption disappeared completely and itching was gone.
We speculate that a cross-sensitization between ipragliflozin and depagliflozin must be a complicating factor. On the barrier of fragile skin surface, built by ipragliflozin, dapagliflozin might have made the condition worse, which leads to the recurrence of complications. In addition, life style change, especially drinking alcohol, might have been another complicating factor, because there is an association between alcohol consumption and allergy sensitization and because alcohol consumption weakens the barrier of skin surface. In conclusion, this is the first report, in the sense that it demonstrate that dapagliflozin could trigger the recurrence of skin complication caused by ipragliflozin.
The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 14 、2015.
The First Case of Type 2 Diabetes who Received SGLT2 inhibitor Therapy after Kidney Transplantation
Y.Suzuki, Diabetes Department, HDC Atlas Clinic , Tokyo, Japan
The First Case of Type 2 Diabetes who Received SGLT2 Inhibitor Therapy after Kidney Transplantation
Yoshihiko Suzuki Diabetes Department, HDC Atlas Clinic, Japan
We report a case of 54 y/o man who received sodium glucose co-transporter inhibitor (SGLT2i) treatment after kidney transplantation. Kidney was donated from his wife. Right after kidney transplantation, he had to inject insulin twice a day. Insulin daily total dose was 16 units per day with novolin 30R. Also, he had to continue immunosuppressive therapy. However, his GFR rose to over 50 mL/minutes/1.73m2 after kidney transplantation. Subsequently, informed concent was obtained for the treatment change. Then, after dapagliflozin (one of SGLT2i) 5 mg/day add-on treatment on insulin, he could maintain excellent glycemic control with once daily glargin insulin injection before bed, which raised QOL. HbA1c remained less than 6.5%. No adverse event occurred. Insulin daily dose reduced to 10 units of glargine without hypoglycemia. 2 kg of weight reduced. There are so many merits of kidney transplantation. Patient can live longer. Patients do not need restriction of water and/or foods. Therefore, improved QOL would contribute a lot to the patient`s life schedule. In contrast, there are demerits of kidney transplantation. The most important issue is weakened immune system. Because SGLT2i is known to complicate genital infection such as balanitis in man, it is necessary to keep the environment healthy and clean with polite education. To our knowledge, this is the first case report in the literature in the sense that SGLT2i is applied to the patient who had kidney transplantation. More careful observation should be needed further in practice.
The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 15 、2015.
A Case of Type 2 Diabetes who Improved Carpal Tunnel Syndrome after Taking SGLT2 Inhibitors
Y.Suzuki, Diabetes Department, HDC Atlas Clinic , Tokyo, Japan
A Case of Type 2 Diabetes who Improved Carpal Tunnel Syndrome after Taking SGLT2 Inhibitors
Yoshihiko Suzuki, Shin Kameyama2 Department of Orthopedics, Saiseikai Central Hospital, Japan
Carpal tunnel syndrome (hereinafter referred to as CTS) is known to be more prevalent in diabetics than in normal population. SGLT2 (sodium-glucose transporter 2) inhibitor is a medication for glycemic control. We experienced a patient who improved symptoms of CTS dramatically after taking SGLT2 inhibitors.
65 years of old, female. CTS was diagnosed two years ago. Several medical doctors diagnosed the symptom as CTS definitively. Because the symptoms did not relieve for long time, surgical indications was recommended. However, after SGLT2 inhibitor medication, symptoms of CTS (such as pain or numbness) have improved dramatically. So far, similar case has not been reported in literature.
As for the mechanism, we speculate that SGLT2 inhibitor has a beneficial effect by reducing the body fluid volume, and releasing the pressure on the strangulated nerves, which leads to the release of the CTS symptoms. We hope that SGLT2 inhibitor can be one of choices for the oral treatment of CTS with diabetes.
The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 16 、2015.
A Case of Diabetes who Experienced Improvement of Skin Complication after the Change from Luseogliflozin to Dapagliflozin
Y.Suzuki, Diabetes Department, HDC Atlas Clinic , Tokyo, Japan
A Case of Diabetes who Experienced Improvement of Skin Complication after the Change from Luseogliflozin to Dapagliflozin
Yoshihiko Suzuki Department of diabetes, HDC Atlas Clinic, Japan
Skin complication (hereinafter referred to as SC) has been controversial issue for treatment of SGLT2i (sodium-glucose co-transporter 2 inhibitor). Among the out-patients of HDC Atlas clinic, we experienced a patient who suffered from SC 10 days after taking luseogliflozin. He had an unique history which might give a hint to solve why SC is so often accompanied among certain individuals.
36 y/o. male. SC appeared on the skin around belly and forearm. It gets worsened onto the skin-surface where he sweats in sauna. Because the patient strongly wished to continue SGLT2 medication, luseogliflozin was switched to dapagliflozin. And he stopped to drink alcohol. Soon after the switch and temperance, the eruption relieved surprisingly. Although the true mechanism is unknown, association of cholinergic urticaria with sweat is recently reported. In addition, association between alcohol consumption and allergy sensitization is also reported. Therefore, we speculate that not only the different characteristics of SGLT2 inhibitors but also other environmental factors such as temperance and change of sweating condition could be synergistically causative factors.
In conclusion, this is the first report in literature, in terms of that switching of SGLT2 inhibitor from luseogliflozin to depagliflozin happens to be beneficial.
The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 17 、2015.
Compensatory Overeating(COE) could be a Problem of Diabetes Diet Education after Sodium-Glucose Co-Transporter 2 Inhibitor Treatment
Y.Suzuki, Diabetes Department, HDC Atlas Clinic , Tokyo, Japan
Compensatory Overeating (COE) Could be a Problem of Diabetes Diet Education after Sodium-Glucose Co-Transporter 2 Inhibitor Treatment
Yoshihiko Suzuki Department of Diabetes, HDC Atlas Clinic, Japan
Background: Compensatory overeating (hereinafter referred to as COE) has been controversial issue for treatment of SGLT2i (sodium-glucose co-transporter 2 inhibitor). Among the out-patients of HDC Atlas clinic, we experienced high percentage of patients who suffered from COE after taking SGLT2i.
Method: 172 type 2 diabetes ambulatory patients were subjected. Male 133, female 39. Interview survey was conducted after 2 weeks and 6 weeks of STLT2i treatment start. Carbohydrate depletion feeling, trend of meal, and trend of overeating were investigated.
Result: After two weeks, carbohydrate depletion feeling occurs in 28%. Carbohydrate sense of loss occurs in 19%. After 6 weeks, 74% noticed the overeating of carbohydrate, sweets, and fruits. As for COE, after 2 weeks, 18% noticed COE, and after 6 weeks, 29% noticed COE. This suggests that COE is likely to increase as time goes by.
Conclusion: Theoretically, diabetes patients under SGLT2i therapy lose 300 – 400 kcal in urine. However, practically, patients become likely to take more foods, especially carbohydrate, sweets, and fruits. The data suggest persistent urinary glucose excretion induced by SGLT2i was accompanied by compensatory overeating (COE), which attenuated the weight loss induced by SGLT2 inhibition. Therefore, COE could be a problem of diabetes diet education
The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 18 、2015.
Gain of Muscle Strength in Mitochondrial Diabetes Treated with SGLT2 Inhibitor
Y.Suzuki, Diabetes Department, HDC Atlas Clinic , Tokyo, Japan
Gain of Muscle Strength in Mitochondrial Diabetes Treated with SGLT2 Inhibitor
Yoshihiko Suzuki1, Soroku Yagihashi2, Shigeo Ohta3 1diabetes department, HDC Atlas Clinic, Japan 2Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Japan 3Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medici, Graduate School of Medicine, Nippon Medical School,, Japan
In 1996, we reported the first identified case of mitochondrial diabetes caused by a T-to-C transition at position 3271. 58-year-old male. He received SGLT2 inhibitor. Then, he lost weight and attained improvement of glycemic control with HbA1c from 6.5 % to 6.3%. Body weight decreased from 64.7 kg to 58.7 kg within three months (height 174cm. BMI: from 21.4 to 19.4). These two phenomena suggested that this patient relieved insulin resistance.
Sarcopenia is a complication of SGLTi treatment. The patients with sarcopenia have been believed to suffer from loss of muscle power and frailty. Therefore, it is noteworthy that, in this patient, his grip strength (GS) and back strength (BS) got stronger despite robust weight loss. Before SGLT2i treatment, GS was 37.6 kg in right and 30.5 kg in left hand, respectively. BS was 82kg. After three months of SGLT2i, GS of right hand grew stronger to 39.4kg (+1.8kg) and left hand to 32.2kg (+1.7kg). BS also grew stronger to 105kg (+23kg).
Discussion: Insulin resistance is known to be one of risk factors of sarcopenia, and weight loss with preservation of muscle weight relative to adipose tissues is encountered in SGLT2i treated patients. Hence, the recovery of muscle strength after SGLT2i treatment in our patient may be attributed to regained energy from restored mitochondria.
We speculate that SGLT2i treatment upon the patient of mitochondrial dysfunction due to the 3271 tRNALeu(UUR) mutation could induce decrease of insulin resistance, which in turn compensated genetic deficit of mitochondrial DNA.
The 6th International Conference on Fixed Combination in the Treatment of Hypertension, Dyslipidemia and Diabetes Mellitus, Berlin, Germany : P 19 、2015.