糖尿病をもつ患者の手根管症候群に対して、SGLT2阻害剤が効く、事を世界で最初に報告
Carpal tunnel syndrome treated by SGLT2 inhibitor

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　手根管症候群(Carpal tunnel syndrome:以下、CTSと略す)は、正中神経支配領域の知覚障害と運動障害を病態とする正中神経の絞扼神経障害である。知覚障害は、主として、母指、示指、中指、環指橈側の疲れと、チクチクとした痛みを特徴とする。一方、運動障害は母指の掌側外転と対立運動が、主立ったものである。CTSは、絞扼神経障害のうち最も頻度の高いものであり、糖尿病患者における有病率も高い。 
　糖尿病は手根管症候群の危険因子の一つとして認識されている。大規模研究の結果、糖尿病がある患者では糖尿病のない患者に比べその危険率は1.51倍と報告されている1)。両側例が多く、加齢、体重の増加によって発症しやすくなることがわかっている。 
　糖尿病に伴うCTSでは、臨床的な神経障害発症の時点で、正中神経に脱髄、軸索変性を高率に生じているといわれ、この点が診断、治療を困難にしている。総じて女性が男性より有病率が高く、年齢別でみると、男性は４５〜５４歳が多く、女性は３５〜６４歳の広範囲に及び発症することが知られている。 当院では、CTSの顕著な改善を示した女性を経験し、学会で報告することとしました。文献上、世界で最初の報告になります。

　　　　　　 
　糖尿病に伴うCTSの有病率は１０〜３０％におよび、症状を伴わないCTSは２２％で、症状を伴うCTSの有病率（１１％）の２倍であるとの報告がある２）。糖尿病多発神経炎を伴う場合にはCTSは約３０％合併するが、それを伴わない場合には半減するとの報告もある1)。このように、糖尿病臨床において、CTSは、頻繁に遭遇する障害である。その診断および治療は、主として整形外科医師の指導に従っていた。また、CTSの診断には、Gold-standardがないといわれている。CTSに伴う自覚症状などについて、医師が問診と理学的所見と、電気生理学的検査（神経伝導速度など）を、どのように組み合わせておこなうのが最良の方法かについてもGold standardはなく総合的な判断が優先されている。なお、電気整理学的検査は、アメリカ整形外科学会のガイドラインでは、必ずしも診断に必要な検査と位置づけていない３）。 
　当院でSGLT2阻害剤が顕著に反応した患者さんは、神経伝導速度の遠位潜時延長は認めなかったものの、Tinel徴候と、Phalenテストは陽性であり、複数の整形外科専門医よりCTSの確定診断をうけ手術を勧められていた。そのような状態である患者が、ＳＧＬＴ２阻害剤の服用によって、ＣＴＳが劇的に改善したとするケースは、筆者らの調べたところ報告されていない。

　通常のCTSでは，手根管内での正中神経周囲の構造物（屈筋腱，滑膜，など）の容積増加が背景原因として存在することのコンセンサスは得られている。従って、ＳＧＬＴ２阻害剤を服用し、CTSが改善する機序は、体液水分量の減少機序を介した事象で、上記構造物の容積減少によるものと解釈すると理解しやすい。CTSは妊娠に伴いやすく、特に、妊娠に伴う浮腫で起こりやすい事が知られている。厚木らも、帝王切開後に全身性浮腫を認め、手術翌日からCTSを発症したが、フロセミドの投与によってCTSが改善した症例を報告している４）。 
　糖尿病では､フロセミドなどの利尿剤は血糖コントロールを悪化させる事から、治療選択薬剤から避けられる傾向にある。逆に、ピオグリタゾンは浮腫を惹起しやすい。また、インスリン製剤や、SU剤やＤＰＰ４阻害剤などによって膵臓から分泌されるインスリンは、腎臓でのナトリウム再吸収を高めることで体重を増加させることもしられている。血糖コントロールを急激に行った場合には、インスリン浮腫という現象が起こることもある。したがって、従来の、糖尿病治療は、体内血漿量を増やす傾向にある事が多く、それが、糖尿病におけるＣＴＳの合併頻度が高いという現象と相関していた可能性は否定できない。 
　さらに、一方で、CTSで手指屈筋腱滑膜炎がひどく，手指の疼痛，可動域制限を主訴としている患者にプレドニン（10~20mg）の内服を、我々（亀山ら）は期間限定で行うようにしている５）。しかし、プレドニン内服治療には糖尿病患者では血糖コントロール悪化のリスクがあり、臨床上での障害になっている。 
　こうした実状がある中で、ＳＧＬＴ２阻害剤が、糖尿病治療選択薬剤の一助となり、体液循環血漿量を減らしながら、血糖コントロールができるという状態を作ることができるとすれば画期的な治療法となりうる。本報告は、今後、糖尿病患者におけるＣＴＳの治療の選択肢のひとつとして、ＳＧＬＴ２阻害剤を試してみる、という治療法が生まれる事を示唆する。 
　なお、一般的に妊娠におけるCTSでも、神経伝導速度の遅延が認められるのは、約５０％と報告されている６）。本症例も遅延は認めなかった。その意味では本症例の障害は、ＣＴＳでも、軽い障害であったケースであろうと推察される。したがって、ＳＧＬＴ２阻害剤を投与しても改善しない重度なＣＴＳにおいては、やはり手術などの適応が残されるだろう。 
　また、我々は、超音波エコーでCTS患者の正中神経の形状を調べ、手外科領域では手根管レベルで治療前後の正中神経の断面積，扁平率をモニタリングし、臨床症状と正中神経の断面積は相関する事を報告している５）。今後、SGLT2投与前後で、こうした手根管レベルのモニタリングを行い比較することで、さらに客観的な成績が見いだされることが期待される。

 

結語

　ＳＧＬＴ２阻害剤の登場によって、糖尿病患者において、体液量が減少する機会が増えることになる。その場合、従来、体液量が増えることで増悪するとされていた種々の疾患において、ＳＧＬＴ２阻害剤が、治療改善に寄与することは容易に推測できる。海外ではＳＧＬＴ２阻害剤が特にピオグリタゾンを服用中の心不全の改善に効果がある事が示されていたが７）、CTSなどのような疾患における報告は、本例が世界でも最初である。今後、糖尿病においてＣＴＳをもつ患者を診察した場合には、ＳＧＬＴ２阻害剤を投与し症状の推移をみて、治療の一助として考慮することが肝要である。

 

引用文献 
１）今枝敏彦。手根管症候群の疫学。ＭＢ　Orthop. 20:1-7, 2002
２）Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'Brien PC, Melton LJ 3rd, Service FJ.The prevalence of staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 43:817-824, 1993
３）Keith MW, Masear V, Chung K, et al.: Diagnosis of carpal tunnel syndrome. J Am Acad Orthop Surg 17: 389-396, 2009 
４）厚木俊明、佐伯昇、濱田宏、河本昌志。帝王切開を契機に発症した手根管症候群の１例。麻酔と蘇生。４６：４５−４７，２０１０ 
５）亀山真。糖尿病患者の手根管症候群。糖尿病合併症　２７：１６９−１７２，２０１３ 
６）高山真一郎、内西兼一郎、飯島謹之介：妊娠に関連する手根管症候群について。臨床整形外。２０：１３８１−１３８６，１９８５ 
７）Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 35:1473-8, 2012

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SGLT2阻害剤開始後の、食生活の変化　（2014年、糖尿病近畿地方会で報告）
 

２型糖尿病患者の外来通院患者１６８名にSGLT2阻害剤開始後の食生活について、問診調査を行った。その結果、２週間後に、糖質枯渇感を自覚するのは２０％におこり、糖質や炭水化物を欲しがっているのは２９％と多かった。以前より多く食事を食べるようになった患者は１９％いた。６週間後に再調査をした所、過食傾向を続ける患者は２０％と同率で、その中では、炭水化物や、お菓子、果物まどを食べ過ぎている患者が多かった。一方で食欲が低下した患者が９％と増えた。糖質が排泄された分、糖質をとりたがる欲求がでてきて過食傾向になる患者がいることが分かったが、一方で、SGLT2阻害剤開始後６週間すると、食欲が落ち着く場合がある事も判明した。糖質枯渇感がでた患者に対しは、糖質摂取を許容する必要があるか、指示表の変更が必要かどうかは今後、議論がある問題になると考えた。

 

Compensatory overeating (COE) could be a problem of diabetes diet education after sodium-glucose co-transporter 2 inhibitor treatment.

 

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.

 

亀頭炎は、若い世代ほど、頻度が高く認められます。
 

Background: 
 SGLT2i (sodium-glucose transporter 2 inhibitors) has been used in Japan since April, 2014. Four products of SGLTi have been released and widely prescribed. One is ipragliflozin, and the others are dapagliflozin, luseogliflozin, and tofogliflozin. In common, genital infection was thought to be common in the elderly. However, practically, the question what kind of patients are likely to be affected regarding balanitis has not been clarified. Therefore, we reported the adverse effect of balanitis through closed SNS service, called as TmDance, and also gathered the official drug information from eight pharmaceutical companies.

Methods: 
About 200 patients of type 2 diabetes were subjected at our HDC Atlas Clinic. They were equally out-patients. Their complaints were questioned and each of adverse effect was reported through TmDance (closed SNS service). TmDance is one of social medical network system, which composed of closed and secret communication system between medical doctors and medical representatives independently. Medical doctor reported adverse effects soon after he noticed the adverse effect by using copy&past from electronic chart to the dairy of TmDance. Throudh TmDance, medical representitives of pharmaceutical companies promptly noticed and could gather the adverse effect information as soon as possible.
 In addition, by making use of TmDance, the occurrence of adverse effect, especially regarding balanitis, was collected from medical representatives. Data of adverse effect in Japan, especially of balanitis, were based on the description of drug information which has been reported every month from eight pharmaceutical companies.

Result:
According to the database of drug information, in ipargliflozin, totally 22 patients of balanitis were reported. (less than 50 y/o:12, 50-59 y/o:4, 60-69 y/o:3, 70-: 3). In dapagliflozin, totally 3 patients were reported. (less than 50 y/o:0, 50-59 y/o:1, 60-69 y/o:1, 70-: 1). In luseogliflozin, totally 3 patients were reported. (less than 50 y/o:3, 50-59 y/o:0, 60-69 y/o:0, 70-: 0). In tofogliflozin, totally 2 patients were reported. (less than 50 y/o:1, 50-59 y/o:0, 60-69 y/o:0, 70-: 1).  According to the result reported by TmDance from HDC Atlas clinic, in ipragliflozin, totally 5 patients of balanitis were reported. (less than 50 y/o:3, 50-59 y/o:0, 60-69 y/o:1, 70-: 1). In dapagliflozin, none patients were reported. In luseogliflozin, 1 patients were reported. (less than 50 y/o:1, 50-59 y/o:4, 60-69 y/o:3, 70-: 0). In tofogliflozin, totally 1 patient was reported. (less than 50 y/o:0, 50-59 y/o:4, 60-69 y/o:3, 70-: 1). Thus, 7 (23%) out of 30 were reported from HDC Atlas clinic through closed SNS of TmDance. In total of Japan, 16 (54%) out of 30 were under 49 years of old. At HDC Atlas Clinic, 4 (57%) out of 7 were under 49 years of old. Interestingly, 7 (23%) out of 30 patients were reported through closed SNS of TmDance. It suggests that the closed SNS system of TmDance can be fully applied with high quality and accuracy for reporting the adverse effect in medical practice.

Conclusion; 
Contrary to the prediction, the adverse effect of balanitis was frequently found in the patients who were under 49 years of old. It was possibly due to the high opportunity of sex intercourse during the younger period than older period. For instance, some patients were worried about the pain of balanitis when morning erection occurred. 26 percentage of balanitis was reported through internet media of TmDance. Hence, closed SNS communication system such as TmDance will bring a lot of benefits on reporting adverse effect of new drugs like SGLT2i.

Reference:                                                                                      
Johnsson KM, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013 Sep-Oct;27(5):479-84. 
Home page of explanation of TmDance: www.iryoo.net
Login: https://www.tmdance.com/

 

Suzuki Y.

HIGH OCCURRENCE OF BALANITIS AS AN ADVERSE EFFECT CAUSED BY SGLT2 INHIBITORS IS FREQUENTLY FOUND IN THE YOUNG

GENERATIONS BELOW 50 YESRS OF OLD

Diabetes Research and Clinical Practice ,Vol.106,S266-S267

Published in issue:November,2014

 

SGLT2阻害剤が「黄砂」により皮膚障害を悪化させる仮説を、世界で最初に発表。

 　

　 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. However, the incidence of skin complication has not been reported at any institute. 
  At our clinic, ipragliflozin was prescribed towards 142 patients of type 2 diabetes (male 112、female 30, aged 61.8＋10.0 y/o (Mean + SD)). 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. 
  In result, 22 patients dropped out, and 120 patients remained and switched ipragliflozin to luseogliflozin. 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. 
  The true reason why skin complication is so highly found in patients with ipragliflozine after the release has not been clarified. One reason might be that the itching is so mild as not have 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 skin complication. 
  Environmental air change by Asian dust has been emerging problem recently in Japanese. 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 3 trial period of ipragliflozin when the problem of Asian dust was not serious in Japan.. To confirm these, more long time safety study should be needed.  

　　

References

1. 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. Interview Form of luseogliflozin; http://www.info.pmda.go.jp/go/interview/1/400059_3969020F1020_1_001_1F
: 2014. p 61 (in Japanese)

1. Otani S1, Onishi K, Mu H, Yokoyama Y, Hosoda T, Okamoto M, Kurozawa Y. The relationship between skin symptoms and allergic reactions to Asian dust. Int J Environ Res Public Health. 2012;9:4606-14.

2. 4. 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 randomised, double-blind, placebo-controlled study.Diabetes Obes Metab. 2014;12. doi: 10.1111/dom.12331 ​

3. SKIN COMPLICATIONS OF SGLT2 INHIBITOR TRETMENT IN JAPANESE

   Diabetes Research and Clinical Practice ,Vol.106,S265

   Published in issue:November,2014

 

イプラグリフロジンで、乾癬と、慢性湿疹が改善
Improvement of Psoriasis and Chronic eruption after taking SGLT2 inhibitor: ipragliflozin in diabetes of Japanese.

 

  SGLT2 inhibitor  (Sodium glucose transporter 2：SGLT2i ) is medication to treat diabetes, being used all over the world. The pre-release clinical trials showed that SGLT2i affect few skin complication. However, after release of ipragliflozin, SGLT2i showed high incidence of skin complications in Japanese. The summary of ipragliflozin’s adverse effect reported some severe cases. According to the condition, Japan Diabetes Society published a warning recommendation in June 2014, towards a proper usage of SGLT2i. 1). 
  At our clinic, seventeen patients were found who had eruption and/or itching after ipragliflozin treatment. Severe cases among them showed increased eosinophil and DLST (Drug-induced Lymphocyte Stimulation Test) was positive. Some cases noticed eruption and/or itching after taking one or two tablets of ipragliflozine. Other cases noticed the symptoms after 10-30 days of taking ipragliflozine. The true pathogenesis has not been clarified. 
  Surprisingly, two patients were found whose skin disorder relieved after taking ipragliflozin. The episodes indicate that skin effect of ipragliflozin is not only harmful but also beneficial among individuals. Case 1：67  y/o. man. He had suffered from psoriasis for 4 years, and was treated by steroid and anti-histamine treatment 2). His symptoms abruptly relieved after taking ipragliflozin (Fig.1-a). The condition improved and became stable after two months. Case 2: 63 y/o. man. He had suffered three years from chronic eruption 3). Over the years consultations with multiple dermatologists did not elicit a diagnosis, and symptoms did not improve after numerous trials of topical corticosteroids and systemic antihistamines. But, his symptom abruptly relieved after taking ipragliflozin (Fig.1-b). The symptoms in the photo finally disappeared and he does not need topical medications. Thus, improvement of two different skin disorders was associated with taking ipragliflozin. The association in case 2 was distinct. Ipragliflozin might have an intra-skin-tissue effect possibly associated with immunologic factors 4). 
  In conclusion, although two cases episode is insufficient to determine the etiology and mechanism, they suggest a distinct association among ipragliflozin and skin function from a different point of view. The phenomena might give a new light in the treatment of psoriasis and chronic eruption of unknown etiology.

(/349 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.Di Meglio P, Villanova F, Nestle FO. Psoriasis. Cold Spring Harb Perspect Med. 2014;4. pii: a015354. doi: 10.1101/cshperspect.a015354.
3.Convers KD1, Sturm JM, Slavin RG. Chronic bilateral pruritic arm dermatitis in a 61-year-old woman. Allergy Asthma Proc. 2013; 34:558-61. 
4.Wu JJ, Nguyen TU, Poon KY, Herrinton LJ. The association of psoriasis with autoimmune diseases. J Am Acad Dermatol. 2012; 67:924-30.

 

Suzuki Y.

IMPROVEMENT OF PSORIASIS AND CHRONIC ERUPTION AFTER TAKING SGLT2 INHIBITOR:IPRAGLIFLOZIN IN DIABETES OF JAPANESE

Diabetes Research and Clinical Practice ,Vol.106,S266

Published in issue:November,2014

 

Change of Grip Strength and Back Strength after SGLT2 inhibitors treatment in diabetes
SGLT2阻害剤で、筋力が改善するケースが多い。

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 muscle is one of the causes of insulin resistance (3). SGLT2i ameliorate hypertriglycemia and　insulin resistance, which causes a reduction of TGA in muscle. Because muscli trunci is richer of TGA than musculi　thoracici, the expression of SGLT2i’s effect could appear stronger in muscli trunci than in muscli thoracici, which makes　the different patterns of muscle power and their change between GS and BS.
In conclusion, this is a preliminary study. But the phenomena are intriguing to understand the potential mechanism of　SGLT2i therapy. Therefore, further profound study is needed in　practice.

 

References: 
1: Bolinder J et al.  Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over　2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.Diabetes Obes Metab.  2013 Aug 1.doi: 10.1111/dom.12189. [Epub ahead of print], 
2:Cetinus E. et al.Hand grip strength in patients with type 2 diabetes　mellitus. Diabetes Res Clin Pract.70:278-86.2005 
3: Man ZW et al. Decrease in triglyceride accumulation in tissues by　restricted diet and improvement of diabetes in Otsuka Long-Evans Tokushima fatty rats, a non-insulin-dependent　diabetes model.Metabolism 49:108-14.2000

 

Suzuki Y.

CHANGE OF GRIP STRENGTH AND BACK STRENGTH AFTER SGLT2 INHIBITORS TREATMENT IN DIABETES

Diabetes Research and Clinical Practice ,Vol.106,S265-266

Published in issue:November,2014

 

日本におけるSGLT2阻害剤の皮膚障害についての、一考察

Consideration of skin complication caused by treatment of SGLT2 inhibitor in Japanese

HDC　アトラスクリニック　鈴木吉彦

 

　SGLT2阻害剤（以下SGLT2iと略す）は2014年春に皮膚障害が多数報告された。小生はイプラグリフロジン（以下ipraと略す）にて皮膚障害を142例中17例（12%）に認め報告した１）。通常、薬疹は内服投与約４日後から数週間後に起こり症状は多彩である。しかし、2014年春のSGLT2i関連薬疹は症状が多彩で各SGLT2i同士で交差反応があり2)、特に内服開始後短期間で生じる点が「通常ではない」とされている。 
　SGLT2iの皮膚障害が日本でだけ騒動になった理由を下記に推理してみた。1: インタビューフォームにて皮膚障害発症頻度で２％を超え他のSGLT2iより皮膚障害を起こしやすいipraから発売された3)。2：内服初日１錠目から起こる薬疹は、別の原因によるアレルギー素因が先に潜在していた可能性がある。SGLT2iの内服をきっかけにI型皮膚アレルギーとして顕在化しただけかもしれない。3：通年でみるとSGLT2iの新規処方例で皮膚障害発症頻度は夏から秋冬にかけて減っている。ipraの情報提供活動副作用集計結果（2015年2月報告）では薬疹が0.3%と低いが、それはPM2.5の影響が及ばない時期やエリアにて処方されたからでなかろうか。当院では2014年春、東京にて、ヒノキやPM2.5が飛散していた時期に処方し、それが高頻度の皮膚障害を起こした原因ではなかろうか。 
　以上よりSGLT2iの皮膚障害の背景には、皮膚障害発症確率が高いipraの発売が最初であった偶然と、直後に他のSGLT2iが発売され交差反応を有した偶然と、SGLT2i治験時には影響が少なかったが市販後に影響が拡大したPM2.5などがSGLT2i内服前から潜在し、ヒノキ飛散時期とも重なり皮膚アレルギーを起こしやすくしていた状態が、相乗した事で、「通常ではない薬疹を惹起したのではないか」と考察してみた。 
  他にも例えば発売当初では副作用の報告意識も高かった可能性も否定できないが、ならば欧米諸国で同様の騒動があってよいはずである。偶然に市販前と市販後の間に何らかの干渉要因が加わり騒動となったと思考するほうが科学的である。 
  PM2.5が問題となりI型皮膚アレルギーとの相関については近年報告がある4,5)。2013年以降春から初夏に集中する健康被害の原因にPM2.5を想定する事は常識的で本考察は論理的に考えやすい6,7)。さらに本年になり、再度、当院ではPM2.5が飛散した直後１週間後の間に、SGLT2阻害剤を服用している患者の皮膚障害が増えてきており、再現性も確認されている。

 

 

引用文献　

1. Suzuki Y. Skin complication of SGLT2 inhibitor treatment in Japanese. Diab.Res.Clic. Prac. 106, sup1:272, 2014

2. 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

3. Interview Form of ipragliflozin. http://www.info.pmda.go.jp/go/interview/1/800126_3969018F1022_1_1F

2014. p73 (in Japanese)

1. Otani S, Onishi K, Mu H, Hosoda T, Kurozawa Y Ikeguchi M. Associations between subjective symptoms and serum immunoglobulin E levels during Asian dust events. Int J Environ Res Public Health. 11:7636-41, 2014

2. Takeshita S, Tokunaga T, Tanabe Y, Arinami T, Ichinose T, Noguchi E.

Asian sand dust aggregate causes atopic dermatitis-like symptoms in Nc/Nga mice.Allergy Asthma Clin Immunol. 11:3,2015

1. Otani S, Onishi K, Mu H, Yokoyama Y, Hosoda T, Okamoto M, Kurozawa Y. The relationship between skin symptoms and allergic reactions to Asian dust.Int J Environ Res Public Health. 9:4606-14, 2012

2. Ogi K, Takabayashi T, Sakashita M, Susuki D, Yamada T, Manabe Y, Fujieda S. Effect of Asian sand dust on Japanese cedar pollinosis.Auris Nasus Larynx. 41:518-22, 2014

3. ​