A case of diabetes mellitus in which the drug eruption of luseogliflozin improved after switching to dapagliflozin
A case of Diabetes who experienced improvement of Skin Complication after the change from Luseogliflozin to Dapagliflozin

The fact that SGLT2 inhibitors are prone to cause SC has not received much attention overseas. Even in the clinical trial stage conducted in Japan, the frequency of SC is likely to occur between 0.8 and 2.9%, and it was not predicted before the launch that there are many serious cases 1, 2, 3, 4). Comparing the SC frequencies of the four SGLT2 inhibitors based on the clinical trial, ipragliflozin was 2.9%, tofogliflozin was 1.5%, dapagliflozin was 1.2%, and luseogliflozin was 0.8%. Therefore, since this case had atopic dermatitis, the prescription was started from luceophlorizin, which was considered to be the most unlikely to develop SC. However, contrary to the initial prediction, drug eruption developed with luceoflorizin and the event disappeared by switching to dapagliflozin.

Luceophlorizin and dapagliflozin are similar in structure, but it cannot be denied that some structural differences may trigger the onset of SC. Since this case has been taking canagliflozin as a drug for clinical trials for one year, allergic reactions that do not respond to dapagliflozin or canagliflozin but only to luceoflorizin or its metabolites are SC. It is natural to think that it was the cause of. Since there is atopic dermatitis in the background of the patient, it is no wonder that there is a background that tends to have a constitution that can cause an allergic reaction only to some specific substance.
What is interesting is the fact that drug eruption was likely to occur in areas where sweating was high. Drug eruption occurred in areas where sweat was likely to accumulate when entering the sauna, such as the abdomen and the lateral parts of both forearms, and itching was also present. This is because luceophlorizin is more likely to stagnate on the skin surface due to the outflow of luceophlorizin itself or its metabolites to the skin surface due to sweating, and dapagliflozin and canagliflozin have differences between formulations lacking such properties. It may be. No similar tendency was observed in SC in diabetic patients caused by ipraphlorizin, dapagliflozin, tofogliflozin, etc. that we experienced (unpublished data). On the other hand, it is also known that patients with cholinergic urticaria are more likely to respond to sweating and to unknown serum factors 5). Therefore, in a study discussing the difference between SGLT2 inhibitors, the relationship between sweating and drug eruption may be an interesting theme in the future.
In this patient, when the drug eruption appeared, he was worried about the worsening of the drug eruption and stopped drinking. Since drinking alcohol worsens the inflamed area, it is highly possible that abstinence led to improvement of SC6). The original tendency to overdrink increased triglyceride, caused acute pancreatitis, caused diabetes, and caused atopy, as in the past 7). It is undeniable that the risk factors disappeared and the rash seemed to have recovered when the drug was switched to dapagliflozin, which coincided with the abstinence from drinking when switching from luceoflorizin to dapagliflozin. Therefore, when switching SGLT2 inhibitors in the future, careful observation of how the drinking tendency has changed is also necessary.

Conclusion: SGLT2 inhibitors are drugs that are prone to cause SC in Japanese. Among them, at the stage when the clinical trial results are presented, luceophlorizin is considered to have the lowest incidence of SC. However, it has not been reported so far that there are cases in which SC appears in luceoflorizin and does not appear in dapagliflozin or canagliflozin, as in this case. Therefore, it is important for doctors to jointly conduct post-marketing surveillance and take measures to investigate the cause without relying entirely on clinical trial reports voluntarily conducted by pharmaceutical manufacturers.

Consideration

1) Taisho Toyama Pharmaceutical Co., Ltd., Novartis Pharma Co., Ltd .: Pharmaceutical Interview Form, Lucefi 2.5 mg, Lucefi 5 mg (Revised in August 2014, 3rd edition)
2) AstraZeneca Co., Ltd., Ono Pharmaceutical Co., Ltd .: Pharmaceutical Interview Form, Fossiga 5 mg, 10 mg (2014 revised, 2nd edition)
3) Astellas Pharma Co., Ltd., Kotobuki Pharmaceutical Co., Ltd., MSD Co., Ltd .: Pharmaceutical Interview Form, Sugra 25 mg Sugra 50 mg (revised April 2104)
4) Sanofi Co., Ltd., Kowa Pharmaceutical Co., Ltd .: Pharmaceutical Interview Form, Appleway Tablets 20 mg, Develza Tablets 20 mg (Revised May 2014, 2nd Edition)
5) Kim JE 1, 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 A 1, 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 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.

A case of cross-reactivity in skin disorders with Sugra and Fossiga.
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 complications 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 subsequently 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- 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 further investigations are needed to gain a more complete understanding of this important topic. An association between alcohol consumption and allergy sensitization and because alcohol consumption weakens the barrier of skin surface [3,4].
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 A 1, 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 subsequently 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. Thus, 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. Patients can live longer. Patients do not need restriction of water and / or foods. Therefo Re, 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 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 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 immunod 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 2 Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Japan 3 Department 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 achieved 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 174 cm. 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 82 kg. After three months of SGLT2i, GS of right hand grew stronger to 39.4 kg (+ 1.8 kg) 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. 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.