https://orcid.org/0000-0002-8872-3697
1 Introduction
Type 1 diabetes Mellitus (T1DM) is widely known to affect people of all ages, including children and young adults. T1DM is an autoimmune disease whose predominant condition is complete lack of insulin secretion. Inevitably, insulin management is an effective and important treatment for T1DM patients. In addition, insulin pumps, continuous glucose monitoring systems, and insulin pumps with glucose monitoring systems are now the standard treatment in the United States; however, not in Japan.
These efforts have resulted in slightly improved management of T1DM; however, are yet to meet our expectations. In Japan, only around 24% of adult patients managed to achieve HbA1c of below 7% in 2018 and according to US T1D exchange data, about 20%, on average, from 2016 to 2018 attained this benchmark [Citation1,Citation2].
Traditionally, T1DM patients were said to have normal weight and high insulin sensitivity [Citation3]. However, the diabetes management and complications trials (DCCT) have shown that intensive insulin therapy to improve glycemic control is associated with hypoglycemia and weight gain [Citation4]. Excessive weight gain in patients with T1DM causes central obesity, increased insulin resistance, dyslipidemia, persistent elevated blood pressure, and widespread atherosclerosis. These effects to the pathology of T1DM patients cause increased risk of chronic kidney disease (CKD), heart failure (HF), cardiovascular disease (CVD), and death [Citation5].
Sodium glucose cotransporter 2 (SGLT2) inhibitors for Type 2 Diabetes Mellitus (T2DM) were approved in the US and EU in 2013, and Japan in 2014. SGLT2 inhibitors manage to improve glycemic control, independent of insulin secretion. Moreover, in patients with T2DM, SGLT2 inhibitors may have the tendency to reduce the risk of body weight, visceral fat, subcutaneous fat, proteinuria, CKD and CVD, as well as improve insulin resistance and reduce mortality in some cases; shown in clinical trials [Citation6–8]. Of note, these effects have only been demonstrated in patients with T2DM. Recently, these effects are thought to be beneficial to patients with T1DM, and SGLT2 inhibitors are being used as one of the treatment options for T1DM in some countries and regions.
2 Trials and recommendations
Several clinical trials of administrating SGLT2 inhibitors to T1DM patients, in combination with insulin therapy, were performed in 2017 and 2018. DEPICT1 and DEPICT2 investigated dapagliflozin, EASE2 and EASE3 investigated empagliflozin [Citation9]. Sotagliflozin, unlike the above two drugs, is also known as a dual inhibitor that inhibits intestinal sodium glucose cotransporter 1 and renal SGLT2 [Citation10]. Canagliflozin and ipragliflozin were also investigated in 2015 and 2016 [Citation11,Citation12]. Dapagliflozin, empagliflozin, sotagliflozin and ipragliflozin were approved, while canagliflozin is not considered for use for T1DM patients.
In all of the above clinical trials, HbA1c showed significant improvement. The decrease in HbA1c was 0.3% versus the placebo group, with the largest improvement being 0.5%. The “time in range (goal)” assessed using continuous glucose monitoring was also improved with dapagliflozin, empagliflozin, and sotagliflozin. In addition, a significant decrease in body weight was observed, a decrease of -1.8 kg versus the placebo group, up to -4.3 kg [Citation9,Citation11,Citation12]. Furthermore, daily total insulin dose was also reduced, showing rate changes versus the placebo group -6.3% to -13.2% [Citation9,Citation11,Citation12]. In all studies, improved HbA1c did not increase hypoglycemia or weight gain. However, adverse events in the SGLT2 inhibitor group included genital infections, volume depletion, and diarrhea. As a serious concern, the incidence of DKA (including euglycemic DKA) increased significantly in all clinical trials [Citation9]. In spite of the said side effects, the SGLT2 inhibitor was approved in Europe in 2018 and in Japan in 2019 for the treatment of T1DM.
In November 2019, the Food and Drug Administration (FDA) showed that SGLT2 inhibitors are promising drugs; however, high risks of diabetic ketoacidosis (DKA) and ketosis throughout the clinical trial periods were demonstrated, and clinical practices such as discontinuation of drug administration, and hospitalization also showed occurrences of critical events. Also, because of the relatively short duration of clinical trials, it is difficult to build confidence in the drug risk and benefit profile, and to assess whether SGLT2 inhibitors reduce cardiovascular risks as with T2DM patients. Therefore, more large-scale clinical trials of T1DM are needed [Citation13]. For the above reasons, SGLT2 inhibitors are not approved in the United States for the treatment of T1DM.
Expert committees of approved regions and countries made recommendations for using SGLT2 inhibitors to T1DM patients. The committees stated that administration should be avoided in patients with the following requirements to prevent DKA: BMI <27 kg/m2, Insulin dose<0.5 U/kg of body weight/day, poor compliance, history of DKA over the last 12 months, recurrent fungal infections, failure of regular glucose and ketone monitoring, aggressive weight loss (such as low carbohydrate or ketone diet), excessive alcohol use, controlled substance use, GFR <60 ml/min/1.73 m2, age <18 or 75 years and older, women of childbearing potential or pregnant [Citation9].
The Japanese Expert Committee further stated that a clinical trial of dapagliflozin in Japanese T1DM patients showed that patients with a BMI of less than 25 kg/m2 had a higher incidence of DKA than patients with a BMI of 25 kg/m2 or more (occurrence rate%; BMI ≤ 25 kg/m2: 4.5%, BMI> 25 kg/m2: 0%). It was announced that extreme caution should be exercised when administering SGLT2 inhibitors to Japanese T1DM patients [Citation14]. It has been pointed out that both patients and medical staff need to be educated to prevent risk, but it is very difficult to completely prevent DKA.
3 Expert opinion
SGLT2 inhibitors have been shown to be beneficial agents in various T2DM clinical trials. However, administering SGLT2 inhibitors to T1DM patients should not be considered simple, inclusive of the difficulty to completely prevent DKA, even with recommendations of expert groups.
Factors that cause DKA in clinical trials include excessive alcohol intake, infection, and reduced insulin doses (insulin pump dysfunction, inaccurate insulin doses), but are more complex in clinical practice. In many cases, the cause cannot be identified. Also, some patients may only suffer from ketosis without acidosis. As mentioned above, it is not easy to predict the occurrence of DKA in clinical practice.
Therefore, all T1DM patients treated with SGLT2 inhibitors need to understand the various situations caused by ketone levels in the body and self-measure the ketone bodies in the body. The patients also need to be able to decide when to stop taking SGLT2 inhibitors, depending on the situation, so as not to cause serious metabolic problems. Consequently, at present it is demanded, though challenging, to clinically monitor blood ketone body levels in all patients who receive SGLT2 inhibitors.
Physicians should also consider the risks of administrating SGLT2 inhibitors to slowly progressing insulin-dependent diabetes mellitus (SPIDDM) and adult latent autoimmune diabetes mellitus (LADA). There are few reports of SGLT2 inhibitors being used in SPIDDM or LADA, but serious complications can occur if insulin deficiency progresses rapidly due to changes in the condition.
It has also been reported that DKA occurred in T1DM patients and a LADA patient who were SGLT2 inhibitor administered after approval in Japan. The incidence is unknown because it is under post-marketing surveillance investigation, but it is certain that it has occurred in clinical practice [Citation15].
In addition, SGLT2 inhibitors have not been shown to be safe for pregnant women and fetuses, and can be life-threatening at times. It should not be given to women who are pregnant or may become pregnant. In the unlikely event that a pregnancy is discovered during treatment, SGLT2 inhibitor administration should be discontinued promptly to attain intensive insulin control to ensure the safety of the mother and fetus.
It is well known that SGLT2 inhibitors have beneficial effects on T2DM. However, longer clinical trials are needed to see if SGLT2 inhibitors also have the same effects on T1DM.
Although some expert groups have advocated caution regarding the use of SGLT2 inhibitors, it is difficult to prevent all complications, especially serious DKA; therefore, both the medical staff and patients require in-depth education to minimize complications.
Further consideration should be given to the use of SGLT2 inhibitors to T1DM patients, using the clinical results of countries and regions where SGLT2 inhibitors are currently approved for T1DM.
Given the above, the use of SGLT2 inhibitors in T1DM is not a trivial task, even for professionals and specialized staff, and is a treatment that should be considered with extreme caution at this time.
Declaration of interest
Y Terauchi has received lecture fees from: Merck Sharp & Dohme, Ono Pharmaceutical Co., Ltd., Novartis, Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo, Sanwa Kagaku Kenkyusho, Novo Nordisk A/S, Eli Lilly Japan K.K., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., AstraZeneca, Takeda Pharmaceutical Company Limited, Boehringer Ingelheim Pharmaceuticals, Inc., Taisho Pharmaceutical Co., Ltd., Kowa Company, Ltd and Terumo Medical Corporation. He has also received grants from Merck Sharp & Dohme, Ono Pharmaceutical Co., Ltd., Novartis, Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo, Novo Nordisk A/S, Eli Lilly Japan K.K., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited and Boehringer Ingelheim Pharmaceuticals, Inc. Y Koike meanwhile has received lecture fees from Novo Nordisk Co. Japan and Mitsubishi Tanabe Pharma Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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References
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