Insulin was discovered by Banting and Best in 1921, and was subsequently applied for the treatment of diabetes. Porcine or bovine insulin purified from their pancreas had been used clinically for >50 years until the development of the methods to produce recombinant human insulin by genetic engineering techniques. The Diabetes Control and Complications Trial1 and our Kumamoto Study2 provided the evidence that better glycemic control could be obtained by intensive insulin therapy consisting of the supplementation of both basal and postprandial insulin, which in turn resulted in the prevention of the initiation and progression of diabetic microvascular complications.

For the intensive insulin therapy with multiple insulin injections of these studies, a combination of intermediate‐acting neutral protamine Hagedorn insulin and short‐acting (regular) insulin, which covers basal insulin secretion and postprandial insulin secretion, respectively, was used. Since the late 1990s, in order to achieve longer and flatter action than neutral protamine Hagedorn insulin, long‐acting insulin analogs have been developed, and to achieve quicker onset and shorter duration of action than regular insulin, rapid‐acting insulin analogs have been invented. Utilization of these insulin analogs could reduce the risk of hypoglycemia and achieve better glycemic control in patients with diabetes.

In addition to the improvement of insulin therapy using such insulin analogs, new oral anti‐diabetic agents, including dipeptidyl peptidase‐4 inhibitors and sodium–glucose cotransporter 2 inhibitors (SGLT2i), have been recently developed and are now used together with the insulin therapy.

In contrast, several social issues that affect the treatment of diabetes, such as an aged society and the approaches to provide acceptable insulin therapy for elderly diabetes patients, have drawn considerable attention.

Therefore, in this JDI Updates, we focus on three recent topics that are related to insulin therapy: (i) impacts of newly developed insulin analogs; (ii) effects of oral antidiabetic agents in addition to insulin therapy; and (iii) recent social issues surrounding insulin treatment.

Impacts of newly developed insulin analogs

Recently, two new long‐acting basal analogs (U‐300 glargine and degludec) have become clinically available. Compared with U‐100 glargine, which is a long‐acting basal analog and has been widely used, both U‐300 glargine and degludec showed comparable efficacy with regard to the reduction in glycated hemoglobin (HbA1c) and lower rates of hypoglycemia in patients with type 1 diabetes and those with type 2 diabetes3.

The direct comparison of U‐300 glargine and degludec in insulin‐naïve patients with type 2 diabetes, named as the BRIGHT trial, was reported4. In the study, patients were randomized and treated for 24 weeks by either U‐300 glargine (n  = 466) or degludec (n  = 463), and the insulin dose was titrated to fasting glucose of 80–100 mg/dL. As the results, HbA1c showed significant and comparable improvement, and hypoglycemia incidence and event rates over a period of 24 weeks were also comparable with both insulins, whereas hypoglycemia during the active titration period (0–12 weeks) was lower with U‐300 glargine. Like the BRIGHT trial, there were two studies that compared the effects of U‐300 glargine and degludec by cross‐over study, one using continuous glucose monitoring5 and another using flash glucose monitoring6 in Japanese patients with type 2 diabetes. Both studies reported comparable efficacy with regard to the HbA1c reduction, and less risk of hypoglycemia or nocturnal hypoglycemia in U‐300 glargine compared with degludec. There was an inquiry about the result by citing the BRIGHT trial and two real‐world, propensity‐matched studies termed CONFIRM (Clinical Outcome Assessment of the Effectiveness of Insulin Degludec in Real‐life Medical Practice) and DELIVER (Differentiate Gla‐300 clinical and Economic in Real‐World Via EMR) that also compared the U‐300 glargine and degludec, and reported different conclusions with regard to the incidence of hypoglycemia7. The authors suggested that the different results might be caused by differences in various factors, including patient characteristics, study design, background therapy and ethnicity8. Therefore, further investigations are necessary to evaluate the usefulness of these new insulin analogs.

Effects of oral antidiabetic agents in addition to insulin therapy

An addition of oral antidiabetic agents on top of insulin therapy is now recognized as a useful method to obtain better glycemic control and to reduce the amount of insulin used. In a meta‐analysis of randomized control trials that studied the effect of dipeptidyl peptidase‐4 inhibitors in addition to insulin treatment in patients with type 2 diabetes, improved glycemic control without an increased risk of hypoglycemia or weight gain compared with insulin treatment alone was reported9. In contrast, in a meta‐analysis of randomized control trials that investigated the effect of SGLT2i in addition to insulin treatment on cardiovascular risk factors in patients with type 2 diabetes, better glycemic control and greater reductions of blood pressure, uric acid, bodyweight and daily insulin doses compared with insulin treatment alone were reported10. These effects of SGLT2i might provide beneficial effects to suppress cardiovascular events, but the increased risk of hypoglycemia, and urinary tract and genital infection related to SGLT2i should be of note. Another study compared the impacts of SGLT2i with pioglitazone when added to insulin therapy in patients with type 2 diabetes with an indirect comparison meta‐analysis11. As the results, SGLT2i and pioglitazone achieved comparable reductions in HbA1c and fasting blood glucose, SGLT2i showed greater weight reduction, and pioglitazone achieved a higher reduction of daily insulin doses.

Recent social issues surrounding insulin treatment

An increase in the number of elderly patients with diabetes has become an important issue, especially in developed countries. The Japan Diabetes Society reported the results of a survey of severe hypoglycemia showing that 60.8% of patients who experienced severe hypoglycemia were insulin users, and their mean age was 74.0 years (Figure 1)12. Therefore, educating elderly diabetes patients about diabetes management, including the insulin self‐injection technique and countermeasure methods for hypoglycemia, is very important. In this regard, Minami et al. 13 reported the usefulness of a method to evaluate the cognitive ability of elderly diabetes patients by counting the number of animal names recalled in 1 min. Lipohypertrophy at the insulin injection site is one of the causes of increased fluctuation of blood glucose levels after insulin injection, especially for long‐term insulin users. Recently, insulin amyloid formation at the insulin injection site was reported to be a potential mechanism to increase subcutaneous insulin resistance14. In a systematic review and meta‐analysis that investigated the prevalence of lipohypertrophy in insulin‐treated patients, its very high prevalence (38%) was reported, again suggesting the importance of education regarding self‐injection technique15.

The three topics that were highlighted in this JDI Update teach us the importance of having a good understanding of the characteristics of various insulin formulations and non‐insulin glucose‐lowering agents, and proper education of the insulin injection procedure for patients of diverse backgrounds.

中文翻译：

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胰岛素治疗的新观点。

胰岛素是由Banting和Best在1921年发现的，随后被用于糖尿病的治疗。从胰腺中纯化的猪或牛胰岛素已在临床上使用了50多年，直到通过基因工程技术生产重组人胰岛素的方法得到发展。糖尿病控制与并发症试验1和我们的熊本研究2提供了证据，表明通过强化胰岛素治疗（包括补充基础和餐后胰岛素）可以更好地控制血糖，从而预防了糖尿病的发生和发展。糖尿病微血管并发症。

对于这些研究中多次注射胰岛素的强化胰岛素治疗，使用了中效中性鱼精蛋白Hagedorn胰岛素和短效（常规）胰岛素的组合，分别涵盖了基础胰岛素分泌和餐后胰岛素分泌。自1990年代后期以来，为了实现比中性鱼精蛋白Hagedorn胰岛素更长和更平坦的作用，已开发出长效胰岛素类似物，并且与常规胰岛素相比起更快的起效和更短的作用持续时间，已经发明了速效胰岛素类似物。这些胰岛素类似物的使用可以降低糖尿病患者发生低血糖的风险，并实现更好的血糖控制。

除了改进使用此类胰岛素类似物的胰岛素治疗外，最近还开发了新型口服抗糖尿病药，包括二肽基肽酶-4抑制剂和钠葡萄糖共转运蛋白2抑制剂（SGLT2i），现已与胰岛素治疗一起使用。

相反，一些影响糖尿病治疗的社会问题，例如老年社会以及为老年糖尿病患者提供可接受的胰岛素治疗的方法，引起了相当大的关注。

因此，在此JDI更新中，我们重点关注与胰岛素治疗有关的三个最新主题：（i）新开发的胰岛素类似物的影响；（ii）除胰岛素治疗外，口服降糖药的作用；（iii）最近有关胰岛素治疗的社会问题。

新开发的胰岛素类似物的影响

最近，有两种新的长效基础类似物（U-300甘精氨酸和地格列酮）已在临床上可用。与长期使用的长效基础类似物U-100甘精氨酸相比，U-300甘精氨酸和地格列酮在降低糖化血红蛋白（HbA1c）和降低低血糖发生率方面均具有相当的疗效。 1型糖尿病和2型糖尿病3。

有报道称，在未接受胰岛素治疗的2型糖尿病初治患者中，U-300甘精氨酸和地高地松的直接比较被报道为4。在这项研究中，患者被随机分配并接受U-300甘精胰岛素（n  = 466）或地格列松（n = = 463），并且将胰岛素剂量调整为空腹血糖80–100 mg / dL。结果，HbA1c表现出显着且可比的改善，两种胰岛素在24周内的低血糖发生率和事件发生率也与两种胰岛素相当，而U-300甘精胰岛素在主动滴定期间（0-12周）的低血糖发生率更低。像BRIGHT试验一样，有两项研究通过交叉研究比较了U-300甘精氨酸和地高地松的疗效，一项使用连续血糖监测5，另一项使用闪血糖监测6在日本2型糖尿病患者中。两项研究均报告了与地德格雷相比，H-A1c降低具有相当的疗效，U-300甘精氨酸的低血糖或夜间低血糖的风险更低。通过引用BRIGHT试验和两项现实世界，倾向匹配的研究对结果进行了询问，这两项研究被称为CON​​FIRM（现实生活中的临床实践中胰岛素Degludec有效性的临床结果评估）和DELIVER（区分Gla-300临床和临床试验）。 《通过EMR在现实世界中进行经济学研究》，该报告还比较了U-300甘精氨酸和地高地松，并就低血糖发生率报告了不同的结论7。作者认为，不同的结果可能是由于各种因素的差异所引起的，这些因素包括患者特征，研究设计，背景治疗和种族8。因此，需要进一步的研究来评估这些新的胰岛素类似物的有效性。

除胰岛素治疗外，口服降糖药的作用

现在公认在胰岛素治疗的基础上增加口服抗糖尿病药是获得更好的血糖控制和减少胰岛素用量的有用方法。在一项随机对照试验的荟萃分析中，研究了二肽基肽酶-4抑制剂与2型糖尿病患者在胰岛素治疗之外的作用，与单独使用胰岛素治疗相比，血糖控制得到改善，而血糖或体重增加的风险没有增加9。相反，在一项随机对照试验的荟萃分析中，研究了除胰岛素治疗外，SGLT2i对2型糖尿病患者心血管危险因素的影响，更好的血糖控制以及血压，尿酸，体重和每日血压的更大降低据报道与单独使用胰岛素治疗相比，胰岛素剂量10。SGLT2i的这些作用可能提供抑制心血管事件的有益作用，但应注意与SGLT2i相关的低血糖，尿路和生殖器感染的风险增加。另一项研究通过间接比较荟萃分析比较了SGLT2i与吡格列酮对2型糖尿病患者胰岛素治疗的影响[ 11]。。结果，SGLT2i和吡格列酮在HbA1c和空腹血糖方面的降低相当，SGLT2i体重减轻了更多，吡格列酮的每日胰岛素剂量降低了。

有关胰岛素治疗的近期社会问题

老年糖尿病患者人数的增加已成为一个重要问题，特别是在发达国家。日本糖尿病学会报告了一项严重低血糖症的调查结果，该结果显示，发生严重低血糖症的患者中有60.8％是胰岛素使用者，他们的平均年龄为74.0岁（图1）12。因此，对老年糖尿病患者进行糖尿病管理教育，包括胰岛素自我注射技术和降低血糖的对策方法，非常重要。在这方面，Minami等。13报道了一种方法的有效性，该方法通过计算1分钟内召回的动物名字的数量来评估老年糖尿病患者的认知能力。胰岛素注射部位的肥大是胰岛素注射后血糖水平波动增加的原因之一，特别是对于长期使用胰岛素的人。最近，据报道在胰岛素注射部位形成胰岛素淀粉样蛋白是增加皮下胰岛素抵抗的潜在机制14。在一项系统的回顾和荟萃分析中，研究了胰岛素治疗的患者的肥大性高血压的患病率，该病的患病率非常高（38％），再次表明接受自我注射技术教育的重要性15。

本JDI更新中突出显示的三个主题向我们说明了对各种胰岛素制剂和非胰岛素降糖药的特征有充分了解的重要性，以及对不同背景的患者进行适当的胰岛素注射程序教育的重要性。