A century has elapsed since the first formulated insulin made a debut. Progressive techniques and materials have overcome many problems of insulin therapy, including impurities, duration of action, antibodies against porcine or bovine insulin, and the expense of production¹.

Despite the advances in oral antidiabetic drugs (OADs), insulin injection remains the keystone therapy in type 1 diabetes, type 2 diabetes with significantly impaired renal function, pregnant women, pancreoprivic diabetes, hospitalized patients, and those who cannot take oral pills. According to the American Diabetes Association, the early initiation of insulin therapy is recommended in the presence of ongoing catabolism (weight loss), symptoms of hyperglycemia, or when the A1c levels are >10% (86 mmol/mol) or blood glucose levels are ≥300 mg/dL (16.7 mmol/L)². Moreover, insulin therapy always plays a role in the treatment for individuals who suffer treatment failure with oral antidiabetic drugs. As type 2 diabetes is a progressive disease, a significant number of individuals will ultimately need a daily injection of insulin as a result of declining pancreatic beta-cell function. For example, a nationwide cohort study revealed that adolescents with type 2 diabetes mellitus progressively required more intensive treatment after 1 year on oral antidiabetic drugs, with the majority eventually needing insulin therapy³. A significant subset of people with adult diabetes exhibit a combination of traits seen in both type 1 and type 2 diabetes. They are recognized as having a slowly progressive autoimmune form of diabetes, yet they do not initially require insulin upon diagnosis. These individuals are classified as having adult latent autoimmune diabetes, constituting approximately 2–12% of all cases of diabetes⁴.

Intermediate-acting and long-acting insulin are used as basal insulin, which is usually the beginning of insulin therapy. Common available insulin products are listed in Table 1. Insulin glargine and insulin degludec are deemed to be the most useful basal insulin currently. The DEVOTE Trial (Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events) was the first study to compare the cardiovascular safety of insulin degludec with insulin glargine U100 in patients with type 2 diabetes at high risk of cardiovascular events. Both insulins demonstrated comparable efficacy in the cardiovascular events outcome (hazard ratio 0.91; 95% CI 0.78–1.06). Degludec exhibited significantly reduced occurrences of severe hypoglycemia and nocturnal severe hypoglycemia (with rate ratios of 0.60; 95% CI 0.48–0.76 and 0.47; 95% CI 0.31–0.73, respectively)⁵. Another study assessing the effectiveness and safety of insulin glargine U300 and insulin degludec in managing glycemic control through continuous glucose monitoring also revealed no significant difference in the mean percentage of time within the target glucose range between glargine U300 and degludec (77.8 ± 19.2 vs 76.9 ± 18.3%, P = 0.848). In contrast, the mean percentage duration of hypoglycemia was notably reduced with glargine U300 compared with degludec (1.3 ± 2.7 vs 5.5 ± 6.4%, P = 0.002)⁶.

A combined injectable therapy should be considered if the basal insulin has been adjusted to achieve a desirable fasting blood glucose level, and the A1c still exceeds the desired target. This strategy may involve the addition of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or a combination of glucose-dependent insulinotropic polypeptide and GLP-1 RA to the existing basal insulin or multiple insulin doses². Fixed ratio combination products, such as insulin glargine U100 plus lixisenatide, are available to achieve better adherence for selected patients. Other considered options in combined therapy include degludec. It has a duration exceeding 40 h and can attain a steady plasma concentration for 3–5 days. In contrast to glargine and detemir insulins, degludec may be mixed with rapid-acting insulins without significantly altering the kinetics of either medication compared with other forms of basal insulin⁷.

Insulin icodec is a novel basal insulin that has been designed for weekly subcutaneous administration. The implementation of this regimen will markedly reduce the need for weekly injections, leading to increased patient satisfaction and adherence. The ONWARDS (Once Weekly Insulin Icodec in Diabetes) trials demonstrated a more pronounced decrease in HbA1c levels among insulin-naïve patients and a similar effect in those already undergoing insulin treatment. Although the overall rate of combined clinically significant or severe hypoglycemia was significantly higher among the icodec group compared with the degludec group, the adverse effect of severe hypoglycemia did not increase^{8, 9}.

Basal insulin-Fc (LY3209590) is an investigational ultra-long-acting immunoglobulin G Fc-fusion insulin, also designed to be administered subcutaneously and weekly. In a phase 2 trial including 399 adults with type 2 diabetes, the basal insulin Fc (BIF) groups exhibited a comparable reduction in the HbA1C level with degludec (0.1% [90% CI –0.1 to 0.3]) despite higher fasting glucose targets in the BIF groups. The hypoglycemia event rates in the BIF groups were 25% lower than those of the degludec group. These findings suggest further investigation of BIF as a once-weekly insulin treatment for diabetic patients. More trials are required to address its safety and efficacy in the treatment of type 1 and type 2 diabetes¹⁰.

The development of insulin treatment devices and continuous glucose monitoring facilitate diabetes control. Different treatment strategies, such as continuous subcutaneous insulin infusion plus glucose monitoring, and sensor-augmented pump (SAP) therapy are also under investigation¹¹. Six type 1 diabetes patients underwent post-simultaneous kidney/pancreas or pancreas only transplant were studied. All of them were taking immunosuppressants and multiple daily insulin injections for hyperglycemia after surgery. Diabetes technologies were provided to help achieve better glucose control in those who had dysfunction of the pancreatic graft¹².

However, it is worth noting that insulin allergy and anti-insulin antibodies may cause severe adverse effects. A case of type 2 diabetes was reported as having severe diabetic ketoacidosis triggered by an allergic reaction to insulin and the presence of anti-insulin antibodies. In addition, other life-threatening events such as angioedema and anaphylaxis may also occur, although they are rare¹³.

Additionally, there are concerns about how the changes in the structure of insulin to its analogs would increase mitogenic activities due to the enhanced affinity to the IGF-1 (Insulin-like Growth Factor) receptor and the prolonged residence on the receptors for insulin, leading to neoplastic consequences¹⁴. Few trials in the past have addressed this issue and have demonstrated conflicting results. A meta-analysis performed in 2023 compiled the risk of cancer among patients taking anti-diabetic medications. Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01–1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08–2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08–5.36)¹⁵. However, due to the limited number of samples, further research is required to confirm such findings.

This article highlights the integral role of long-acting insulin as a sole or combined regimen in the treatment of type 1 diabetes or type 2 diabetes after first-line agents have failed. Other novel agents such as basal insulin-Fc may be considered after the establishment of solid evidence supporting its benefits. Although neoplastic consequences such as pancreatic cancer may occur, more robust studies are required to verify such a hypothesis. The integration of the current insulin therapies with SAP and other continuous glucose monitoring devices allow close monitoring of glucose levels among patients, especially those under a combined regimen. This will foster opportunities for research and ensure a higher safety when administering insulin regimens.

自第一个配方胰岛素首次亮相以来已经过去了一个世纪。先进的技术和材料已经克服了胰岛素治疗的许多问题，包括杂质、作用持续时间、针对猪或牛胰岛素的抗体以及生产费用¹。

尽管口服抗糖尿病药物 (OAD) 取得了进展，但胰岛素注射仍然是 1 型糖尿病、肾功能明显受损的 2 型糖尿病、孕妇、胰脏糖尿病、住院患者和无法服用口服药的患者的主要治疗方法。根据美国糖尿病协会的说法，如果存在持续分解代谢（体重减轻）、高血糖症状，或者糖化血红蛋白水平 >10% (86 mmol/mol) 或血糖水平低于正常水平，建议及早开始胰岛素治疗。 ≥300 毫克/分升 (16.7 毫摩尔/升) ² .此外，对于口服抗糖尿病药物治疗失败的个体，胰岛素治疗始终发挥着重要作用。由于 2 型糖尿病是一种进行性疾病，由于胰腺 β 细胞功能下降，许多人最终需要每天注射胰岛素。例如，一项全国性队列研究显示，患有 2 型糖尿病的青少年在服用口服降糖药物一年后逐渐需要更强化的治疗，其中大多数最终需要胰岛素治疗³。很大一部分成人糖尿病患者表现出 1 型和 2 型糖尿病的特征组合。他们被认为患有缓慢进展的自身免疫性糖尿病，但在诊断后他们最初不需要胰岛素。这些人被归类为患有成人潜伏性自身免疫性糖尿病，约占所有糖尿病病例的 2-12% ⁴。

中效和长效胰岛素用作基础胰岛素，通常是胰岛素治疗的开始。常见的胰岛素产品列于表1。甘精胰岛素和德谷胰岛素被认为是目前最有用的基础胰岛素。 DEVOTE 试验（比较德谷胰岛素与甘精胰岛素在心血管事件高风险 2 型糖尿病患者中的心血管安全性的试验）是第一项比较德谷胰岛素与甘精胰岛素 U100 在 2 型糖尿病患者中的心血管安全性的研究。心血管事件的高风险。两种胰岛素在心血管事件结局方面表现出相当的功效（风险比 0.91；95% CI 0.78–1.06）。德谷降糖显着降低了严重低血糖和夜间严重低血糖的发生率（比率分别为 0.60；95% CI 0.48–0.76 和 0.47；95% CI 0.31–0.73）⁵。另一项评估甘精胰岛素 U300 和德谷胰岛素通过连续血糖监测管理血糖控制的有效性和安全性的研究也显示，甘精胰岛素 U300 和德谷胰岛素在目标血糖范围内的平均时间百分比没有显着差异（77.8 ± 19.2 vs 76.9 ± 18.3%，P  = 0.848）。相反，与德谷胰岛素相比，甘精胰岛素 U300 的平均低血糖持续时间百分比显着缩短（1.3 ± 2.7 vs 5.5 ± 6.4%，P  = 0.002）⁶。

如果已调整基础胰岛素以达到理想的空腹血糖水平，并且 A1c 仍超过预期目标，则应考虑联合注射治疗。该策略可能涉及在现有基础胰岛素或多剂量胰岛素中添加胰高血糖素样肽-1 受体激动剂 (GLP-1 RA) 或葡萄糖依赖性促胰岛素多肽和 GLP-1 RA 的组合²。固定比例的组合产品，例如甘精胰岛素 U100 加利西拉来，可以帮助特定患者实现更好的依从性。联合治疗中其他考虑的选择包括德谷。持续时间超过40小时，可在3-5天内达到稳定的血药浓度。与甘精胰岛素和地特胰岛素相比，与其他形式的基础胰岛素相比，德谷胰岛素可以与速效胰岛素混合，而不会显着改变任一药物的动力学⁷。

胰岛素 icodec 是一种新型基础胰岛素，设计用于每周皮下注射。该方案的实施将显着减少每周注射的需要，从而提高患者满意度和依从性。 ONWARDS（糖尿病患者每周一次胰岛素 Icodec）试验表明，未接受过胰岛素治疗的患者的 HbA1c 水平下降更为明显，而已经接受胰岛素治疗的患者也有类似的效果。尽管与德谷组相比，icodec 组中合并临床显着或严重低血糖的总体发生率显着较高，但严重低血糖的不良反应并未增加^{8, 9}。

基础胰岛素-Fc (LY3209590) 是一种正在研究的超长效免疫球蛋白 G Fc 融合胰岛素，也设计为每周一次皮下注射。在一项包含 399 名 2 型糖尿病成人的 2 期试验中，基础胰岛素 Fc (BIF) 组与德谷胰岛素组相比，尽管空腹血糖目标较高，但 HbA1C 水平显着降低（0.1% [90% CI –0.1 至 0.3]）。 BIF 组。 BIF 组的低血糖事件发生率比德谷组低 25%。这些发现建议进一步研究 BIF 作为糖尿病患者每周一次的胰岛素治疗方法。需要更多的试验来确定其治疗 1 型和 2 型糖尿病的安全性和有效性¹⁰。

胰岛素治疗设备和连续血糖监测的发展促进了糖尿病的控制。不同的治疗策略，例如持续皮下胰岛素输注加血糖监测和传感器增强泵（SAP）治疗也正在研究中¹¹。研究人员对 6 名 1 型糖尿病患者进行了肾/胰腺同步移植或仅胰腺移植后的研究。他们都在手术后服用免疫抑制剂并每天多次注射胰岛素来治疗高血糖。提供糖尿病技术是为了帮助胰腺移植功能障碍的患者更好地控制血糖¹²。

但值得注意的是，胰岛素过敏和抗胰岛素抗体可能会引起严重的不良反应。据报道，一例 2 型糖尿病患者因胰岛素过敏反应和抗胰岛素抗体的存在而引发严重的糖尿病酮症酸中毒。此外，也可能发生其他危及生命的事件，例如血管性水肿和过敏反应，尽管这种情况很少见¹³。

此外，人们担心胰岛素与其类似物的结构变化会增加促有丝分裂活性，因为它与 IGF-1（胰岛素样生长因子）受体的亲和力增强，并且在胰岛素受体上的停留时间延长，从而导致肿瘤后果¹⁴．过去很少有试验解决这个问题，并且结果相互矛盾。 2023 年进行的一项荟萃​​分析汇总了服用抗糖尿病药物的患者患癌症的风险。胰岛素促分泌剂与胰腺癌之间存在正相关（n  = 5；RR = 1.26；95% CI = 1.01–1.57），胰岛素与肝脏之间存在正相关（n  = 7；RR = 1.74；95% CI = 1.08–2.80）和胰腺癌（n  = 8；RR = 2.41；95% CI = 1.08–5.36）¹⁵。然而，由于样本数量有限，需要进一步的研究来证实这一发现。

本文强调了长效胰岛素作为单一或联合治疗方案在一线药物失败后治疗 1 型糖尿病或 2 型糖尿病中的不可或缺的作用。在建立支持其益处的确凿证据后，可以考虑其他新型药物，例如基础胰岛素-Fc。尽管可能会发生胰腺癌等肿瘤后果，但需要更强有力的研究来验证这一假设。当前的胰岛素疗法与 SAP 和其他连续血糖监测设备的集成可以密切监测患者的血糖水平，特别是那些接受联合治疗的患者。这将促进研究机会并确保胰岛素治疗方案的更高安全性。