免疫疗法
1 型糖尿病是由细胞毒性 T 细胞所介导的自身免疫性疾病。目前多种针对新发疾病治疗药物已在研究阶段。已发现非抗原特异性系统性免疫治疗,包括 T 细胞抑制剂(环孢素)、生长抑制剂(甲氨蝶呤、硫唑嘌呤)和抗胸腺细胞球蛋白等有很强的不良反应。尽管使用环孢素确实可在短期内降低胰岛素需求,但它具有肾毒性,且对 β 细胞的作用也会在治疗停止后减弱。在某些患者中,诊断为 1 型糖尿病的 3 个月内使用重组谷氨酸脱羧酶的抗原特异性疫苗可以刺激 C 肽的分泌。[93]Ludvigsson J, Faresjö M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1909-20.
https://www.nejm.org/doi/full/10.1056/NEJMoa0804328
http://www.ncbi.nlm.nih.gov/pubmed/18843118?tool=bestpractice.com
一些研究 1 型糖尿病患者治疗的试验仍在进行阶段,包括有关树突状细胞、间充质干细胞、输脐带血和在其他疾病中使用的免疫调节剂,比如粒细胞集落刺激因子或肿瘤坏死因子-α 抑制剂等。[94]Rewers M, Gottlieb P. Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes Care. 2009 Oct;32(10):1769-82.
http://care.diabetesjournals.org/content/32/10/1769.long
http://www.ncbi.nlm.nih.gov/pubmed/19794002?tool=bestpractice.com
Tepilizumab
一项关于在新发糖尿病患者中使用抗 CD3 单克隆抗体 teplizumab 的临床试验表明,β 细胞功能下降(通过 C 肽测量)减慢,并且用于控制血糖的胰岛素需求量减少。[95]Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011 Aug 6;378(9790):487-97.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191495/
http://www.ncbi.nlm.nih.gov/pubmed/21719095?tool=bestpractice.com
[96]Hagopian W, Ferry RJ Jr, Sherry N, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes. 2013 Nov;62(11):3901-8.
https://www.doi.org/10.2337/db13-0236
http://www.ncbi.nlm.nih.gov/pubmed/23801579?tool=bestpractice.com
在一项针对没有糖尿病但处于高风险(≥2 种 1型糖尿病自身抗体和血糖异常) 患者的研究中,teplizumab 延缓了病程发展至临床疾病的进展。[97]Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019 Aug 15;381(7):603-13.
https://www.doi.org/10.1056/NEJMoa1902226
http://www.ncbi.nlm.nih.gov/pubmed/31180194?tool=bestpractice.com
美国食品药品监督管理局已授予 teplizumab 为突破性治疗药物,用于预防或延迟有风险人群的临床 1 型糖尿病,这可能会加快该药物的审批过程。
胰岛细胞移植
移植的胰岛细胞通过门静脉注入患者体内。胰岛细胞在肝脏定植,并产生胰岛素。经此手术的患者术后需要进行免疫抑制剂的治疗。目前该术获得初步的成功,但是长远来看,其结果仍不甚满意。即使在最好的研究中心,仅有低于50%的患者在1年内不再需要胰岛素治疗,5年内仅10%的患者不再需要胰岛素治疗。[98]Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006 Sep 28;355(13):1318-30.
https://www.nejm.org/doi/full/10.1056/NEJMoa061267
http://www.ncbi.nlm.nih.gov/pubmed/17005949?tool=bestpractice.com
[99]Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005 Jul;54(7):2060-9.
http://diabetes.diabetesjournals.org/content/54/7/2060.long
http://www.ncbi.nlm.nih.gov/pubmed/15983207?tool=bestpractice.com
美国糖尿病协会 (ADA) 推荐该手术目前仅在研究中心开展。
吸入胰岛素
2014 年 6 月,美国 FDA 批准了一种速效吸入性胰岛素。可在餐前使用,并应配合长效胰岛素共同降糖。在有哮喘和慢性阻塞性肺疾病的患者中,吸入性胰岛素可导致支气管痉挛,因此暂不允许在这类疾病患者中使用。在一项为期 24 周、关于吸入性胰岛素的安全性和有效性的临床试验中,发现其最常见的副作用为低血糖、咳嗽和咽部感染。尚缺乏其长期使用的安全性相关数据。[100]US Food and Drug Administration. FDA approves Afrezza to treat diabetes. Jun 2014 [internet publication].
https://wayback.archive-it.org/7993/20170112222845/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm
并且,它仅有 4 或 8 单位的固定剂量规格。因此,只能以 4 的倍数调整剂量,在 1 型糖尿病患者中,微调剂量可能有困难。在吸入性胰岛素常规用于 1 型糖尿病患者之前,需要更多经验。
胰岛细胞再生
使用小鼠模型进行的研究表明,从胰岛炎发作开始,炎症环境中存在大量 β 细胞,这些 β 细胞可恢复并在未来充当功能性 β 细胞。[101]Akirav E, Kushner JA, Herold KC. Beta-cell mass and type 1 diabetes: going, going, gone? Diabetes. 2008 Nov;57(11):2883-8.
http://diabetes.diabetesjournals.org/content/57/11/2883.long
http://www.ncbi.nlm.nih.gov/pubmed/18971435?tool=bestpractice.com
目前有多项试验正在进行中,研究控制炎症以及可能使得 β 细胞再生的单一和联合治疗。
胰岛素增敏剂
一项系统评价指出,经过 1 年的随访,在 1 型糖尿病患者中使用二甲双胍可以减少胰岛素需求量,但是并不能降低 HbA1c 水平。[102]Vella S, Buetow L, Royle P, et al. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia. 2010 May;53(5):809-20.
https://link.springer.com/article/10.1007%2Fs00125-009-1636-9
http://www.ncbi.nlm.nih.gov/pubmed/20057994?tool=bestpractice.com
进一步的研究需要阐明该方案的适应征及在1型糖尿病中使用该治疗的益处。[103]DeGeeter M, Williamson B. Alternative agents in type 1 diabetes in addition to insulin therapy: metformin, alpha-glucosidase inhibitors, pioglitazone, GLP-1 agonists, DPP-IV inhibitors, and SGLT-2 inhibitors. J Pharm Pract. 2016 Apr;29(2):144-59.
http://www.ncbi.nlm.nih.gov/pubmed/25312263?tool=bestpractice.com
[104]Petrie JR, Chaturvedi N, Ford I, et al; REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):597-609.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641446/
http://www.ncbi.nlm.nih.gov/pubmed/28615149?tool=bestpractice.com
钠-葡萄糖协同转运蛋白 2 抑制剂
钠-葡萄糖协同转运蛋白 2 (Sodium-glucose co-transporter 2, SGLT2) 抑制剂是一种口服药物,能抑制近端肾小管中的 SGLT2 以及阻滞葡萄糖重吸收,从而以非胰岛素依赖性方式降低血糖。它们能轻微减少体重并降低血压。SGLT2 抑制剂已被批准用于 2 型糖尿病患者。多份报告强调,2 型和 1 型糖尿病患者存在血糖正常的糖尿病酮症酸中毒的风险。[105]Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017 Dec 14;377(24):2337-48.
https://www.nejm.org/doi/10.1056/NEJMoa1708337
http://www.ncbi.nlm.nih.gov/pubmed/28899222?tool=bestpractice.com
[106]Hampp C, Swain RS, Horgan C, et al. Use of sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes and rates of diabetic ketoacidosis. Diabetes Care. 2020 Jan;43(1):90-7.
https://www.doi.org/10.2337/dc19-1481
http://www.ncbi.nlm.nih.gov/pubmed/31601640?tool=bestpractice.com
目前正在进行研究,以评估这类药物用于治疗 1 型糖尿病的安全性和有效性。[1]American Diabetes Association. Standards of medical care in diabetes - 2020. Diabetes Care. 2020;43(suppl 1):S1-212.
https://care.diabetesjournals.org/content/43/Supplement_1
[107]Chen J, Fan F, Wang JY, et al. The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis. Sci Rep. 2017 Mar 9;7:44128.
https://www.nature.com/articles/srep44128
http://www.ncbi.nlm.nih.gov/pubmed/28276512?tool=bestpractice.com
[108]Taylor SI, Blau JE, Rother KI, et al. SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks. Lancet Diabetes Endocrinol. 2019 Dec;7(12):949-58.
https://www.doi.org/10.1016/S2213-8587(19)30154-8
http://www.ncbi.nlm.nih.gov/pubmed/31585721?tool=bestpractice.com
欧洲药品管理局人用药品委员会 (European Medicines Agency's Committee for Medicinal Products for Human Use, CHMP) 批准将选择性 SGLT2 抑制剂达格列净用于体重指数≥27 kg/m² 的 1 型糖尿病患者,作为胰岛素的辅助药物,尽管胰岛素治疗最佳,但仅使用胰岛素不能提供足够的血糖控制。[109]Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Sep 14;5(11):864-76.
http://www.ncbi.nlm.nih.gov/pubmed/28919061?tool=bestpractice.com
[110]Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care. 2018 Oct 23;41(12):2552-9.
http://www.ncbi.nlm.nih.gov/pubmed/30352894?tool=bestpractice.com
[111]Mathieu C, Dandona P, Gillard P, et al; DEPICT-2 Investigators. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 Study): 24-week results from a randomized controlled trial. Diabetes Care. 2018 Jul 19;41(9):1938-46.
http://care.diabetesjournals.org/content/41/9/1938.long
http://www.ncbi.nlm.nih.gov/pubmed/30026335?tool=bestpractice.com
2019 年 3 月,CHMP 推荐批准将索格列净(sotagliflozin, SGLT1 和 SGLT2 的双重抑制剂)用于同一适应证。[105]Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017 Dec 14;377(24):2337-48.
https://www.nejm.org/doi/10.1056/NEJMoa1708337
http://www.ncbi.nlm.nih.gov/pubmed/28899222?tool=bestpractice.com
[112]Danne T, Cariou B, Buse JB, et al. Improved time in range and glycemic variability with sotagliflozin in combination with insulin in adults with type 1 diabetes: a pooled analysis of 24-week continuous glucose monitoring data from the inTandem Program. Diabetes Care. 2019 May;42(5):919-30.
http://www.ncbi.nlm.nih.gov/pubmed/30833371?tool=bestpractice.com
[113]Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 Study. Diabetes Care. 2018 Jun 24;41(9):1970-80.
http://care.diabetesjournals.org/content/41/9/1970.long
http://www.ncbi.nlm.nih.gov/pubmed/29937430?tool=bestpractice.com
[114]Danne T, Cariou B, Banks P, et al. HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 Study. Diabetes Care. 2018 Jun 24;41(9):1981-90.
http://care.diabetesjournals.org/content/41/9/1981.long
http://www.ncbi.nlm.nih.gov/pubmed/29937431?tool=bestpractice.com
[115]Musso G, Gambino R, Cassader M, et al. Efficacy and safety of dual SGLT 1/2 inhibitor sotagliflozin in type 1 diabetes: meta-analysis of randomised controlled trials. BMJ. 2019 Apr 9;365:l1328.
https://www.doi.org/10.1136/bmj.l1328
http://www.ncbi.nlm.nih.gov/pubmed/30967375?tool=bestpractice.com
然而美国食品药品监督管理局 (FDA) 在 2019 年 3 月拒绝批准将索格列净用于治疗 1 型糖尿病。患者必须满足多种要求,以最大限度地降低这两种药物对糖尿病酮症酸中毒风险的影响。
胰高血糖素样肽-1 (GLP-1) 激动剂
GLP-1 是一种肠肽,可以葡萄糖依赖性方式增加胰岛素分泌,降低胰高血糖素分泌。在 2 型糖尿病患者中,GLP-1 受体激动剂能升高 GLP-1 水平,导致更多的葡萄糖依赖性胰岛素分泌,更少的胰高血糖素分泌,延迟胃排空,增加饱腹感。GLP-1 激动剂的具体优势是减轻体重,这可能是一些 1 型糖尿病患者所希望的。[116]Janzen KM, Steuber TD, Nisly SA. GLP-1 agonists in type 1 diabetes mellitus. Ann Pharmacother. 2016 Aug;50(8):656-65.
http://www.ncbi.nlm.nih.gov/pubmed/27252246?tool=bestpractice.com
在胰岛素中添加 GLP-激动剂利拉鲁肽在 1 型糖尿病的临床试验中改善了葡萄糖控制,但也增加了患酮症性低血糖和高血糖的风险。因此,GLP-1 激动剂不宜作为 1 型糖尿病常规用药。