Immunotherapy
Type 1 diabetes is an autoimmune disease modulated by cytotoxic T cells. Several agents have been studied for treatment of new-onset disease. Nonantigen-specific systemic immunotherapies, including T-cell suppressors (cyclosporine), antiproliferative agents (methotrexate, azathioprine), and antithymocyte globulin have shown a strong tendency to adverse effects. Although cyclosporine use did reduce insulin requirements in the short term, it was associated with nephrotoxicity, and the effect on beta cells waned with treatment cessation. Antigen-specific vaccination with recombinant glutamic acid decarboxylase was shown to increase stimulated C-peptide in patients treated within 3 months of diagnosis.[94]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
Trials are under way to investigate treatment of type 1 diabetes with dendritic cells, mesenchymal stem cells, cord blood transfusion, and immunomodulators currently approved for use in other diseases, such as granulocyte colony stimulating factor or tumor necrosis factor-alpha inhibitors.[95]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
One clinical trial of the anti-CD3 monoclonal antibody, teplizumab, in patients with new-onset diabetes shows that the decline in beta-cell function (measured by C-peptide) is slowed and insulin requirements for glycemic control are reduced.[96]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
[97]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
In one study of patients who did not have diabetes, but who were at high-risk (≥2 type 1 diabetes auto-antibodies and dysglycemia), teplizumab delayed progression to clinical disease.[98]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
The Food and Drug Administration has granted teplizumab breakthrough therapy designation for the prevention or delay of clinical type 1 diabetes in at-risk individuals, which may expedite the review process for approval of this drug.
Islet cell transplantation
Islet cells prepared from a donor pancreas are injected into the portal vein. The cells seed in the liver and produce insulin. Patients who undergo this procedure require immunosuppressive therapy afterwards. There is some initial success with this procedure but the long-term results remain disappointing. Even in the best centers, less than 50% of patients are free of insulin requirement at 1 year and only 10% at 5 years.[99]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
[100]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
The American Diabetes Association (ADA) recommends that this procedure be performed only within the context of a controlled research study at this time.
Inhaled insulin
In June 2014, the FDA approved a rapid-acting inhaled insulin. It can be administered before meals and should be used in combination with long-acting insulin. It can cause bronchospasm in patients with asthma and chronic obstructive pulmonary disease, and should not be used if these conditions are present. The most common side effects in a 24-week safety and efficacy trial were hypoglycemia, cough, and throat infection. Long-term safety data are lacking.[101]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
Moreover, it is available only in fixed doses of 4 or 8 units. Therefore, dose adjustments can be made only in multiples of 4 which may present difficulty in fine-tuning the dose in patients with type 1 diabetes. More experience is needed before inhaled insulin is routinely prescribed in type 1 diabetes.
Islet cell regeneration
Studies done in mouse models show that from the onset of insulinitis, there is a mass of beta cells within an inflammatory milieu that may be recoverable and serve as a future source of functioning beta cells.[102]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
Several trials are under way to investigate mono- and combination therapies to arrest inflammation and possibly allow beta-cell regeneration.
Insulin sensitizers
A systematic review suggested that use of metformin in type 1 diabetes reduced insulin requirements but not HbA1c levels after 1 year of follow-up.[103]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
Further research is indicated to better delineate the potential indications and benefits of this treatment in type 1 diabetes.[104]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
[105]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
Sodium-glucose co-transporter 2 inhibitors
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral medications that reduce glucose in an insulin-independent manner, by inhibiting SGLT2 in the proximal renal tubule and blocking glucose reabsorption. They are associated with modest weight loss and blood pressure reduction. SGLT2 inhibitors are approved for use in individuals with type 2 diabetes. Several reports have highlighted the risk of euglycemic diabetic ketoacidosis in both type 2 and type 1 diabetes.[106]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
[107]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
Studies are ongoing to assess safety and efficacy of this class of medications in type 1 diabetes.[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
[108]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
[109]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
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has approved the selective SGLT2 inhibitor dapagliflozin for use in patients with type 1 diabetes mellitus and a body mass index ≥27 kg/m² as an adjunct to insulin, when insulin alone does not provide adequate glycemic control despite optimal insulin therapy.[110]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
[111]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
[112]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
In March 2019, the CHMP recommended that sotagliflozin, a dual inhibitor of SGLT1 and SGLT2, also be approved for the same indication.[106]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
[113]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
[114]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
[115]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
[116]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
However, the Food and Drug Administration (FDA) rejected approval of sotagliflozin for type 1 diabetes in March 2019. Patients must fulfill requirements to minimize the increased risk of diabetic ketoacidosis with both of these drugs.
Glucagon-like peptide-1 (GLP-1) agonists
GLP-1 is a gut peptide that increases insulin secretion and decreases glucagon secretion in a glucose-dependent manner. In patients with type 2 diabetes, GLP-1 receptor agonists increase levels of GLP-1 and lead to more glucose-dependent insulin secretion, less glucagon secretion, delayed gastric emptying, and increased satiety. The specific advantage of GLP-1 agonists is weight loss, which may be desirable in some patients with type 1 diabetes.[117]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
The GLP-agonist liraglutide added to insulin improved glucose control in clinical trials with type 1 diabetes, but also increased the risk of both hypoglycemia and hyperglycemia with ketosis. Therefore, GLP-1 agonists should not routinely be used in type 1 diabetes.