Therapeutic approaches for latent autoimmune diabetes in adults: One size does not fit all
成人隐匿性自身免疫性糖尿病的治疗方法:不能千篇一律
Theocharis Koufakis
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Search for more papers by this authorNiki Katsiki
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Search for more papers by this authorPantelis Zebekakis
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Search for more papers by this authorGeorge Dimitriadis
Research Institute and Diabetes Center, Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece
Search for more papers by this authorCorresponding Author
Kalliopi Kotsa
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Correspondence
Kalliopi Kotsa, Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.
Email: [email protected]
Search for more papers by this authorTheocharis Koufakis
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Search for more papers by this authorNiki Katsiki
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Search for more papers by this authorPantelis Zebekakis
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Search for more papers by this authorGeorge Dimitriadis
Research Institute and Diabetes Center, Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece
Search for more papers by this authorCorresponding Author
Kalliopi Kotsa
Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
Correspondence
Kalliopi Kotsa, Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.
Email: [email protected]
Search for more papers by this authorFunding information: None
Abstract
enRecent advances in the understanding of latent autoimmune diabetes in adults (LADA) pathophysiology make it increasingly evident that people with LADA comprise a heterogenous group of patients. This makes the establishment of a standard treatment algorithm challenging. On top of its glucose-lowering action, insulin may exert anti-inflammatory effects, rendering it an attractive therapeutic choice for a type of diabetes in which autoinflammation and beta cell insufficiency play major pathogenetic roles. However, there is growing evidence that other antidiabetic drugs, such as metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and thiazolidinediones, might have a role in optimizing glycemic control and preserving beta cell function in individuals with LADA, either alone or in combination with insulin. Although most of these drugs have been routinely used in the daily clinical setting for years, large prospective randomized trials are needed to assess whether they are capable of delaying progression to insulin dependence as well as their effects on diabetic complications. The aim of the present review is to discuss the current state and future perspectives of LADA therapy, emphasizing the need for individualized and patient-centered therapeutic approaches.
摘要
zh近年来对成人隐匿性自身免疫性糖尿病(latent autoimmune diabetes in adults, LADA)的病理生理学认识的研究越来越多地表明, LADA患者是一组具有异质性的患者群体。因此如何制定标准治疗策略非常具有挑战性。自身炎症以及β细胞功能不全是LADA的主要致病因素, 对于这一类型的糖尿病患者来说, 因为胰岛素首先具有降糖作用, 其次还具有抗炎作用, 因此是理想的治疗药物。然而, 越来越多的证据表明, 其他降糖药物, 例如二甲双胍、二肽基肽酶-4抑制剂、胰高血糖素样肽-1受体激动剂和噻唑烷二酮类药物, 单独或联合胰岛素使用, 对于LADA患者来说可能能够优化血糖控制并发挥保护β细胞功能的作用。尽管这些药物中大多数已在日常临床环境中常规使用多年, 但仍需要大规模的前瞻性随机试验来评估它们是否能够延缓胰岛素依赖性的进展以及对糖尿病并发症的影响。本综述旨在讨论LADA治疗的现状与未来前景, 强调需要采用个体化并且以患者为中心的治疗方法。
CONFLICT OF INTEREST
None.
REFERENCES
- 1Naik RG, Brooks-Worrell BM, Palmer JP. Latent autoimmune diabetes in adults. J Clin Endocrinol Metab. 2009; 94: 4635-4644.
- 2Koufakis T, Karras SN, Zebekakis P, Kotsa K. Results of the first genome-wide association study of latent autoimmune diabetes in adults further highlight the need for a novel diabetes classification system. Ann Transl Med. 2018; 6: S102.
- 3 American Diabetes Association. (2) classification and diagnosis of diabetes. Diabetes Care. 2015; 38: S8-S16.
- 4Pieralice S, Pozzilli P. Latent autoimmune diabetes in adults: a review on clinical implications and management. Diabetes Metab J. 2018; 42: 451-464.
- 5Mishra R, Hodge KM, Cousminer DL, Leslie RD, Grant SFA. A global perspective of latent autoimmune diabetes in adults. Trends Endocrinol Metab. 2018; 29: 638-650.
- 6Rolandsson O, Palmer JP. Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! Diabetologia. 2010; 53: 1250-1253.
- 7Zhou Z, Wu H. Diagnosis and treatments of latent autoimmune diabetes in adults. Chin J Endocrinol Metab. 1998; 14: 1-2.
- 8Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care. 2001; 24: 1460-1467.
- 9Hwangbo Y, Kim JT, Kim EK, et al. Prevalence and clinical characteristics of recently diagnosed type 2 diabetes patients with positive anti-glutamic acid decarboxylase antibody. Diabetes Metab J. 2012; 36: 136-143.
- 10Hampe CS, Hall TR, Agren A, et al. Longitudinal changes in epitope recognition of autoantibodies against glutamate decarboxylase 65 (GAD65Ab) in prediabetic adults developing diabetes. Clin Exp Immunol. 2007; 148: 72-78.
- 11Daka B, Svensson MK, Lernmark K, Mincheva-Nilsson L, Hallmans G, Rolandsson O. Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes. Autoimmunity. 2009; 42: 507-514.
- 12Buzzetti R, Zampetti S, Maddaloni E. Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol. 2017; 13: 674-686.
- 13Zampetti S, Campagna G, Tiberti C, et al. High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7). Eur J Endocrinol. 2014; 171: 697-704.
- 14Gale EA. Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia. 2005; 48: 2195-2199.
- 15Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet. 1997; 350: 1288-1293.
- 16Lohmann T, Kellner K, Verlohren HJ, et al. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia. 2001; 44: 1005-1010.
- 17Brophy S, Yderstraede K, Mauricio D, et al. Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults. Diabetes Care. 2008; 31: 439-441.
- 18Fourlanos S, Dotta F, Greenbaum CJ, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia. 2005; 48: 2206-2212.
- 19Zhou Z, Xiang Y, Ji L, et al. Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China Study): a nationwide, multicenter, clinic-based cross-sectional study. Diabetes. 2013; 62: 543-550.
- 20Buzzetti R, Di Pietro S, Giaccari A, et al. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care. 2007; 30: 932-938.
- 21Zampetti S, Capizzi M, Spoletini M, et al. GADA titer-related risk for organ-specific autoimmunity in LADA subjects subdivided according to gender (NIRAD study 6). J Clin Endocrinol Metab. 2012; 97: 3759-3765.
- 22van Deutekom AW, Heine RJ, Simsek S. The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitus. Diabet Med. 2008; 25: 117-125.
- 23Hoppener JW, Lips CJ. Role of islet amyloid in Type 2 diabetes mellitus. Int J Biochem Cell Biol. 2006; 38: 726-736.
- 24Buzzetti R, Spoletini M, Zampetti S, et al. Tyrosine phosphatase-related islet antigen 2(256–760) autoantibodies, the only marker of islet autoimmunity that increases by increasing the degree of BMI in obese subjects with type 2 diabetes. Diabetes Care. 2015; 38: 513-520.
- 25Redondo MJ. LADA: time for a new definition. Diabetes. 2013; 62: 339-340.
- 26Behme MT, Dupre J, Harris SB, Hramiak IM, Mahon JL. Insulin resistance in latent autoimmune diabetes of adulthood. Ann N Y Acad Sci. 2003; 1005: 374-377.
- 27Hjort R, Ahlqvist E, Carlsson PO, et al. Overweight, obesity and the risk of LADA: results from a Swedish case-control study and the Norwegian HUNT Study. Diabetologia. 2018; 61: 1333-1343.
- 28Cousminer DL, Ahlqvist E, Mishra R, et al. First genome-wide association study of latent autoimmune diabetes in adults reveals novel insights linking immune and metabolic diabetes. Diabetes Care. 2018; 41: 2396-2403.
- 29Manchia M, Cullis J, Turecki G, Rouleau GA, Uher R, Alda M. The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases. PLoS One. 2013; 8:e76295.
- 30Koufakis T, Karras SN, Zebekakis P, Ajjan R, Kotsa K. Should the last be first? Questions and dilemmas regarding early short-term insulin treatment in type 2 diabetes mellitus. Expert Opin Biol Ther. 2018; 18: 1113-1121.
- 31Fuchtenbusch M, Kredel K, Bonifacio E, Schnell O, Ziegler AG. Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens. Diabetes. 2000; 49: 918-925.
- 32Schloot N, Eisenbarth GS. Isohormonal therapy of endocrine autoimmunity. Immunol Today. 1995; 16: 289-294.
- 33Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care. 2009; 32: S246-S252.
- 34Aaen K, Rygaard J, Josefsen K, et al. Dependence of antigen expression on functional state of beta-cells. Diabetes. 1990; 39: 697-701.
- 35Cabrera-Rode E, Perich P, Diaz-Horta O, et al. Slowly progressing type 1 diabetes: persistence of islet cell autoantibodies is related to glibenclamide treatment. Autoimmunity. 2002; 35: 469-474.
- 36 Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002; 346: 1685-1691.
- 37Petrie JR, Chaturvedi N, Ford I, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017; 5: 597-609.
- 38Al Khalifah RA, Alnhdi A, Alghar H, Alanazi M, Florez ID. The effect of adding metformin to insulin therapy for type 1 diabetes mellitus children: a systematic review and meta-analysis. Pediatr Diabetes. 2017; 18: 664-673.
- 39Finegood DT, McArthur MD, Kojwang D, et al. Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes. 2001; 50: 1021-1029.
- 40Zhou Z, Li X, Huang G, et al. Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA). Diabetes Metab Res Rev. 2005; 21: 203-208.
- 41Kawano Y, Irie J, Nakatani H, Yamada S. Pioglitazone might prevent the progression of slowly progressive type 1 diabetes. Intern Med. 2009; 48: 1037-1039.
- 42Maruyama T, Tanaka S, Shimada A, et al. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab. 2008; 93: 2115-2121.
- 43Kobayashi T, Nakanishi K, Murase T, Kosaka K. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes. 1996; 45: 622-626.
- 44Zhao Y, Yang L, Wang X, Zhou Z. The new insights from DPP-4 inhibitors: their potential immune modulatory function in autoimmune diabetes. Diabetes Metab Res Rev. 2014; 30: 646-653.
- 45Tian L, Gao J, Hao J, et al. Reversal of new-onset diabetes through modulating inflammation and stimulating beta-cell replication in nonobese diabetic mice by a dipeptidyl peptidase IV inhibitor. Endocrinology. 2010; 151: 3049-3060.
- 46Duvnjak L, Blaslov K, Vučić Lovrenčić M, Knežević ĆJ. Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes. Diabetes Res Clin Pract. 2016; 121: 119-126.
- 47Awata T, Shimada A, Maruyama T, et al. Possible long-term efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for slowly progressive type 1 diabetes (SPIDDM) in the stage of non-insulin-dependency: an open-label randomized controlled pilot trial (SPAN-S). Diabetes Ther. 2017; 8: 1123-1134.
- 48Zhao Y, Yang L, Xiang Y, et al. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab. 2014; 99: E876-E880.
- 49Wang X, Yang L, Cheng Y, et al. Altered T-cell subsets and transcription factors in latent autoimmune diabetes in adults taking sitagliptin, a dipeptidyl peptidase-4 inhibitor: a 1-year open-label randomized controlled trial. J Diabetes Investig. 2019; 10: 375-382.
- 50Johansen OE, Boehm BO, Grill V, et al. C-peptide levels in latent autoimmune diabetes in adults treated with linagliptin versus glimepiride: exploratory results from a 2-year double-blind, randomized, controlled study. Diabetes Care. 2014; 37: e11-e12.
- 51Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev. 2016; 32: 289-296.
- 52Rapti E, Karras S, Grammatiki M, et al. Combined treatment with sitagliptin and vitamin D in a patient with latent autoimmune diabetes in adults. Endocrinol Diabetes Metab Case Rep. 2016; 2016: 150136.
- 53Grammatiki M, Karras S, Kotsa K. The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review. Hormones (Athens). 2019; 18: 37-48.
- 54Riachy R, Vandewalle B, Moerman E, et al. 1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor. Apoptosis. 2006; 11: 151-159.
- 55Pettus J, Hirsch I, Edelman S. GLP-1 agonists in type 1 diabetes. Clin Immunol. 2013; 149: 317-323.
- 56Pozzilli P, Leslie RD, Peters AL, et al. Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): a post-hoc analysis of the AWARD-2, −4 and −5 trials. Diabetes Obes Metab. 2018; 20: 1490-1498.
- 57Wang W, Gao Y, Chen D, Wang C, Feng X, Ran X. Efficacy and safety of incretin-based drugs in patients with type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2017; 129: 213-223.
- 58Mathieu C, Zinman B, Hemmingsson JU, et al. ADJUNCT ONE investigators. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCTONE treat-to-target randomized trial. Diabetes Care. 2016; 39: 1702-1710.
- 59Sfairopoulos D, Liatis S, Tigas S, Liberopoulos E. Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones (Athens). 2018; 17: 333-350.
- 60Jones AG, McDonald TJ, Shields BM, et al. Markers of β-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes. Diabetes Care. 2016; 39: 250-257.
- 61Lawrence L, Menon V, Kashyap S. Cardiovascular and renal outcomes of newer anti-diabetic medications in high-risk patients. Curr Cardiol Rep. 2018; 20: 65.
- 62Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER trial investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375: 311-322.
- 63Hernandez AF, Green JB, Janmohamed S, et al. Harmony outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (harmony outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018; 392: 1519-1529.
- 64Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375: 1834-1844.
- 65Patoulias D, Manafis A, Mitas C, et al. Sodium-glucose cotransporter 2 inhibitors and the risk of diabetic ketoacidosis; from pathophysiology to clinical practice. Cardiovasc Hematol Disord Drug Targets. 2018; 18: 139-146.
- 66Benmoussa J, Clarke M, Penmetsa A, et al. Euglycemic diabetic ketoacidosis: the clinical concern of SGLT2 inhibitors. J Clin Transl Endocrinol Case Rep. 2016; 2: 17-19.
10.1016/j.jecr.2016.05.002 Google Scholar
- 67Frumento D, Ben Nasr M, El Essawy B, D'Addio F, Zuccotti GV, Fiorina P. Immunotherapy for type 1 diabetes. J Endocrinol Invest. 2017; 40: 803-814.
- 68Latres E, Finan DA, Greenstein JL, Kowalski A, Kieffer TJ. Navigating two roads to glucose normalization in diabetes: automated insulin delivery devices and cell therapy. Cell Metab. 2019; 29: 545-563.
- 69Greenbaum C, VanBuecken D, Lord S. Disease-modifying therapies in type 1 diabetes: a look into the future of diabetes practice. Drugs. 2019; 79: 43-61.
- 70Pinheiro MM, Pinheiro FMM, Torres MA. Four-year clinical remission of type 1 diabetes mellitus in two patients treated with sitagliptin and vitamin D3. Endocrinol Diabetes Metab Case Rep. 2016; 2016: 16-0099.
- 71Pinheiro MM, Pinheiro FMM, Trabachin ML. Dipeptidyl peptidase-4 inhibitors (DPP-4i) combined with vitamin D3: an exploration to treat new-onset type 1 diabetes mellitus and latent autoimmune diabetes in adults in the future. Int Immunopharmacol. 2018; 57: 11-17.
- 72Warnes H, Helliwell R, Pearson SM, Ajjan RA. Metabolic control in type 1 diabetes: is adjunctive therapy the way forward? Diabetes Ther. 2018; 9: 1831-1851.
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