How is Latent Autoimmune Diabetes in Adults Best Diagnosed and Treated?
Q: What is latent autoimmune diabetes in adults (LADA)?
A: In LADA, patients appear to have type 2 diabetes phenotypically. They do not, however, have an early requirement for insulin. They are also positive for autoantibodies usually associated with type 1 diabetes. When compared to those with type 1 diabetes, these patients generally have greater preservation of ß-cell function with a slower development of absolute insulin deficiency; however, they do invariably develop a need for insulin.1
The proposed diagnostic criteria for LADA include:
1) Adult age at diagnosis (usually ≥30).
2) Positivity for at least one antibody usually seen in type 1 diabetes including islet cell autoantigen-2 antibodies, islet cell antibodies, insulin antibodies, and glutamic acid decarboxylase 65 antibodies (anti-GAD).
3) Evidence of at least temporary preservation of ß-cells with a delay in the need for insulin therapy at least 6 months after initial diagnosis.2 These patients usually will require insulin within 6 years of diagnosis as ß-cells fail with the autoimmune pancreatic effects.
Q: Should I check antibody levels on all new onset adult patients with diabetes to evaluate for the presence of LADA?
A: No. LADA accounts for approximately 10% of cases of diabetes in adults.3 In a majority of patients presenting in the ambulatory setting, the determination of type 1 versus type 2 diabetes is often based on the clinical presentation at diagnosis. However, in patients where the diagnosis is not clear—eg, patients who have little evidence of insulin resistance but whose apparent type 2 diabetes is controlled by oral medications or those who are of normal weight, have an active lifestyle, and do not have a family history of diabetes—checking antibodies is a reasonable approach to help guide therapy. Note: Testing anti-GAD may be of the greatest value as it is the most commonly occurring autoantibody seen in patients with LADA.
Q: Are there any distinguishing clinical features in patients with LADA versus type 2 diabetes?
A: Patients with LADA and type 2 diabetes may be indistinguishable at diagnosis due to similar lifestyle choices that result in obesity and insulin resistance. However, patients with LADA progress more rapidly to insulin dependence than those with type 2 diabetes—as quickly as within 6 months and may maintain insulin independence for as long as 6 years (Table).
Q: What predicts rapid progression to insulin dependence in patients with LADA?
A: Not surprisingly, the tendency to progress to insulin dependence in patients with LADA is likely multifactorial. Some studies suggest that progression is closely associated with the level of autoantibody titers; patients with lower antibody titers progress more slowly versus patients with higher antibody titers who progress more rapidly.4 However, other studies have shown that this may not be the case and that other factors such as low body mass index, high-risk human leucocyte antigen groups (HLA-DRB1, DQA1, DQB1), thyroper oxidase antibody positivity, and female gender may pose an increased risk.5
Q: What is the best management approach to take with newly diagnosed LADA patients?
A: Unless antibody levels are checked first, initial therapeutic strategies for patients with LADA are often indistinguishable from strategies for patients with type 2 diabetes. Initial therapy includes oral hypoglycemic agents such as metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 analogues.
However, because evidence suggests that the ß-cell function is impaired at diagnosis in LADA, and given the more rapid decline in ß-cell function and consequent insulin requirement, therapeutic options aimed at preserving ß-cell function have been investigated.3 A 2008 study found that early insulin treatment in patients with LADA slowed progression to insulin dependence when compared to sulfonylurea therapy.6 This study showed that C-peptide levels, a marker of endogenous insulin secretion, remained better preserved for more than 5 years with insulin therapy compared to sulfonylurea therapy. Because preservation of ß-cell function may reduce long-term complications, particularly hypoglycemic episodes, early insulin therapy may be considered in patients who are willing to take a more aggressive approach.
Patients who are reluctant to start insulin therapy early in treatment should receive counseling regarding the likelihood of rapid progression to insulin dependence. This helps foster acceptance, and possibly compliance, when ß-cells fail and the patient must begin insulin therapy. ■
References
1.Leslie RD, Williams R, Pozilli P. Clinical review: type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab. 2006;91(5):1654-1659.
2.Naik R, Brooks-Worrell B, Palmer J. Latent autoimmune diabetes in adults. J Clin Endocrinol Metab. 2009;94(12):4635-4644.
3.Stenström G, Gottsäter A, Bakhtadze E, et al. Latent autoimmune diabetes in adults: definition, prevalence, ß-cell function and treatment. Diabetes. 2005;54 Suppl 2:S68-S72.
4.Mollo A, Hernandez M, Marsal JR, et al. Latent autoimmune diabetes (LADA) is perched
between type 1 and type 2: evidence from adults in one region of Spain. Diabetes Metab Res Rev. 2013 Mar 9. [Epub ahead of print]
5.Maioli M, Pes GM, Delitala G, et al. Number of autoantibodies and HLA genotype, more than high titers of glutamic acid decarboxylase autoantibodies, predict insulin dependence in latent autoimmune diabetes of adults. Eur J Endocrinol. 2010;163(4):541-549.
6.Maruyama T, Tanaka S, Shimada A, et al. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab. 2008;93(6):2115-2121.