ABSTRACT
Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes that shares features of type 1 and type 2 diabetes, often leading to misdiagnosis and a delay in starting needed insulin therapy. This review summarizes LADA’s presentation, diagnostic criteria, and management, emphasizing the importance of testing for antibodies early in the course of disease when patients have atypical features of type 2 diabetes.
LADA is a slowly progressive autoimmune-mediated form of diabetes that is often misdiagnosed as type 2 diabetes.
To detect LADA promptly, diabetes-associated antibody testing should be obtained in patients with diabetes who are lean and do not have metabolic syndrome or in those with a personal or family history of autoimmune disease.
Noninsulin therapies can be used in the early stages, but patients eventually require insulin months to years after their diagnosis, as guided by C-peptide and hemoglobin A1c monitoring.
Rather than waiting for noninsulin therapies to fail, proactive antibody testing and subsequent monitoring can ensure that patients with LADA benefit from the appropriate use of insulin.
Further research is needed on beta-cell preservation and immunosuppressive therapies to slow the progression of LADA.
Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes that emerges in adulthood and shares characteristics with both type 1 and type 2 diabetes. The condition was initially called “type 1.5 diabetes” to reflect its clinical overlap with both major diabetes types; however, this term is now considered outdated because it lacks specificity and a clear, universally accepted definition. The term LADA was introduced by Tuomi et al1 in 1993, marking its recognition as a distinct autoimmune subtype.
See related editorial, page 764
About 4% to 14% of all patients diagnosed with type 2 diabetes mellitus may actually have LADA instead, making it a significant yet underdiagnosed condition.2 LADA is present in all major ethnic groups studied, but the prevalence appears to be highest in people of northern European origin and lower in Asian populations. Misclassification as type 2 diabetes is common, leading to delay in starting insulin therapy and insufficient glycemic control. Recognizing LADA early through antibody testing is essential to optimize management and prevent adverse outcomes.
GRADUAL IMMUNE DESTRUCTION OF BETA CELLS
LADA is characterized by pancreatic islet autoantibodies, with gradual immune-mediated destruction of pancreatic beta cells. Glutamic acid decarboxylase 65 (GAD65) antibodies are most common, being present in approximately 90% of patients, but other autoantibodies such as insulinoma-associated protein 2 (IA-2), zinc transporter 8 (ZnT8), or islet cell antibody (ICA) may also be present.3,4
Genetic susceptibility plays a significant role, with specific human leukocyte antigen (HLA) genotypes, particularly HLA-DR3, -DR4, -DQB1, and -DRB1 alleles, conferring risk of LADA but overlapping with those found in classic type 1 diabetes mellitus.5–7 However, the onset of LADA is likely influenced by environmental triggers and epigenetic factors interacting with genetic predisposition.8,9 Notably, current data do not demonstrate consistent evidence of sex differences in LADA prevalence.
Patients with LADA still have some endogenous insulin production at diagnosis, experiencing a “honeymoon period” during which partial beta-cell function is maintained. This phase is followed by gradual deterioration in beta cells, eventually leading to insulin dependence months to years later; over 80% of patients require insulin at 6 years.10
CLINICAL PRESENTATION MIRRORS OTHER FORMS OF DIABETES
The initial symptoms of LADA mirror those of other forms of diabetes, and include fatigue, polyuria, polydipsia, blurred vision, weight loss, recurrent infections, and delayed wound healing due to hyperglycemia.
In uncommon cases, patients with LADA may present with diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome. Despite the slow progression of beta-cell failure, acute hyperglycemic crises can occur in the context of physiologic stress, delayed diagnoses, or high-risk medication use.11,12 Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome are characterized by rapid breathing, fruity-smelling breath, nausea, vomiting, abdominal pain, dehydration, headache, altered mental status, or coma.
DIAGNOSTIC CRITERIA
Diagnosing LADA requires careful consideration of clinical and laboratory findings. The following criteria are used, although none are categorical13:
Adult-onset diabetes (age generally ≥ 30 years)
Presence of diabetes-associated autoantibodies (eg, GAD65, IA-2, ZnT8, ICA)
Absence of insulin requirement for at least 6 months after diagnosis.
These criteria reflect the slower progression to insulin dependence in LADA than in type 1 diabetes while emphasizing the autoimmune nature of the disease.
Cutoff values for GAD65 antibody positivity are assay dependent and should be interpreted according to the manufacturer’s reference range; most commercial enzyme-linked immunosorbent assays define a positive result as greater than 5.0 U/mL. Serial monitoring of GAD65 antibodies is not standard because titer fluctuations do not meaningfully correlate with disease activity or progression. In patients with negative GAD65 antibody results, repeat testing is not generally recommended because seroconversion is unlikely. However, patients with high clinical suspicion should be tested for other diabetes-associated autoantibodies (eg, IA-2, ZnT8, ICA).
DIFFERENTIATING LADA FROM TYPE 1 AND TYPE 2 DIABETES
The features of LADA overlap with those of both type 1 and type 2 diabetes mellitus (Table 1).
Features of type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults (LADA)
Compared with type 1 diabetes, which typically presents in childhood or adolescence with acute onset and rapid beta-cell destruction, LADA presents in adulthood and follows a slower course. There is no clear age cutoff, but an age older than 30 years is a commonly cited threshold at which one might start considering LADA as opposed to type 1 diabetes.
While both type 1 diabetes and LADA are associated with positive diabetes-related autoantibodies and a lean phenotype, patients with LADA retain endogenous insulin secretion for a longer time—the honeymoon period. Insulin therapy is necessary at diagnosis of type 1 diabetes, but the need for insulin in LADA is delayed months to years after diagnosis. Genetic susceptibility also overlaps between LADA and type 1 diabetes, with shared HLA haplotypes conferring increased risk for both conditions.5,14
Compared with type 2 diabetes, which patients with LADA are most often misdiagnosed as having, patients with LADA are typically younger at diagnosis (< 50 years old), more likely to have a lean or normal body mass index, and less likely to have insulin resistance or features of metabolic syndrome.15 Patients with LADA also have a higher prevalence of personal or family history of autoimmune disease.
There is also a genetic overlap between LADA and type 2 diabetes; studies have shown an association between the main type 2 diabetes risk locus, TCF7L2, and LADA.14 Unlike type 2 diabetes, LADA is characterized by diabetes-associated autoantibodies, most commonly GAD65.
Not all patients with type 2 diabetes require insulin, but all patients with LADA will gradually progress to insulin dependence. Accordingly, C-peptide levels in LADA are usually low to normal at diagnosis, reflecting partial preservation of beta-cell function, but these decline over time with progression of autoimmune beta-cell destruction.
Given the overlapping characteristics and the need for early identification to guide appropriate management, LADA should be considered in patients with newly or previously diagnosed type 2 diabetes who have a normal or slightly elevated body mass index (≤ 27 kg/m2), were younger at diagnosis (< 50 years), or have a personal or family history of autoimmune disease. Applying these clinical criteria helps selectively identify patients at higher risk for autoimmune diabetes, thereby improving diagnostic yield and reducing unnecessary testing and associated healthcare costs.
Screening for LADA includes a C-peptide and a GAD65 antibody level, but can also include ICA, IA-2, and ZnT8 autoantibody screening if the initial GAD65 autoantibody screen is negative.
MANAGEMENT VARIES BY C-PEPTIDE AND A1C LEVELS
Management of LADA varies by residual beta-cell function and glycemic control. Hemoglobin A1c targets should be individualized: lower than 7% for most adults, lower than 6.5% for younger patients with long life expectancy, and lower than 8% for older adults or those at risk of hypoglycemia. As with any type of diabetes, regular monitoring of hemoglobin A1c every 3 months is recommended, with attention to the patient’s nutrition and concurrent medications (including steroid use).16
C-peptide monitoring and staging
Initial and subsequent C-peptide levels can be used as a surrogate marker of residual beta-cell function to help stratify management and predict insulin dependence (Table 2).13
Recommendations for monitoring and treatment of latent autoimmune diabetes in adults based on C-peptide level
If the C-peptide level is higher than 0.7 nmol/L, beta-cell function is considered preserved. In this group, annual monitoring of C-peptide is recommended, and treatment may include insulin or noninsulin therapies, following an approach similar to that used in type 2 diabetes.
If the C-peptide level is 0.3 to 0.7 nmol/L, the patient has partial beta-cell function. For patients in this range, treatment may still include insulin or noninsulin therapies, but the frequency of C-peptide monitoring should be increased to every 6 months.
If the C-peptide level is below 0.3 nmol/L, beta-cell function is significantly impaired. In these cases, further routine C-peptide monitoring is not necessary, and insulin therapy should be used.
In LADA, C-peptide levels typically decline by less than 0.01 nmol/L per year, but they can decline more rapidly in the first 5 years after diagnosis.17 Residual beta-cell function is influenced by age at onset and GAD65 autoantibody titer elevation: individuals diagnosed at an older age tend to retain greater beta-cell function over time,17 and those with higher GAD65 autoantibody titers at baseline (≥ 180 U/mL) tend to experience a more rapid decline in C-peptide levels.18
C-peptide samples should always be drawn with a concurrent blood glucose level. Fasting, postprandial, and random C-peptide levels can all be used, provided that the accompanying blood glucose value is between 80 and 180 mg/dL.13 Glucose values outside of this range will raise or lower the C-peptide result. Additionally, many pharmacotherapies for diabetes can artificially raise the C-peptide level. Given these confounders of C-peptide level, if glycemic control is worsening and pharmacotherapy needs to be rapidly escalated, suspicion should be high for worsening beta-cell function even if C-peptide levels are still higher than 0.3 nmol/L.
Noninsulin therapies
Early-stage LADA (C-peptide > 0.3 nmol/L) can often be treated similarly to type 2 diabetes while monitoring for disease progression.13 Lifestyle modification is a mainstay, with balanced low-carbohydrate diet, regular physical activity, moderation of alcohol intake, and smoking cessation.8
We have limited evidence with which to compare the utility of noninsulin pharmacotherapies in early LADA. Studies have focused on the impact of medications on beta-cell preservation, which does not necessarily translate to improved blood glucose control or reduced risk of complications, but is thought to delay insulin dependence (Table 3).9,11,13,19–31
Impact of noninsulin antihyperglycemic therapies for beta-cell preservation in latent autoimmune diabetes in adults
Metformin, a biguanide, improves insulin sensitivity but does not delay beta-cell decline. It may be used for glycemic control but has no disease-modifying effect.
Thiazolidinediones improve insulin sensitivity, have anti-inflammatory effects, and may help maintain C-peptide levels, as suggested in small randomized controlled trials.9,19,20 However, they should be used cautiously or avoided in heart failure, as they can cause fluid retention.
Sulfonylureas stimulate pancreatic insulin secretion but accelerate beta-cell decline, according to evidence from randomized trials.20–22 Avoid them in LADA.13
Dipeptidyl peptidase 4 inhibitors increase incretin levels and may increase C-peptide levels and preserve beta-cell function (per pilot and prospective studies).23–28 Consider using them, with potential benefit when combined with vitamin D or insulin.
Glucagon-like peptide 1 receptor agonists increase incretin levels, may preserve beta-cell function (according to early data from randomized controlled trials),29 and provide cardiorenal benefits.30 They are a favorable option for patients with LADA.31
Sodium-glucose cotransporter 2 inhibitors, which prevent renal reabsorption of glucose, offer cardiorenal benefits30 but increase risk of diabetic ketoacidosis.11 Use them cautiously and monitor for diabetic ketoacidosis if the patient is not on concomitant insulin therapy.
Larger, randomized controlled studies would be beneficial to confirm the role of these medications in early LADA treatment.
Insulin therapy
Insulin therapy can be used for LADA management at any C-peptide level, and many experts advocate for consideration of insulin as an initial choice of medication in patients with LADA, though there is insufficient data for this to be a universal recommendation at this time.13 Early exogenous insulin use is effective for blood glucose control, is inexpensive, and has a well-established safety profile. Additionally, starting insulin early may help preserve residual beta-cell function and reduce the risk of future diabetic ketoacidosis, even though data on beta-cell preservation are mixed.32,33 Given the progressive decline in endogenous insulin secretion characteristic of LADA, early insulin therapy should be considered, especially when glycemic targets are not met with noninsulin pharmacotherapies.
Once fasting C-peptide levels fall below 0.3 nmol/L, this is no longer considered early LADA, and insulin therapy is recommended.13,34 When insulin is initiated in LADA, a basal-only or basal-bolus approach could be used, tailored to the individual’s glycemic profile and needs.
Immunosuppressive therapy
Different lines of immune-modulating therapy have been explored to slow down pancreatic beta-cell destruction and progression to insulin dependence. Often, this immunosuppressive therapy targets B- and T-cell activity.35,36 While few studies have been done specifically in people with LADA, therapies that slow the progression of type 1 diabetes will likely have efficacy for LADA as well. The following are examples of such therapies.
Teplizumab-mzwv infusions, aimed at blunting autoreactive T-cell activation and proliferation through binding to CD3, are approved for stage 2 type 1 diabetes (dysglycemia) to slow progression to stage 3 (dysglycemia with clinical symptoms) and have recently also been shown to potentially preserve beta-cell function in those with stage 3 type 1 diabetes.37,38 There may be an additional role for this agent in LADA to delay or prevent the onset of insulin dependence.
GAD-alum, targeting the GAD autoantibody, has also been proposed, and preliminary studies suggest this approach may have merit.39
Vitamin D supplementation may also have immunoregulatory properties leading to a reduced immune response at the pancreas.40
However, at this time, no immunosuppressive therapy has been clearly demonstrated to reduce progression to insulin dependence in LADA or is approved by the US Food and Drug Administration for this indication.
ASSOCIATED COMORBIDITIES
Screening for other autoimmune diseases in patients with LADA should be targeted toward conditions with established associations and clinical relevance. Routine assessment for autoimmune thyroid disease (eg, thyroid-stimulating hormone and thyroid peroxidase antibodies) is recommended.13,41,42 Screening for celiac disease (eg, tissue transglutaminase immunoglobulin A) and pernicious anemia (eg, vitamin B12 levels, and, if indicated, intrinsic factor antibodies) should be considered based on symptoms or risk factors.13,41,42
Broad screening for nonspecific autoantibodies such as antinuclear antibody or rheumatoid factor is not recommended unless there are specific clinical indications.
COMPLICATIONS
Patients with LADA often present with fewer microvascular complications at diagnosis compared with those with type 2 diabetes, likely because they are younger and have had a shorter duration of undiagnosed hyperglycemia.43 However, long-term data suggest that this initial advantage diminishes over approximately a decade; a post hoc analysis of the UK Prospective Diabetes Study showed that people with LADA experienced higher rates of microvascular complications later in the disease course, primarily due to poorer long-term glycemic control.44
Additional registry data indicate that patients with LADA may have the highest rates of nephropathy and neuropathy among all major diabetes types, with prevalence similar to or exceeding that in type 2 diabetes.45
Furthermore, recent cohort studies have associated LADA with increased risks of cardiovascular disease, retinopathy, and all-cause mortality compared with both type 1 and type 2 diabetes.46
Given these findings, patients with LADA should undergo the same regimen of complication screening as recommended for other forms of diabetes, despite their initially milder rate of complications.
TAKE-HOME POINTS
LADA is a distinct autoimmune subtype of diabetes that requires heightened clinical suspicion and early antibody testing for accurate diagnosis.
Clinicians should consider LADA in adults over age 30 who are lean, lack features of metabolic syndrome, or have a personal or family history of autoimmune disease, especially if glycemic control deteriorates rapidly despite oral therapy.
Routine monitoring of glycemic control and pancreatic beta-cell function with measurement of C-peptide levels facilitates timely therapeutic interventions.
Noninsulin therapies may be used selectively during early stages; however, progressive beta-cell failure necessitates transition to insulin therapy to achieve optimal glycemic control and prevent complications.
Referral to an endocrine specialist is appropriate if there is any uncertainty in the diagnosis or management.
Ongoing research into therapies that preserve beta-cell function, including immune-modulating agents, remains a priority for this unique population.
DISCLOSURES
Dr. Lundholm has disclosed consulting for MDCalc (MDCalc.com). Dr. Zhou has disclosed serving as a research principal investigator for NeuroSolutions 100 and teaching and speaking for Xeris.
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