What is LADA (Latent Autoimmune Diabetes in Adults) in diabetes?

What is LADA in Diabetes?

LADA (Latent Autoimmune Diabetes in Adults) is a slowly progressive form of autoimmune type 1 diabetes that occurs in adults and initially presents with features resembling type 2 diabetes but is characterized by the presence of islet cell autoantibodies and eventual progression to insulin dependence over several years. 1

Definition and Clinical Characteristics

LADA is defined by three key diagnostic criteria 2:

• Adult age at onset (typically diagnosed after age 30-35 years) 1, 2
• Presence of circulating islet autoantibodies (particularly glutamic acid decarboxylase antibodies [GADA], protein tyrosine phosphatase antibodies, insulin autoantibodies, or zinc transporter protein antibodies), which distinguishes it from type 2 diabetes 1
• Initial insulin independence at diagnosis (not requiring insulin for at least 6 months after diagnosis), which distinguishes it from classical type 1 diabetes 1, 2

The key pathophysiological feature is autoimmune destruction of pancreatic beta-cells that progresses more slowly than classical type 1 diabetes, with insulin dependence typically developing over a few years rather than weeks to months. 1

Prevalence and Clinical Presentation

• LADA accounts for approximately 5-10% of adults initially diagnosed with apparent type 2 diabetes 1, 3
• Patients often present with a phenotype that appears similar to type 2 diabetes: adult onset, initially responsive to oral agents, and may have some features of metabolic syndrome 1, 3
• However, they typically have lower BMI, fewer metabolic risk factors, and better lipid profiles compared to true type 2 diabetes patients 4

Diagnostic Approach

Testing for islet autoantibodies (particularly GADA) should be considered in adults presenting with diabetes who have clinical features suggestive of autoimmune diabetes 1:

• Younger age at diagnosis (typically <50 years)
• Unintentional weight loss
• Lean body habitus (BMI <25 kg/m²) 1
• Ketoacidosis or rapid progression to insulin requirement
• Personal or family history of autoimmune diseases 1

A critical caveat: routine antibody screening in all adults with apparent type 2 diabetes is not recommended, as the low prevalence of LADA in unselected populations leads to high false-positive rates. 5 Testing should be reserved for those with clinical features suggesting autoimmune diabetes to maintain adequate test specificity 5.

Clinical Course and Prognosis

LADA patients demonstrate poorer glycemic control (higher HbA1c levels) compared to type 2 diabetes throughout follow-up, particularly in those with higher autoantibody titers (LADAhigh). 4

• Progression to insulin dependence is common, with studies showing 30-64% requiring insulin within 2-5 years 6
• Despite having fewer traditional cardiovascular risk factors than type 2 diabetes, LADA carries equal or higher risks of mortality, cardiovascular disease, and diabetic retinopathy 4
• The rate of beta-cell destruction is intermediate between classical type 1 diabetes and type 2 diabetes 3

Management Implications

Evidence suggests that sulfonylureas should be avoided in LADA, as they are associated with earlier insulin dependence and poorer metabolic control compared to early insulin therapy. 6

• Meta-analysis of four studies showed sulfonylureas resulted in significantly worse HbA1c control (mean difference -1.3%, 95% CI -2.4 to -0.1) compared to insulin 6
• Sulfonylureas led to 30% requiring insulin at 2 years versus only 5% with conventional care (P < 0.001) 6
• Early insulin therapy appears to better preserve beta-cell function (measured by stimulated C-peptide levels) compared to sulfonylureas 6

In lean patients presenting with diabetes, measuring GADA titers can aid identification of LADA and encourage more rapid transition to insulin therapy. 1

Important Clinical Pitfalls

• High misdiagnosis rate: Many LADA patients are initially misclassified as type 2 diabetes and treated inappropriately with oral agents that may accelerate beta-cell loss 3
• Heterogeneous population: Current LADA definitions may capture a mixed population including both true autoimmune diabetes and false-positive antibody results in patients with type 2 diabetes 5
• Antibody testing limitations: Islet autoantibodies are not detectable in all patients and decrease with age; approximately 5-10% of type 1 diabetes patients may be antibody-negative 1
• No role for serial antibody monitoring: Repeated measurement of islet autoantibodies has no clinical utility in established diabetes 1