LADA: Time to Update Diabetes Classification?

The discovery of autoantibodies in T1DM set up an assumption that T1DM and T2DM are two separate disease categories, but is the distinction really that clear? 

A third type of presentation-adult onset autoimmune diabetes-muddies the picture. Between 4-14% of individuals diagnosed with T2DM may have islet cell autoantibodies.¹ However, the lack of clear-cut diagnostic criteria and guidelines in adult onset autoimmune diabetes can make diagnosing and deciding when to start insulin a challenge.

Three nonspecific criteria are usually used to define adult onset autoimmune diabetes: age at diagnosis (which may range from 15-30, all the way up to 70), presence of islet cell antibodies, and need for insulin. Individuals with autoantibodies but without the need for insulin for six months after diagnosis are usually designated as having latent autoimmune diabetes in adults (LADA).¹

While LADA comprises the majority of adult onset autoimmune diabetes cases, LADA patients are often misdiagnosed with T2DM. However, certain clinical features may distinguish LADA patients from those with T2DM. LADA patients are usually younger at diagnosis, have a lower BMI, and better metabolic profiles, including lower triglycerides, higher HDL levels, lower waist-to-hip ratios, and lower blood pressure. They often have lower C-peptide levels and worse glycemic control, with more progressive loss of beta cells and more rapid progression to insulin. Though microvascular complications appear to be similar, LADA patients may have lower risk of nephropathy and an improved CV risk profile than those with T2DM. On the other hand, LADA patients have a higher frequency of thyroid and gastric autoantibodies.^1,2

Compared to childhood onset T1DM, LADA patients usually have less aggressive beta cell loss, lack a tendency toward ketoacidosis, have fewer multiple autoantibodies, and lower titers of islet cell antibodies. While often characterized by human leucocyte antigen (HLA) DR3 and DR4 haplotypes, LADA patients may have lower HLA-associated genetic risk than T1DM patients.^1,2

Studies have suggested that LADA has genetic features of both T1D and T2D, suggesting that LADA may be a genetic admixture of the two. Other factors, such as level of insulin secretion that lies between T1DM and T2DM, may point to LADA as an intermediate disorder.² In addition, levels of glutamic acid decarboxylase autoantibodies (GADA), the dominant autoantibody in LADA (particularly GADA65), may be associated with different presentations. Low-titer individuals appear to be more similar to T2DM patients, while individuals with high titer GADA appear to be more similar to T1DM, with younger age at diagnosis, lower BMI, better metabolic profiles, and greater risk of progression to insulin therapy.¹

Do we need a new classification system? 

Whether or not LADA represents a separate disease entity, or lies on an autoimmune continuum as a slowly progressive form of T1DM, has been a matter of debate. Some experts believe that LADA highlights drawbacks of the current diabetes classification system, pointing to the need for more personalized, precision medicine.³

Recently, Schwartz and colleagues proposed a new beta-centric classification system for diabetes.⁴

In the beta-centric construct, the primary defect in DM lies in the abnormal beta cell, which is influenced by a number of factors such as genetics, the environment, and the immune system. The construct identifies eleven interlocking pathways in the pathogenesis of diabetes, such as systemic low-grade inflammation, changes in gut microbiota, or defects at the level of the stomach or small intestine.

Schwartz and colleagues suggest that the theory would promote precision medicine in DM. Additional diagnostic testing for C-peptide levels, islet cell antibodies, markers of inflammation, and insulin resistance could help pinpoint the damaged pathway(s), and guide treatment accordingly. For example, incretins, anti-inflammatories, or immune modulators may be considered in the case of immune dysregulation. Or probiotics and prebiotics may be helpful in a patient with an abnormal microbiome. 

They recommend the least number of agents that target the greatest number of mediating pathways, while advocating for early intervention, early use of combination therapy, and preferential use of agents that preserve beta cell function. Insulin should be used as add-on therapy rather than substituting for noninsulin antihyperglycemics. And they warn against the use of sulfonylureas and glinides, due to the risk of hypoglycemia and weight gain, as well as high rates of treatment failure and increased risk of CV events. 

They stressed: “[W]e urge that the time is right to convene a committee of diabetes community leaders and researchers to reevaluate the current outmoded DM classification system. Members of the American Diabetes Association, American Association of Clinical Endocrinologists, European Association for the Study of Diabetes, International Diabetes Federation, and World Health Organization should come together to address this immense, but vital, task toward delivering state-of-the-art, optimal patient care and directing future research.”

Take-home Points

• Three nonspecific criteria are usually used to define adult onset autoimmune diabetes: age at diagnosis, presence of islet cell antibodies, and need for insulin.

• Individuals with autoantibodies but without the need for insulin for six months after diagnosis are usually designated as having latent autoimmune diabetes in adults (LADA), the most prevalent form of adult onset autoimmune diabetes.

• Some features of LADA appear to be intermediate between T1DM and T2DM, raising the question of whether it falls on a continuum or represents a separate disease entity, and whether current diabetes classification systems are inadequate.

• Some experts have proposed a beta cell-centric classification system, which may promote personalized, precision medicine in diabetes care.  

References:

1. Laugesen E, et al. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabet Med. 2015 Jul;32(7):843-852.

2. Pipi E, et al. Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus. World J Diabetes. 2014 Aug 15;5(4):505-510.

3. Østergaard JA, et al. Should there be concern about autoimmune diabetes in adults? Current evidence and controversies. Curr Diab Rep. 2016 Sep;16(9):82.

4. Schwartz SS, et al. The time is right for a new classification system for diabetes: rationale and implications of the β-cell-centric classification schema. Diabetes Care. 2016 Feb;39(2):179-86.