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Management of Latent Autoimmune Diabetes in Adults

By Lourdes Cross posted 11-29-2021 10:05

  

Management of Latent Autoimmune Diabetes in Adults
Samantha Copley, PharmD Candidate 2022
Lourdes Cross, PharmD, BCACP, CDCES
Sullivan University College of Pharmacy & Health Sciences

Background

Latent autoimmune diabetes in adults (LADA) is an understudied form of diabetes with features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). According to recent studies, LADA may account for 2%-12% of all diabetes diagnoses in adult populations.1 LADA is a slow-progressing form of autoimmune diabetes.2 Similar to T1D, LADA can occur when pancreatic β-cells stop producing adequate insulin, most likely due to some "insult" that slowly damages those cells. However, unlike T1D, insulin may not be needed for several months to years after diagnosis. Patients with LADA are more likely to experience worse glycemic control and higher A1C levels compared to those with T2D. As the prevalence of diabetes continues to rise, it is important to consider the potential diagnosis of LADA in patients with characteristics associated with this condition.

Diagnostic Tests

While genetic susceptibility suggests an autoimmune component, pathological features of LADA are much closer to T2D. Diagnosis includes blood tests to check for islet cell antibodies (ICA) and glutamic acid decarboxylase 65 (GAD65) antibodies. Patients with high GAD65 antibody titers are more likely to develop insulin dependency. C-peptide, a marker for how much insulin the body makes, is also a key component for a LADA diagnosis. Many patients with LADA are misdiagnosed with T2D and started on non-insulin agents which may be ineffective for these patients as insulin production decreases quickly.2,3

Patients with LADA tend to meet the following criteria:

  • Absence of obesity
  • Over 30 years of age upon diagnosis
  • Unable to manage diabetes with non-insulin medications or lifestyle/dietary modifications

 

Management and Prevention of LADA

Metformin and Thiazolidinediones
Insulin sensitizers such as metformin and thiazolidinediones (e.g., pioglitazone, rosiglitazone) work to lower blood glucose levels by increasing muscle, fat, and liver sensitivity to insulin. These oral medications may eventually be ineffective for a patient with LADA due to a decrease in insulin production. Another limitation to the use of thiazolidinediones is that they are associated with the potential risk of atypical bone fractures, edema, and weight gain.

Sulfonylureas (SU)
Sulfonylureas (e.g., glipizide, glimepiride, glyburide) are not recommended for the treatment of LADA. Sulfonylureas increase the release of insulin from pancreatic β-cells. This mechanism solely depends on functioning β-cells, which is not often present in LADA. There is also an increased risk of hypoglycemia when combining sulfonylureas and insulin therapy.

Dipeptidyl Peptidase 4 Inhibitors (DPP-4i)
Dipeptidyl peptidase 4 inhibitors (e.g., linagliptin, saxagliptin, sitagliptin) are usually well-tolerated agents that may improve glycemic control in patients with LADA. Larger randomized studies are warranted to assess if these agents may preserve insulin secretion.

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)
Sodium-glucose cotransporter 2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) reduce reabsorption of glucose in kidney tubules. A few studies suggest that this medication class may be promising for LADA. The increased risk of ketoacidosis in patients with medium to low C-peptide is a limiting factor to the use of SGLT2is in patients with LADA. Ketoacidosis may be more common in patients who are not overweight (BMI <27 kg/m2).1

GlucagonLike Peptide-1 Receptor Agonists (GLP-1RA)
Glucagon-like peptide-1 receptor agonists (e.g., dulaglutide, liraglutide, semaglutide) have shown beneficial results in terms of improving metabolic control in patients with LADA, unless C-peptide levels are very low. The AWARD trial studied the effect of dulaglutide on glycemic control in a small portion of patients with LADA. Results showed comparable A1C reductions in both populations that were GAD65 antibody positive and negative at 12 months. This data was the first to represent GLP-1RA effectiveness in patients with LADA.4 More evidence is needed for further treatment recommendations.

Insulin
Insulin intervention is effective and safe for patients with LADA. However, it is unknown whether insulin should be administered in the early stages of LADA, especially when substantial residual β-cell function is present. The rationale for early insulin therapy would be to improve glycemic control while protecting β-cells. Long-acting insulin should be the initial choice in early insulin intervention in patients with LADA.

LADA Treatment Algorithm


ASCVD: atherosclerotic cardiovascular disease, BMI: body mass index, CKD: chronic kidney disease,
CVD: cardiovascular disease, eGFR: estimated glomerular filtration rate, GLP-1RA: glucagon‐like peptide-1 receptor agonist, HF: heart failure, SGLT2i: sodium-glucose cotransporter 2 inhibitor, SU: sulfonylurea

Recreated from Figures 1 and 2 in “Management of Latent Autoimmune Diabetes in Adults: A consensus Statement from an International Expert Panel” 1

Conclusion

There are estimates that 4 to 14% of adult patients diagnosed with T2D have insulin antibodies that are diagnostic for LADA.2 Currently, there is no known methodology to prevent LADA. LADA consists of a genetic component which plays a role in the progression of the disease. Early detection, correct diagnosis, and symptom management are important to avoid complications from LADA.

References 

  1. Buzzetti R, Tuomi T, Mauricio D, et al. Management of latent autoimmune diabetes in adults: a consensus statement from an international expert panel. Diabetes. 2020;69(10):2037-2047.
  2. Pozzilli P, Pieralice S. Latent autoimmune diabetes in adults: current status and new horizons. Endocrinol Metab (Seoul, Korea). 2018;33(2):147-159.
  3. Castro R. Latent autoimmune diabetes in adults (LADA): what is it. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/expert-answers/lada-diabetes/faq-20057880. Published 2021. Accessed February 15, 2021.
  4. Pozzilli 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(6):1490-1498.
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