Latent Autoimmune Diabetes of Adults
Authors: Dorothy Holzum, PharmD Candidate 2018,
St. Louis College of Pharmacy
Weston Thompson, PharmD, LCDR, BCPS, NCPS
Latent autoimmune diabetes of adults (LADA) is an intricate subset of diabetes that is complex and difficult to diagnosis. The American Diabetes Association (ADA) does not specify LADA as a separate diagnostic entity with confirmed treatments. As a result, the exact prevalence of LADA is unknown. However, 10% of patients in the United Kingdom Prospective Diabetes Study (UKPDS) trial most likely met criteria for LADA, totaling around 500 patients.1
Patients with LADA present with symptoms of type 2 diabetes, including BMI > 30 kg/m2, adult onset, and comorbidities including hypertension and hyperlipidemia. However, they also test positive for a glutamic acid decarboxylase (GAD) antibody, which resembles type 1 diabetes.1-5
While it can be difficult to clinically diagnose LADA based on patient symptoms and history on presentation, there are three set diagnostic criteria that a patient must have in order to be diagnosed with LADA. Patients first must have a GAD antibody. The GAD acts as an autoantigen, which provokes the generation of antibodies. The patient’s T cells mistakenly identify beta cells in the pancreas as foreign and thus produce antibodies to destroy the beta cells. This is consistent with type 1 diabetes. In addition, patients present with diabetes at an older age, specifically over the age of 18 years. Finally, patients must have retention of their beta cell function, meaning they will not require insulin for at least six months. The last two characteristics are consistent with type 2 diabetes.1,2
There are two subsets of LADA, based on bimodal distribution of GAD titers. Patients that have high GAD titers will resemble type 1 diabetics, as they are younger and leaner.6 These patients generally have higher A1c levels and lower C-peptide levels. On the other hand, patients with low GAD titers will resemble type 2 diabetics, as they are older and have a high BMI.6,7
The pathophysiology of LADA is a combination of the autoimmune destruction of pancreatic beta cells, which leads to insulin deficiency, as well as insulin resistance. Insulin resistance is the result of several risk factors including age > 45 years, BMI > 25 kg/m2, and habitual physical inactivity. Due to these risk factors, the body’s normal response to a given amount of insulin is reduced. As a result, higher levels of insulin are needed in order for insulin to have its proper effects.6,8
Patients can present with polydipsia, or increased thirst, polyuria, or increased urination, polyphagia or increased hunger, or they can be asymptomatic. Laboratory tests will show a positive GAD antibody and elevated blood glucose levels. Patients can progress into diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome and develop microvascular complications including retinopathy, peripheral neuropathy, and nephropathy, as well as macrovascular complications including peripheral artery disease and cerebrovascular disease.1
Currently there is not an established therapeutic regimen for the treatment of LADA. Ultimately, treatment is tailored to preserve beta cell function as long as possible. Clinical trials are difficult to design because there is not a gold standard method to measure beta cell mass.1 A few studies have shown sulfonylureas are harmful in LADA patients, causing them to require insulin at an accelerated rate.9 Sulfonylureas stimulate the pancreas to secrete insulin. This stimulation causes an increased autoantigen expression, which further augments the autoimmune process in LADA patients.1 Thus, sulfonylureas should not be used in LADA patients. If the patient is still secreting some insulin, metformin is the first line medication, as it is the only medication shown by the UKPDS trial to decrease the development of macrovascular complications.9 Metformin should be titrated to a maximum of 2,000 mg per day and then all other oral antidiabetic therapies should be maximized.6 Once all oral therapies are at the maximum dose and the patient is still not at their A1c goal, insulin must be initiated.5
The goals of therapy for LADA include reducing the risk of any acute complications and preventing micro and macrovascular complications. Blood sugars should be treated to an A1c of < 7%, FPG 80-130 mg/dl and PPG < 180 mg/dl per the ADA guidelines. There are some circumstances where a patient’s goal A1c is only < 8%, particularly in elderly patients with a decreased life expectancy or if the patient has several episodes of hypoglycemia when trying to treat their A1c to < 7%. On the other hand, there are some patients whose A1c goal will be < 6.5%, specifically if the patient is young and the goal can be obtained without significant hypoglycemia. Furthermore, for non-pharmacological treatment, patients should be educated about the disease state, the importance of keeping their blood sugars controlled, and signs of hypo and hyperglycemia. Medical nutrition therapy, a nutrition assessment to evaluate a patient’s nutrition intake and metabolic status should also be recommended. Furthermore, patients should get 150 minutes of exercise per week and check their blood sugars regularly, which is different for every patient.10
In conclusion, LADA is a subset of diabetes where patients present with symptoms of type 2 diabetes, however they also have a positive GAD antibody. These patients will require insulin sooner than traditional type 2 diabetes patients.1 Pharmacists must address barriers to insulin therapy early in LADA patients. In addition, robust clinical trials are needed to determine the appropriate treatment that will lengthen the beta cell function in these patients.
References: 1. Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care. 2009;32(2):246-252.
2. Laugesen E, Ostergaard JA, Leslie RD. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. DIABETICMedicine. 2015;32(7):843-852.
3. Hernadez M, Lopez C, Real J, et al. Preclinical carotid atherosclerosis in patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes. Cardiovasc Diabetol. 2017;16:94:1-9.
4. Grant SA, Hakonarson H, Schwartz S. Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocrine Reviews. 2010;31(2):183-193.
5. Stenstrum G, Gottsatter A, Bakhtaedze E, et al. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes. 2005;54(2):68-72.
6. Yang Z, Zhou Z, Li X, et al. Rosiglitazone preserves islet beta-cell function of adult-onset latent autoimmune diabetes in 3 years follow-up study. 2009;83:54-60.
7. Lu J, Hou X, Pang C, et al. Pancreatic volume is reduced in patients with latent autoimmune diabetes in adults. Diabetes Metab Res Rev. 2016;32:858-866.
8. Grant SA, Hakonarson H, Schwartz S. Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocrine Reviews. 2010;31(2):183-193.
9. Brophy S, Brunt H, Davies H, et al. Interventions for latent autoimmune diabetes (LADA) in adults (review). Cochrane Database of systematic Reviews. 2007;3:1-3.
10. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2017;41(Supplement 1). doi:10.2337/dc18-s002.