What if some patients with diabetes didn’t require insulin therapy? MODY testing could help prevent unnecessary treatment.
Patients with maturity-onset diabetes of the young (MODY) can often have reasonable long-term glycemic control without insulin. Why, then, are they often prescribed insulin regimens? MODY is uncommon, affecting 1-4% of pediatric patients diagnosed with diabetes. The most common type of MODY is glucokinase MODY, which requires no treatment. The other two common types of MODY are hepatocyte nuclear factor 1-α (HNF1A) MODY and HNF4A MODY, both of which have low-dose sulfonylureas as the optimal treatment when pharmacotherapy is necessary. In addition to its low incidence, MODY diagnosis is difficult because no single commonly used clinical criteria separates it from type 1 or 2 diabetes. Islet autoantibodies are widely found in type 1 diabetes but are rarely found in patients with MODY. With the difference in therapy between type 1 diabetes and MODY, a correct diagnosis of MODY leads to improved care, improved outcomes, decreased cost for the patient.
MODY diagnosis is currently based on clinical features that appear at follow-up, rather than a diagnosis of diabetes. This study sought to find the differentiating features of MODY that could be seen at diagnosis so that optimal treatment could be started as soon as possible. In this study, individuals between 1 and 18 years old with a new diagnosis of diabetes were studied across 42 Swedish hospitals, totaling 4,574 young people that were diagnosed with type 1 diabetes. Of these, 3,933 were recruited into the cohort. HbA1c, islet autoantibodies GADA, IA-2A, ZnT8A, and IAA, HLA type, and C-peptide were all collected when the patient was diagnosed. Molecular testing to identify the most common causes of MODY (GCK, HNF1A, and HNF4A) was performed. Most of these molecular tests were requested in patients that were autoantibody-negative. Of the patients who were islet autoantibody negative, 386 of the 462 patients were not clinically tested. Of these, 227 had enough DNA for sequencing that was performed to see if MODY was missed.
When all four autoantibodies were checked, 88% of patients were positive for one or more autoantibody. If only tested for GADA, 49% of patients came back as autoantibody-negative. 17% with GADA and IA-2A, 13% with GADA, IA-2A, and ZaT8A, and 12% with all four autoantibodies tested. Of the auto-antibody positive patients, none were identified with MODY. The most discriminating clinical feature of MODY was a negative test for all four autoantibodies (P = 2*10-44). Other discriminatory features were: lower HbA1c (P = 1*10-20), lower random blood glucose (P = 3*10-19), parental diabetes (P = 3*10-19), and lack of DKA (P = 0.001). This study found that 15% of the 303 autoantibody-negative patients had MODY, resulting in a 1.2% prevalence. Clinical differences between patients with type 1 diabetes and those with MODY included less polyurea and polydipsia as well as weight loss. Looking for an HbA1c of <7.5% in patients who were autoantibody negative identified 78% of patients with MODY. This was best at detecting GCK MODY (29 of 29 patients) but also detected 41% of those with HNF1A and HNF4A MODY (7 of 17). If family history were consulted in patients who were also autoantibody negative, 63% of case subjects with MODY would have been detected, with a similar proportion of patients with GCK and HNF1A/4A. If HbA1c was <7.5% or there was a family history of diabetes, then 96% of case subjects with MODY would have been detected.
With all these different criteria compared, the authors recommend testing for MODY in patients who have an HbA1c of <7.5% and those with a family history of diabetes. HbA1c was both more sensitive and more specific than family history. Of the 46 patients diagnosed with MODY, 91% were not on any insulin and had excellent glycemic control after a mean of 5.9 years after their diabetes diagnosis. Patients with GCK MODY had no treatment; patients with HNF1A or HNF4A MODY were on a diet or a sulfonylurea. Of the patients that were started on insulin therapy, 14 of the 18 patients had stopped once they were diagnosed with MODY. Unfortunately, as this study was based in Sweden, it may not be generalizable to the rest of the world, though the rates of MODY detected in Sweden (1.2% of patients newly diagnosed with type 1 diabetes) is the same as in the U.S. This is the first study that has been done looking at patients at the time of their diagnosis with type 1 diabetes – a major strength of this study.
- The authors of this study recommend testing patients that are autoantibody-negative with an HbA1c of <7.5%.
- Most patients diagnosed with MODY do not need insulin therapy.
- Testing the suggested patients for MODY can result in lower costs of therapy and will avoid unnecessary adverse effects as well as unnecessary treatment.
Carlsson, Annelie, et al. “Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study.” Diabetes Care, American Diabetes Association, 1 Jan. 2020, care.diabetesjournals.org/content/43/1/82.
George McConnell, PharmD. Candidate, LECOM School of Pharmacy