In this issue of the Journal, Lundholm and Zhou1 provide a review of latent autoimmune diabetes in adults (LADA), including the need to consider LADA in adults with diabetes mellitus, approaches to the diagnosis, and recommended strategies for glycemic management. They describe the shared features of type 1 diabetes mellitus and type 2 diabetes mellitus observed in LADA as largely being a result of some genetic overlap among these conditions, and propose generally initiating glycemic management with medications commonly used in type 2 diabetes mellitus, in accordance with published consensus documents.2 Insulin therapy is deferred until there is evidence of declining C-peptide levels or inadequate glycemic control during treatment with other glucose-lowering agents. The authors acknowledge that “many experts advocate for consideration of insulin as an initial choice of medication in patients with LADA” but that “there is insufficient data for this to be a universal recommendation at this time.”
See related article, page 757
This editorial supports the case that insulin therapy should be started at the time of diagnosis in patients with LADA. This recommendation is based on the following general considerations:
LADA is type 1 diabetes mellitus—it has autoimmune features and is characterized by declining beta-cell insulin production that inevitably leads to the need for insulin administration
Insulin therapy has been shown to be associated with benefits on cardiovascular disease in type 1 diabetes mellitus, and early insulin initiation is associated with durable benefits, sometimes called “metabolic memory” or the “legacy effect”
Early insulin use may reduce the risk for diabetic ketoacidosis, especially when diabetic ketoacidosis is associated with sodium-glucose cotransporter (SGLT) inhibitor use
Cost considerations include not only the fact that insulin is inexpensive but also that using insulin at diagnosis of LADA eliminates the need for serial C-peptide testing.
Starting insulin therapy at the onset of disease does not preclude using other therapies that have favorable effects on both glycemic and weight control and have suggested cardiorenal risk benefits.
Insulin dependence is inevitable in LADA
Data from over the past decades have shown that residual beta-cell function in patients with type 1 diabetes is linked to both age at diabetes onset and duration of disease.3–5
Madsbad et al3 compared residual beta-cell function using meal- or glucagon-stimulated C-peptide in 267 patients with onset of type 1 diabetes between 10 and 19.9 years of age and 158 patients with onset between 30 and 30.9 years. Residual beta-cell function was more common in the older age group, suggesting that the older a patient is at diagnosis, the more likely they are to have residual beta-cell function over time.
Family genetic studies in type 1 diabetes from the University of Minnesota reported on meal-stimulated C-peptide values in 171 patients with type 1 diabetes and 272 siblings without diabetes from 169 unrelated families.4 The percentage of patients with type 1 diabetes who had C-peptide values above a predefined post-meal cutoff was consistently higher in older patients, and higher values persisted for type 1 diabetes durations of up to 15 years. C-peptide values in some patients with type 1 diabetes overlapped with values in the siblings without diabetes mellitus.
A more recent large multicenter dataset confirmed these findings, showing residual beta-cell function for more than 40 years after diagnosis in patients diagnosed with type 1 diabetes after age 18.5
These data suggest that residual beta-cell function in type 1 diabetes mellitus may be a continuum across the age range into what is now called LADA. Whereas older patients with type 1 diabetes, including those with LADA, have greater residual beta-cell function, the progressive decline in beta-cell function inevitably requires the need for insulin. There is no current evidence that the presence of genes associated with type 2 diabetes in LADA affect the ultimate need for insulin in LADA.
In Table 1 of their article, Lundholm and Zhou1 report that C-peptide is “very low” in type 1 diabetes. This statement is not entirely accurate. The studies above show that the range of C-peptide levels in type 1 diabetes overlap values currently reported for LADA.3–5 Since residual insulin production in type 1 diabetes is on a continuum, and since insulin therapy is standard treatment for all type 1 diabetes, starting insulin from the time of diagnosis in LADA is a logical consideration.
Early intensive therapy reduces diabetes complications
A case for initiating insulin therapy at diagnosis is supported by data from the Diabetes Control and Complications Trial (DCCT)6 and the Epidemiology of Diabetes Interventions and Complications (EDIC) study,7 a long-term observational follow-up study of the DCCT cohort. These studies were performed exclusively in patients with type 1 diabetes, and the only glucose-lowering therapy used in the DCCT was insulin administered via 2 different strategies. Early intensive insulin therapy with mean hemoglobin A1c reduction to about 7% compared with a conventional insulin approach with a mean hemoglobin A1c of about 9% showed the benefits of glycemic control on the primary endpoint of retinopathy.6 After the DCCT concluded, the 2 treatment groups had similar hemoglobin A1c values.7 Thirty years after trial initiation, the reductions in cardiovascular disease and microvascular complications were consistently lower in the intensive treatment group.8 Data analyses showed that the effect of early intensive insulin therapy was an important predictor of the results.9 Although DCCT participants were younger than the typical patient with LADA, these observations contrast with the results of intensive glycemic therapy trials in patients with type 2 diabetes mellitus10 and provide support for early insulin therapy in the LADA variant of type 1 diabetes.
Insulin can mitigate diabetic ketoacidosis risk
Diabetic ketoacidosis is a serious complication of type 1 diabetes. The seminal observations from Foster and McGarry11 showed that the key regulator of ketogenesis is the glucagon-to-insulin ratio. Low insulin levels favor ketogenesis. Concomitant use of SGLT inhibitors is now well known to be associated with an increased risk for ketosis in type 1 diabetes. Insulin use significantly mitigates the metabolic underpinning for the development of ketosis. In addition, general risk-mitigation strategies recommend maintaining insulin doses to reduce SGLT inhibitor–related diabetic ketoacidosis.12 A rational approach to risk mitigation would be to start insulin at the time of diagnosis. If the addition of an SGLT inhibitor to insulin is deemed clinically appropriate, an important strategy to reduce diabetic ketoacidosis risk would already be in place.
Insulin therapy is simple, effective, and inexpensive
Finally, there are issues of simplicity and cost-effectiveness. Approaches to insulin therapy in type 1 diabetes have been well characterized over the past 100 years. The authors note that insulin is “effective for glucose control, is inexpensive” and has a “well-established safety profile.”1 Each statement is true and supports insulin initiation at diagnosis in LADA. Early insulin initiation also eliminates the clinical burden and costs of C-peptide monitoring to decide when to start insulin therapy.
In summary, a strong case can be made for starting insulin therapy at LADA diagnosis based on mechanisms of disease (progressive insulinopenia), potential cardiovascular and microvascular benefits, insulin’s effect on diabetic ketoacidosis risk, and simplicity and cost considerations.
DISCLOSURES
Dr. Hoogwerf has disclosed ownership interest (stock in a publicly traded company) in Eli Lilly.
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