Treating latent autoimmune diabetes in adults in the era of cardiovascular outcomes trials: Old dog should learn new tricks

Abstract

Background Latent autoimmune diabetes in adults (LADA) is characterised by pathophysiological and clinical heterogeneity. Hence, the optimal treatment strategy for this type of diabetes remains a clinical challenge. Aim To discuss the potential of a modern therapeutic approach for LADA in the context of the novel findings of cardiovascular outcomes trials and stress the controversies surrounding LADA and the barriers in the effective management of people with this type of diabetes. Methods We performed a literature search in major biomedical databases in order to retrieve relevant literature. The results of key studies, along with the authors' clinical experience and perspective, are summarised and discussed in this narrative, mini review article. Results Insulin remains the primary treatment choice in individuals with low C‐peptide levels. Although cardiovascular outcomes trials have mainly recruited participants with type 2 diabetes, recent data suggest that the cardiorenal protective properties of the new therapies are even present in people without diabetes and thus, the extrapolation of their results on LADA individuals sounds reasonable. Therefore, sodium–glucose co‐transporter 2 inhibitors (SGLT2is) and glucagon‐like peptide‐1 receptor agonists should be considered for the management of people with preserved insulin production being at high cardiovascular risk. The risk of diabetic ketoacidosis with SGLT2is requires increased vigilance by treating physicians. Conclusions Individualisation, preservation of beta‐cell mass and function and cardiorenal protection are the new challenges in LADA therapy.

The role of autoimmunity in the pathophysiology of type 2 diabetes: Looking at the other side of the moon

“…Abbreviations: T1D, type 1 diabetes; T2D, type 2 diabetes difficult to be classified. 78,79 Thus, it has been increasingly recognized that there are at least two distinct LADA phenotypes, which also correlate well with GADA titer. GADA high (>10,000 U/ml) present at younger age, have greater glycated hemoglobin (HbA1c) concentrations, lower body weight and C-peptide levels, and higher risk for diabetic ketoacidosis compared with GADA low.…”

“…Recently, an international expert panel suggested an algorithm for the management of hyperglycemia in LADA according to C-peptide levels. 85 The proposed algorithm addresses for the first time the need for cardiorenal protection in LADA, 79 recommending the use of sodium glucose cotransporter 2 inhibitors and/or glucagonlike peptide-1 receptor agonists (GLP-1 RA) in LADA patients with C-peptide levels >0.3 mmol/L and high CV risk, such as those with established atherosclerotic disease, kidney disease or heart failure (HF).…”

“…Whether the above-mentioned differences in complication risk between LADA and classical T2D reflect the role of autoimmunity or derive from dissimilarities between the two groups in the way that hyperglycemia and other risk factors for CV disease (e.g., dyslipidemia) are treated, deserves further evaluation. 79 Taken together, the case of LADA emphasizes the need for collectively evaluating phenotypic and laboratory data before classifying diabetes as autoimmune and planning its therapeutic approach.…”

“…Recent progress in the understanding of the pathogenesis of diabetes has resulted in the introduction of drugs typically considered for T2D treatment into the management of autoimmune diabetes and vice versa, underlying the perception that the border lines between classical diabetes types are becoming less clear than they were in the past. 79 Although the positive effects of hypoglycemic agents on autoimmunity are partially driven by their anti-inflammatory potency, there is evidence that they have parallel effects on the autoimmune process.…”

“…95 Another class of oral glucose-lowering agents, dipeptidyl peptidase-4 (DPP-4) inhibitors, is known to exert immunomodulatory actions and has the potential to improve glycemic control and preserve β-cell mass in autoimmune diabetes. 78,79 Animal research has demonstrated that linagliptin prevents the autoimmune β-cell destruction and improves lumphocyte insulinitis in nonobese diabetic mice. 96 Although the exact mechanisms behind these observations are still unclear, it has been proposed that these agents coordinate a T-cell specific modulation of autoimmunity by downregulating pathogenic Th1 and Th17 cells and inversely upregulating Th2 and Treg cells, finally leading to the amelioration of immune-mediated β-cell damage.…”