**8. Therapeutic update for DM type LADA**

Currently there is no established intervention for patients with LADA-type DM, despite the fact that they represent a considerable number of patients with diabetes. Considering that these patients present hyperglycemia, there is no doubt that they require specific therapy to control blood glucose levels.

Therefore, there is no doubt that the best therapeutic option in patients with LADA (while trials are expected to prevent the depletion of B cells) is to achieve good metabolic control and prevent chronic complications.

As a cornerstone in the treatment it is important to keep in mind that glycemic control is a strong risk factor for the development of cardiovascular disease in patients with LADA at a higher level than in patients with type 2 diabetes and could be related to the lower prevalence of the metabolic syndrome in the first ones [60].

Different studies show that insulin therapy is the ideal treatment to achieve a better metabolic control in subjects with type LADA DM.

This procedure is useful to reduce the destruction of β-cells when there is a break in their activity, which determines a decrease in the expression of pancreatic antigens in β-cells [3, 61–68].

The application of an early insulin treatment in subjects with LADA who present a discrete insulin secretion is beneficial, and influences the preservation of pancreatic β-cell function. The early and correct identification of the LADA is necessary to define the adequate therapeutic behavior and improve the prognosis of these individuals.

In patients initially diagnosed as type 2 diabetic, a number of therapeutic options are possible that coincide with present available treatments of hyperglycemia.

It is at this moment where conjecturing or establishing a therapeutic goal is a challenge; because alternatives have been sought for the management of our patients, among which are mentioned.

#### **8.1. Sulfonylureas**

with more than 300 patients (5.3% classified as LADA, 70% in insulin therapy), reveals that the risk of developing microvascular complications is similar to diabetic patients type 1 and 2 [55, 56].

It has been observed that the prevalence of microvascular complications in LADA is broadly similar to that observed in patients with type 2 diabetes, however in a small study conducted

It is important to mention that patients with LADA generally have a more favorable cardiovascular risk profile than those with type 2 diabetes. However, to date, different studies have found no evidence of a lower risk of macrovascular disease in patients with DM type LADA [51, 55, 57]. The independent associations of hypertension, hyperlipidemia, obesity and hyperglycemia with macrovascular disease in diabetic patients are well established. Interestingly, hypertension, hyperlipidemia and obesity were less frequent in LADA than in type 2 diabetes [55], but the rates of macrovascular complications were similar. Possible explanations include differ-

Given the autoimmune pathology, patients with LADA may have greater systemic inflamma-

It is a fact that patients with LADA can be treated suboptimally because they often start treatment with insulin later than clinically indicated, due to unrecognized insulin deficiency,

They are also likely to have a shorter duration of treatment with metformin, an oral agent

Although these studies were small, there is no evidence to support a less aggressive treatment

Currently there is no established intervention for patients with LADA-type DM, despite the fact that they represent a considerable number of patients with diabetes. Considering that these patients present hyperglycemia, there is no doubt that they require specific therapy to

Therefore, there is no doubt that the best therapeutic option in patients with LADA (while trials are expected to prevent the depletion of B cells) is to achieve good metabolic control and

As a cornerstone in the treatment it is important to keep in mind that glycemic control is a strong risk factor for the development of cardiovascular disease in patients with LADA at a

detection of specific antibodies and a reluctance to change oral therapies to injections.

associated with a lower rate of ischemic heart disease in the UKPDS [59].

policy for cardiovascular risk factors in patients with LADA.

**8. Therapeutic update for DM type LADA**

**7.2. Diabetes microvascular and macrovascular complications**

by Myhill et al., reported a lower risk of nephropathy [51, 55–57].

ences in pathogenesis or treatment.

30 Diabetes and Its Complications

control blood glucose levels.

prevent chronic complications.

tion, involved in vascular pathology [58].

Beside diet, sulfonylureas are largely used in patients with type 2 diabetes. Sulfonylureas stimulate insulin secretion by promoting closure of the ATP-dependent potassium channels on pancreatic b-cells.

They are effective as blood glucose reducers, however, there is experimental evidence that they can increase the immune response, so they are considered imprudent, as they could accelerate the progression towards insulin dependence [3, 22].

In 1996, Kobayashi and 114 others observed that the administration of small doses of insulin was an effective treatment in individuals with recently diagnosed LADA, which is expressed by a high rate of negative conversion of the AHF and an increase in the levels of C-peptide. In serum, on the other hand, when a sulfonylurea (glibenclamide) is used alone in these diabetics, the persistence of the ICA is maintained and there is a progressive decrease in the levels of C-peptide in the serum.

#### **8.2. Biguanides**

Treatment with metformin has no direct action on the β cell, and it could be indicated in patients with LADA with clinical characteristics of metabolic syndrome or with obesity. This treatment allowed a good control of HbA1c and caused a drastic decrease in insulinemia [69]. In these cases, a combination therapy of metformin with insulin could also be considered.

Nevertheless, one potential problem associated with the use of metformin is the development of lactic acidosis in a patient at high risk of becoming insulin-dependent.

#### **8.3. Glitazones**

Theoretically they could have their value in the treatment, not only to improve the sensitivity of the insulin but also to exert an anti-inflammatory effect that would favor the preservation of the β cell mass [2, 70].

**9. Conclusions**

**Author details**

**References**

Javier Eduardo Escober Torres

2016;**39**(Suppl 1):S13-S22

2005;**54**(2):62-67

tion. Diabetes Care. 2001;**24**:1460-1467

mellitus. Diabetic Medicine. 2008;**25**:117-125

Address all correspondence to: jetorres.9307@gmail.com

Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras

**9.1. Summary: knowledge and uncertainty**

**9.2. Summary: knowledge and uncertainty**

Patients with DM type LADA are more likely to have lower C-peptide, associated with fewer signs of metabolic syndrome; higher levels of HbA1c, faster progress to insulin therapy. It is not yet clear how DM type LADA is associated with the loss of insulin secretion capacity.

Latent Autoimmune Diabetes in Adults http://dx.doi.org/10.5772/intechopen.72685 33

There are no clear clinical features that distinguish autoimmune diabetes from type 2 diabetes. However, there is a tendency for adult patients with GADA, even when they do not require insulin, being younger at the time of diagnosis and thinner with a greater tendency to progress to treatment with insulin. Within a cohort of positive GADA adult patients, the GADA title and the number of LADA patients impact the clinical and biochemical differences

[1] American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care.

[2] Stenstrom G, Gottsa A, Bakhtadze E, Berger B, Sundkvist G. Latent autoimmune diabetes in adults: Definition, prevalence, cell function, and treatment. Diabetes. 2005;**54**(2):68-72

[3] Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): Definition, characterization, and potential preven-

[4] Fourlanos S, Dotta F, Greenbaum C, Palmer J, Rolandsson O, Colman P, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia. 2005;**48**:2206-2212

[5] Van Deutekom A, Heine R, Siemsek S. The islet autoantibody titres: Their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes

[6] Palmer J, Hampe C, Chiu H, Goel A, Brooks-Worrell B. Is latent autoimmune diabetes in adults distinct from type 1 diabetes or just type 1 diabetes at an older age? Diabetes.

of type 2 diabetes. The clinical phenotype should drive the management strategy.

There is interesting evidence that glitazones increase insulin synthesis and the insulin content of islet cells as well as improve the secretory response of islets [71].

Zhou and others have demonstrated the efficacy of treatment with rosiglitazone in combination with insulin, which helps preserve the function of the cell compared to insulin alone in LADA [2, 70, 71].

Sitagliptin is a potent DPP-4 inhibitor which results in the delay of degradation of incretin hormones (glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP)), thereby improving beta-cell function and resulting in better glycemic control in patients with T2D.

Recent studies demonstrate that the use of sitagliptin in individuals with T1D improved overall the glycemic control and reduced insulin requirements without altering the amount of endogenous insulin production [72].

A prospective study of 1-year duration demonstrated maintenance of beta-cell function through the administration of sitagliptin in patients with recent-onset LADA [73]. A similar study proved that c-peptide secretion and glycemic control was improved by the use of another DPP-4 inhibitor, saxagliptin, versus placebo in LADA patients [74, 75]. All these accumulating evidences support the hypothesis that this may be a class effect; however, further studies are required.

#### **8.4. Potential strategies for preventing b-cell destruction in LADA**

A clinical trial showed that insulin therapy was the best treatment in this type of diabetic, and that the use of glibenclamide produced a persistence of the ICA (the ICA persisted in 100% of the subjects with LADA treated with glibenclamide + insulin), and that its exclusion decreased the presence of these antibodies (the ICA disappeared in 75% of the individuals with LADA treated only with insulin) [76, 77].

The use of glibenclamide or another sulphonylurea is not recommended in the treatment of these patients or their combination with insulin [65, 66], since it could contribute to the persistence of the autoimmune process and the probable progressive destruction of pancreatic cells.

Finally, a meta-analysis on pharmacological treatment [71], with a total of 8 publications (735 patients), concludes that:

