By definition, LADA patients have functioning β-cells at diagnosis indicating that it is imperative to implement therapeutic strategies targeted to improve metabolic control but also to preserve the insulin-secreting capacity (53). To make a proposal for treatment of LADA, the panel reviewed current clinical trial data and reiterated the conclusions of the Cochrane Review regarding lack of good-quality, large-scale, controlled trials with long-term follow-up (54). As mentioned earlier, the criteria used to define LADA are shown in Table 1. Of note, our proposal only applies to patients who initially were considered not to need insulin.
Hypoglycemic Agents
Insulin Sensitizers (Metformin, Thiazolidinediones).
The majority of LADA patients are clinically diagnosed as having T2D and treated initially with metformin before they are identified as having LADA. The panel concluded that although there is little evidence for the use of metformin, there is no evidence against its use. Metformin can increase insulin sensitivity in T1D (55) without evidence that it could improve long-term glycemic control; in addition, it might reduce weight, LDL cholesterol levels, and the risk of atherosclerosis progression (56). Results from ongoing clinical trials, investigating the effects in LADA patients of monotherapy/adjunct metformin on metabolic control, β-cell function, and tolerability, will provide more evidence on the precise role of metformin.
In a small study (n = 23 patients), thiazolidinediones (TZD), when combined with insulin, preserved β-cell function in LADA, although the study needs to be replicated (57).
In a four-arm, randomized trial performed in 54 Chinese subjects, LADA patients were assigned to either sulfonylurea (SU) (n = 14) or rosiglitazone (n = 15) therapy if GADA was <175 units/mL and fasting C-peptide was >0.3 nmol/L. While fasting C-peptide was not different between the two groups, C-peptide levels post–oral glucose and delta C-peptide were higher with rosiglitazone as compared with the SU group after 18 months and up to 36 months (P < 0.05 for all comparisons) (58).
The panel concluded that there is limited evidence supporting the use of metformin and few studies using TZD, so the efficacy of both compounds appears inconclusive. For TZD, the potential risk of atypical bone fractures, macular edema, and weight gain could be a limitation to the use of these compounds.
Insulin.
While therapy with insulin is essential in all cases with undetectable C-peptide, patients diagnosed with LADA have, by definition, residual β-cell function and, in general, slow progression toward insulin dependency. A major question is whether insulin therapy should be the initial treatment for LADA (59). There are no data from large randomized, controlled trials with sufficient length of follow-up to draw a conclusion. A Japanese randomized trial comparing insulin (n = 30) with an SU (n = 30) over a 5-year period showed significantly better integrated C‐peptide response with insulin. Thus, in the insulin-treated group, progression to insulin-requiring diabetes was lower compared with SU (P = 0.003) (60). On the other hand, Thunander et al. (61) concluded that early insulin treatment for LADA did not lead to preservation of β-cell function (n = 37), although it was well tolerated and resulted in better metabolic control (in the control group but not in the insulin-treated group, HbA1c increased significantly at 36 months compared with baseline [P = 0.006], while C-peptide decline was progressive, irrespective of age, sex, BMI, HbA1c values, and autoantibody levels). Interestingly, UKPDS found that 11.6% of patients were autoantibody-positive and that they tended to require insulin treatment sooner, irrespective of other allocated therapy (4,62). The data available, although limited, indicate that insulin intervention is effective for metabolic control in LADA patients. However, it remains to be established whether insulin should be administered at an early stage of the clinical disease or whether it is the optimal therapy regardless of the stage of the disease process. Further studies are needed to clarify the impact of insulin therapy and the optimum time for intervention.
The panel concluded that insulin intervention is effective and safe for LADA patients; however, it still remains to be established whether insulin should be administered in the early stages of LADA, especially when substantial residual β-cell function is present.
Sulfonylureas.
As with previous agents discussed, there is limited evidence to suggest the efficacy of SU in subjects with LADA (19). In a multicenter, randomized, nonblinded clinical study, Japanese patients with LADA, randomized to insulin or glibenclamide (n = 30 in each group), were followed for up to 5 years. During follow-up, the SU group had worse metabolic control and a more rapid decline in C-peptide level compared with the group treated with insulin (P = 0.005) (63). More recently, a post hoc exploratory analysis of a small subgroup of LADA patients (n = 38), enrolled in a randomized, controlled trial comparing glimepiride and linagliptin (n = 21 linagliptin, n = 17 glimepiride) at 28 weeks as add-on therapy to metformin in T2D, revealed that despite similar glycemic efficacy, fasting C-peptide at 28, 52, and 104 weeks decreased in patients treated with glimepiride. Conversely, an increase in C-peptide level was observed in those subjects treated with linagliptin; the difference between groups was significant at 28 and 58 weeks (P < 0.01 for all comparisons) (64). As previously described, in a four-arm pilot, randomized, controlled trial performed in 54 Chinese subjects with LADA, comparison of 3-year follow-up data between subjects treated with SU (n = 14) showed a lower delta C-peptide as well as C-peptide after 2-h 75-g glucose load compared with patients treated with rosiglitazone (n = 15) (P < 0.05 for all comparisons), with no differences in glycemic control (58). Overall, the current data are inconclusive, but it cannot be excluded that treatment of LADA with SU results in a decreased insulin secretion. SU are not therefore recommended for the treatment of LADA, nor are they generally recommended as first-line therapy for T2D.
The panel concluded that sulfonylureas are not recommended for the treatment of LADA, as deterioration of β-cell function as a consequence of this treatment cannot be ruled out.
Dipeptidyl Peptidase 4 Inhibitors.
Small clinical trials with dipeptidyl peptidase 4 inhibitors (DPP‐4i) in patients with LADA suggest that this class of hypoglycemic agents might improve glycemic control and preserve β‐cell function with a good safety profile compared with placebo, glimepiride, and pioglitazone (64–66). In a post hoc analysis of pooled data from five randomized, placebo-controlled studies (n = 2,709), saxagliptin improved β-cell function as assessed by HOMA2 of β-cell function and postprandial C-peptide from baseline in both GADA-positive (n = 98) and GADA-negative subjects (n = 1,849) (67). A recent study (68) compared the outcome of glucagon-stimulated C-peptide tests after 21-month treatment with either insulin or sitagliptin in GADA-positive LADA patients (n = 64) without any clinical indication for insulin treatment less than 3 years from diagnosis. The metabolic control during intervention did not differ between the two treatment arms, and post-intervention β-cell function was similar in the insulin- and sitagliptin-treated patients. Of note, the stimulated C-peptide response deteriorated significantly more in the group with high GADA level compared with the group with low level regardless of the treatment. Another small study (n = 30) found that sitagliptin, as an add-on treatment to insulin, had a beneficial effect on C-peptide decline compared with insulin alone (65).
Moreover, a recent trial evaluated the effect of saxagliptin in combination with vitamin D3 in subjects with LADA with promising results (69). Although these studies have several limitations (i.e., post hoc analyses, small sample size, short periods of follow-up, interstudy heterogeneity), DPP-4i agents represent a potential therapeutic alternative for effective management of LADA.
The panel concluded that DPP-4i may improve glycemic control in LADA patients with a good safety profile. Larger randomized studies are warranted to prove that DPP-4i might preserve C-peptide secretion.
Sodium–Glucose Cotransporter 2 Inhibitors.
Sodium–glucose cotransporter 2 inhibitors (SGLT2i) improve glycemic control without hypoglycemia and are currently used for the management of T2D. Although no interventional studies have been conducted in LADA patients, international, multicenter, randomized clinical trials in over 5,000 T1D patients confirm the efficacy and safety of adding SGLT2i to existing insulin regimens (70–77). One SGLT2i, dapagliflozin, has been recently approved by the European Medicines Agency for use in adults with T1D with BMI of at least 27 kg/m2 who failed to achieve adequate glycemic control despite optimal insulin therapy. However, in the U.S., the use of SGLT2i in T1D still remains off-label. The approval was based on data from phase III DEPICT clinical program (70). SGLT inhibition confers additional benefits in terms of HbA1c reduction, reduced glucose variability, small reduction in weight, and reduced total daily insulin doses without increasing the risk of hypoglycemia. However, there is an increased risk of ketoacidosis, often not associated with hyperglycemia, especially in patients not overweight (BMI <27 kg/m2). This feature is of special importance in those LADA patients with medium to low C-peptide levels and not on insulin, considering their increased risk of developing insulin deficiency. Treatment with SGLT2i might mask the signs of progression to insulin deficiency (often presenting as postprandial hyperglycemia) and yet increase the risk of ketoacidosis; therefore, patients should be advised to monitor for ketosis, i.e., measure ketonemia and ketonuria regularly, even daily, as recommended (78), and to discontinue SGLT2i prior to scheduling surgical procedures or exposure to metabolically stressful conditions associated with potential symptoms or signs of ketoacidosis.
The panel concluded that the approved use of SGLT2i in both T2D and selected T1D patients, in particular those overweight, suggests that they may be promising agents in LADA. However, no studies have been performed in LADA and attention should be paid to ketoacidosis in patients with medium to low C-peptide.
Glucagon‐Like Peptide 1 Receptor Agonists.
Glucagon‐like peptide 1 receptor agonists (GLP‐1RA) reduce hyperglycemia (with low rates of hypoglycemia), reduce and maintain weight control, and may suppress appetite, reduce food intake, and slow gastric emptying. A post hoc analysis of pooled data from three randomized phase III trials (AWARD-2, -4, and -5; patients with GADA assessment) indicated that dulaglutide is effective in reducing HbA1c in LADA patients. Dulaglutide treatment resulted in a comparable decrease in HbA1c values in GADA-negative (−1.09%) and GADA-positive (−0.94%) patients at 1 year post-diagnosis, and it appears to be slightly more effective in LADA patients with low autoantibody levels compared with those with high autoantibody levels (79). However, as expected, there was a reduced glycemic response to GLP-1RA analogs (exenatide/liraglutide) in a small patient group (n = 19) with diabetes-associated autoantibodies and low fasting C-peptide levels (≤0.25 nmol/L) (80). Large-scale, prospective, randomized trials with long-term follow-up are required to confirm the efficacy of GLP‐1RA in preserving metabolic control and delaying progression to insulin dependence in LADA.
The panel concluded that GLP-1RA have shown beneficial results in terms of improving metabolic control in LADA patients unless C-peptide levels are very low. These drugs are approved in T2D and in insulin-treated patients, but more evidence is required in patients with LADA.
Immune Intervention
There is only one immune intervention study in LADA patients. Alum-formulated recombinant GADA (GAD-alum) was used in a small phase 2 study that was placebo-controlled with dose escalation in GADA-positive non–insulin-requiring patients (n = 47), who received subcutaneous injections of GAD-alum in different doses (81). The primary outcome was safety as assessed by neurological tests, medication use, and β-cell function evaluated over 5 years, representing the end of the trial (82). No severe study-related adverse events occurred during the 5-year follow-up, and active treatment was not associated with increased risk of starting insulin treatment compared with placebo. After 5 years, fasting C-peptide levels declined in the placebo group compared with the two highest dose intervention groups. The authors concluded that in this small study, the primary outcome of safety was achieved, with evidence of a beneficial effect on β-cell function. A more extensive trial is required before such treatment can be recommended and is currently under way.
The panel concluded that current data on immune intervention in LADA are very limited, and more extensive phase 2 studies are required before drawing any conclusions.
Lifestyle Modifications
LADA is associated with factors that favor insulin resistance and T2D, including low birth weight, overweight/obesity, physical inactivity, smoking, and consumption of sweetened drinks (12). The role of obesity and insulin resistance as risk factors for LADA is abundantly documented (83). It may therefore be possible to treat LADA by a combination of lifestyle changes much as is done in T2D. Among these, medically assisted weight loss if necessary, increased physical activity, and cessation of smoking should be promoted. Thus, intervention studies examining the role of lifestyle factors in the development of LADA are necessary, as our current knowledge is hampered because the small number of studies were conducted exclusively in Scandinavian populations (83).
The panel concluded that lifestyle modifications are important in treatment of T2D. Intervention studies examining the role of weight reduction and physical activity in the development of LADA are required.
