Discussion
adult-onset type, LADA, ’, adult-onset diabetes, Autoimmune diabetes, adult-onset type 1 diabetes, diabetes
TYPE 1 DIABETES, DISEASE, RECRUITMENT, AUTOIMMUNITY, AUTOIMMUNE DIABETES, TYPE 2 DIABETES, LACK OF VITAMINS, DIABETES
In this randomized controlled trial with 24-month follow-up, saxagliptin and vitamin D when added to the conventional regimen including metformin and insulin, resulted in improved endogenous pancreatic β-cell function, as indicated by the 2-h C-peptide AUC and decreased exogenous insulin requirement. The protective effect of saxagliptin and vitamin D was most prominent among patients with higher GADA level, who usually have a more rapid decline in β-cell function. This study provides the first clear evidence that an adjunctive combination of saxagliptin and vitamin D to insulin and metformin can be valuable in the management of adult-onset type 1 diabetes. Given the paucity of data in this field, and the uncertainty regarding optimal therapy, our data provide evidence of the beneficial effects of even modest preservation of C-peptide for saxagliptin combined with vitamin D, and deserves further study.Although stimulated C-peptide levels have been considered as a gold standard of β-cell function evaluation in type 1 diabetes trials,This current study showed that saxagliptin alone led to a non-significant C-peptide preservation compared with conventional therapy. Findings from previous small trials of DPP-4 inhibitors in LADA have been conflicting,Our findings that adjunctive vitamin D to saxagliptin monotherapy seems to enhance treatment effect indicated a valuable effect of vitamin D on C-peptide preservation. Due to the lack of vitamin D monotherapy arm, the contribution of each component in the combination therapy is unclear. But given that saxagliptin alone showed a non-significant trend of benefits towards C-peptide preservation, we speculate that both vitamin D and saxagliptin might contribute to the efficacy of combination therapy. The effect of vitamin D as monotherapy on C-peptide is not clear. Pre-clinical studies showed a pleiotropic role in islet autoimmunity. Vitamin D supplementation prevented diabetes accompanied with reduced inflammatory CD8 + T cells and increases regulatory T cells in NOD mice,Autoimmune diabetes is highly heterogeneous in clinical features and autoimmunity.The strengths of this study include its rational design of combination therapy, large sample size, completeness of long-term follow-up for clinical examinations and MMTT tests, as well as centralized repeated measurements of C-peptide, 25(OH)D and GADA. Moreover, the overall adherence was high, and the use of outside-of-trial vitamin D supplements was similarly low across three groups (two, five and six participants in the saxagliptin plus vitamin D group, the saxagliptin alone group and in the conventional therapy received additional vitamin D3 or calcitriol, respectively). The large sample size enabled evaluation with substantial statistical power for treatment efficacy, even within a range of study subgroups. Importantly, saxagliptin did not lead to an inferior response here compared with conventional treatment. Given that, insulin aside, there is no other therapy approved for such cases of autoimmune diabetes, our trial suggests oral saxagliptin and vitamin D should be considered.Several limitations in this study should be mentioned. Firstly, we did not include an arm of vitamin D monotherapy given the difficulty in recruitment, so we are unable to make any conclusions about the efficacy of vitamin D and the contribution of each individual component of the combination therapy. Secondly, the homogenous population of Asian participants in this study may limit generalizability of these findings to other ethnic groups. Our findings should be re-examined in other populations of different ethnic/racial participants. Third, it is recognised that a proportion of cases with autoantibody positive adult-onset diabetes cases may have a false positive autoantibody test, for example up to 20% of cases in our study might have type 2 diabetes with a false positive GADA. However, our results remained unchanged after excluding patients with transient positive GADA. Two observations further suggest that false positivity is not relevant to our broad conclusion. First, the optimum response to saxagliptin and vitamin D was in those with the highest, not lowest, level of GADA. Second, our cases largely had C-peptide in the category designated type 1 diabetes or ‘uncertain classification’ in the recent reports.In conclusion, oral saxagliptin and vitamin D added to conventional therapy regimen ameliorated pancreatic β-cell function loss in patients with adult-onset type 1 diabetes, especially those with high GADA levels. This large-scale trial demonstrated an effective and novel approach to broaden current treatment strategies in cases with adult-onset type 1 diabetes, including LADA, and provides additional evidence for precision medicine in the management of this disease.