Читать книгу Clinical Dilemmas in Diabetes - Группа авторов - Страница 48

Tertiary prevention is aimed at delaying or preventing the development of complications in subjects who already have T1D. A landmark trial investigating patients with T1D showed that good glycemic control [31] as well as low glycemic variability [32] can reduce the likelihood of microvascular complications leading to blindness or kidney disease, but the trend toward a decrease in macrovascular disease was not statistically significant. Diabetes education of health care professionals and those affected by diabetes plays a key role in the tertiary prevention of the disease. Tertiary prevention is identified by the maintenance of the residual β‐cell function present at disease onset and can be realized by immune suppression or immune modulation since the time of clinical diagnosis of T1D (Figure 2.2).

The best results in this field were obtained 30 years ago with the use of cyclosporine, subsequently abandoned because of transient benefits and undesired adverse effects [33].

In the following years none of the several treatments that have been proposed has obtained appreciable results but for nicotinamide [34] (Table 2.1).

Over the last few decades, there has been growing interest in vitamin D and its active metabolites in relation to T1D and its immune pathogenesis. Vitamin D metabolites have been shown to exert several immunomodulatory effects and 1,25‐dihydroxyvitamin D3 [1,25‐(OH)2D3] can either prevent or suppress autoimmune encephalomyelitis, inflammatory bowel disease, and other autoimmune diseases. Based on this rationale, several interventional and randomized controlled trials evaluated the role for vitamin D in the treatment of T1D, with mixed results.

Previous data in humans have demonstrated that reduction in vitamin D supplementation is associated with a higher risk of the disease, whereas its supplementation is associated with a decreased frequency of T1D [35]. Other authors observed a significant increase in T‐reg cells in T1D patients supplemented with cholecalciferol at different dosages [36, 37]. Similar effects were reported by Treiber et al., who administrated 70 IU/Kg of cholecalciferol daily for 12 months, demonstrating not only the enhancement of the T‐reg cells, but also an increased T‐reg cell suppressive capacity among the supplemented group [38].

Different trials showed a better preservation of residual pancreatic β‐cell function in T1D patients supplemented with different forms of vitamin D (cholecalciferol, alfacalcidiol or calcitriol), as proven by the significantly higher level of fasting C‐peptide and/or lower needed daily insulin dose observed in supplemented groups [37, 39]. However, there are also studies that indicate no significant role for vitamin D in the treatment of T1D. The IMDIAB XI trial was an open‐label randomized trial designed to determine whether supplementation with the active form of vitamin D (calcitriol) at diagnosis of T1D could improve parameters of glycemic control [40]. The secretion of C‐peptide as an index of residual pancreatic β‐cell function was the primary end point, with HbA1c and insulin requirement as secondary end points. The aim of this study was to investigate whether supplementation with the active form of vitamin D (calcitriol) in subjects with recent‐onset T1D, protects residual pancreatic β‐cell function and improves glycemic control (HbA1c and insulin requirement). In this open‐label randomized trial, 70 subjects with recent‐onset T1D, mean age 13.6 ± 7.6 years, were randomized to calcitriol (0.25 microg on alternate days) or nicotinamide (25 mg/kg daily) and were followed up for 1 year. Intensive insulin therapy was implemented with three daily injections of regular insulin + NPH insulin at bedtime. No significant differences were observed between calcitriol and nicotinamide groups in respect of baseline/stimulated C‐peptide or HbA1c 1 year after diagnosis, but the insulin dose at 3 and 6 months was significantly reduced in the calcitriol group. In conclusion, at the dosage used, calcitriol had a modest effect on residual pancreatic β‐cell function and only temporarily reduced the insulin dose [40]. These results were confirmed later by the same group (IMDIAB XIII Trial), who found no effect of calcitriol in protecting β‐cell function in subjects with recent‐onset T1D and high C‐peptide at diagnosis followed‐up for 2 years [41]. Currently, a pilot study (POSEIDON) is investigating the safety and efficacy of a regimen that combines Omega‐3 fatty acids and cholecalciferol in subjects at T1D onset (NCT03406897). Thus, omega‐3 fatty acids have effects on several immunotypes and are known to increase T‐reg cell differentiation. The recruitment is still open.