Abstract: Searches identified 13,306 citations. Fifteen publications (ten studies) were included, involving 1019 participants who were followed between three months to 10 years (1060 randomised). All studies had a high risk of bias. Sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone at three months (one study, n = 15) and at 12 months (one study, n = 14) of treatment and follow-up. SU (with or without metformin) gave poorer metabolic control compared to insulin alone (mean difference in glycosylated haemoglobin A1c (HbA1c) from baseline to end of study, for insulin compared to oral therapy: -1.3% (95% confidence interval (CI) -2.4 to -0.1; P = 0.03, 160 participants, four studies, follow-up/duration of therapy: 12, 30, 36 and 60 months; however, heterogeneity was considerable). In addition, there was evidence that SU caused earlier insulin dependence (proportion requiring insulin at two years was 30% in the SU group compared to 5% in conventional care group (P < 0.001); patients classified as insulin dependent was 64% (SU group) and 12.5% (insulin group, P = 0.007). No intervention influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5)). In a five year follow-up of GAD65 (glutamic acid decarboxylase formulated with aluminium hydroxide), improvements in fasting and stimulated C-peptide levels (20 μg group) were maintained after five years. Short term (three months) follow-up in one study (n = 74) using Chinese remedies did not demonstrate a significant difference in improving fasting C-peptide levels compared to insulin alone (0.07 µg/L (95% CI -0.05 to 0.19). One study using vitamin D with insulin showed steady fasting C-peptide levels in the vitamin D group but declining fasting C-peptide levels (368 to 179 pmol/L, P = 0.006) in the insulin alone group at 12 months follow-up. Comparing studies was difficult as there was a great deal of heterogeneity in the studies and in their selection criteria. There was no information regarding health-related quality of life, complications of diabetes, cost or health service utilisation, mortality and limited evidence on adverse events (studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic episodes). Two studies show SU leading to earlier insulin dependence and a meta-analysis of four studies with considerable heterogeneity showed poorer metabolic control if SU is prescribed for patients with LADA compared to insulin. One study showed that vitamin D with insulin may protect pancreatic beta cells in LADA. Novel treatments such as GAD65 in certain doses (20 μg) have been suggested to maintain fasting and stimulated C-peptide levels. However, there is no significant evidence for or against other lines of treatment of LADA.

Plain-language summary: We identified 15 publications (10 studies) looking at 1019 patients who were followed between three months to 10 years. We found many of the publications had poor quality of reporting and had small numbers of participants. However, there does seem to be evidence from this review that the drug sulphonylurea (like glibenclamide or glyburide, gliclazide) could make patients insulin dependent sooner and it does not control blood sugar as well as insulin. Therefore, this suggests that this drug should not be a first line treatment for patients with LADA. In addition, insulin combined with vitamin D, or Chinese herbs may maintain natural insulin production better than insulin alone. Similarly, glutamic acid decarboxylase (GAD65) may maintain natural insulin production. However, there was no conclusive evidence that any of the other remaining treatment methods were better than each other. Studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic attacks. This review represents very early days of our understanding of the best way to treat LADA. It is limited by the poor reporting quality of the studies, small sample sizes, no clear single definition of LADA and many of the studies being carried out in different ethnic groups (China, Japan, Cuba, UK, Sweden) with different clinical care systems.  None of the publications reported on complications of diabetes, health-related quality of life, costs or health service utilisation. All but one of the publications reported there were no deaths.  In summary, this review demonstrates that insulin treatment may be preferable compared to sulphonylurea treatment but there is little evidence regarding other forms of treatment. Future studies are needed, should have a clear definition of LADA, investigate patient-important outcomes and use a common method of measuring stimulated C-peptide (a marker of natural insulin production reflecting improved beta-cell function of the pancreas).