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Secondary failure is defined as a deterioration of glucose control in patients with Type 2 diabetes on oral antidiabetic drugs (OAD), mainly due to the progressive decline in beta-cell function and reduction in insulin secretion. The consequent hyperglycemia is the most important determinant for the development of microvascular and macrovascular complications, so that an early recognition of this phenomenon can improve long-term outcomes. The recent lowering of target glycosylated hemoglobin (HbA1c) levels by international guidelines not only emphasises the importance of tight glycemic control, but also means that secondary failure to OAD will occur much sooner and is almost unavoidable. Accordingly, in the last years, new different therapeutic strategies were explored to improve the treatment of this condition. The aim of this review is to examine current approaches for treating patients with secondary failure, barriers to achieving and maintaining glycemic control, and recent evidence for emerging therapies which may represent a valid therapeutic option in subjects failing on oral hypoglycemic agents by acting mainly, but not only, at a beta-cell level. In particular, we will focus on the co-administration of OAD plus a novel drug class known as incretin mimetics (e.g. exenatide and liraglutide), which target insulin secretion, and on thiazolidinediones, which act on insulin resistance. Only incretin-mimetics have a lowering HbA1c action, due to the improvement in beta-cell function, which is coupled to significant weight loss. Even if these new options seem to improve the outcome of secondary failure, further investigation is needed to confirm positive results in the long term.

Current strategies for the treatment of osteoporosis rely almost exclusively on agents whose pharmacological actions are primarily antiresorptive. There is, therefore, growing interest in developing agents able to stimulate bone formation, such as GH and IGF-I, which play an important role in bone metabolism, being essential for the development and growth of the skeleton and for the maintenance of bone mass. Furthermore, the decline in GH/IGF-I axis with aging, is correlated with the increased risk of osteoporosis and fragility fractures in elderly population. Several studies investigated the potential of GH and/or IGF-I as therapeutic agents in osteoporotic patients (post-menopausal women and idiopathic osteoporotic men), showing a clear correlation between the used GH dosage (and the obtained IGF-I plasmatic levels) and the increase in bone turnover markers and/or bone mineral density (BMD) at different skeletal sites. In particular, the use of IGF-I/IGFBP-3 complex seems to be very useful and safe in older women with recent hip fracture. Also the possibility of combining GH/IGF-I treatment with antiresorptive drugs (such as calcitonin and alendronate) has been explored, showing controversial results on BMD at different skeletal sites. In summary, based on the current evidence, it is clear that circulating GH and IGF-I are critical for skeletal modeling, bone acquisition and age related bone loss. Nevertheless, controlled studies with fracture incidence as endpoints are needed to fully assess the potential of these bone anabolic agents in the treatment of osteoporosis.