Diabet. Med. 30, 179–188 (2013)
Despite improvements in the pharmacodynamics of injectable insulin and better insulin delivery systems, glucose control remains suboptimal in the majority of individuals with Type 1 diabetes. Profound defects in the physiological processes that normally maintain glucose homeostasis contribute to the difficulty in achieving glycaemic targets. Non-insulin-based adjunct treatments offer a potential means of complementing intensive insulin therapy in Type 1 diabetes through addressing some of the physiological disturbances that result from endogenous β-cell destruction, particularly through preservation of β-cell mass and prevention of apoptosis, and suppression of α-cell glucagon release in the postprandial state. The former approach applies most readily to newly diagnosed C-peptide-positive Type 1 diabetes, while the latter to established C-peptide-negative Type 1 diabetes. This review focuses primarily on the clinical trial data available on the use of non-insulin-based therapies in longer-duration Type 1 diabetes. We conclude that metformin may prove useful in macrovascular disease reduction, while pramlintide, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors and leptin co-therapies may reduce HbA1c, glucose variability, postprandial glucose excursions and body weight. These early studies are encouraging and offer novel and potentially very effective approaches to the treatment of Type 1 diabetes, but the evidence is largely restricted to small, often uncontrolled trials. As such, these therapies cannot be currently recommended for routine clinical practice. There is a clear need to support large, multi-centre randomized controlled trials designed to establish whether adjunct insulin therapy has a place in the modern management of Type 1 diabetes.