Stop or Replace: Effect of stopping sulfonylureas or replacing sulfonylureas with a dipeptidyl peptidase 4 (DPP-IV) inhibitor in Type 2 diabetes patients on pre-mix insulin.

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The emerging epidemic of type 2 diabetes, coupled with finite health resources, requires the treatment of hyperglycaemia to be simple and efficiently managed. Type 2 diabetes is a progressive disease and eventually most patients will require insulin at a certain stage to maintain good glycaemic control. The key to when to start insulin is to identify the appropriate glycated haemoglobin (HbA1c) target for an individual patient. If target A1C is not achieved with metformin combined with sulfonylurea, the most commonly used 2nd line oral hypoglycaemic agents, insulin therapy is usually started. In patients on sulfonylureas and metformin who are starting insulin therapy, metformin is usually continued. Part of the rationale for combination oral hypoglycaemic agents and insulin therapy is that by suppressing hepatic glucose production, the patient can retain the convenience of oral agents while minimizing total insulin requirements and, therefore, the degree of hyperinsulinemia. GLP-1 agonists, DPP-4 inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors can also be continued when insulin is added, however, they are currently not PBS listed for being combined with insulin. There are no clear guidelines as to whether and at what time point SU are to be discontinued or continued when insulin is introduced. Data from the UKPDS and meta-analyses of several randomized placebo-controlled trials report modest but consistent benefits of a combination of sulfonylurea and metformin with insulin therapy compared with insulin monotherapy. However, the combination of sulfonylurea and insulin is less efficacious and results in more weight gain than metformin and insulin. Furthermore, insulin and sulfonylureas have similar effects of increasing circulating insulin levels, and the same glucose-lowering effect can usually be achieved, and at a lower cost and better prediction, with a modestly higher dose of insulin alone. Furthermore, a recent retrospective Danish study has found that patients with a combination with SU and insulin had an increased mortality compared to metformin and insulin. Studies also report increased risks of weight gain and hypoglycaemia when left on SU while starting basal or pre-mixed insulins. Based on this recent literature review, it is a concern that many patients with Type 2 Diabetes are continuing their SU together with their pre-mix insulin, with limited evidence for an added benefit, but a growing evidence of increased risk of hypoglycaemia, weight gain and possibly increased mortality. The outcome of this study will give as important information which could lead to a change in current practice guidelines. The aim of our study is to assess whether SU should be stopped, continued or replaced with a DPP4 Inhibitor once pre-mixed insulin therapy has been started. We hypothesise that SU will not have a significant additive effect on glycaemic control in patients on pre-mix insulin, but contribute significantly to increased risk of hypoglycaemia and weight gain. A similar glycaemic control can be achieved by a dose adjustment of the insulin dose, or by adding a DPP-IV inhibitor without the side effects of SU, such as hypoglycaemia and weight gain. Results of this study could have an important impact on how type 2 diabetes patients are treated safely and effectively. PRIMARY OUTCOMES: To measure the change in glycaemic control when stopping SU or replacing SU with a DPP-4 inhibitor in patients on pre-mix insulin. SECONDARY OUTCOMES To compare the side effects (weight gain) and safety (hypoglycaemia) of stopping SU or replacing SU with a DPP-4 inhibitor in patients with pre-mix insulin. This is a prospective, randomised, open label controlled single centre trial with three arms: a) Patients continue SU b) Patients stop SU c) Patients replace SU with the DPP4 inhibitor Linagliptin (5mg/day) Patient characteristics: Patients with Type 2 Diabetes treated with pre-mix insulin (NovoMix30 or HumalogMix25), at least twice daily for at least 6 months, and also treated with SU since at least 4 years. 99 patients in total (33 patients per arm) will be recruited at St Vincent’s Hospital, Sydney.

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