Insulin Therapy for Type 2 Diabetes

A number of landmark randomized clinical trials established that insulin therapy reduces microvascular complications (1,2). In addition, recent follow-up data from the U.K. Prospective Diabetes Study (UKPDS) suggest that early insulin treatment also lowers macrovascular risk in type 2 diabetes (3). Whereas there is consensus on the need for insulin, controversy exists on how to initiate and intensify insulin therapy. The options for the practical implementation of insulin therapy are many. In this presentation, we will give an overview of the evidence on the various insulin regimens commonly used to treat type 2 diabetes. Secondary analyses of the aforementioned landmark trials endeavored to establish a glycemic threshold value below which no complications would occur. The UKPDS found no evidence for such a threshold for A1C, but instead showed that better glycemic control was associated with reduced risks of complications over the whole glycemic range (“the lower the better”) (4). For the management of type 2 diabetes, this resulted in the recommendation to “maintain glycemic levels as close to the nondiabetic range as possible” (5). However, in contrast to the UKPDS, the Kumamoto study observed a threshold, with no exacerbation of microvascular complications in patients with type 2 diabetes whose A1C was 6.5%, suggesting no additional benefit in lowering A1C below this level (2). Moreover, the intensive glycemia treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, targeting A1C 6.0%, was discontinued because of higher mortality in this group compared with the standard therapy group targeting A1C from 7.0 to 7.9% (6). Therefore, the American Diabetes Association (ADA) recommendation of an A1C target 7.0% seems the most balanced compromise at present (7). Another important conclusion of the UKPDS was that the risk reductions in long-term complications were related to the levels of glycemic control achieved, rather than to a specific glucose-lowering agent (1). This has left health care providers and patients with the difficult task of choosing from the wide variety of glucose-lowering interventions currently available. When considering the effectiveness, tolerability, and cost of the various diabetes treatments, insulin is not only the most potent, but also the most costeffective intervention (8). Although insulin has no upper dose limit and numerous trials established that glycemic goals could be attained by using adequate insulin doses (5,8), in clinical practice, many patients have elevated A1C levels and experience years of uncontrolled hyperglycemia (9). Moreover, the Steno-2 Study demonstrated that only a minority of patients reached the intensive A1C target of 6.5%, compared with a far greater percentage of patients who reached the respective intensive treatment goals for blood pressure and serum lipid levels (10). Apparently, the initiation and intensification of insulin therapy is not as straightforward and simple as we had hoped. In accordance with the ADA and the European Association for the Study of Diabetes (EASD) (5,7), we advocate an algorithmic approach for the start and adjustment of insulin treatment, with modifications for individual patients as needed. This review contains an overview of the currently available insulin preparations and an outline of the merits and disadvantages of the various regimens commonly used for the initiation and intensification of insulin therapy in patients with type 2 diabetes. Our aim is to assist clinicians in designing individualized management plans for insulin therapy in type 2 diabetic patients.