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A number of DPP-4 inhibitors are currently in late-stage clinical development, including alogliptin and saxagliptin. The efficacy and safety of both agents have been evaluated as monotherapy and as combination therapy. Early data suggests that both alogliptin and saxagliptin also effectively lower glucose and HbA1c as monotherapy in treatment naïvepatients. 51,52 These agents also appear to be effective as combination therapy in type 2 diabetes patients inadequately controlled on monotherapy with currently available antidiabetic agents.53–56 In addition, currently available data suggest that they have a similar safety profile to sitagliptin and vildagliptin.
To date, the clinical outcomes of incretin-based therapies have not been directly compared in a type 2 diabetes patient population, and can be attempted only indirectly. However, comparisons based exclusively on the HbA1c effect are of little relevance for the purpose of estimating practical clinical benefit, as populations and designs differ among studies. Study participants in the exenatide studies typically had a longer diabetes duration (4.9–9.9 years) compared with the DPP-4 inhibitor study patients (1.9–6.5 years). One may conclude that DPP-4 inhibitors are a good treatment option for patients with a shorter diabetes duration as they do not cause weight gain and have low hypoglycemic risk—important advantages over sulfonylureas or thiazolidinediones. Nevertheless, the effect of exenatide in terms of glycemic control has been demonstrated in insulin non-inferiority studies. Exenatide is the only antidiabetic with an additional weight-reduction effect—a desired goal of treatment in any stage of type 2 diabetes, especially in obese patients.57
Summary and Conclusions
Type 2 diabetes is a progressive disease that is a growing health problem. Several classes of drug are available to treat the condition, many of which have a long history of use. Some of the earlier drugs have known side effects that limit their use in certain patient populations. For example, sulfonylureas can cause weight increase and hypoglycemia and are not advised in patients with advanced liver or kidney disease; rapid-acting variants of this class appear to cause fewer side effects, but are not as well studied. Metformin is part of a widely prescribed class of drugs, but may have GI side effects in a significant percentage of patients. It also may have a rare risk for lactic acidosis, and may be contraindicated in patients with cardiac or respiratory insufficiency. TZDs have a very slow onset of action and have an attendant risk for fluid retention. There is also some concern about possible cardiovascular effects such as aggrevation of congestive heart failure. Incretin-based therapies are the newest additions to the antidiabetic fold, and offer the promise of controlling blood glucose through stimulation of the pancreatic b cells. The incretin mimetic exenatide mimics human GLP-1 but is not degraded by DPP-4, thus extending its half-life. It has so far been shown to reduce HbA1c and stimulate weight loss without serious adverse events. It is also non-inferior to many other available antidiabetic drugs, and may even be diseasemodifying. DPP-4 inhibitors have also had positive results, although they are not associated with weight loss and have not yet been compared with either insulin or exenatide. Nevertheless, the addition of these new drugs brings new hope to those with type 2 diabetes, and more studies will help reveal the best patient populations for each one.