Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin for Patients With Type 2 Diabetes Mellitus

Tina Vilsbøll


Expert Rev Endocrinol Metab. 2008;3(1):13-19. 

In This Article

Expert Commentary & Five-year View

With the two active components, sitagliptin and metformin, Janumet has a comprehensive mechanism of action that targets all three key defects of T2DM for improved glycemic control: diminished insulin release, uncontrolled production of glucose (by the liver due to both α-cell and ß-cell dysfunction) and insulin resistance. By inhibiting the DPP-4 enzyme, sitagliptin significantly increases the levels of active incretin hormones, increasing the synthesis and release of insulin from the pancreatic ß-cells and decreasing the release of glucagon from the pancreatic α-cells. Janumet also contains metformin, which addresses the other key defect: insulin resistance. Thereby, metformin increase uptake and utilization of glucose by the muscles and tissues of the body and decreases hepatic glucose production in a manner that is complementary to sitagliptin. Janumet provides powerful HbA1c lowering through combined reductions of both postprandial glucose and fasting plasma glucose. Janumet, as with metformin, is dosed twice daily with meals. Consistent with the labeling for metformin alone, the labeling for Janumet contains a boxed warning for lactic acidosis, a rare but serious metabolic complication that can occur due to metformin accumulation during treatment with Janumet.

Finally, DPP-4 inhibitors may have long-term beneficial effects on ß-cell function and mass, although so far, this has only been demonstrated in animal models and with limited results in human studies evaluating the ß-cell function during treatment with the DPP-4 inhibitors.[32,33,36,42] However, the studies are not conclusive and it is important to note that long-term studies are necessary in order to see whether these effects are durable and whether they change the secondary failure seen with other secretagogues. However, it seems evident that a GLP-1-based therapy is going be a valuable tool in the treatment of patients with T2DM. Further studies will, hopefully, elucidate whether this new approach will have the aptitude to modify progression of the disease that inescapably accompanies existing therapeutic modalities.


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