Novel combination treatment of type 2 diabetes DPP-4 inhibition + metformin

Abstract

Inhibition of dipeptidyl peptidase-4 (DPP-4) as a novel therapy for type 2 diabetes is based on prevention of the inactivation process of bioactive peptides, the most important in the context of treatment of diabetes of which is glucagon-like peptide-1 (GLP-1). Most clinical experience with DPP-4 inhibition is based on vildagliptin (GalvusR, Novartis) and sitagliptin (JanuviaR, Merck). These compounds improve glycemic control both in monotherapy and in combination with other oral hyperglycemic agents. Both have also been shown to efficiently improve glycemic control when added to ongoing metformin therapy in patients with inadequate glycemic control. Under that condition, they reduce HbA1C levels by 0.65%-1.1% (baseline HbA1C 7.2-8.7%) in studies up to 52 weeks of duration in combination versus continuous therapy with metformin alone. Sitagliptin has also been examined in initial combination therapy with metformin have; HbA1 was reduced by this combination by 2.1% (baseline HbA1C 8.8%) after 24 weeks of treatment. Both fasting and prandial glucose are reduced by DPP-4 inhibition in combination with metformin in association with improvement of insulin secretion and insulin resistance and increase in concentrations of active GLP-1. The combination of DPP-4 inhibition and metformin has been shown to be highly tolerable with very low risk of hypoglycemia. Hence, DPP-4 inhibition in combination with metformin is an efficient, safe and tolerable combination therapy for type 2 diabetes.

Figure 1

Time course of HbA_1c in a 12 week core study and a 40 week extension study when vildagliptin (LAF; 50 mg once daily) was given as add-on to metformin (MET). PBO = placebo. Reproduced from Ahrén et al 2004a after permission from the American Diabetes Association.

Figure 2

Time course of mean HbA_1c levels during 24 week treatment with vildagliptin at 50 mg daily (Δ) or 100 mg daily (▲) or placebo (○) in patients with type 2 diabetes continuing stable metformin treatment (≥1.5 g daily). Reproduced from Bosi et al 2007 after permission from the American Diabetes Association.

Figure 3

Time course of mean HbA_1c levels during 24 week treatment with sitagliptin (100 mg once daily; ●) or placebo (○) in patients with type 2 diabetes with on-going treatment with (≥1.5 g daily). Reproduced from Charbonnel et al 2006 after permission from the American Diabetes Association.

Figure 4

Changes in HbA_1c, fasting and 2 h prandial glucose and insulin secretion (as determined by 2 hr AUC_insulin divided by AUC_glucose after a meal tolerance test) after 24 weeks treatment of sitagliptin and/or metformin, as indicated in bottom. Results reported are adjusted for changes after treatment with placebo. fig. is drawn after results reported in Goldstein et al 2007.

Figure 5

Insulin secretion (evaluated as the 30 min suprabasal AUC_C-peptide following meal ingestion divided by the 30 min increase in glucose), insulin sensitivity (evaluated by the OGIS estimation) and adaptation index (insulin secretion times insulin sensitivity) at baseline and after 12, 24 and 52 weeks of treatment with vildagliptin at 50 mg daily in combination with metformin (n = 31) versus treatment with metformin (n = 26). Low right panel shows the change in HbA_1c after the 52 week treatment period as a function of change in adaptation index in the same study. Reproduced from Ahrén et al 2005 after permission from the American Diabetes Association.