Vildagliptin and Metformin vs Metformin Titration in T2DM
Vildagliptin and Metformin vs Metformin Titration in T2DM
The inability of monotherapies to act on the multiple pathophysiological mechanisms involved in T2DM and to maintain good glycemic control as a result of progressive deterioration of β-cell function provide the rationale for the early use of combination therapy with different classes of drugs. As metformin lowers plasma glucose levels without affecting insulin secretion, the addition of an agent such as vildagliptin which has a stimulatory action on insulin secretion is a suitable choice for combination therapy in patients with T2DM. Metformin has shown an incremental effect on levels of GLP-1 in obese subjects without diabetes via mechanisms other than DPP-IV inhibition. An additive effect on levels of intact GLP-1 has also been reported in patients with T2DM receiving metformin and vildagliptin concomitantly as compared with drug-naïve patients receiving only vildagliptin, which further supports the use of this combination of drugs.
The efficacy and safety of metformin and vildagliptin combination therapy has been evaluated in several placebo-controlled and active-controlled trials. The addition of vildagliptin to a stable dose of metformin monotherapy has been shown to be effective in sustaining glycemic control for at least 1 year, and in improving β-cell function and reducing insulin resistance and inflammatory markers. A recent study of vildagliptin/low-dose metformin combination therapy in treatment-naïve patients with T2DM showed superior glycemic control and favorable GI tolerability compared with high-dose metformin therapy. This suggests the potential of vildagliptin/metformin combination therapy in the management of T2DM. A recent phase III study in patients with inadequate glycemic control on low-dose metformin (500 mg bid) demonstrated that the addition of vildagliptin 100 mg qd to low-dose metformin 500 mg bid resulted in a larger reduction in HbA1c as compared with up-titration of metformin therapy to 1000 mg bid. Moreover, the combination therapy was well tolerated without any increase in hypoglycemic events, and fewer GI events as compared with high-dose metformin monotherapy. Thus, early and more aggressive therapy in T2DM is more beneficial and can be considered in patients with poor glycemic control with metformin monotherapy.
In comparison with Caucasians, Asians have higher body fat at lower BMI levels and are thus more prone to obesity and related disorders such as diabetes mellitus, dyslipidemia, and hypertension at a lower BMI. Consequently, in China, the BMI cut-offs for 'overweight' (24 kg/m) and 'obesity' (28 kg/m) are lower than those of the WHO criteria, and the population aged 60 years or more is defined as 'elderly'. The VISION study will include Chinese patients with inadequate glycemic control (HbA1c 6.5%-9.0%), despite being on metformin monotherapy. The study will categorize patients into 4 subgroups according to their age and BMI. Patients in each group will be randomized to receive vildagliptin (50 mg bid) plus metformin (500 mg bid) or metformin (1000 mg bid) in a ratio of 5:1. As both obesity and age are independent risk factors for the development of T2DM and also influence the efficacy of any antidiabetic therapy, the VISION study will evaluate the efficacy and safety of the vildagliptin/metformin combination according to age and BMI in comparison with high-dose metformin.
Discussion
The inability of monotherapies to act on the multiple pathophysiological mechanisms involved in T2DM and to maintain good glycemic control as a result of progressive deterioration of β-cell function provide the rationale for the early use of combination therapy with different classes of drugs. As metformin lowers plasma glucose levels without affecting insulin secretion, the addition of an agent such as vildagliptin which has a stimulatory action on insulin secretion is a suitable choice for combination therapy in patients with T2DM. Metformin has shown an incremental effect on levels of GLP-1 in obese subjects without diabetes via mechanisms other than DPP-IV inhibition. An additive effect on levels of intact GLP-1 has also been reported in patients with T2DM receiving metformin and vildagliptin concomitantly as compared with drug-naïve patients receiving only vildagliptin, which further supports the use of this combination of drugs.
The efficacy and safety of metformin and vildagliptin combination therapy has been evaluated in several placebo-controlled and active-controlled trials. The addition of vildagliptin to a stable dose of metformin monotherapy has been shown to be effective in sustaining glycemic control for at least 1 year, and in improving β-cell function and reducing insulin resistance and inflammatory markers. A recent study of vildagliptin/low-dose metformin combination therapy in treatment-naïve patients with T2DM showed superior glycemic control and favorable GI tolerability compared with high-dose metformin therapy. This suggests the potential of vildagliptin/metformin combination therapy in the management of T2DM. A recent phase III study in patients with inadequate glycemic control on low-dose metformin (500 mg bid) demonstrated that the addition of vildagliptin 100 mg qd to low-dose metformin 500 mg bid resulted in a larger reduction in HbA1c as compared with up-titration of metformin therapy to 1000 mg bid. Moreover, the combination therapy was well tolerated without any increase in hypoglycemic events, and fewer GI events as compared with high-dose metformin monotherapy. Thus, early and more aggressive therapy in T2DM is more beneficial and can be considered in patients with poor glycemic control with metformin monotherapy.
In comparison with Caucasians, Asians have higher body fat at lower BMI levels and are thus more prone to obesity and related disorders such as diabetes mellitus, dyslipidemia, and hypertension at a lower BMI. Consequently, in China, the BMI cut-offs for 'overweight' (24 kg/m) and 'obesity' (28 kg/m) are lower than those of the WHO criteria, and the population aged 60 years or more is defined as 'elderly'. The VISION study will include Chinese patients with inadequate glycemic control (HbA1c 6.5%-9.0%), despite being on metformin monotherapy. The study will categorize patients into 4 subgroups according to their age and BMI. Patients in each group will be randomized to receive vildagliptin (50 mg bid) plus metformin (500 mg bid) or metformin (1000 mg bid) in a ratio of 5:1. As both obesity and age are independent risk factors for the development of T2DM and also influence the efficacy of any antidiabetic therapy, the VISION study will evaluate the efficacy and safety of the vildagliptin/metformin combination according to age and BMI in comparison with high-dose metformin.
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