Factors for Efficacy of Sitagliptin and Metformin in T2DM

Factors for Efficacy of Sitagliptin and Metformin in T2DM

Abstract and Introduction

Abstract

Objective We assessed the predictive parameters for therapeutic efficacy of initial combination therapy with sitagliptin and metformin in drug-naïve type 2 diabetic patients.
Design, Patients, and Measurements In this 52-week treatment study, 150 patients (mean age, 54·9 ± 12·5 years) with type 2 diabetes and HbA1c of 7·0–10% were treated with sitagliptin 100 mg once and metformin 500 mg twice daily. To assess the predictive parameters for therapeutic efficacy, a multivariate regression analysis was performed with baseline fasting glucose, insulin, C-peptide, and glucagon levels, homoeostasis model assessment-insulin resistance (HOMA-IR) and β-cell function (HOMA-B), insulinogenic index (IGI, defined as 30–0 min insulin/30–0 min glucose), and area under the curve for glucose, insulin, and C-peptide obtained after 75-g oral glucose tolerance test.
Results After 52 weeks, mean HbA1c levels and fasting and postload 2-h glucose were significantly decreased from 8·7 ± 1·4% to 7·2 ± 1·3%, 9·2 ± 3·0 to 7·2 ± 1·8 mm, and 17·5 ± 5·1 to 10·9 ± 3·6 mm, respectively (P < 0·01). HOMA-B and IGI increased significantly from 50·3 ± 33·5 to 75·1 ± 32·8 and from 11·3 ± 1·3 to 35·0 ± 6·3 at 52 weeks, respectively (P < 0·01). Multivariate regression analysis indicated that the reduction in HbA1c was significantly associated with high baseline HbA1c, low IGI, and short duration of diabetes after adjusting for age, sex, body mass index, blood pressure, triglycerides, creatinine, high-sensitivity CRP, glucagon, C-peptide, HOMA-B, and HOMA-IR. No severe adverse events were observed.
Conclusion These results suggest that drug-naïve type 2 diabetic patients with low β-cell function would benefit the most from early initial combination therapy of sitagliptin and metformin.

Introduction

It has been well established that inhibition of dipeptidyl peptidase-4 (DPP-4) reduces blood glucose levels in both fasting and postprandial states and preserves pancreatic β-cell function in patients with type 2 diabetes. The mechanism of action of DPP-4 inhibitors is to increase the levels of active incretin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion as well as insulin biosynthesis while inhibiting glucagon release from pancreatic islets. DPP-4 inhibitors also have better safety and tolerability profiles (e.g., weight neutrality and less hypoglycaemia) compared with other hypoglycaemic agents. When considering combination therapy with DPP-4 inhibitors, metformin is the most commonly used agent, which has been shown to be effective and well tolerated from previous studies. Besides the glucose-lowering effect by reducing hepatic glucose output and improving insulin resistance, metformin without inhibiting DPP-4 activity also increases active GLP-1 concentrations by 1·5- to 2-fold following an oral glucose load in obese, nondiabetic subjects. Accordingly, this effect of metformin may provide a unique benefit when combined with DPP-4 inhibitors through a substantial enhancement of the incretin axis, which provides effective and potentially additive glycaemic improvement.

Because of its favourable pharmacological properties, combination of a DPP-4 inhibitor and metformin has been increasingly used to achieve rapid glycaemic goal with low risk of hypoglycaemia and no weight gain and to delay the need for subsequent regimen changes. DPP-4 inhibitors block DPP-4 enzyme and preserve endogenous incretins, whereas metformin increases the active form of GLP-1, both of which may enhance the secretory function of pancreas. However, the response to DPP-4 inhibitors and metformin combination therapy may be different in individuals according to their pancreatic function and insulin resistance status. In fact, previous studies with DPP-4 inhibitors showed different potency in glycaemic controls depending on various patient characteristics including the severity of diabetes and the use of other antidiabetic drug. Consequently, it would be clinically important to identify the most appropriate candidate for this combination therapy. However, there has been little knowledge about the predictive factors for therapeutic efficacy of initial combination therapy with DPP-4 inhibitors and metformin.

In this study, we investigated the parameters that can predict the therapeutic efficacy of combination of sitagliptin, a DPP-4 inhibitor, and metformin in drug-naïve type 2 diabetic patients.