Safety and tolerability of vildagliptin vs. thiazolidinedione as add-on to metformin in type 2 diabetic patients with and without mild renal impairment: A retrospective analysis of the GALIANT study

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Abstract

Objective

This retrospective analysis assessed safety and tolerability of vildagliptin (Vilda) as an add-on to metformin in type 2 diabetes mellitus (T2DM) patients with normal renal function (GFR > 80 mL/min/1.73 m2) and mild renal impairment (GFR: >50 to ≤80 mL/min/1.73 m2).

Methods

Adverse events (AE) from this 12-week, randomized, open-label study comparing Vilda 100 mg and thiazolidinediones (TZD) as an add-on therapy in patients with T2DM inadequately controlled (HbA1c: 7–10%) on a stable dose of metformin (≥1000 mg/day) were analyzed.

Results

Of 2627 randomized patients, 1278 in the Vilda and 635 in the TZD groups had normal renal function; 463 in the Vilda and 230 in the TZD groups had mild renal impairment. Higher incidence of headache and rash was noted in both Vilda groups, whereas those with mild renal impairment receiving TZD experienced a higher incidence of peripheral edema and URI. Fewer patients in the Vilda group discontinued the study due to AEs compared to TZD group. Serious AEs were greater in TZD groups (normal: 2.4%; mild renal impairment: 3.0%) compared to Vilda groups (normal: 1.6%; mild renal impairment: 2.4%).

Conclusion

The safety profile of Vilda or TZD as an add-on to metformin was similar in patients with mild renal impairment and normal renal function.

Introduction

Approximately 180,000 people in the United States have renal failure as a result of diabetes [1], [2]. Diabetes is the leading cause of kidney failure, accounting for 44% of all new cases in 2005. Key causes for deterioration of renal function include poor glucose and blood pressure control. Patients with diabetes and deteriorating renal function may be exposed to higher concentrations of drugs that are renally excreted. While strict control of blood glucose with hypoglycemic agents may result in the prevention or delay of renal impairment in patients with type 2 diabetes mellitus (T2DM), the selection of antidiabetic agents is challenging as most of these agents are primarily eliminated by the kidney. Current oral antidiabetic treatment options are limited because of safety and tolerability issues associated with increased drug concentration and altered metabolism. Thus, glycemic management of patients with type 2 diabetes and renal impairment needs special consideration.

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycemic control by increasing the ability of both pancreatic α- and β-cells to sense and respond appropriately to glucose [3], [4]. Vildagliptin is metabolized in the liver and excreted primarily through kidneys with approximately 85% of the oral dose unchanged in the urine [5]. Vildagliptin is metabolized in humans primarily by hydrolysis with two major metabolites; LAY151 and BQS867. Although the BQS867 metabolite has DPP-IV activity, it is considerably less than vildagliptin. In patients with renal impairment, systemic exposure to vildagliptin is slightly increased (Cmax 8–66%; AUC 32–134%) and total body clearance reduced compared to subjects with normal renal function. Vildagliptin is effective and well tolerated when used as monotherapy or in combination with other oral antidiabetic drugs including metformin [6], [7], [8], [9], [10], [11], [12], [13]. However, there is limited data for its use in renally impaired patients [14].

Thiazolidinediones (TZD), the second-line option [15] in the treatment of patients with T2DM, have been shown to be effective and well tolerated as an add-on therapy to metformin [16], [17]. Thiazolidinediones (rosiglitazone and pioglitazone) are metabolized by the liver and may be ideal for the management of glycemic control in T2DM patients with all stages of impaired renal status. Nevertheless, adverse events associated with this class of compounds such as congestive heart failure secondary to fluid overload [18] and increased bone fractures [19] calls for caution in using TZDs in this population [20].

The objective of this retrospective analysis of the GALIANT (GALvus In Addition to metformiN vs. TZD/metformin in T2DM) study [21] was to assess the safety profile of vildagliptin compared to TZD as an add-on to metformin in patients with T2DM with mild renal impairment and with normal renal function.

Section snippets

Study design

This is a retrospective analysis of a 12-week, multicenter, randomized, open-label study conducted in 796 primary care sites in the USA [21]. Full details of the study design have been described previously [21]. Eligible patients aged ≥18 years with T2DM diabetes who were inadequately controlled (HbA1c of 7–10%) on a stable dose of metformin monotherapy (≥1000 mg/day) for ≥4 weeks were randomized using an automated central telephone system in a ratio of 2:1 to receive either vildagliptin 100 mg

Patient disposition and baseline characteristics

Of the 2664 randomized patients in the original study, 2627 were analyzed. In total 1918 patients (vildagliptin, 1279; TZD, 639) had normal renal function, 695 patients (vildagliptin, 464; TZD, 231) had mild renal impairment, and 14 patients (vildagliptin, 9; TZD, 5) had moderate renal impairment, as assessed by the MDRD formula. Thirty-seven patients were not analyzed because of the missing data at baseline and patients with moderate renal impairment were also not included in this analysis as

Discussion

This retrospective analysis showed that vildagliptin was well tolerated and the safety profile in patients with mild renal impairment was similar to that noted in those patients with normal renal function. The overall incidence of AEs in patients with mild renal impairment (vildagliptin, 37.8% and TZD, 40.4%) was comparable to those with normal renal function (vildagliptin, 40.1% and TZD, 34.8%). In all subgroups and across the treatments, headache was the most common AE reported. Dizziness was

Conclusion

This retrospective analysis demonstrated that the safety profile and tolerability of the combination of vildagliptin and metformin in T2DM patients with mild renal impairment was similar to that in patients with normal renal function. Furthermore these results were similar to those in patients receiving a combination of TZD and metformin. Additional, prospective studies in more advanced renal insufficiency are necessary to confirm these findings.

Conflict of interest

The authors have a competing interest to declare. Dr. M.A. Banerji was a member of the speakers’ bureau for Merck and Sanofi-Aventis; was consultant for Roche, Boehringer-Ingleheim, Sanofi-Aventis, Novartis, and BMS; received research grants from Roche, Boeringer-Ingleheim, Takeda, Novartis, and Merck. Dr. Francis and D. Purkayastha are employees and shareholders of Novartis Pharmaceuticals Corporation.

Grant support: This study was funded by Novartis Pharmaceuticals Corporation, East Hanover,

Acknowledgements

We acknowledge the investigators and other staff members who participated in this study. The authors were assisted in the preparation of this manuscript by Linda Ali-Cruz, Ashwin Kittur, Thej Kumar Nallagangula, and Ashish Agarwal (all Novartis).

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