Effect of Sitagliptin and Metformin on Prediabetes Progression to Type 2 Diabetes - A Randomized, Double-Blind, Double-Arm, Multicenter Clinical Trial: Protocol for the Sitagliptin and Metformin in PreDiabetes (SiMePreD) Study.

BACKGROUND: The high prevalence and incidence of type 2 diabetes mellitus (DM), and its associated morbidity and mortality, has prompted growing international interest and effort in the primary prevention of this disease. Primary prevention is possible since type 2 DM is preceded by prediabetes, offering a window opportunity to treat patients, and prevent the emergence of advanced disease. Sitagliptin is an oral dipeptidyl peptidase-IV inhibitor that preserves existing beta cell function and increases beta cell mass. These two effects have been demonstrated both in vitro and in animal studies, and current clinical data show that sitagliptin is safe. Metformin, a biguanide, reduces insulin resistance and inhibits hepatic gluconeogenesis, and has an excellent safety profile. The combination of metformin and sitagliptin, targeting both characteristics of prediabetes (insulin resistance and progressive beta cell degeneration), may potentially slow or halt the progression from prediabetes to type 2 DM. This paper describes the rationale and design of the Sitagliptin and Metformin in PreDiabetes (SiMePreD) study.

OBJECTIVE: The aim of this study is to determine the effect of sitagliptin and metformin on progression from prediabetes to type 2 DM. The objectives of the study are to determine the effects of metformin and placebo on glycemic endpoints, the effects of sitagliptin and metformin on glycemic endpoints, the effects of metformin and placebo on incidence of cardiovascular disease and death, and the effects of sitagliptin and metformin on incidence of cardiovascular disease and death.

METHODS: This is a randomized, double-blind, multicenter clinical study that will determine if the combination of metformin and sitagliptin is effective in preventing the progression from prediabetes to type 2 DM. The study will contain two arms (metformin/sitagliptin and metformin/placebo). Primary endpoints include the number of subjects progressing from prediabetes to type 2 DM, the number of cardiovascular events, and the number of deaths. The planned duration of the study is five years, and 410 subjects will be included in each group. Data analyses will include clinically relevant measures (eg, numbers needed to treat and numbers needed to harm) and will be performed according to the intention-to-treat principle.

RESULTS: This study is currently in the process of acquiring research funding.

CONCLUSIONS: The SiMePreD study is the first study to investigate the utility of sitagliptin in combination with metformin for the primary prevention of type 2 DM. .