Randomized Evaluation of Anagliptin vs Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) Trial: A 52-week, open-label, randomized clinical trial

Abstract

Additional reductions in low-density lipoprotein-cholesterol (LDL-C) via antidiabetic therapies should be considered in statin-using patients with sub-optimal LDL-C levels. We compared the efficacy of anagliptin and sitagliptin, two antidiabetic therapies, in reducing LDL-C in type 2 diabetic patients. A randomized, open-label, parallel-group trial was conducted at 17 centres in Japan between April 2015 and January 2018. Adults (age ≥20 years) with type 2 diabetes, any atherosclerotic vascular lesions, and statin prescriptions were included. Anagliptin or sitagliptin were administered for 52 weeks. Primary and secondary endpoints were changes in LDL-C and haemoglobin A1C (HbA1c) levels, respectively. We assessed the superiority (primary endpoint) and non-inferiority (secondary endpoint) of anagliptin over sitagliptin. This study was registered at Clinicaltrials.gov (NCT02330406). Of 380 participants, 353 were eligible and randomized. Mean participant age was 68 years, and 61% were males. Baseline median LDL-C and HbA1c were 108 mg/dL and 6.9%, respectively. Changes in LDL-C were −3.7 mg/dL with anagliptin and +2.1 mg/dL with sitagliptin at 52 weeks, and the estimated treatment difference was a significant −4.5 mg/dL (P = 0.01 for superiority). Changes in HbA1c were +0.02% with anagliptin and +0.12% with sitagliptin (P < 0.0001 for non-inferiority). Overall, anagliptin was superior to sitagliptin in lowering LDL-C without deteriorating HbA1c.

Dissimilar Effects of Anagliptin and Sitagliptin on Lipoprotein Subclass in Standard or Strong Statin-Treated Patients with Type-2 Diabetes Mellitus: A Subanalysis of the REASON (Randomized Evaluation of Anagliptin versus Sitagliptin on Low-Density LipoproteiN Cholesterol in Diabetes) Trial

“…We found that only anagliptin reduced LDL-C levels, even under treatment with statin [10]. Among the 353 participants in the trial, the frequencies of standard and strong statin users were 278 (78.8%) and 75 (21.2%), respectively [10]. However, the LDL-C lowering effect of anagliptin were not compared between standard and strong statin treatment in the REASON trial.…”

“…Statistical analysis was performed as previously described [9,10]. In brief, categorical variables are shown as number and percentage, and continuous variables as mean and standard derivation or median and quartile, if appropriate.…”

“…The primary end point was the change in LDL-C levels at 52 weeks, and the secondary endpoint was the change in HbA1c levels at 52 weeks. The detailed design of the REASON Trial has been described previously [9,10]. We used an electronic data capture (EDC) system to register and randomize participants and collect data.…”

“…Randomization to anagliptin or sitagliptin in a 1:1 ratio was performed centrally through the EDC system, with a stochastic minimization algorithm to balance treatment assignment within the strata of center: HbA1c (≥8.0%, <8.0%), use of DPP-4 inhibitors prior to trial registration, sex, BMI (≥25 kg/m 2 , <25 kg/m 2 ), and LDL-C (≥130 mg/dL, <130 mg/dL) [9,10]. In this subanalysis of the REASON Trial, 50 participants each from the anagliptin-or sitagliptin-treated groups were randomly selected from the 353 subjects enrolled in the REASON Trial [10]. The Trial and this subanalysis were conducted in accordance with the guidelines established by the Declaration of Helsinki and Japanese clinical study guidelines regarding human subjects in research.…”

“…A Randomized Evaluation of Anagliptin versus Sitagliptin on low-density lipoproteiN cholesterol in diabetes (REASON) Trial was a multicenter, randomized, open-label, parallel-group trial to determine the effectiveness of anagliptin versus sitagliptin on reduction in LDL-C in patients with type-2 diabetes with either prior coronary artery disease (CAD) or CAD risk factors under statin therapy [9]. We found that only anagliptin reduced LDL-C levels, even under treatment with statin [10]. Among the 353 participants in the trial, the frequencies of standard and strong statin users were 278 (78.8%) and 75 (21.2%), respectively [10].…”