Data Sources
This was a post hoc analysis of pooled data from subjects who participated in one of three randomized, double-blind trials in which sitagliptin was compared to a sulfonylurea, had mild renal impairment (eGFR of ≥60 to <90 mL/min/1.73 m
2) at baseline as determined by the 4-variable MDRD equation [
17] (meeting eGFR criteria for mild [Stage 2] CKD [
20]), had glycated hemoglobin (HbA
1c) data at the analysis time points, and had no major protocol violations. There was no rescue therapy in these trials, as subjects with persistent hyperglycemia were discontinued.
In Study 1 (Sitagliptin Protocol 010, ClinicalTrials.gov#NCT00482079) [
21], 743 subjects were 21–76 years of age with baseline HbA
1c from 6.5 to <10.0% on diet alone; for Study 2 (Sitagliptin Protocol 024, ClinicalTrials.gov#NCT00094770) [
22,
23], 1,172 subjects were 18–78 years of age with baseline HbA
1c from 6.5 to 10.0% on background metformin monotherapy; and for Study 3 (Sitagliptin Protocol 803; ClinicalTrials.gov#NCT00701090) [
24], 1,034 subjects were ≥18 years of age with baseline HbA
1c from 6.5 to 9.0% on background metformin monotherapy.
In Study 1, a dose-range finding study, subjects were randomized in an equal ratio among six treatment groups, of which two are appropriate for inclusion in the present analyses: the group randomized to sitagliptin (100 mg per day administered as 50 mg twice daily) and the group randomized to glipizide (in titrated doses). The primary study duration was 12 weeks, subsequently extended to 104 weeks. In Study 2, subjects were randomized 1:1 to sitagliptin (100 mg per day) or glipizide (in titrated doses). Study duration was 104 weeks with the primary time point at Week 52. In Study 3, subjects were randomized 1:1 to sitagliptin (100 mg per day) or glimepiride (in titrated doses). Study duration was 30 weeks. In all 3 studies, sulfonylureas (or matching placebo) were titrated based on self-performed fingerstick glucose values. Up-titration was withheld if the investigator considered that up-titration would place the subject at unacceptable risk for hypoglycemia, and down-titration could be done at any time during the study to prevent recurrent hypoglycemic events. The mean ± standard deviation dose of sulfonylurea achieved during the analysis period in subjects included in this analysis was 10.9 ± 5.9 mg glipizide per day, 10.4 ± 6.5 mg glipizide per day, and 2.0 ± 1.4 mg glimepiride per day in studies 1, 2, and 3, respectively.
As indicated above, the three studies had slight differences in their protocols, including background therapy (i.e., diet/exercise or metformin) and specific sulfonylurea comparator. However, efficacy and safety in both backgrounds are relevant to this analysis. Therefore, because it is not expected that a stable metformin background would impact body weight or hypoglycemic events, and because similar efficacy and side effect profiles of the two second-generation sulfonylureas were expected, data were combined from the three studies in order to increase the power and generalizability of the analysis.
All studies contributing data to the analysis reported here were conducted in accordance with principles of Good Clinical Practice and were approved by the appropriate institutional review boards and regulatory agencies. The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.
Analysis Endpoints
Evaluation endpoints were changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight. The percentages of subjects with HbA1c < 7.0%, the percentages of subjects with HbA1c decrease >0.5%, and the percentages of subjects meeting a composite endpoint of HbA1c decrease >0.5% with no symptomatic hypoglycemia and no body weight gain at the end of the study periods were calculated. The percentages of subjects reporting at least one adverse event (AE) of symptomatic hypoglycemia, and the exposure-adjusted event rate of reported AEs of symptomatic hypoglycemia that occurred during the analysis period were also calculated. An AE of symptomatic hypoglycemia was defined as any episode with symptoms consistent with hypoglycemia; there was no requirement for confirmation of hypoglycemia by a measurement of blood glucose levels. Severe hypoglycemia was defined as an episode of hypoglycemia that required assistance, either medical or non-medical. Episodes with a markedly depressed level of consciousness, a loss of consciousness, or seizure were classified as having required medical assistance, whether or not medical assistance was obtained.
Statistical Analysis
In each study, the period evaluated began at first dose of sitagliptin or sulfonylurea and ended as close as possible to the final time point for the study of shortest duration (Week 30 of Study 3).For Study 1, Week 25 data were used for all endpoints. For Study 2, Week 30 data were used for HbA
1c and FPG and Week 24 data for body weight. For Study 3, Week 30 data were used for all endpoints. The incidence of hypoglycemia was assessed through Week 25 (Study 1) or 30 (Studies 2 and 3). Since treatment effects for both sitagliptin and sulfonylurea generally plateau by 6 months, these time points were considered to be similar with regard to the endpoints of interest. Further, any minor effects related to the 5 week difference would be equally balanced between the two treatment groups. Results at the time point used for this analysis, for each individual study for the full per-protocol analysis population, are provided in supplementary Table
1.
Table 1
Baseline demographic and anthropometric characteristics of randomized subjects in pooled study cohorts
Age (years) | 57.7 ± 8.5 | 57.6 ± 9.4 |
Male gender [n (%)] | 326 (54.2) | 357 (58.5) |
Race [n (%)] |
White | 428 (71.2) | 416 (68.2) |
Asian | 56 (9.3) | 80 (13.1) |
Black | 18 (3.0) | 21 (3.4) |
Other | 99 (16.5) | 93 (15.2) |
Body weight (kg) | 85.8 ± 16.6 | 86.4 ± 16.8 |
Body mass index (kg/m2) | 30.4 ± 4.7 | 30.8 ± 4.8 |
Estimated GFR [mL/min/1.73 m2 (interquartile range)] | 75.9 ± 7.6 (69.6, 81.6) | 75.9 ± 7.2 (70.4, 81.3) |
HbA1c [% (range)] | 7.6 ± 0.8 (6.1 to 10.5) | 7.6 ± 0.9 (5.8 to 11.0) |
FPG (mg/dL) | 154.9 ± 35.9 | 156.9 ± 40.1 |
Duration of T2DM (years) | 6.4 ± 4.9 | 5.8 ± 4.5 |
To be included in the analysis population, subjects with appropriate eGFR at baseline had to have completed Study 1 through Week 25 or Studies 2 or 3 through Week 30, have a baseline and end of analysis period HbA1c measurement, and have no major protocol violations.
Analysis of covariance was used to compare the treatment group changes from baseline for the continuous endpoints, at time points indicated. The model controlled for treatment, study, and baseline value. The difference between treatment groups in change from baseline was assessed by testing the difference in the least squares mean change from baseline. Percentages and event rates were assessed using the method of Miettinen & Nurminen [
25], stratified by study to calculate a nominal
P value for between-group differences. The event rate was calculated as number of events divided by total subject-years of exposure. The total subject-years of exposure were calculated as the sum, over all subjects, of the time from the first dose to last dose of study medication for the time period included in this analysis.
Using all available data from Study 3, baseline eGFR and mild renal impairment classification using the 4-variable MDRD equation was compared with the baseline values and classification obtained using the CKD-epi creatinine equation, considering CKD-epi eGFR to be the reference value. All analyses were done using SAS (developed by SAS Institute Inc., Cary, NC, USA.), version 9.3.