Efficacy of Alogliptin in Type 2 Diabetes Treatment
Efficacy of Alogliptin in Type 2 Diabetes Treatment
Computer based search for literature on alogliptin was performed by AB in MEDLINE, Cochrane library, and HINARI databases. Via HINARI, literature search were also conducted on publishers' websites (Elsevier Science-Science Direct, Nature Publishing Group, Oxford University Press, PsycARTICLES, Science, Wiley-Blackwell and Springer Link). The search was further strengthened by searching relevant literature from the reference lists of retrieved articles. The search terms include: alogliptin or NESINA® or SYR-322, type 2 diabetes mellitus, dipeptidyl peptidase-4 (DPP-4) inhibitors, hemoglobin A1C, FPG and body weight. During searching, the term alogliptin was used alone and in an alternate combination with other search terms with the help of Boolean logic (and/or).
The inclusion criteria for this meta-analysis were: 1) double-blind randomized controlled studies that weighted the efficacy and tolerability of alogliptin against placebo or other antidiabetic drugs in patients with type 2 diabetes; 2) studies that were published in English and have a duration of therapy not less than 12 weeks; and 3) studies which recruited patients with baseline glycosylated hemoglobin level (HbA1c) ≥ 7% and studies that provide information on change in percentage of HbA1c for every treatment group (alogliptin 12.5 mg, alogliptin 25 mg and placebo or other drug). The study selection was independently conducted by both authors. When there were discrepancies, it was resolved by discussion and by reviewing the studies in detail.
After developing a common data extraction template, the following information were abstracted from the selected studies by both authors separately with standard Excel spreadsheet: name of authors, year of publication, study design, study location, drugs before and after recruitment, duration of therapy, sample size, least squared (LS) mean and standard deviation (SD) or standard error (SE) of changes (in hemoglobinA1c, FPG, body weight and serum lipids), number of patients achieving HbA1c ≤ 7%, number of patients with reduction of HbA1c by ≥ 1.0%, number of discontinued patients due to adverse event, and number of patients with a specific adverse events.
In the selected studies, controls could receive placebo or other antidiabetic drug or other antidiabetic drug plus placebo. In this meta-analysis, the term alogliptin alone is to mean that patients were given either only alogliptin 25 mg or 12.5 mg. Similarly, alogliptin add-on is to mean that patients received either alogliptin 12.5 mg or 25 mg plus other antidiabetic drugs. Antidiabetic naïve is to mean patients who were not on antidiabetic drug; while antidiabetic drug experienced patients were on antidiabetic therapy before the start of the studies.
Before the actual meta-analysis was conducted, some mathematical transformations and unit conversions were done. In case of continuous variables (change in HbA1c, FPG, body weight and serum lipids), where SE was reported instead of SD, we changed it to SD by multiplying the SE by the square root of sample size (SD = SE*√N). In studies where the change in FPG was reported as mg/dl, it was converted to mmol/l by using an online converter. In one study, we have extrapolated values for reduction of HbA1c by ≥ 1.0% from a bar graph.
The effectiveness and tolerability of the two doses of alogliptin (12.5 mg and 25 mg) alone and as an added-on with other antidiabetic drug as compared to placebo or other antidiabetic drug were determined using the random effects model. SMDs and Mantel-Haenszel (M-H) odds ratios were determined. SMD and 95% confidence intervals (95% CI) for the mean change in HbA1c, FPG, body weight and serum lipids from baseline were computed using the inverse variance method. The odds ratios and the 95% confidence intervals for achieving HbA1c ≤ 7%, reduction HbA1c by ≥ 1%, treatment discontinuations due to adverse events and experiencing adverse events (hypertension, hypoglycemia, skin or subcutaneous adverse events etc.) were computed with Mantel-Haenszel method.
To assess the heterogeneity among the studies, chi-squared test (Cochran Q test) and I statistics were used. An I value of ≥ 50% was considered as statistically significant. Subgroup analysis based on the use of alogliptin as monotherapy or add-on therapy (alogliptin alone vs alogliptin with other antidiabetic drug), patients' antidiabetic drug exposure history (antidiabetic drug experienced vs antidiabetic naïve) and the sites of the studies (studies in a single country at multiple sites vs multiple country studies) were planned and conducted. On the other hand, meta-regression was limited to one covariate (duration of therapy) to avoid false-positive findings. Sensitivity analysis was also conducted to see the stability of the pooled values and the change in I when any of the study was withdrawn from the analysis.
Risk of bias of individual studies was assessed with the Cochrane risk of bias tool. The predefined key domains include: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. A bias that is unlikely to affect the result was considered as "low risk of bias", while a bias that raises doubt about the results was considered as "unclear risk of bias" and bias that seriously affect the results was considered as "high risk of bias". To evaluate publication/disclosure bias, we have used funnel plots. Nevertheless, the tests for funnel plot asymmetry were not done as recommended in meta-analyses of randomized controlled trials with fewer than ten studies. We reported the meta-analysis by following the PRISMA checklist. The analyses were conducted with Review Manager (RevMan) Version 5.1 software and Comprehensive Meta-Analysis Software.
Methods
Search Strategy
Computer based search for literature on alogliptin was performed by AB in MEDLINE, Cochrane library, and HINARI databases. Via HINARI, literature search were also conducted on publishers' websites (Elsevier Science-Science Direct, Nature Publishing Group, Oxford University Press, PsycARTICLES, Science, Wiley-Blackwell and Springer Link). The search was further strengthened by searching relevant literature from the reference lists of retrieved articles. The search terms include: alogliptin or NESINA® or SYR-322, type 2 diabetes mellitus, dipeptidyl peptidase-4 (DPP-4) inhibitors, hemoglobin A1C, FPG and body weight. During searching, the term alogliptin was used alone and in an alternate combination with other search terms with the help of Boolean logic (and/or).
Study Selection
The inclusion criteria for this meta-analysis were: 1) double-blind randomized controlled studies that weighted the efficacy and tolerability of alogliptin against placebo or other antidiabetic drugs in patients with type 2 diabetes; 2) studies that were published in English and have a duration of therapy not less than 12 weeks; and 3) studies which recruited patients with baseline glycosylated hemoglobin level (HbA1c) ≥ 7% and studies that provide information on change in percentage of HbA1c for every treatment group (alogliptin 12.5 mg, alogliptin 25 mg and placebo or other drug). The study selection was independently conducted by both authors. When there were discrepancies, it was resolved by discussion and by reviewing the studies in detail.
Data Extraction
After developing a common data extraction template, the following information were abstracted from the selected studies by both authors separately with standard Excel spreadsheet: name of authors, year of publication, study design, study location, drugs before and after recruitment, duration of therapy, sample size, least squared (LS) mean and standard deviation (SD) or standard error (SE) of changes (in hemoglobinA1c, FPG, body weight and serum lipids), number of patients achieving HbA1c ≤ 7%, number of patients with reduction of HbA1c by ≥ 1.0%, number of discontinued patients due to adverse event, and number of patients with a specific adverse events.
Operational Definitions
In the selected studies, controls could receive placebo or other antidiabetic drug or other antidiabetic drug plus placebo. In this meta-analysis, the term alogliptin alone is to mean that patients were given either only alogliptin 25 mg or 12.5 mg. Similarly, alogliptin add-on is to mean that patients received either alogliptin 12.5 mg or 25 mg plus other antidiabetic drugs. Antidiabetic naïve is to mean patients who were not on antidiabetic drug; while antidiabetic drug experienced patients were on antidiabetic therapy before the start of the studies.
Data Synthesis & Statistical Analysis
Before the actual meta-analysis was conducted, some mathematical transformations and unit conversions were done. In case of continuous variables (change in HbA1c, FPG, body weight and serum lipids), where SE was reported instead of SD, we changed it to SD by multiplying the SE by the square root of sample size (SD = SE*√N). In studies where the change in FPG was reported as mg/dl, it was converted to mmol/l by using an online converter. In one study, we have extrapolated values for reduction of HbA1c by ≥ 1.0% from a bar graph.
The effectiveness and tolerability of the two doses of alogliptin (12.5 mg and 25 mg) alone and as an added-on with other antidiabetic drug as compared to placebo or other antidiabetic drug were determined using the random effects model. SMDs and Mantel-Haenszel (M-H) odds ratios were determined. SMD and 95% confidence intervals (95% CI) for the mean change in HbA1c, FPG, body weight and serum lipids from baseline were computed using the inverse variance method. The odds ratios and the 95% confidence intervals for achieving HbA1c ≤ 7%, reduction HbA1c by ≥ 1%, treatment discontinuations due to adverse events and experiencing adverse events (hypertension, hypoglycemia, skin or subcutaneous adverse events etc.) were computed with Mantel-Haenszel method.
To assess the heterogeneity among the studies, chi-squared test (Cochran Q test) and I statistics were used. An I value of ≥ 50% was considered as statistically significant. Subgroup analysis based on the use of alogliptin as monotherapy or add-on therapy (alogliptin alone vs alogliptin with other antidiabetic drug), patients' antidiabetic drug exposure history (antidiabetic drug experienced vs antidiabetic naïve) and the sites of the studies (studies in a single country at multiple sites vs multiple country studies) were planned and conducted. On the other hand, meta-regression was limited to one covariate (duration of therapy) to avoid false-positive findings. Sensitivity analysis was also conducted to see the stability of the pooled values and the change in I when any of the study was withdrawn from the analysis.
Risk of bias of individual studies was assessed with the Cochrane risk of bias tool. The predefined key domains include: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. A bias that is unlikely to affect the result was considered as "low risk of bias", while a bias that raises doubt about the results was considered as "unclear risk of bias" and bias that seriously affect the results was considered as "high risk of bias". To evaluate publication/disclosure bias, we have used funnel plots. Nevertheless, the tests for funnel plot asymmetry were not done as recommended in meta-analyses of randomized controlled trials with fewer than ten studies. We reported the meta-analysis by following the PRISMA checklist. The analyses were conducted with Review Manager (RevMan) Version 5.1 software and Comprehensive Meta-Analysis Software.