Williams‐Herman 2010.
| Study characteristics | ||
| Methods | Study design: parallel RCT | |
| Participants |
Inclusion criteria: T2DM, age between 18 – 78 Exclusion criteria: T1DM, unstable cardiac disease, significant renal impairment (estimated creatinine clearance < 60 mL/min), or elevated (more than twofold the upper limit of normal) alanine aminotransferase or aspartate aminotransferase Diagnostic criteria: not reported |
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| Interventions |
Intervention(s): metformin (1000 mg/day), metformin (2000 mg/day) Comparator(s)1: sitagliptin Duration of intervention: 104 weeks Duration of follow‐up: 104 weeks Run‐in period: participants with HbA1c between 7.5% to 11% and not on any glucose‐lowering agents for 8 weeks were eligible to directly enter a 2‐week, single‐blind, placebo run‐in period. Participants with HbA1c > 11% and not on any glucose‐lowering drug entered a diet and exercise run‐in period of up to 6 weeks, and people on an glucose‐lowering drug with HbA1c between 7% to 10.5% had the agent(s) discontinued and entered a wash‐off period of 6 to 10 weeks (8 to 12 weeks for those on thiazolidinediones). After the wash‐off/run‐in period, participants with HbA1c between 7.5% to 11% entered a 2‐week, single‐blind, placebo run‐in period. All participants with adequate compliance (≥ 75% as assessed by tablet counts) during the placebo run‐in period had baseline assessments and were randomised. Participants who met non‐glycaemic eligibility criteria but who had HbA1c > 11% or a fasting glucose value > 280 mg/dL after the run‐in period were not randomised Number of study centres: 140 in base study and 117 in extension study |
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| Outcomes | Reported outcome(s) in full text of publication: glycaemic variables, anthropometric measures, safety, lipid profile | |
| Study details |
Trial identifier:NCT00103857 Trial terminated early: no |
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| Publication details |
Language of publication: English Funding: commercial funding Merck & Co., Inc., Whitehouse Station, NJ Publication status: peer‐reviewed journal/full article |
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| Stated aim for study |
Quote from publication: "To evaluate the longer term efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy..." |
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| Notes | 1There were more comparators in this study which were not of interest to this review | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk |
Quote from publication: "Patients then had baseline assessments and were randomized to one of six treatments using a computer‐generated allocation schedule" Comment: method of random sequence generation adequately described |
| Allocation concealment (selection bias) | Unclear risk |
Quote from publication: "Patients then had baseline assessments and were randomized to one of six treatments using a computer‐generated allocation schedule" Comment: method of allocation concealment inadequately described |
| Blinding of participants and personnel (performance bias) all‐cause mortality | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of participants and personnel (performance bias) cardiovascular mortality | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of participants and personnel (performance bias) non‐fatal myocardial infarction | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of participants and personnel (performance bias) non‐fatal stroke | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of participants and personnel (performance bias) serious adverse events | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of participants and personnel (performance bias) severe hypoglycaemia | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of outcome assessment (detection bias) all‐cause mortality | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of outcome assessment (detection bias) cardiovascular mortality | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of outcome assessment (detection bias) non‐fatal myocardial infarction | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of outcome assessment (detection bias) serious adverse events | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of outcome assessment (detection bias) severe hypoglycaemia | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Blinding of outcome assessment (detection bias) non fatal stroke | Low risk |
Quote from publication: "... double‐blind, double‐dummy..." "Laboratory measurements and ECGs were analysed at central laboratories... by technicians blinded to treatment group..." Comment: investigator‐assessed outcome measurement, blinding inadequately described, however, outcome not judged to be influenced by a lack of blinding |
| Incomplete outcome data (attrition bias) all‐cause mortality | Low risk |
Quote from publication: "The population for the safety analysis included all randomized patients... who received at least one dose of blinded study medication during the 104‐week treatment period... All serious adverse experiences and reported deaths are summarized herein regardless of initiation of glycaemic rescue therapy." Comment: 100% of randomised participants included in the analysis, high dropout rate (36.3% to 52.2% of participants completed the study) and not balanced between arms, reasons for missing data balanced between arms, unclear how missing data were handled, it is assumed that mortality status has been investigated in death registers at the end of the study |
| Incomplete outcome data (attrition bias) cardiovascular mortality | Low risk |
Quote from publication: "The population for the safety analysis included all randomized patients... who received at least one dose of blinded study medication during the 104‐week treatment period... All serious adverse experiences and reported deaths are summarized herein regardless of initiation of glycaemic rescue therapy." Comment: 100% of randomised participants included in the analysis, high dropout rate (36.3% to 52.2% of participants completed the study) and not balanced between arms, reasons for missing data balanced between arms, unclear how missing data were handled, it is assumed that mortality status has been investigated in death registers at the end of the study and none of the reported deaths were of cardiovascular nature |
| Incomplete outcome data (attrition bias) non‐fatal myocardial infarction | High risk |
Quote from publication: "The population for the safety analysis included all randomized patients... who received at least one dose of blinded study medication during the 104‐week treatment period... All serious adverse experiences and reported deaths are summarized herein regardless of initiation of glycaemic rescue therapy." Comment: 100% of randomised participants included in the analysis, high dropout rate (36.3% to 52.2% of participants completed the study) and not balanced between arms, reasons for missing data similar between arms, unclear how missing data were handled, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate |
| Incomplete outcome data (attrition bias) non‐fatal stroke | High risk |
Quote from publication: "The population for the safety analysis included all randomized patients... who received at least one dose of blinded study medication during the 104‐week treatment period... All serious adverse experiences and reported deaths are summarized herein regardless of initiation of glycaemic rescue therapy." Comment: 100% of randomised participants included in the analysis, high dropout rate (36.3% to 52.2% of participants completed the study) and not balanced between arms, reasons for missing data similar between arms, unclear how missing data were handled, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate |
| Incomplete outcome data (attrition bias) serious adverse events | High risk |
Quote from publication: "The population for the safety analysis included all randomized patients... who received at least one dose of blinded study medication during the 104‐week treatment period... All serious adverse experiences and reported deaths are summarized herein regardless of initiation of glycaemic rescue therapy." Comment: 100% of randomised participants included in the analysis, high dropout rate (36.3% to 52.2% of participants completed the study) and not balanced between arms, reasons for missing data similar between arms, unclear how missing data were handled, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate |
| Incomplete outcome data (attrition bias) severe hypoglycaemia | High risk |
Quote from publication: "The population for the safety analysis included all randomized patients... who received at least one dose of blinded study medication during the 104‐week treatment period... All serious adverse experiences and reported deaths are summarised herein regardless of initiation of glycaemic rescue therapy." Comment: 100% of randomised participants included in the analysis, high dropout rate (36.3% to 52.2% of participants completed the study) and not balanced between arms, reasons for missing data similar between arms, unclear how missing data were handled, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate |
| Selective reporting (reporting bias) | High risk | Comment: study protocol available. Several differences in study results between the main publication after 104 weeks of intervention and the trial in the trial registry. Intervention failure reported in an inadequate format that could not be used in our meta‐analysis, since it was unclear which population was used to calculate the risk of intervention failure. |
| Other bias | Unclear risk |
Quote: "The study was funded by Merck & Co., Inc., Whitehouse Station" Comment: received funding from a pharmaceutical company |