Umpierrez 2014.
| Study characteristics | ||
| Methods | Study design: parallel RCT | |
| Participants |
Inclusion criteria: age above 18 years, T2DM, duration between 3 months to 5 years inclusive, HbA1c between 6.5% to 9.5% inclusive, diet and exercise alone or on one oral glucose‐lowering drug for more than or equal to 3 months prior to screening. Individuals who were receiving glucose‐lowering drugs were only eligible if they were taking ≤ 50% of the approved maximum daily dose per respective labels in participating countries Exclusion criteria: previously taking thiazolidinediones or GLP‐1 receptor agonists during the 3 months prior to screening or had ever received chronic insulin therapy Diagnostic criteria: not reported |
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| Interventions |
Intervention(s): metformin Comparator(s): dulaglutide (1.5 mg/week), dulaglutide (0.75 mg/week) Duration of intervention: 52 weeks Duration of follow‐up: 56 weeks Run‐in period: 2 weeks without any glucose‐lowering drugs Number of study centres: not reported |
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| Outcomes | Reported outcome(s) in full text of publication: glycaemic variables, anthropometric measures, safety, blood pressure | |
| Study details |
Trial identifier:NCT01126580 Trial terminated early: no |
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| Publication details |
Language of publication: English Funding: commercial funding (Eli Lilly and Company) Publication status: peer‐reviewed journal full article |
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| Stated aim for study | Quote from publication: "[...] to evaluate the efficacy and safety of monotherapy with once‐weekly dulaglutide compared with daily metformin in patients with early stage type 2 diabetes over a period of 52 weeks." | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk |
Quote from publication: "Randomization occurred, stratified by country and prior OAM use, according to a computer‐generated random sequence using an interactive voice response system" Comment: method of random sequence generation adequately described |
| Allocation concealment (selection bias) | Low risk |
Quote from publication: "Randomization occurred, stratified by country and prior OAM use, according to a computer‐generated random sequence using an interactive voice response system" Comment: method of allocation concealment adequately described |
| Blinding of participants and personnel (performance bias) all‐cause mortality | Low risk |
Quote from publication: "...double‐blind, double‐dummy (both injectable and oral placebo)..." Comment: investigator‐assessed outcome, 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 (both injectable and oral placebo)..." "Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by an external committee of physicians with cardiology expertise" Comment: adjudicated‐assessed outcome, 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 (both injectable and oral placebo)..." "Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by an external committee of physicians with cardiology expertise" Comment: adjudicated‐assessed outcome, adequate blinding |
| Blinding of participants and personnel (performance bias) non‐fatal stroke | Low risk |
Quote from publication: "...double‐blind, double‐dummy (both injectable and oral placebo)..." "Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by an external committee of physicians with cardiology expertise" Comment: adjudicated‐assessed outcome, adequate blinding |
| Blinding of participants and personnel (performance bias) serious adverse events | Low risk |
Quote from publication: "...double‐blind, double‐dummy (both injectable and oral placebo)..." Comment: investigator‐assessed outcome, 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 (both injectable and oral placebo)..." Comment: investigator‐assessed outcome, 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 (both injectable and oral placebo)..." Comment: investigator‐assessed outcome, 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 (both injectable and oral placebo)..." "Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by an external committee of physicians with cardiology expertise" Comment: adjudicated‐assessed outcome, adequate blinding |
| Blinding of outcome assessment (detection bias) non‐fatal myocardial infarction | Low risk |
Quote from publication: "...double‐blind, double‐dummy (both injectable and oral placebo)..." "Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by an external committee of physicians with cardiology expertise" Comment: adjudicated‐assessed outcome, adequate blinding |
| Blinding of outcome assessment (detection bias) serious adverse events | Low risk |
Quote from publication: "...double‐blind, double‐dummy (both injectable and oral placebo)..." Comment: investigator‐assessed outcome, 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 (both injectable and oral placebo)..." Comment: investigator‐assessed outcome, 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 (both injectable and oral placebo)..." "Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by an external committee of physicians with cardiology expertise" Comment: adjudicated‐assessed outcome, adequate blinding |
| Incomplete outcome data (attrition bias) all‐cause mortality | Low risk |
Quote from publication: "The analyses of efficacy and safety were based on the intent‐to‐treat population consisting of all randomized patients who received at least one dose of study treatment." "The last observation was carried forward (LOCF) for missing data" Comment: 100% of participants included in the analysis, high drop out rate (79.5% to 81.8% of participants completed the study) but balanced between arms, reasons for missing data not similar between arms, inappropriate use of LOCF for handling missing data, 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 analyses of efficacy and safety were based on the intent‐to‐treat population consisting of all randomized patients who received at least one dose of study treatment." "The last observation was carried forward (LOCF) for missing data" Comment: 100% of participants included in the analysis, high drop out rate (79.5% ‐ 81.8% of participants completed the study) but balanced between arms, reasons for missing data not similar between arms, inappropriate use of LOCF for handling missing data, it is assumed that mortality status has been investigated in death registers at the end of the study |
| Incomplete outcome data (attrition bias) non‐fatal myocardial infarction | High risk |
Quote from publication: "The analyses of efficacy and safety were based on the intent‐to‐treat population consisting of all randomized patients who received at least one dose of study treatment." "The last observation was carried forward (LOCF) for missing data" Comment: 100% of participants included in the analysis, high drop out rate (79.5% to 81.8% of participants completed the study) but balanced between arms, reasons for missing data not similar between arms, inappropriate use of LOCF for handling missing data, 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 analyses of efficacy and safety were based on the intent‐to‐treat population consisting of all randomized patients who received at least one dose of study treatment." "The last observation was carried forward (LOCF) for missing data" Comment: 100% of participants included in the analysis, high drop out rate (79.5% to 81.8% of participants completed the study) but balanced between arms, reasons for missing data not similar between arms, inappropriate use of LOCF for handling missing data, 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 analyses of efficacy and safety were based on the intent‐to‐treat population consisting of all randomized patients who received at least one dose of study treatment." "The last observation was carried forward (LOCF) for missing data" Comment: 100% of participants included in the analysis, high drop out rate (79.5% ‐ 81.8% of participants completed the study) but balanced between arms, reasons for missing data not similar between arms, inappropriate use of LOCF for handling missing data, 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: "For the assessment of efficacy and hypoglycemia, only data obtained prior to rescue medication were used" "The last observation was carried forward (LOCF) for missing data" Comment: 100% of participants included in the analysis, high drop out rate (79.5% to 81.8% of participants completed the study) but balanced between arms, reasons for missing data not similar between arms, inadequate population used for analysis since only data prior to rescue medication were used, inappropriate use of LOCF for handling missing data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate |
| Selective reporting (reporting bias) | Low risk | Comment: study protocol available. All prespecified outcomes of interest to this review reported adequately |
| Other bias | Unclear risk |
Quote: "G.U. has received research funding for investigator‐initiated studies from Sanofi, Merck, Novo Nordisk, and Boehringer Ingelheim. S.T.P. has received honoraria for lectures and research funding from Eli Lilly and Company. L.S. and V.P. are employees of Eli Lilly and Company. V.P. is a stock/shareholder at Eli Lilly and Company." Comment: risk of funding bias |