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IntroductionParticipants in randomised controlled trials (trials) are generally younger and healthier than many individuals encountered in clinical practice. Consequently, the applicability of trial findings is often uncertain. To address this, results from trials can be calibrated to more representative data sources. In a network meta-analysis, using a novel approach which allows the inclusion of trials whether or not individual-level participant data (IPD) is available, we will calibrate trials for three drug classes (sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor analogues and dipeptidyl peptidase-4 (DPP4) inhibitors) to the Scottish diabetes register.Methods and analysisMedline and EMBASE databases, the US clinical trials registry (clinicaltrials.gov) and the Chinese Clinical Trial Registry (chictr.org.cn) will be searched from 1 January 2002. Two independent reviewers will apply eligibility criteria to identify trials for inclusion. Included trials will be phase 3 or 4 trials of SGLT2 inhibitors, GLP1 receptor analogues or DPP4 inhibitors, with placebo or active comparators, in participants with type 2 diabetes, with at least one of glycaemic control, change in body weight or major adverse cardiovascular event as outcomes. Unregistered trials will be excluded.We have identified a target population from the population-based Scottish diabetes register. The chosen cohort comprises people in Scotland with type 2 diabetes who either (1) require further treatment due to poor glycaemic control where any of the three drug classes may be suitable, or (2) who have adequate glycaemic control but are already on one of the three drug classes of interest or insulin.Ethics and disseminationEthical approval for IPD use was obtained from the University of Glasgow MVLS College Ethics Committee (Project: 200160070). The Scottish diabetes register has approval from the Scottish A Research Ethics Committee (11/AL/0225) and operates with Public Benefit and Privacy Panel for Health and Social Care approval (1617-0147).PROSPERO registration numberCRD42020184174.

Background Although there is general agreement that metformin should be used as first-line pharmacotherapy in patients with type 2 diabetes, uncertainty remains regarding the choice of second-line therapy once metformin is no longer effective. We conducted a systematic review and meta-analysis to assess the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Methods MEDLINE, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to October 2009. Additional citations were obtained from grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected studies, extracted data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, quality of life, long-term diabetes-related complications, serious adverse drug events and mortality. Mixed-treatment comparison and pairwise meta-analyses were conducted to pool trial results, when appropriate. Results We identified 49 active and non-active controlled randomized trials that compared 2 or more of the following classes of antihyperglycemic agents and weight-loss agents: sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins, alpha-glucosidase inhibitors, sibutramine and orlistat. All classes of second-line antihyperglycemic therapies achieved clinically meaningful reductions in hemoglobin A1c (0.6% to 1.0%). No significant differences were found between classes. Insulins and insulin secretagogues were associated with significantly more events of overall hypoglycemia than the other agents, but severe hypoglycemia was rarely observed. An increase in body weight was observed with the majority of second-line therapies (1.8 to 3.0 kg), the exceptions being DPP-4 inhibitors, alpha-glucosidase inhibitors and GLP-1 analogues (0.6 to –1.8 kg). There were insufficient data available for diabetes complications, mortality or quality of life. Interpretation DPP-4 inhibitors and GLP-1 analogues achieved improvements in glycemic control similar to those of other second-line therapies, although they may have modest benefits in terms of weight gain and overall hypoglycemia. Further long-term trials of adequate power are required to determine whether newer drug classes differ from older agents in terms of clinically meaningful outcomes.