TY - JOUR AB - INTRODUCTION: The relative efficacy and safety of tirzepatide was compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM) treated with basal insulin using a network meta-analysis (NMA). METHODS: A systematic literature review was performed to identify randomized controlled trials of GLP-1 RAs in patients with T2DM treated with insulin and an antihyperglycaemic drug. For the NMA, studies included trials with 100% of patients treated with basal insulin background therapy with a titration scheme comparable to the SURPASS-5 trial. The following data were extracted for efficacy and safety assessment at the primary endpoint of each study: changes from baseline in glycated haemoglobin (HbA1c) and body weight and the incidence of nausea, vomiting or diarrhoea, hypoglycaemia, and patients discontinuing treatment because of adverse events. In this study, a comparative analysis of tirzepatide was performed with the GLP-1 RAs dulaglutide, exenatide, and lixisenatide in addition to placebo. RESULTS: A total of six studies were included across the analyses. Tirzepatide 5, 10, and 15 mg showed statistically significant, greater reductions in HbA1c and body weight at the primary endpoint versus all GLP-1 RA comparators and placebo. Tirzepatide 5, 10, and 15 mg showed a statistically significant, higher likelihood of experiencing nausea compared with those who received placebo or exenatide 2 mg; no statistically significant differences were observed when compared with all other GLP-1 RA comparators. No statistically significant differences were observed in the proportions of patients who discontinued treatment because of adverse events when tirzepatide 5, 10, and 15 mg were compared with GLP-1 RA comparators, apart from tirzepatide 10 and 15 mg versus placebo. CONCLUSION: Tirzepatide demonstrated statistically significantly greater reductions in HbA1c and body weight when compared with selected GLP-1 RAs and placebo in patients with T2DM treated with basal insulin. Overall, the safety profile of tirzepatide was similar to that of GLP-1RAs. AU - Osumili, B.* AU - Sapin, H.* AU - Yang, Z.* AU - Ranta, K.* AU - Paik, J.S.* AU - Blüher, M. C1 - 74055 C2 - 57315 CY - Tiergartenstrasse 17, D-69121 Heidelberg, Germany SP - 1279-1311 TI - Efficacy and safety of tirzepatide compared with GLP-1 RAs in patients with type 2 diabetes treated with basal insulin: A network meta-analysis. JO - Diabetes Ther. VL - 16 IS - 6 PB - Springer Heidelberg PY - 2025 SN - 1869-6961 ER - TY - JOUR AB - The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut-brain communication can be leveraged to achieve sustained body weight loss without adverse effects. AU - Gutgesell, R.M. AU - Nogueiras, R.* AU - Tschöp, M.H. AU - Müller, T.D. C1 - 70435 C2 - 55625 CY - Tiergartenstrasse 17, D-69121 Heidelberg, Germany SP - 1069-1084 TI - Dual and triple incretin-based co-agonists: Novel therapeutics for obesity and diabetes. JO - Diabetes Ther. VL - 15 IS - 5 PB - Springer Heidelberg PY - 2024 SN - 1869-6961 ER - TY - JOUR AB - Plain Language Summary Blood glucose progressively increases over time in type 2 diabetes and is currently treated in a stepwise fashion, with more medications added when a single treatment fails. The VERIFY trial studied people with newly or recently diagnosed type 2 diabetes. Treating people early with two glucose-lowering drugs given together could slow the worsening of blood glucose levels, compared with starting with metformin first and then adding a second treatment later. Taking the two treatments together was as well tolerated as taking the single treatment alone. Starting treatment with two glucose-lowering drugs given together lengthened the time before insulin was needed, compared with starting with metformin and then adding a second treatment later. This is important to people with diabetes, as early treatment is straightforward but becomes increasingly complicated in later stages. The long-term benefits of this early combination treatment are awaited. In the meantime, the VERIFY trial has shown that combination therapy given at the start of treatment with medication can improve blood glucose levels and delay the need for insulin.The treatment aims for type 2 diabetes are to prevent complications and premature mortality, and improve quality of life. Glycaemic control is central to these aims; clinical guidelines have sought to achieve this with a stepwise approach starting with lifestyle measures and metformin, adding further medications once glycated haemoglobin (HbA(1c)) levels rise above a predefined threshold. However, treatment intensification can be delayed when HbA(1c)levels increase, and HbA(1c)levels become inadequately controlled in many patients. Clinical inertia can result in sustained elevated levels of HbA(1c); when combined with a late diagnosis, this negatively impacts patients' prognosis. Early combination therapy using medications with complementary modes of action could achieve optimal glycaemic targets and alter the course of the disease more than metformin alone. The multinational VERIFY study (clinicaltrials.gov NCT01528254) provided evidence accrued over 5 years, demonstrating the potential of early combination therapy: time to loss of glycaemic control was nearly doubled, and more than twice the number of patients experienced extended glycaemic control, with a vildagliptin-metformin combination therapy versus metformin alone. The study also showed a delay in secondary treatment failure in patients receiving the combination. Early combination therapy therefore offers a different trajectory to the stepwise approach. Translating these findings into clinical practice will require early detection and diagnosis of type 2 diabetes plus a shift in disease management. Nonetheless, the potential benefits of sustained and continuous disease control that early combination therapy offers represent the start of a new era in early diagnosis and intensive management, to achieve the treatment aims of type 2 diabetes. AU - Matthews, D.* AU - Del Prato, S.* AU - Mohan, V.* AU - Mathieu, C.* AU - Vencio, S.* AU - Chan, J.C.N.* AU - Stumvoll, M. AU - Paldánius, P.M.* C1 - 60172 C2 - 49427 CY - Tiergartenstrasse 17, D-69121 Heidelberg, Germany SP - 2465-2476 TI - Insights from VERIFY: Early combination therapy provides better glycaemic durability than a stepwise approach in newly diagnosed type 2 diabetes. JO - Diabetes Ther. VL - 11 IS - 11 PB - Springer Heidelberg PY - 2020 SN - 1869-6961 ER - TY - JOUR AB - Introduction: Treatment options and decisions are often based on the results of clinical trials. We have evaluated the public availability of results from completed, registered phase III clinical trials on diabetic nephropathy and current treatment options. Methods: This was a cross-sectional analysis in which STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. In June 2017, 34 completed phase III clinical trials on diabetic nephropathy in the ClinicalTrials. gov registry were identified and matched to publications in the ClinicalTrials.gov registry and to those in the PubMed and Google Scholar databases. If no publication was identified, the principal investigator was contacted. The ratio of published and non-published studies was calculated. Various parameters, including study design, drugs, and comparators provided, were analyzed. Results: Drugs/supplements belonged to 26 different categories of medications, with the main ones being angiotensin-converting enzyme inhibitors, angiotensin-II receptors blockers, and dipeptidyl-peptidase-4-inhibitors. Among the trials completed before 2016 (n = 32), 22 (69%) were published, and ten (31%) remained unpublished. Thus, data on 11 different interventions and more than 1000 patients remained undisclosed. Mean time to publication was 26.5 months, which is longer than the time constrictions imposed by the U.S. Food and Drug Administration Amendments Act. Most trials only showed weak effects on micro- and macroalbuminuria, with an absolute risk reduction of 1.0 and 0.3%, respectively, and the number needed to treat varied between 91 and 333, without any relevant effect on end-stage-renal disease by intensive glucose-lowering treatment. Comparison of the results, however, was difficult since study design, interventions, and the renal outcome parameters vary greatly between the studies. Conclusion: Despite the financial and human resources involved and the relevance for therapeutic guidelines and clinical decisions, about one-third of phase III clinical trials on diabetic nephropathy remain unpublished. Interventions used in published trials showed a low efficacy on renal outcome. Funding: Deutsche Forschungsgemeinschaft (DFG): SFB 1118. AU - Modafferi, S.* AU - Ries, M.* AU - Calabrese, V.* AU - Schmitt, C.P.* AU - Nawroth, P.P. AU - Kopf, S.* AU - Peters, V.* C1 - 55416 C2 - 46280 SP - 229-243 TI - Clinical trials on diabetic nephropathy: A cross-sectional analysis. JO - Diabetes Ther. VL - 10 IS - 1 PY - 2019 SN - 1869-6961 ER -