Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis

Abstract

Aims/hypothesis Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes. Methods We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA1c from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA1c target of <53 mmol/mol (<7.0%), ≤48 mmol/mol (≤6.5%) or <39 mmol/mol (<5.7%), and proportion of individuals with body weight loss of at least 5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. We used version 2 of the Cochrane risk-of-bias tool for randomised trials to assess risk of bias for the primary outcome. Results Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from −17.71 mmol/mol (−1.62%) to −22.35 mmol/mol (−2.06%) vs placebo, −3.22 mmol/mol (−0.29%) to −10.06 mmol/mol (−0.92%) vs GLP-1 RAs, and −7.66 mmol/mol (−0.70%) to −12.02 mmol/mol (−1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality. Conclusions/interpretation A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA1c and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449. Graphical abstract

Optimal dose of tirzepatide for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis

“…Previous meta-analyses have shown that TZP is significantly more effective than GLP-1RA and insulin in lowering glycemia and reducing weight, and does not increase total AEs or cardiovascular risk ( 14 , 53 ), promising a new strategy for the treatment of T2DM. Meta-analyses published by Karagiannis et al ( 20 ) and Bhagavathula et al ( 21 ) comparing the efficacy and safety of TZP with placebo, insulin and GLP-1 RA for the treatment of T2DM confirmed that TZP was significantly more effective in lowering glycemia than placebo, insulin and GLP-1RA. Six clinical studies and a sample size of 4,358 were included in this meta-analysis and TSA, which is the first publication so far to study different doses of TZP in the treatment of T2DM.…”

“…TZP has been reported to lower glycemia and reduce weight significantly better than insulin and GLP-1RA ( 14 ), with the additional benefit of decreasing metabolites such as triglycerides and lipoproteins ( 19 ), and is expected to be a preferred strategy for the treatment of T2DM. The meta-analyses published by Karagiannis et al ( 20 ) and Bhagavathula et al ( 21 ) compared the efficacy and safety of TZP with placebo, insulin and GLP-1 RA in the treatment of T2DM, which confirmed that the hypoglycemic effect of TZP was significantly better than that of placebo, insulin and GLP-1RA. Unfortunately, they did not make an internal comparison of different doses of TZP, and it is unclear the optimal dose and dose adjustment strategy of TZP for the treatment of T2DM.…”

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

“…It has impressive glycemic efficacy. Moreover, it is the first effective drug to have demonstrated notable body weight loss in a phase 3 study in patients with T2D [38][39][40]. Tirzepatide has significantly better therapeutic efficacy than current drugs [20,41].…”

“…Some other additional effects of tirzepatide were noted to lowering of the concentrations of very low-density lipoproteins and triglycerides, in addition to a reduction in blood pressure, as well as an elevation in high-density lipoprotein concentration. The adverse events most commonly reported were nausea, vomiting, and diarrhea, which were mild to moderate and occurred mostly during the dose-escalation period [40,54]. Further, in a phase 2 human clinical study with tirzepatide in conjunction with regulated nutrition and lifestyle The LPPS portion of the synthesis consisted of four steps and was carried out in a plug-flow reactor (PFR) [50].…”

Transitioning to active-controlled trials to evaluate cardiovascular safety and efficacy of medications for type 2 diabetes

“…Tirzepatide is a novel, once-weekly, injectable, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA, is being developed for the treatment of type 2 diabetes (T2D) and obesity [ 26 ] with CV safety demonstrated in the late phase clinical program [ 27 , 28 ]. The ‘Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes (SURPASS CVOT)’ trial is the first trial designed to evaluate the CV efficacy of a novel antihyperglycemic medication for T2DM compared with a blinded active comparator with proven, product labeled CV efficacy, dulaglutide.…”