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This open-label, 40-week, phase 3 trial assessed the efficacy and safety of tirzepatide, a weekly dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist under development for type 2 diabetes. Tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks.

Insulin efsitora alfa (efsitora), a once-weekly basal insulin, has the potential to reduce the treatment burden of people with type 2 diabetes who require insulin. We aimed to assess the efficacy and safety of once-weekly efsitora compared with insulin glargine U100 in adults with type 2 diabetes treated with basal and prandial insulin. This phase 3, randomised, 26-week, parallel-design, open-label, treat-to-target, non-inferiority study was done at 78 outpatient clinics and hospitals in Argentina, Germany, India, Italy, Mexico, Spain, and the USA (including Puerto Rico). Participants with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0–10·0%) treated with basal and prandial insulin and up to three non-insulin glucose-lowering agents were randomly assigned (1:1) to efsitora or glargine U100, both with prandial insulin lispro. Randomisation was stratified by country, baseline HbA1c (<8% vs ≥8%; <63·9 mmol/mol vs ≥63·9 mmol/mol), and routine use of personal continuous glucose monitoring or flash glucose monitoring at randomisation (yes vs no). The primary endpoint was HbA1c change from baseline to week 26 (non-inferiority margin 0·4%). The completed trial is registered at ClinicalTrials.gov (NCT05462756). Between Aug 11, 2022, and Feb 27, 2024, 1037 study participants were screened and 730 were randomly assigned to efsitora (n=365) or glargine U100 (n=365). 369 (51%) of 730 participants were female and 361 (49%) were male, the mean participant age was 58·9 years (SD 10·5), and the mean participant BMI was 31·85 kg/m2 (SD 5·47). Using the treatment regimen estimand, the least-squares mean baseline HbA1c was 8·18% (SE 0·04; 65·9 mmol/mol [SE 0·47]) in the efsitora group and 8·18% (0·04; 65·9 mmol/mol [0·47]) in the glargine U100 group. At week 26, the least-squares mean HbA1c was 7·17% (SD 0·05; 54·8 mmol/mol [0·51]) in the efsitora group and 7·18 (0·05; 55·0 mmol/mol [0·51]) in the glargine U100 group. The change from baseline to week 26 using the treatment regimen estimand was –1·01 percentage points for the efsitora group and –1·00 percentage points for the glargine U100 group, indicating non-inferiority of efsitora versus glargine U100. Rates of overall and nocturnal level 2 (<54 mg/dL; 3·0 mmol/L) or level 3 (severe) hypoglycaemia during the treatment period were similar for efsitora versus glargine U100 (6·6 vs 5·9 events per patient-year of exposure, estimated rate ratio [ERR] 1·11, 95% CI 0·85–1·44; p=0·44; 0·67 vs 1·00 events per patient-year of exposure, ERR 0·67, 95% CI 0·44–1·01; p=0·058), respectively. Adverse event occurrence was similar between efsitora and glargine U100. Serious adverse events were reported by 25 (7%) of 365 participants in the efsitora group and 23 (6%) of 365 participants in the glargine U100 group. Efsitora showed non-inferior HbA1c reductions and similar rates of combined clinically significant or severe hypoglycaemia versus glargine U100 in participants with type 2 diabetes treated with basal and prandial insulin. These findings show that efsitora is a well tolerated and efficacious once-weekly alternative to daily basal insulin, with a reduced injection frequency, for the treatment of adults with type 2 diabetes. Eli Lilly and Company.

We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications. This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were −2·43% (SD 0·05) with 10 mg and −2·58% (0·05) with 15 mg, versus −1·44% (0·03) with glargine. The estimated treatment difference versus glargine was −0·99% (multiplicity adjusted 97·5% CI −1·13 to −0·86) for tirzepatide 10 mg and −1·14% (−1·28 to −1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite <1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose <54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. Eli Lilly and Company.

Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Furthermore, patients with T2DM and acute coronary syndrome (ACS) have a particularly high risk of CV events. The glucagon-like peptide 1 receptor agonist, lixisenatide, improves glycemia, but its effects on CV events have not been thoroughly evaluated. ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of lixisenatide in patients with T2DM and a recent ACS event. The primary aim is to evaluate the effects of lixisenatide on CV morbidity and mortality in a population at high CV risk. The primary efficacy end point is a composite of time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Data are systematically collected for safety outcomes, including hypoglycemia, pancreatitis, and malignancy. Enrollment began in July 2010 and ended in August 2013; 6,068 patients from 49 countries were randomized. Of these, 69% are men and 75% are white; at baseline, the mean ± SD age was 60.3 ± 9.7 years, body mass index was 30.2 ± 5.7 kg/m2, and duration of T2DM was 9.3 ± 8.2 years. The qualifying ACS was a myocardial infarction in 83% and unstable angina in 17%. The study will continue until the positive adjudication of the protocol-specified number of primary CV events. ELIXA will be the first trial to report the safety and efficacy of a glucagon-like peptide 1 receptor agonist in people with T2DM and high CV event risk.