Dulaglutide

Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.

Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain. We conducted an active-comparator-controlled, double-blind, noninferiority trial in which patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned in a 1:1 ratio to receive a weekly subcutaneous injection of tirzepatide (up to 15 mg) or dulaglutide (1.5 mg), an agent that has been shown to reduce the incidence of cardiovascular events. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke and was tested for noninferiority of tirzepatide to dulaglutide with a margin of 1.05 for the upper limit of the 95.3% confidence interval for the hazard ratio. An upper limit of less than 1.00 was considered to indicate superiority of tirzepatide to dulaglutide. A total of 13,299 patients underwent randomization; 134 were subsequently excluded because they did not meet inclusion criteria. The modified intention-to-treat population thus included 6586 patients in the tirzepatide group and 6579 in the dulaglutide group. The mean (±SD) age of the patients was 64.1±8.8 years, 29.0% were women, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 32.6±5.5, the mean glycated hemoglobin level was 8.4±0.9%, and the mean duration of diabetes was 14.7±8.8 years. A primary end-point event occurred in 801 patients (12.2%) in the tirzepatide group and 862 (13.1%) in the dulaglutide group (hazard ratio, 0.92; 95.3% confidence interval, 0.83 to 1.01; P = 0.003 for noninferiority; P = 0.09 for superiority). The incidence of adverse events appeared to be similar in the two groups, although more gastrointestinal adverse events were observed in the tirzepatide group. Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, tirzepatide was noninferior to dulaglutide with respect to a composite of death from cardiovascular causes, myocardial infarction, or stroke. (Funded by Eli Lilly; SURPASS-CVOT ClinicalTrials.gov number, NCT04255433.).

Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial.

Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes. This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA1c 7&#xb7;0-10&#xb7;5% (53&#xb7;0-91&#xb7;0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0&#xb7;5 mg, dulaglutide 0&#xb7;75 mg, semaglutide 1&#xb7;0 mg, or dulaglutide 1&#xb7;5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA1c; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA1c non-inferiority (margin 0&#xb7;4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204. Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to semaglutide 0&#xb7;5 mg, 299 to dulaglutide 0&#xb7;75 mg, 300 to semaglutide 1&#xb7;0 mg, and 299 to dulaglutide 1&#xb7;5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0&#xb7;5 mg, 13 receiving dulaglutide 0&#xb7;75 mg, 21 receiving semaglutide 1&#xb7;0 mg, and 16 receiving dulaglutide 1&#xb7;5 mg). From overall baseline mean, mean percentage HbA1c was reduced by 1&#xb7;5 (SE 0&#xb7;06) percentage points with semaglutide 0&#xb7;5 mg versus 1&#xb7;1 (0&#xb7;05) percentage points with dulaglutide 0&#xb7;75 mg (estimated treatment difference [ETD] -0&#xb7;40 percentage points [95% CI -0&#xb7;55 to -0&#xb7;25]; p<0&#xb7;0001) and by 1&#xb7;8 (0&#xb7;06) percentage points with semaglutide 1&#xb7;0 mg versus 1&#xb7;4 (0&#xb7;06) percentage points with dulaglutide 1&#xb7;5 mg (ETD -0&#xb7;41 percentage points [-0&#xb7;57 to -0&#xb7;25]; p<0&#xb7;0001). From overall baseline mean, mean bodyweight was reduced by 4&#xb7;6 kg (SE 0&#xb7;28) with semaglutide 0&#xb7;5 mg compared with 2&#xb7;3 kg (0&#xb7;27) with dulaglutide 0&#xb7;75 mg (ETD -2&#xb7;26 kg [-3&#xb7;02 to -1&#xb7;51]; p<0&#xb7;0001) and by 6&#xb7;5 kg (0&#xb7;28) with semaglutide 1&#xb7;0 mg compared with 3&#xb7;0 kg (0&#xb7;27) with dulaglutide 1&#xb7;5 mg (ETD -3&#xb7;55 kg [-4&#xb7;32 to -2&#xb7;78]; p<0&#xb7;0001). Gastrointestinal disorders were the most frequently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0&#xb7;5 mg, 133 (44%) of 300 patients receiving semaglutide 1&#xb7;0 mg, 100 (33%) of 299 patients receiving dulaglutide 0&#xb7;75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1&#xb7;5 mg. Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group. At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile. Novo Nordisk.

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study.

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7&#xb7;0-10&#xb7;5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1&#xb7;5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58&#xb7;9 years, HbA1c was 8&#xb7;1%, BMI was 35&#xb7;2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2&#xb7;10% (-1&#xb7;67% placebo adjusted), versus -0&#xb7;43% with placebo and -1&#xb7;10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0&#xb7;8% to -1&#xb7;7%). Change in mean bodyweight at week 26 was up to -10&#xb7;1 kg (95% CI -11&#xb7;5 to -8&#xb7;7; 7&#xb7;9 kg placebo adjusted [-9&#xb7;9 to -5&#xb7;9]) with orforglipron versus -2&#xb7;2 kg (-3&#xb7;6 to -0&#xb7;7) for placebo and -3&#xb7;9 kg (-5&#xb7;3 to -2&#xb7;4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61&#xb7;8% to 88&#xb7;9% in orforglipron-treated participants, compared with 61&#xb7;8% with placebo and 56&#xb7;0% with dulaglutide. The majority were gastrointestinal events (44&#xb7;1% to 70&#xb7;4% with orforglipron, 18&#xb7;2% with placebo, and 34&#xb7;0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company.

Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial.

As the disease progresses, many patients with type 2 diabetes have difficulty in reaching treatment goals. We aimed to assess the efficacy and safety of tirzepatide, a novel GIP and GLP-1 receptor agonist, compared with dulaglutide in Japanese patients with type 2 diabetes. This multicentre, randomised, double-blind, parallel, active-controlled, phase 3 trial was conducted in 46 medical research centres and hospitals in Japan. Adults aged 20 years or older with type 2 diabetes who had discontinued oral antihyperglycaemic monotherapy or were treatment-na&#xef;ve were included. Participants were randomly assigned (1:1:1:1) to receive tirzepatide (5, 10, or 15 mg) or dulaglutide (0&#xb7;75 mg) once per week using a computer-generated random sequence with an Interactive Web Response System. Participants were stratified based on baseline HbA1c (&#x2264;8&#xb7;5% or >8&#xb7;5%), baseline BMI (<25 or &#x2265;25 kg/m2), and washout of antidiabetic medication. Participants, investigators, and the sponsor were masked to treatment assignment. The starting dose of tirzepatide was 2&#xb7;5 mg once per week for 4 weeks, which was then increased to 5 mg in the tirzepatide 5 mg treatment group. For the tirzepatide 10 and 15 mg treatment groups, increases by 2&#xb7;5 mg occurred once every 4 weeks until the assigned dose was reached. The primary endpoint was mean change in HbA1c from baseline at week 52 measured in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03861052. Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n=159), 10 mg (n=158), or 15 mg (n=160), or dulaglutide 0&#xb7;75 mg (n=159). 615 (97%) participants completed the study and 21 (3%) discontinued. Participants had a mean age of 56&#xb7;6 years (SD 10&#xb7;3) and were mostly male (481 [76%]). At week 52, HbA1c decreased from baseline by a least squares mean of -2&#xb7;4 (SE 0&#xb7;1) for tirzepatide 5 mg, -2&#xb7;6 (0&#xb7;1) for tirzepatide 10 mg, -2&#xb7;8 (0&#xb7;1) for tirzepatide 15 mg, and -1&#xb7;3 (0&#xb7;1) for dulaglutide. Estimated mean treatment differences versus dulaglutide were -1&#xb7;1 (95% CI -1&#xb7;3 to -0&#xb7;9) for tirzepatide 5 mg, -1&#xb7;3 (-1&#xb7;5 to -1&#xb7;1) for tirzepatide 10 mg, and -1&#xb7;5 (-1&#xb7;71 to -1&#xb7;4) for tirzepatide 15 mg (all p<0&#xb7;0001). Tirzepatide was associated with dose-dependent reductions in bodyweight with a least square mean difference of -5&#xb7;8 kg (SE 0&#xb7;4; -7&#xb7;8% reduction) for 5 mg, -8&#xb7;5 kg (0&#xb7;4; -11&#xb7;0% reduction) for 10 mg, and -10&#xb7;7 kg (0&#xb7;4; -13&#xb7;9% reduction) for 15 mg of tirzepatide compared with -0&#xb7;5 kg (0&#xb7;4; -0&#xb7;7% reduction) for dulaglutide. The most common treatment-emergent adverse events were nausea (19 [12%] participants in the 5 mg group vs 31 [20%] in the 10 mg group vs 32 [20%] in the 15 mg group all receiving tirzepatide vs 12 (8%) in the group receiving dulaglutide), constipation (24 [15%] vs 28 [18%] vs 22 [14%] vs 17 [11%]), and nasopharyngitis (29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]). The most frequent adverse events were gastrointestinal (23 [4%] of 636). Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 diabetes. Eli Lilly and Company. For the Japanese translation of the abstract see Supplementary Materials section.

Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.

Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Explore mechanisms of glucose control by tirzepatide. Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Forty-seven sites in 4 countries. Three hundred and sixteen subjects with type 2 diabetes. Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P &#x2264; .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P &#x2264; .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P &#x2264; .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P &#x2264; .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

Comparison of Dose Escalation Versus Switching to Tirzepatide Among People With Type 2 Diabetes Inadequately Controlled on Lower Doses of Dulaglutide : A Randomized Clinical Trial.

Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for the treatment of adults with type 2 diabetes or obesity, showed clinically meaningful reductions in hemoglobin A1c (HbA1c) and body weight in the SURPASS phase 3 clinical trial program. To compare efficacy and safety of escalation of dulaglutide dose versus switching to tirzepatide in inadequately controlled type 2 diabetes. Multicenter, randomized, open-label, phase 4 trial (SURPASS-SWITCH [A Phase 4, Randomized, Open-Label, Active-Controlled Study to Investigate the Efficacy and Safety of Switching from Weekly Dulaglutide to Weekly Tirzepatide in Adults with Type 2 Diabetes], ClinicalTrials.gov: NCT05564039). 38 sites across 5 countries. Adults with HbA1c 7.0% or greater to 9.5% or less, stable body weight, body mass index of 25 kg/m2 or greater, receiving a stable dose of dulaglutide (0.75 or 1.5 mg) for at least 6 months and 0 to 3 oral antihyperglycemic medications for at least 3 months. Escalation of dulaglutide to 4.5 mg or maximum tolerated dose (MTD) or switching to tirzepatide. The primary end point was change from baseline in HbA1c at week 40. The key secondary end point was change from baseline in weight at week 40. A total of 282 adults were randomly assigned to tirzepatide (n&#x2009;= 139) or dulaglutide (n&#x2009;= 143). Change from baseline in HbA1c at week 40 was -1.44% (SE, 0.07) with tirzepatide, 15 mg or MTD, and -0.67% (SE, 0.08) with dulaglutide, 4.5 mg or MTD (estimated treatment difference, -0.77% [95% CI, -0.98% to -0.56%; P&#x2009;<&#x2009;0.001]). Change from baseline in weight at week 40 was -10.5 kg (SE, 0.5) with tirzepatide and -3.6 kg (SE, 0.5) with dulaglutide (estimated treatment difference, -6.9 kg [CI, -8.3 to -5.5 kg; P&#x2009;<&#x2009;0.001]). Serious adverse events were reported by 10 (7.2%) tirzepatide and 10 (7.0%) dulaglutide participants. The most common treatment-emergent adverse events were nausea and diarrhea. Open-label design. In SURPASS-SWITCH, switching treatment to tirzepatide provided additional HbA1c reduction and weight loss compared with escalating treatment with dulaglutide. Eli Lilly and Company.

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial.

LY3298176 is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is being developed for the treatment of type 2 diabetes. We aimed to examine the efficacy and safety of co-stimulation of the GLP-1 and GIP receptors with LY3298176 compared with placebo or selective stimulation of GLP-1 receptors with dulaglutide in patients with poorly controlled type 2 diabetes. In this double-blind, randomised, phase 2 study, patients with type 2 diabetes were randomly assigned (1:1:1:1:1:1) to receive either once-weekly subcutaneous LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1&#xb7;5 mg), or placebo for 26 weeks. Assignment was stratified by baseline glycated haemoglobin A1c (HbA1c), metformin use, and body-mass index (BMI). Eligible participants (aged 18-75) had type 2 diabetes for at least 6 months (HbA1c 7&#xb7;0-10&#xb7;5%, inclusive), that was inadequately controlled with diet and exercise alone or with stable metformin therapy, and a BMI of 23-50 kg/m2. The primary efficacy outcome was change in HbA1c from baseline to 26 weeks in the modified intention-to-treat (mITT) population (all patients who received at least one dose of study drug and had at least one postbaseline measurement of any outcome). Secondary endpoints, measured in the mITT on treatment dataset, were change in HbA1c from baseline to 12 weeks; change in mean bodyweight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, and proportion of patients reaching the HbA1c target (&#x2264;6&#xb7;5% and <7&#xb7;0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% bodyweight loss from baseline to 26 weeks. This study is registered with ClinicalTrials.gov, number NCT03131687. Between May 24, 2017, and March 28, 2018, 555 participants were assessed for eligibility, of whom 318 were randomly assigned to one of the six treatment groups. Because two participants did not receive treatment, the modified intention-to-treat and safety populations included 316 participants. 258 (81&#xb7;7%) participants completed 26 weeks of treatment, and 283 (89&#xb7;6%) completed the study. At baseline, mean age was 57 years (SD 9), BMI was 32&#xb7;6 kg/m2 (5&#xb7;9), duration from diagnosis of diabetes was 9 years (6), HbA1c was 8&#xb7;1% (1&#xb7;0), 53% of patients were men, and 47% were women. At 26 weeks, the effect of LY3298176 on change in HbA1c was dose-dependent and did not plateau. Mean changes from baseline in HbA1c with LY3298176 were -1&#xb7;06% for 1 mg, -1&#xb7;73% for 5 mg, -1&#xb7;89% for 10 mg, and -1&#xb7;94% for 15 mg, compared with -0&#xb7;06% for placebo (posterior mean differences [80% credible set] vs placebo: -1&#xb7;00% [-1&#xb7;22 to -0&#xb7;79] for 1 mg, -1&#xb7;67% [-1&#xb7;88 to -1&#xb7;46] for 5 mg, -1&#xb7;83% [-2&#xb7;04 to -1&#xb7;61] for 10 mg, and -1&#xb7;89% [-2&#xb7;11 to -1&#xb7;67] for 15 mg). Compared with dulaglutide (-1&#xb7;21%) the posterior mean differences (80% credible set) for change in HbA1c from baseline to 26 weeks with the LY3298176 doses were 0&#xb7;15% (-0&#xb7;08 to 0&#xb7;38) for 1 mg, -0&#xb7;52% (-0&#xb7;72 to -0&#xb7;31) for 5 mg, -0&#xb7;67% (-0&#xb7;89 to -0&#xb7;46) for 10 mg, and -0&#xb7;73% (-0&#xb7;95 to -0&#xb7;52) for 15 mg. At 26 weeks, 33-90% of patients treated with LY3298176 achieved the HbA1c target of less than 7&#xb7;0% (vs 52% with dulaglutide, 12% with placebo) and 15-82% achieved the HbA1c target of at least 6&#xb7;5% (vs 39% with dulaglutide, 2% with placebo). Changes in fasting plasma glucose ranged from -0&#xb7;4 mmol/L to -3&#xb7;4 mmol/L for LY3298176 (vs 0&#xb7;9 mmol/L for placebo, -1&#xb7;2 mmol/L for dulaglutide). Changes in mean bodyweight ranged from -0&#xb7;9 kg to -11&#xb7;3 kg for LY3298176 (vs -0&#xb7;4 kg for placebo, -2&#xb7;7 kg for dulaglutide). At 26 weeks, 14-71% of those treated with LY3298176 achieved the weight loss target of at least 5% (vs 22% with dulaglutide, 0% with placebo) and 6-39% achieved the weight loss target of at least 10% (vs 9% with dulaglutide, 0% with placebo). Changes in waist circumference ranged from -2&#xb7;1 cm to -10&#xb7;2 cm for LY3298176 (vs -1&#xb7;3 cm for placebo, -2&#xb7;5 cm for dulaglutide). Changes in total cholesterol ranged from 0&#xb7;2 mmol/L to -0&#xb7;3 mmol/L for LY3298176 (vs 0&#xb7;3 mmol/L for placebo, -0&#xb7;2 mmol/L for dulaglutide). Changes in HDL or LDL cholesterol did not differ between the LY3298176 and placebo groups. Changes in triglyceride concentration ranged from 0 mmol/L to -0&#xb7;8 mmol/L for LY3298176 (vs 0&#xb7;3 mmol/L for placebo, -0&#xb7;3 mmol/L for dulaglutide). The 12-week outcomes were similar to those at 26 weeks for all secondary outcomes. 13 (4%) of 316 participants across the six treatment groups had 23 serious adverse events in total. Gastrointestinal events (nausea, diarrhoea, and vomiting) were the most common treatment-emergent adverse events. The incidence of gastrointestinal events was dose-related (23&#xb7;1% for 1 mg LY3298176, 32&#xb7;7% for 5 mg LY3298176, 51&#xb7;0% for 10 mg LY3298176, and 66&#xb7;0% for 15 mg LY3298176, 42&#xb7;6% for dulaglutide, 9&#xb7;8% for placebo); most events were mild to moderate in intensity and transient. Decreased appetite was the second most common adverse event (3&#xb7;8% for 1 mg LY3298176, 20&#xb7;0% for 5 mg LY3298176, 25&#xb7;5% for 10 mg LY3298176, 18&#xb7;9% for 15 mg LY3298176, 5&#xb7;6% for dulaglutide, 2&#xb7;0% for placebo). There were no reports of severe hypoglycaemia. One patient in the placebo group died from lung adenocarcinoma stage IV, which was unrelated to study treatment. The dual GIP and GLP-1 receptor agonist, LY3298176, showed significantly better efficacy with regard to glucose control and weight loss than did dulaglutide, with an acceptable safety and tolerability profile. Combined GIP and GLP-1 receptor stimulation might offer a new therapeutic option in the treatment of type 2 diabetes. Eli Lilly and Company.

Trends in glucagon-like peptide 1 receptor agonist use, 2014 to 2022.

Recent Food and Drug Administration approvals of glucagon-like peptide 1 (GLP-1) receptor agonists linked to substantial weight loss have generated interest in demand projections. However, a longitudinal analysis in a large, diverse, current, real-world database has not been published. The study objective was to determine user frequency of GLP-1 receptor agonist products overall and by type 2 diabetes (T2D), cardiovascular disease (CVD), and overweight or obese status. Secondary objective was monthly growth rate estimation by product since first appearance in University of California Health. This retrospective cohort study included patients who were dispensed a GLP-1 receptor agonist from 2014 to 2022 in the University of California Health Data Warehouse. Exponential growth rates were estimated using a log-linear regression model. Between 2014 and 2018, only Trulicity and Victoza exceeded 5000 annual users. Ozempic users increased from 569 in 2019 to 7667 in 2020. Use accelerated with more than 13,310 users in 2021 to surpass Trulicity. Ozempic count was 22,891 in 2022. Wegovy rose from 989 in 2021 to 2992 in 2022. Mounjaro increased to 1508 users in 2022. Although generally similar trends were observed for T2D, CVD, and overweight or obese subgroups, the ascent of Ozempic as most frequently used was more apparent in the overweight or obese group. The monthly growth rates were 83.9% for Ozempic, 119.2% for Wegovy, 84.8% for Rybelsus, 53.3% for Saxenda, 12.9% for Adlyxin, 78.8% for Trulicity, and 254.3% for Mounjaro. This first cohort study of weight loss-associated GLP-1 receptor agonists in a large, diverse, state-wide health system demonstrated a rapid increased use that represents a clear and likely durable transition in utilization for this category. Informed decision making and longitudinal studies are needed to ensure evidence-concordant prescribing and supply stability.

Effects of dulaglutide on alcohol consumption during smoking cessation.

BACKGROUNDAlcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODSThis is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTSIn the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33-53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52-0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSIONThese results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov NCT03204396.FUNDINGSwiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.

Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes.

The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).

Are Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Central Nervous System (CNS) Penetrant: A Narrative Review.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that modulates glucose metabolism and insulin secretion. Recent translational and clinical research has evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs), a class of drugs that mimic the action of native&#xa0;GLP-1 in the central nervous system (CNS). In addition to the efficacy of GLP-1 for the treatment of diabetes mellitus&#xa0;and obesity, preliminary evidence indicates GLP-1s have neuroprotective, therapeutic, and disease modification effects for select&#xa0;neurodegenerative disorders (e.g. Parkinson's disease, Alzheimer's disease). Among the available GLP-1&#xa0;RAs, relatively few have been shown to be&#xa0;CNS penetrant. This article synthesizes extant literature&#xa0;reporting on CNS penetrants of GLP-1 RAs as proxied by brain imaging studies. Where available, studies that reported on the bioavailability of GLP-1 RAs in the CNS were identified. A comprehensive search of PubMed, Ovid, and Web of Science from database inception to July 2024 was conducted. Inclusion criteria were English language publications with no date restrictions, preclinical and&#xa0;clinical studies with participants aged 18-80 and studies which focused on GLP-1 RAs including: "Semaglutide" or "Ozempic" or "Rybelsus" or "Wegovy" or "Dulaglutide" or "Trulicity" or "Exenatide" or "Byetta" or "Bydureon" or "Liraglutide" or "Lixisenatide" or "Tirzepatide" or "Mounjaro" or "Zepbound" or "Bydureon BCise" or "Adlyxin" or "Victoza" or "Saxenda". We identified 14 studies that were included in this synthesis. Preclinical studies suggest that select GLP-1 RAs cross the blood-brain barrier (BBB) (i.e.&#xa0;liraglutide, semaglutide, and exenatide). Replicated evidence suggests that CNS penetration of GLP-1 RAs can be proxied by reported effects of GLP-1 RAs on brain connectivity in human participants. &#xa0;Preclinical studies indicate that select GLP-1 RAs are CNS penetrant;&#xa0;whether GLP-1 RAs reproducibly engage neural targets hypothesized to subserve dimensions of psychopathology (e.g., general cognitive functions) remains incompletely characterized.

Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial.

New glucose-lowering medications need to be investigated in east Asian populations, as the clinical characteristics of type 2 diabetes differ between western and east Asian patients. The PIONEER 10 study aimed to evaluate the safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes. PIONEER 10 was an open-label, randomised, active-controlled, phase 3a trial done at 36 sites (clinics and university hospitals) in Japan. Patients aged 20 years and older with uncontrolled type 2 diabetes were randomly assigned (2:2:2:1) to receive once-daily oral semaglutide 3 mg, 7 mg, or 14 mg, or once-weekly subcutaneous dulaglutide 0&#xb7;75 mg for 52 weeks, as an add-on to their background medication. The primary endpoint was the number of treatment-emergent adverse events over 57 weeks. Supportive secondary endpoints (not controlled for multiplicity) included mean change from baseline in HbA1c and bodyweight at 52 weeks. This trial is registered with ClinicalTrials.gov, NCT03015220. Between Jan 10, and May 30, 2017, 492 patients were screened and 458 were randomly assigned to oral semaglutide 3 mg (n=131), 7 mg (n=132), or 14 mg (n=130), or dulaglutide 0&#xb7;75 mg (n=65). 448 (98%) patients completed the trial. Adverse events occurred in 101 (77%) of 131 patients with oral semaglutide 3 mg, 106 (80%) of 132 with oral semaglutide 7 mg, 111 (85%) of 130 with oral semaglutide 14 mg, and 53 (82%) of 65 with dulaglutide. The most common adverse events were infections and gastrointestinal events. Gastrointestinal adverse events (mostly mild and transient constipation and nausea) occurred in a dose-dependent manner with oral semaglutide. Adverse events led to premature treatment discontinuation in four (3%) of 131 patients receiving oral semaglutide 3 mg, eight (6%) of 132 receiving oral semaglutide 7 mg, eight (6%) of 130 receiving oral semaglutide 14 mg, and two (3%) of 65 receiving dulaglutide. No deaths or severe hypoglycaemic events were reported. Based on the treatment policy estimand (ie, regardless of study drug discontinuation or rescue medication use), estimated mean reductions in HbA1c from baseline (8&#xb7;3%) to week 52 were -0&#xb7;9 percentage points (SE 0&#xb7;1) with oral semaglutide 3 mg, -1&#xb7;4 percentage points (0&#xb7;1) with oral semaglutide 7 mg, -1&#xb7;7 percentage points (0&#xb7;1) with oral semaglutide 14 mg, and -1&#xb7;4 percentage points (0&#xb7;1) with dulaglutide (estimated treatment difference -0&#xb7;3% [95% CI -0&#xb7;6 to -0&#xb7;1] for oral semaglutide 14 mg vs dulaglutide; p=0&#xb7;0170). Estimated mean changes in bodyweight from baseline (72&#xb7;1 kg) to week 52 were 0&#xb7;0 kg (SE 0&#xb7;3) with oral semaglutide 3 mg, -0&#xb7;9 kg (0&#xb7;3) with oral semaglutide 7 mg, -1&#xb7;6 kg (0&#xb7;3) with oral semaglutide 14 mg, and 1&#xb7;0 kg (0&#xb7;4) with dulaglutide (estimated treatment difference -2&#xb7;6 kg [95% CI -3&#xb7;5 to -1&#xb7;6] for oral semaglutide 14 mg vs dulaglutide; p<0&#xb7;0001). Oral semaglutide was well tolerated in Japanese patients with type 2 diabetes. Once-daily oral semaglutide significantly reduced HbA1c (14 mg dose) and bodyweight (7 mg and 14 mg doses) versus weekly subcutaneous dulaglutide 0&#xb7;75 mg by week 52. Novo Nordisk.

Comparative effectiveness of semaglutide versus liraglutide, dulaglutide or tirzepatide: a systematic review and meta-analysis.

This study seeks to compare the effectiveness of Semaglutide compared to Liraglutide, Dulaglutide, or Tirzepatide. Additionally, it aims to investigate the implications of transitioning from Dulaglutide or Liraglutide to Semaglutide. We searched PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science (ClinicalTrials.gov for unpublished records) from their inception to 5 February 2025, including observational cohort studies and randomized controlled trials. Analyses were conducted using Review Manager (RevMan) version 5.4.1 and STATA 17. The meta-analysis comprised 16 studies and 5,997 patients. Semaglutide significantly reduced hemoglobin A1c (HbA1c) levels compared to Liraglutide (0.56; 95% CI: 0.19-0.94; p < 0.001). However, no significant differences were observed between Semaglutide and Liraglutide in terms of fasting blood sugar (FBS), body mass index (BMI), and weight change. In comparison to Dulaglutide, Semaglutide displayed superior efficacy in reducing HbA1c levels (3.72; 95% CI: 0.02-7.41; p = 0.05) and FBS (2.66; 95% CI: 0.26-5.07; p = 0.03). However, no significant differences were found in weight and BMI change. Tirzepatide exhibited a notable advantage over Semaglutide in reducing HbA1c levels (-0.45; 95% CI: -0.88 to -0.02; p = 0.04). However, no clear superiority was observed for weight and FBS change. Transitions from Liraglutide to Semaglutide did not significantly impact HbA1c levels. However, weight loss (2.48; 95% CI: 0.45-4.51; p = 0.02) and reduced FBS levels (10.76; 95% CI: 0.55-20; p = 0.04) were observed. Transitioning from Dulaglutide to Semaglutide did not significantly affect HbA1c levels and weight change. While the precise source of heterogeneity remains elusive across most studies, analyses consistently demonstrate Semaglutide's superior efficacy compared to Liraglutide in reducing both HbA1c levels and weight. Moreover, it presents advantages over Dulaglutide, specifically in lowering FBS levels. However, Tirzepatide surpasses Semaglutide in its efficacy for reducing HbA1c levels.

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

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the "Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes" trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.

Mazdutide versus dulaglutide in Chinese adults with type 2 diabetes.

Mazdutide is a once-weekly glucagon and glucagon-like peptide&#x2009;1 receptor dual agonist developed for the treatment of type 2 diabetes (T2D)1. Here we report on a randomized phase III trial assessing the efficacy and safety of mazdutide, compared with dulaglutide, in participants with T2D who were also treated with background oral anti-diabetic drugs. In this study, 731 participants with T2D were randomized 1:1:1 to receive 4&#x2009;mg mazdutide, 6&#x2009;mg mazdutide or 1.5&#x2009;mg dulaglutide for 28 weeks. Both doses of mazdutide showed non-inferiority and superiority to the 1.5-mg dose of dulaglutide in terms of the mean change in the diagnostic marker glycated haemoglobin A1c (HbA1c) from baseline to week 28, with a least-squares mean treatment difference of -0.24% (P&#x2009;=&#x2009;0.0032) for 4&#x2009;mg mazdutide and -0.30% (P&#x2009;=&#x2009;0.0003) for 6&#x2009;mg mazdutide, relative to 1.5&#x2009;mg dulaglutide. Significantly greater reductions in body weight were achieved with mazdutide than with dulaglutide, with a least-squares mean treatment difference of -3.78% for 4&#x2009;mg mazdutide and -5.76% for 6&#x2009;mg mazdutide (both P&#x2009;<&#x2009;0.0001), relative to dulaglutide. Moreover, significantly more participants who received mazdutide 4 mg or 6 mg&#xa0;reached the composite end point of HbA1c&#x2009;<&#x2009;7.0% with a body-weight reduction of at least 5% at week 28 (both P&#x2009;<&#x2009;0.0001), compared with those who received dulaglutide. The most common treatment-emergent adverse events were diarrhoea, nausea and vomiting. In summary, we found that in Chinese participants with T2D, 28 weeks of treatment with mazdutide (4&#x2009;mg and 6&#x2009;mg) provided reductions in HbA1c and body weight that were superior to those attained with 1.5&#x2009;mg dulaglutide. Mazdutide was generally safe, although the incidence of gastrointestinal adverse events was higher for mazdutide than for dulaglutide.

Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial.

Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged &#x2265;50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9&#xb7;5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1&#xb7;5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1&#xb7;5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5&#xb7;4 (IQR 5&#xb7;1-5&#xb7;9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4&#xb7;05 per 100 patient-years in participants assigned dulaglutide and 4&#xb7;35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0&#xb7;93, 95% CI 0&#xb7;85-1&#xb7;02; p=0&#xb7;11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0&#xb7;86, 95% CI 0&#xb7;79-0&#xb7;95; p=0&#xb7;0018). Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. Eli Lilly and Company.

Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.

Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. Assess plasma metabolome changes mediated by tirzepatide. Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. Post hoc analysis. 259 subjects with T2D. Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.

Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial.

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycaemic control and reduce bodyweight in patients with type 2 diabetes through different mechanisms. We assessed the safety and efficacy of the addition of the once-weekly GLP-1 receptor agonist dulaglutide to the ongoing treatment regimen in patients whose diabetes is inadequately controlled with SGLT2 inhibitors, with or without metformin. AWARD-10 was a phase 3b, double-blind, parallel-arm, placebo-controlled, 24-week study done at 40 clinical sites in Austria, Czech Republic, Germany, Hungary, Israel, Mexico, Spain, and the USA. Eligible adult patients (&#x2265;18 years) with inadequately controlled type 2 diabetes (HbA1c concentration &#x2265;7&#xb7;0% [53 mmol/mol] and &#x2264;9&#xb7;5% [80 mmol/mol]), a BMI of 45 kg/m2 or less, and taking stable doses (>3 months) of an SGLT2 inhibitor (with or without metformin) were randomly assigned (1:1:1) via an interactive web-response system to subcutaneous injections of either dulaglutide 1&#xb7;5 mg, dulaglutide 0&#xb7;75 mg, or placebo once per week for 24 weeks. Patients and investigators were masked to dulaglutide and placebo assignment, and those assessing outcomes were masked to study drug assignment. The primary objective was to test for the superiority of dulaglutide (1&#xb7;5 mg or 0&#xb7;75 mg) versus placebo for change in HbA1c concentration from baseline at 24 weeks. All analyses were done in the intention-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02597049. Between Dec 7, 2015, and Feb 3, 2017, 424 patients were randomly assigned to dulaglutide 1&#xb7;5 mg (n=142), dulaglutide 0&#xb7;75 mg (n=142), and placebo (n=140). One patient in the dulaglutide 0&#xb7;75 mg group was excluded from the analysis because they did not receive any dose of the study drug. The reduction in HbA1c concentration at 24 weeks was larger in patients receiving dulaglutide (least squares mean [LSM] for dulaglutide 1&#xb7;5 mg -1&#xb7;34% [SE 0&#xb7;06] or -14&#xb7;7 mmol/mol [0&#xb7;6]; dulaglutide 0&#xb7;75 mg -1&#xb7;21% [0&#xb7;06] or -13&#xb7;2 mmol/mol [0&#xb7;6]) than in patients receiving placebo (-0&#xb7;54% [0&#xb7;06] or -5&#xb7;9 mmol/mol [0&#xb7;6]; p<0&#xb7;0001 for both groups vs placebo). The LSM differences were -0&#xb7;79% (95% CI -0&#xb7;97 to -0&#xb7;61) or -8&#xb7;6 mmol/mol (-10&#xb7;6 to -6&#xb7;7) for dulaglutide 1&#xb7;5 mg and -0&#xb7;66% (-0&#xb7;84 to -0&#xb7;49) or -7&#xb7;2 mmol/mol (-9&#xb7;2 to -5&#xb7;4) for dulaglutide 0&#xb7;75 mg (p<0&#xb7;0001 for both). Serious adverse events were reported for five (4%) patients in the dulaglutide 1&#xb7;5 mg group, three (2%) patients in the dulaglutide 0&#xb7;75 mg group, and five (4%) patients in the placebo group. Treatment-emergent adverse events were more common in patients treated with dulaglutide than in patients who received placebo, mainly because of an increased incidence of gastrointestinal adverse events. Nausea (21 [15%] patients in the dulaglutide 1&#xb7;5 mg group vs seven [5%] in the dulaglutide 0&#xb7;75 mg group vs five [4%] in the placebo group), diarrhoea (eight [6%] vs 14 [10%] vs four [3%]), and vomiting (five [4%] vs four [3%] vs one [1%]) were more common with dulaglutide than with placebo. One episode of severe hypoglycaemia was reported in the dulaglutide 0&#xb7;75 mg group. Two (1%) patients receiving dulaglutide 1&#xb7;5 mg died, but these deaths were not considered to be related to study drug; no deaths occurred in the other groups. Dulaglutide as add-on treatment to SGLT2 inhibitors (with or without metformin) resulted in significant and clinically relevant improvements in glycaemic control, with acceptable tolerability that is consistent with the established safety profile of dulaglutide. Eli Lilly and Company.

Comparative Effectiveness of Tirzepatide Versus Dulaglutide or Semaglutide on Major Cardiovascular Events in Type 2 Diabetes and Cardiovascular Disease: Insights From Two Target-Trial Emulations.

To evaluate the comparative effectiveness of dulaglutide or semaglutide versus tirzepatide on cardiovascular outcomes in adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). Two target trial emulations included commercially insured adults (June 2022-December 2024) with T2D and ASCVD who initiated subcutaneous tirzepatide, dulaglutide, or semaglutide. The primary outcome was modified major adverse cardiovascular events (MACE), defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. First, new users of tirzepatide and dulaglutide were propensity score (PS) matched one to one. Second, new users of tirzepatide and semaglutide were PS matched one to one. Incidence rates (IRs) per 1,000 person-years and hazard ratios (HRs) were estimated. After PS matching, 9,233 pairs of tirzepatide or dulaglutide initiators and 25,266 pairs of tirzepatide or semaglutide initiators were identified. Tirzepatide initiators experienced a lower rate of modified MACE versus dulaglutide initiators (IR 31.3 vs. 39.4, respectively; HR 0.80 [95% CI 0.65-0.99]), which seemed to be driven by lower all-cause mortality among tirzepatide versus dulaglutide initiators (HR 0.60 [95% CI 0.43-0.83]). In post hoc analyses, tirzepatide was associated with lower rates of pneumonia-related hospitalization when compared with dulaglutide. Rates of modified MACE were similar among tirzepatide and semaglutide initiators (IR 23.7 vs. 23.2, respectively; HR 1.03 [95% CI 0.90-1.17]). Among adults with T2D and ASCVD in routine care, tirzepatide was associated with a lower risk of modified MACE when compared with dulaglutide, driven by reduction in all-cause mortality. Risks of modified MACE seemed similar with tirzepatide and semaglutide.

Improvement of glycaemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 1 study).

To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycaemic control and treatment satisfaction in patients with type 2 diabetes. In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8&#xa0;mg/day (plan A) or dulaglutide 0.75&#x2009;mg/week (plan B) were either switched to semaglutide or continued current therapy. The primary endpoint was the mean change in glycated haemoglobin over 24&#x2009;weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire scores, body weight and metabolic indices. In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. Glycated haemoglobin levels were significantly reduced in the semaglutide group in both plans [plan A, 7.8%&#x2009;&#xb1;&#x2009;1.0% to 7.8%&#x2009;&#xb1;&#x2009;0.7% (liraglutide) vs. 7.9%&#x2009;&#xb1;&#x2009;0.7% to 7.3%&#x2009;&#xb1;&#x2009;0.7% (semaglutide), p&#x2009;<&#x2009;.01; plan B, 7.8%&#x2009;&#xb1;&#x2009;1.0% to 7.9%&#x2009;&#xb1;&#x2009;1.2% (dulaglutide) vs. 7.8%&#x2009;&#xb1;&#x2009;0.8% to 7.1%&#x2009;&#xb1;&#x2009;0.6% (semaglutide), p&#x2009;<&#x2009;.01]. Semaglutide also improved Diabetes Treatment Satisfaction Questionnaire scores in both groups (plan A, +0.1 vs. +8.3, p&#x2009;<&#x2009;.01; plan B, -1.2 vs. +3.5, p&#x2009;<&#x2009;.01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. Once-weekly semaglutide administration improved glycaemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite glucagon-like receptor-1 receptor agonist treatment.

Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11).

To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients. Mean baseline HbA1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA1c, using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%). In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile.

Effects of a Dulaglutide plus Calorie-Restricted Diet versus a Calorie-Restricted Diet on Visceral Fat and Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.

The effects of dulaglutide and a calorie-restricted diet (CRD) on visceral adipose tissue (VAT) and metabolic profiles in polycystic ovary syndrome (PCOS) have not been extensively investigated. In this study, we investigated whether dulaglutide combined with CRD could further reduce VAT and promote clinical benefits as compared with a CRD regimen alone in overweight or obese PCOS-affected women. Between May 2021 and May 2022, this single-center, randomized, controlled, open-label clinical trial was conducted. Overall, 243 participants with PCOS were screened, of which 68 overweight or obese individuals were randomly randomized to undergo dulaglutide combined with CRD treatment (n = 35) or CRD treatment alone (n = 33). The duration of intervention was set as the time taken to achieve a 7% weight loss goal from baseline body weight, which was restricted to 6 months. The primary endpoint was the difference in the change in VAT area reduction between the groups. The secondary endpoints contained changes in menstrual frequency, metabolic profiles, hormonal parameters, liver fat, and body composition. As compared with the CRD group, the dulaglutide + CRD group had a considerably shorter median time to achieve 7% weight loss. There was no significant between-group difference in area change of VAT reduction (-0.97 cm2, 95% confidence interval from -14.36 to 12.42, p = 0.884). As compared with CRD alone, dulaglutide + CRD had significant advantages in reducing glycated hemoglobin A1c and postprandial plasma glucose levels. The results of the analyses showed different changes in menstruation frequency, additional metabolic profiles, hormonal markers, liver fat, and body composition between the two groups did not differ significantly. Nausea, vomiting, constipation, and loss of appetite were the main adverse events of dulaglutide. These results emphasize the value of dietary intervention as the first line of treatment for PCOS-affected women, while glucagon-like peptide 1 receptor agonist therapy provides an efficient and typically well tolerated adjuvant therapy to aid in reaching weight targets based on dietary therapy in the population of overweight/obese PCOS-affected women.

Comparison of Semaglutide or Dulaglutide Versus Empagliflozin for Risk for Death and Cardiovascular Outcomes Among Patients With Type 2 Diabetes : Two Target Trial Emulation Studies.

Reduction of premature death and adverse cardiovascular outcomes is a key goal in type 2 diabetes management. To compare mortality and cardiovascular event risks in patients treated with semaglutide versus empagliflozin and, secondarily, dulaglutide versus empagliflozin. Target trial emulation studies from observational data comparing semaglutide- or dulaglutide-treated patients with propensity score-matched patients treated with empagliflozin. Health care system of 703 academic and community clinical practices. Patients aged 45 years or older with type 2 diabetes treated from 1 January 2019 to 31 December 2024 with semaglutide, dulaglutide, or empagliflozin. Initial treatment with semaglutide, dulaglutide, or empagliflozin. At baseline, concomitant treatment with other diabetes medication was permitted, excluding other glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors. A composite of death, myocardial infarction (MI), or stroke was the primary outcome, and secondary composite outcomes included death or MI, MI or stroke, and individual cardiac events. Patients treated with semaglutide (n = 7899) versus empagliflozin (n = 7899) were followed for a median of 2.2 years; the respective rates of the composite of death, MI, or stroke were 3.7% versus 4.5% at 2 years and 5.9% versus 6.9% at 3 years. Corresponding incidence rates for the composite outcome were 20.99 versus 23.56 per 1000 person-years, with a hazard ratio (HR) of 0.89 (95% CI, 0.78 to 1.02). The HRs for the individual outcomes were 0.97 (CI, 0.81 to 1.15) for death, 0.85 (CI, 0.68 to 1.05) for MI, and 0.62 (CI, 0.43 to 0.89) for stroke. Risks for dulaglutide- and empagliflozin-treated patients were similar for the composite outcome (HR, 1.03 [CI, 0.90 to 1.16]) and for death, MI, and stroke separately. Observational study design, lack of data on cause-specific mortality, and residual confounding. Semaglutide treatment seems to confer some advantage over empagliflozin. This advantage was not observed for dulaglutide. American Heart Association.

REWIND Diabetes for Octogenarians.

Efficacy and safety of cAMP-biased GLP-1 receptor agonist ecnoglutide versus dulaglutide in patients with type 2 diabetes and elevated glucose concentrations on metformin monotherapy (EECOH-2): a 52-week, multicentre, open-label, non-inferiority, randomised, phase 3 trial.

Ecnoglutide is a novel biased GLP-1 receptor agonist that preferentially activates the cAMP pathway over &#x3b2;-arrestin recruitment. We aimed to assess both non-inferiority and superiority of ecnoglutide versus dulaglutide, also a GLP-1 receptor agonist, in patients with type 2 diabetes. We conducted a 52-week, open-label, active-controlled, phase 3 trial at 52 hospitals in China. Adults aged 18-75 years with a BMI of 20-35 kg/m2, a diagnosis of type 2 diabetes, and elevated glucose concentrations on metformin monotherapy were included. Participants were randomly assigned (1:1:1) to receive subcutaneous ecnoglutide (0&#xb7;6 mg or 1&#xb7;2 mg) or dulaglutide (1&#xb7;5 mg) once weekly. The primary endpoint was mean change from baseline in HbA1c at week 32 (non-inferiority for ecnoglutide 0&#xb7;6 mg and 1&#xb7;2 mg, with a 0&#xb7;4% non-inferiority margin; superiority for ecnoglutide 1&#xb7;2 mg) and was assessed in all randomly assigned participants who received at least one dose of study treatment (full analysis set). Safety was assessed in all randomly assigned participants who received at least one dose of study drug and had at least one safety evaluation after starting treatment. This trial is registered with ClinicalTrials.gov (NCT05680129) and has ended. Between Jan 10 and May 30, 2023, 623 participants were randomly assigned, of whom 621 comprised the full analysis set (mean age 53&#xb7;9 years [SD 10&#xb7;1], 347 [56%] males, 274 [44%] females, and mean HbA1c 8&#xb7;40% [SD 0&#xb7;78]; 68&#xb7;28 mmol/mol [8&#xb7;56]; 206 in the ecnoglutide 0&#xb7;6 mg group, 208 in the ecnoglutide 1&#xb7;2 mg group, and 207 in the dulaglutide 1&#xb7;5 mg group). At week 32, mean HbA1c reductions were 1&#xb7;91% (SE 0&#xb7;05; -20&#xb7;86 mmol/mol [0&#xb7;53]) with ecnoglutide 0&#xb7;6 mg, 1&#xb7;89% (0&#xb7;05; -20&#xb7;69 mmol/mol [0&#xb7;54]) with ecnoglutide 1&#xb7;2 mg, and 1&#xb7;65% (0&#xb7;05; -18&#xb7;02 mmol/mol [0&#xb7;53]) with dulaglutide. Estimated treatment differences versus dulaglutide were -0&#xb7;26% (95% CI -0&#xb7;39 to -0&#xb7;13; -2&#xb7;84 mmol/mol [-4&#xb7;29 to -1&#xb7;38]) with ecnoglutide 0&#xb7;6 mg and -0&#xb7;24% (-0&#xb7;38 to -0&#xb7;11; -2&#xb7;67 mmol/mol [-4&#xb7;14 to -1&#xb7;20]; p=0&#xb7;0002 for superiority) with ecnoglutide 1&#xb7;2 mg. HbA1c reductions were sustained to week 52. During the 52 weeks, six (3%) of 206 patients in the ecnoglutide 0&#xb7;6 mg group, eight (4%) of 208 patients in the ecnoglutide 1&#xb7;2 mg group, and six (3%) of 207 patients in the dulaglutide group discontinued treatment due to adverse events. Once-weekly ecnoglutide 0&#xb7;6 mg and 1&#xb7;2 mg were non-inferior to dulaglutide 1&#xb7;5 mg in reducing HbA1c in adults with type 2 diabetes and elevated glucose concentrations on metformin monotherapy. Although the 1&#xb7;2 mg dose showed statistically significantly greater reductions in HbA1c from baseline to week 32 than dulaglutide 1&#xb7;5 mg, the difference was not considered clinically relevant. Both doses of ecnoglutide were well tolerated. These results suggest that ecnoglutide might offer a new treatment option for type 2 diabetes. Hangzhou Sciwind Biosciences.

Cardiorenal Outcomes With Tirzepatide Compared With Dulaglutide in Patients With Diabetes and Cardiovascular Disease: A Post Hoc Analysis of the SURPASS-CVOT Randomized Clinical Trial.

The dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide was noninferior to a GLP-1 agonist, dulaglutide, for effects on the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke. However, comparison for a comprehensive range of major adverse cardiovascular and kidney outcomes has not been reported. To perform a post hoc analysis for an expanded range of adverse outcomes in a completed randomized clinical trial comparing the effects of tirzepatide and dulaglutide in patients with type 2 diabetes and cardiovascular disease. This parallel-design double-blind trial enrolled patients with diabetes and preexisting cardiovascular disease (from May 29, 2020, to June 27, 2022) at 640 centers in North and South America, Europe, Asia, and Oceania. Data were analyzed from July 2025 to February 2026. Participants were randomized to receive subcutaneous tirzepatide up to 15 mg (n&#x2009;=&#x2009;6586) or a fixed dose of dulaglutide, 1.5 mg (n&#x2009;=&#x2009;6579), administered weekly. The primary efficacy measure was time from randomization to first occurrence of a 6-component composite of cardiorenal adverse outcomes, including all-cause mortality, MI, stroke, coronary revascularization, hospitalization for heart failure, and a composite of adverse kidney outcomes. Among the 13&#x202f;165 patients enrolled, the mean (SD) age was 64 (8.8) years; 9348 patients (71.0%) were male and 3817 were female (29.0%). The mean (SD) hemoglobin A1c was 8.4% (0.93). After a median (IQR) treatment duration of 46.9 (34.6-50.6) months, the primary cardiorenal end point occurred in 1559 tirzepatide-treated patients (23.7%) and 1803 dulaglutide-treated patients (27.4%; hazard ratio [HR], 0.84; 95% CI, 0.79-0.90; P&#x2009;<&#x2009;.001). Sensitivity analyses showed similar hazard ratios for a narrower 5-component end point (without the kidney composite outcomes: HR, 0.86; 95% CI, 0.80-0.93) and the 4-component composite (without either kidney or heart failure end points: HR, 0.86; 95% CI, 0.80-0.93). Gastrointestinal adverse events were more common with tirzepatide (2827 patients [42.5%]) than dulaglutide (2387 patients [35.9%]) treatment. Other adverse events were similar. In this post hoc analysis, the dual GLP-1 and GIP agonist tirzepatide, compared with the GLP-1 agonist dulaglutide, was associated with a lower incidence of a broad 6-component composite cardiovascular and kidney end point in patients with diabetes and established cardiovascular disease. ClinicalTrials.gov Identifier: NCT04255433.

Comparative Gastrointestinal Safety of Dulaglutide, Semaglutide, and Tirzepatide in Adults With Type 2 Diabetes.

The comparative gastrointestinal safety across glucagon-like peptide-1 receptor agonists and tirzepatide is still unclear. To compare the risk for severe gastrointestinal adverse events across dulaglutide, subcutaneous semaglutide, and tirzepatide in patients with type 2 diabetes (T2D) in routine clinical practice. New-user, active-comparator cohort study. Population-based study. Adults with T2D initiating dulaglutide, subcutaneous semaglutide, and tirzepatide between 1 January 2019 and 30 August 2024 in 3 cohorts corresponding to 3 pairwise comparisons. The primary outcome was a composite of acute pancreatitis, biliary disease, bowel obstruction, gastroparesis, and severe constipation. Secondary outcomes of interest were the individual components of the primary outcome. Patients were 1:1 propensity score matched within each comparison. We calculated hazard ratios (HRs) with 95% CIs. There were 65&#x2009;238 matched pairs in the semaglutide versus dulaglutide cohort, 20&#x2009;893 in the tirzepatide versus dulaglutide cohort, and 46&#x2009;620 in the tirzepatide versus semaglutide cohort. The HR of gastrointestinal events was 0.96 (95% CI, 0.87 to 1.06) in the semaglutide versus dulaglutide cohort, 0.96 (CI, 0.77 to 1.20) in the tirzepatide versus dulaglutide cohort, and 1.07 (CI, 0.90 to 1.26) in the tirzepatide versus semaglutide cohort. Possible residual confounding by glycemic control and body mass index. These findings suggest that dulaglutide, semaglutide, and tirzepatide have similar gastrointestinal safety profiles in adults with T2D. This study provides clinicians with evidence to weigh the benefits and risks of these medications. National Institute of Diabetes and Digestive and Kidney Diseases.

Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.

Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. AWARD-7 was a multicentre, open-label trial done at 99 sites in nine countries. Eligible patients were adults with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3-4), with an HbA1c of 7&#xb7;5-10&#xb7;5%, and who were being treated with insulin or insulin plus an oral antihyperglycaemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Participants were randomly assigned (1:1:1) by use of a computer-generated random sequence with an interactive response system to once-weekly injectable dulaglutide 1&#xb7;5 mg, once-weekly dulaglutide 0&#xb7;75 mg, or daily insulin glargine as basal therapy, all in combination with insulin lispro, for 52 weeks. Insulin glargine and lispro doses were titrated as per an adjustment algorithm; dulaglutide doses were masked to participants and investigators. The primary outcome was HbA1c at 26 weeks, with a 0&#xb7;4% non-inferiority margin. Secondary outcomes included estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The primary analysis population was all randomly assigned patients who received at least one dose of study treatment and had at least one post-randomisation HbA1c measurement. The safety population was all patients who received at least one dose of study treatment and had any post-dose data. This study is registered with ClinicalTrials.gov, number NCT01621178. Between Aug 15, 2012, and Nov 30, 2015, 577 patients were randomly assigned, 193 to dulaglutide 1&#xb7;5 mg, 190 to dulaglutide 0&#xb7;75 mg, and 194 to insulin glargine. The effects on HbA1c change at 26 weeks of dulaglutide 1&#xb7;5 mg and 0&#xb7;75 mg were non-inferior to those of insulin glargine (least squares mean [LSM] -1&#xb7;2% [SE 0&#xb7;1] with dulaglutide 1&#xb7;5 mg [183 patients]; -1&#xb7;1% [0&#xb7;1] with dulaglutide 0&#xb7;75 mg [180 patients]; -1&#xb7;1% [0&#xb7;1] with insulin glargine [186 patients]; one-sided p&#x2264;0&#xb7;0001 for both dulaglutide doses vs insulin glargine). The differences in HbA1c concentration at 26 weeks between dulaglutide and insulin glargine treatments were LSM difference -0&#xb7;05% (95% CI -0&#xb7;26 to 0&#xb7;15, p<0&#xb7;0001) with dulaglutide 1&#xb7;5 mg and 0&#xb7;02% (-0&#xb7;18 to -0&#xb7;22, p=0&#xb7;0001) with dulaglutide 0&#xb7;75 mg. HbA1c-lowering effects persisted to 52 weeks (LSM -1&#xb7;1% [SE 0&#xb7;1] with dulaglutide 1&#xb7;5 mg; -1&#xb7;1% [0&#xb7;1] with dulaglutide 0&#xb7;75 mg; -1&#xb7;0% [0&#xb7;1] with insulin glargine). At 52 weeks, eGFR was higher with dulaglutide 1&#xb7;5 mg (Chronic Kidney Disease Epidemiology Collaboration equation by cystatin C geometric LSM 34&#xb7;0 mL/min per 1&#xb7;73 m2 [SE 0&#xb7;7]; p=0&#xb7;005 vs insulin glargine) and dulaglutide 0&#xb7;75 mg (33&#xb7;8 mL/min per 1&#xb7;73 m2 [0&#xb7;7]; p=0&#xb7;009 vs insulin glargine) than with insulin glargine (31&#xb7;3 mL/min per 1&#xb7;73 m2 [0&#xb7;7]). At 52 weeks, the effects of dulaglutide 1&#xb7;5 mg and 0&#xb7;75 mg on UACR reduction were not significantly different from that of insulin glargine (LSM -22&#xb7;5% [95% CI -35&#xb7;1 to -7&#xb7;5] with dulaglutide 1&#xb7;5 mg; -20&#xb7;1% [-33&#xb7;1 to -4&#xb7;6] with dulaglutide 0&#xb7;75 mg; -13&#xb7;0% [-27&#xb7;1 to 3&#xb7;9] with insulin glargine). Proportions of patients with any serious adverse events were similar across groups (20% [38 of 192] with dulaglutide 1&#xb7;5 mg, 24% [45 of 190] with dulaglutide 0&#xb7;75 mg, and 27% [52 of 194] with insulin glargine). Dulaglutide was associated with higher rates of nausea (20% [38 of 192] with dulaglutide 1&#xb7;5 mg and 14% [27 of 190] with 0&#xb7;75 mg, vs 5% [nine of 194] with insulin glargine) and diarrhoea (17% [33 of 192] with dulaglutide 1&#xb7;5 mg and 16% [30 of 190] with 0&#xb7;75 mg, vs 7% [14 of 194] with insulin glargine) and lower rates of symptomatic hypoglycaemia (4&#xb7;4 events per patient per year with dulaglutide 1&#xb7;5 mg and 4&#xb7;3 with dulaglutide 0&#xb7;75 mg, vs 9&#xb7;6 with insulin glargine). End-stage renal disease occurred in 38 participants: eight (4%) of 192 with dulaglutide 1&#xb7;5 mg, 14 (7%) of 190 with dulaglutide 0&#xb7;75 mg, and 16 (8%) of 194 with insulin glargine. In patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide produced glycaemic control similar to that achieved with insulin glargine, with reduced decline in eGFR. Dulaglutide seems to be safe to use to achieve glycaemic control in patients with moderate-to-severe chronic kidney disease. Eli Lilly and Company.

Dulaglutide: first global approval.

Dulaglutide (Trulicity&#x2122;) is a long-acting, glucagon-like peptide-1 (GLP-1) receptor agonist that has been developed by Eli Lilly and Company for the treatment of type 2 diabetes mellitus. It consists of a dipeptidyl peptidase-IV-protected GLP-1 analogue covalently linked to a human IgG4-Fc heavy chain by a small peptide linker. The subcutaneous formulation is approved for use in type 2 diabetes in the US, has been recommended for approval in the EU in this indication, and is under regulatory review in other countries. This article summarizes the milestones in the development of subcutaneous dulaglutide leading to this first approval for type 2 diabetes.

Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types.

Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient's cancer risk profile.

Dulaglutide: A Review in Type 2 Diabetes.

Subcutaneous dulaglutide (Trulicity&#xae;) is a once-weekly glucagon-like peptide-1 receptor agonist that is approved in numerous countries as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D). In the clinical trial and real-world settings, once-weekly subcutaneous dulaglutide, as monotherapy or add-on therapy to other antihyperglycaemic agents (including oral antihyperglycaemic drugs and insulin), was an effective and generally well tolerated treatment in adults with inadequately controlled T2D, including in high-risk patients [e.g. obese and elderly patients, those with stage 3 or 4 chronic kidney disease (CKD) and/or cardiovascular (CV) disease]. In the REWIND CV outcomes trial in patients with T2D with or without CV disease, dulaglutide was associated with a significant reduction in the risk of a major adverse cardiac event (MACE; primary composite outcome comprising CV death, nonfatal myocardial infarction or nonfatal stroke) at a median of 5.4&#xa0;years' follow-up. Given its durable glycaemic efficacy, beneficial effects on bodyweight and MACE outcomes, low inherent risk of hypoglycaemia and convenient once-weekly regimen, dulaglutide remains an important option in the management of T2D.

Advances in the treatment of type 2 diabetes: impact of dulaglutide.

The purpose of this review is to provide a review of current data of the most recently approved glucagon-like peptide (GLP)-1-receptor agonist, dulaglutide, in the treatment of type 2 diabetes. To complete this, a PubMed search was performed to identify manuscripts published from 1947 to July 2015. The search terms "Trulicity", "dulaglutide", and "LY2189265" were utilized, and publications were included if they evaluated the pharmacology, pharmacokinetics, efficacy, safety, or patient-reported outcomes of dulaglutide. Dulaglutide is a GLP-1 receptor agonist that mimics endogenous GLP-1, the hormone produced in response to food intake. Modifications have been made to the molecule to delay breakdown and allow for once-weekly dosing. Dulaglutide has been studied as monotherapy and in combination with several agents, including metformin, glimepiride, pioglitazone, and insulin lispro. Dulaglutide has demonstrated superior efficacy compared to placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide. It was found to be noninferior to liraglutide. The most common adverse effects in clinical studies were gastrointestinal-related adverse events, and patient satisfaction was high with the use of dulaglutide. Dulaglutide is an appealing option for the treatment of type 2 diabetes, based on its once-weekly dosing, A1c lowering comparable to liraglutide, weight reduction comparable to exenatide, and a similar adverse-effect profile to other GLP-1 receptor agonists.

Dulaglutide efficacy.

Efficacy and Safety of Dulaglutide Biosimilar LY05008 Versus the Reference Product Dulaglutide (Trulicity) in Chinese Adults With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Active Comparator Study.

Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been approved for improving glycemic control and reducing the risk of cardiovascular (CV) adverse events. A previous result in healthy Chinese male subjects demonstrated the pharmacokinetic (PK) similarity of LY05008 and the licensed product dulaglutide, with comparable safety and immunogenicity profiles. A well-controlled phase 3 study with an adequate sample size was subsequently conducted for safety and efficacy evaluation. In a multicenter, randomized, open-label, active comparator phase 3 study, Chinese adults diagnosed with type 2 diabetes mellitus (T2DM) were randomly assigned 1:1 to receive a subcutaneous injection of 1.5&#x2009;mg LY05008 or dulaglutide once weekly for 24&#x2009;weeks. The primary endpoint was the mean change in HbA1c from baseline to Week 24. The secondary endpoints included the mean change in HbA1c from baseline to Week 12; the proportion of patients who had achieved HbA1c&#x2009;&#x2264;&#x2009;6.5% at Weeks 12 and 24; and the mean change in body weight, fasting plasma glucose (FPG) level, and 2-h postprandial plasma glucose (PPG) level from baseline to Weeks 12 and 24. Safety, PK, and immunogenicity profiles were also included for data analysis. A total of 440 patients were randomized to receive LY05008 (n&#x2009;=&#x2009;222) or dulaglutide (n&#x2009;=&#x2009;218). The mean changes in HbA1c from baseline to Week 24 in the LY05008 group and dulaglutide group were -1.44% and -1.41%, respectively, with a least square mean difference (LSMD) and 95% confidence interval (CI) of 0.06% (-0.08, 0.19) (p&#x2009;>&#x2009;0.05). Efficacy equivalence could be demonstrated since the 95% CI between the reference drug and a biosimilar fell entirely within the range of (-0.4%, 0.4%). The mean changes in HbA1c from baseline to Week 12 in the LY05008 group and dulaglutide group were -1.47% and -1.39% (p&#x2009;>&#x2009;0.05), respectively. At Week 12, 40.1% of patients who received LY05008 and 42.2% of those who received dulaglutide had a decrease in the HbA1c level to 6.5% or less, and 60.4% and 60.6% of patients in the LY05008 group and the dulaglutide group had a decrease in the HbA1C level <&#x2009;7%, respectively. At Week 24, 41.0% and 43.6% of patients achieved an HbA1c&#x2009;&#x2264;&#x2009;6.5%. 55.9% and 66.5% of patients in the LY05008 group and the dulaglutide group achieved the HbA1c goal of <&#x2009;7%, respectively. The mean changes in body weight from baseline to Weeks 12 and 24 in the LY05008 group and dulaglutide group were -2.01 and -1.71&#x2009;kg (p&#x2009;>&#x2009;0.05) and -2.68 and -2.42&#x2009;kg (p&#x2009;>&#x2009;0.05), respectively. The mean changes in FPG level from baseline to Weeks 12 and 24 in the LY05008 group and dulaglutide group were -2.578 and -2.681&#x2009;mmol/L (p&#x2009;>&#x2009;0.05) and -2.222 and -2.690&#x2009;mmol/L, respectively. In the LY05008 group and the dulaglutide group, the mean changes in 2-h PPG levels from baseline to Weeks 12 and 24 were -4.364 and -4.800&#x2009;mmol/L(p&#x2009;>&#x2009;0.05) and-3.502 and -4.217&#x2009;mmol/L (p&#x2009;>&#x2009;0.05), respectively. The common treatment emergent adverse events (TEAEs) in the LY05008 and dulaglutide groups were decreased appetite, diarrhea, upper respiratory tract infection, hyperuricemia, nausea, urinary tract infection, and vomiting. Most TEAEs were mild to moderate in severity. No significant differences were observed between the groups in terms of TEAEs. Hypoglycemic events were noted in 0.9% of patients who had received LY05008 and in 3.7% of those who had received dulaglutide. Serious adverse events were reported in 4.1% of patients in the LY05008 group and in 3.7% of patients in the dulaglutide group. The PK parameter Ctrough and immunogenicity profiles were similar across the two treatment groups. The primary endpoint was met in this study through the demonstration of equivalent efficacy in HbA1c reduction in Chinese adults with T2DM between LY05008 and dulaglutide. Overall, the biosimilar product LY05008 showed comparable safety, PK, and immunogenicity profiles against the reference drug dulaglutide. ClinicalTrials.gov identifier: CTR20221721.

Dulaglutide (Trulicity)-Induced Acute Pancreatitis: A Case Report.

The article discusses the use of dulaglutide (Trulicity) in treating type 2 diabetes mellitus. Dulaglutide is a synthetic analog of glucagon-like peptide (GLP-1) that binds to GLP-1 receptors, enhancing insulin secretion and reducing postprandial glucagon and food intake. Dulaglutide has a longer half-life than GLP-1, making it more clinically useful. The recommended dosage of dulaglutide is 0.75 mg/0.5 mL subcutaneously once weekly, which can be increased as needed for adequate glycemic control. We describe a case of acute pancreatitis in a 37-year-old male with a past medical history of type 2 diabetes mellitus who was admitted for epigastric pain radiating to the back. Lipase level was elevated at 1508, and a computed tomography (CT) scan of the abdomen showed fat stranding around the pancreas consistent with pancreatitis. The patient was on dulaglutide (Trulicity) at 0.75 mg q. weekly for about two years; this dose was increased to 1.5 mg q. weekly two months ago. He developed symptoms of abdominal pain, nausea, and vomiting after receiving the last dose of Trulicity, which was two weeks before he presented to the emergency department as a cause of acute pancreatitis. Dulaglutide use has been known to cause a mild elevation of pancreatic enzyme levels; there have been few reported cases of dulaglutide-associated acute pancreatitis in the literature. The case report highlights the adverse effects of dulaglutide in diabetic patients and the importance of monitoring pancreatic enzyme levels in patients taking dulaglutide.

Association of tirzepatide with erectile dysfunction in people with type 2 diabetes.

To evaluate the association between tirzepatide and the risk of developing erectile dysfunction (ED) in men with type 2 diabetes (T2D), compared with sitagliptin, injectable semaglutide, and dulaglutide. This retrospective cohort study used the TriNetX global health research network from May 13, 2022 to May 17, 2025. Male patients aged 18-70 with T2D and no prior ED were included. Three 1:1 propensity score-matched comparisons were conducted: tirzepatide vs. sitagliptin, injectable semaglutide, or dulaglutide. The outcome was a diagnosis of ED or prescription of a PDE-5 inhibitor. Tirzepatide was associated with a significantly reduced risk of ED across all comparisons. Risk ratios (RR) for the composite outcome of ED diagnosis or PDE-5 inhibitor use were: tirzepatide vs. sitagliptin: RR, 0.70 (95&#xa0;% CI: 0.64,0.76); tirzepatide vs. injectable semaglutide: RR, 0.67 (95&#xa0;% CI: 0.62,0.72); tirzepatide vs. dulaglutide: RR, 0.55 (95&#xa0;% CI: 0.51,0.59). All comparisons were statistically significant (p&#xa0;<&#xa0;0.001). Tirzepatide was associated with a lower risk of ED in men with T2D compared to sitagliptin, injectable semaglutide, and dulaglutide. Randomized trials are needed to confirm these findings and explore potential mechanisms.

Pharmaceutical approval update.

Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection; dulaglutide (Trulicity) for glycemic control in type-2 diabetes; netupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related to chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in patients with chronic noncancer pain.