Glycemic and Cost Outcomes among Hispanic/Latino People with Type 2 Diabetes in the USA Initiating Dulaglutide versus Basal Insulin: a Real-World Study.

INTRODUCTION: Optimal glycemic management after diabetes onset remains a challenge in Hispanic/Latino adults with type 2 diabetes (T2D), often resulting in poor health outcomes and higher rates of diabetes-related complications. The aim of this study was to examine and compare demographic and clinical characteristics, glycemic outcomes, health care resource utilization (HCRU), and costs among injection-naïve Hispanic/Latino adults with T2D initiating dulaglutide or basal insulin. METHODS: This retrospective, observational study used administrative claims data from the Optum Research Database. Hispanic/Latino adults with T2D were assigned to dulaglutide or basal insulin cohorts on the basis of pharmacy claims and were propensity-score matched on demographic and baseline characteristics. Measures of glycemic management included 12 month follow-up glycated hemoglobin (HbA1c) and change in HbA1c from baseline. Follow-up all-cause and diabetes-related HCRU and costs, including costs per 1% change in HbA1c, were compared between cohorts. RESULTS: The final propensity-score matched sample included 2872 patients: 1436 patients in each cohort. Mean (SD) reduction in HbA1c from baseline to 12 month follow-up was greater in the dulaglutide cohort compared with the basal insulin cohort [-1.40% (1.88) versus -0.92% (2.07); p < 0.001]. The dulaglutide cohort had significantly lower proportions of patients with ≥ 1 all-cause and diabetes-related outpatient visits, emergency room visits, and inpatient stays compared with the basal insulin cohort (p < 0.05). The dulaglutide cohort had significantly lower all-cause total costs per 1% HbA1c reduction than the basal insulin cohort ($13,768 versus $19,128; p < 0.001). Diabetes-related costs per 1% reduction were numerically lower for the dulaglutide cohort, but the difference was not statistically significant ($9737 versus $11,403; p = 0.081). CONCLUSIONS: Dulaglutide demonstrated better glycemic outcomes and lower all-cause costs per 1% HbA1c reduction among Hispanic/Latino adults compared with those initiating basal insulin. Our real-world findings in the Hispanic/Latino population were consistent with results obtained from the overall population and confirm the glycemic benefits of dulaglutide observed in clinical settings.

Practical Applications of a Nausea and Vomiting Model in the Clinical Development of Additional Doses of Dulaglutide.

Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled with metformin and 0.75 or 1.5 mg weekly doses of dulaglutide. Effects such as nausea and vomiting are commonly reported with dulaglutide and other glucagon-like peptide-1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model-informed approach, a stepwise dose-escalation scheme with 4-week intervals between dose increments was suggested to mitigate gastrointestinal events for dulaglutide. These gastrointestinal events are dose dependent and attenuate over time with repeated dosing. A Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed using AWARD-11 data (N = 1842) to optimize dulaglutide dose escalation to 3.0 and 4.5 mg to mitigate gastrointestinal events. Model simulations evaluated probabilities of nausea and vomiting events for various dosing scenarios in patients needing higher doses for additional glycemic control. The model indicated that patients may dose escalate from 1.5 to 3.0 mg, then 4.5 mg weekly after at least 4 weeks on each dose. No clinically meaningful differences in nausea or vomiting events were expected when patients escalated to 3.0 or 4.5 mg following initiation at 0.75 or 1.5 mg dulaglutide. Based on the findings of this model, a minimum 4-week duration at each dose before escalation was appropriate to reduce gastrointestinal events of dulaglutide, consistent with observed gastrointestinal events data from the AWARD-11 study and supporting the currently recommended dose-escalation regimen of dulaglutide doses of 3.0 and 4.5 mg for additional glycemic control.

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

BACKGROUND: 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. METHODS: 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 7·0-10·5%, 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 1·5 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. FINDINGS: 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 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% 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. INTERPRETATION: 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. FUNDING: Eli Lilly and Company.

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity.

BACKGROUND: Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. METHODS: In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). RESULTS: A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. CONCLUSIONS: Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

General versus central adiposity as risk factors for cardiovascular-related outcomes in a high-risk population with type 2 diabetes: a post hoc analysis of the REWIND trial.

BACKGROUND: In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D). METHODS: Data from the REWIND trial placebo group (N = 4952) were analyzed. All participants had T2D, age ≥ 50 years, had either a previous CV event or CV risk factors, and a BMI of ≥ 23 kg/m2. Cox proportional hazard models were used to investigate if BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were significant risk factors for major adverse CV events (MACE)-3, CVD-related mortality, all-cause mortality, and heart failure (HF) requiring hospitalization. Models were adjusted for age, sex, and additional baseline factors selected by LASSO method. Results are presented for one standard deviation increase of the respective anthropometric factor. RESULTS: Participants in the placebo group experienced 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization during the median follow-up of 5.4 years. WHR and WC, but not BMI, were identified as independent risk factors of MACE-3 (hazard ratio [HR] for WHR: 1.11 [95% CI 1.03 to 1.21]; p = 0.009; HR for WC: 1.12 [95% CI 1.02 to 1.22]; p = 0.012). WC adjusted for hip circumference (HC) showed the strongest association with MACE-3 compared to WHR, WC, or BMI unadjusted for each other (HR: 1.26 [95% CI 1.09 to 1.46]; p = 0.002). Results for CVD-related mortality and all-cause mortality were similar. WC and BMI were risk factors for HF requiring hospitalization, but not WHR or WC adjusted for HC (HR for WC: 1.34 [95% CI 1.16 to 1.54]; p < 0.001; HR for BMI: 1.33 [95% CI 1.17 to 1.50]; p < 0.001). No significant interaction with sex was observed. CONCLUSIONS: In this post hoc analysis of the REWIND placebo group, WHR, WC and/or WC adjusted for HC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality; while BMI was only a risk factor for HF requiring hospitalization. These findings indicate the need for anthropometric measures that consider body fat distribution when assessing CV risk.

Real-World Treatment Patterns of Glucose-Lowering Agents Among Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease or At Risk for Cardiovascular Disease: An Observational, Cross-Sectional, Retrospective Study.

INTRODUCTION: There is limited published literature on longitudinal utilization of glucose-lowering agents (GLAs) among patients with type 2 diabetes (T2D) and cardiovascular disease (CVD or risk of CVD). This retrospective, observational study aimed to provide updated evidence on patient characteristics and utilization of GLAs among patients with T2D and CVD or risk of CVD in the United States. METHODS: This was a cross-sectional evaluation of patients with T2D aged 50-89 years with annual continuous enrolment in a Medicare Advantage and Prescription Drug plan, identified from administrative claims data (Humana Research Database). Patients with T2D and atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) (CVD cohort), or T2D and an additional CVD risk factor without pre-existing CVD (CVD risk cohort) were identified from 2015 to 2019. Patients were followed from their first observed ASCVD/HF diagnosis or CVD risk factor for each year they were continuously enrolled or until occurrence of a CVD diagnosis (CVD risk cohort only). Use of GLA classes were reported by year, cohort, and age groups (50-64 years and ≥ 65 years). RESULTS: The percentage of patients on sodium-glucose co-transporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and GLP-1 RAs with proven cardiovascular benefit, respectively, increased from 2015 to 2019 among ≥ 65 years (CVD cohort: 1.1-3.4%, 1.6-4.0%, and 1.2-3.8%; CVD risk cohort: 1.4-3.7%, 2.0-4.3%, and 1.5-4.1%); and among 50-64 years (CVD cohort: 2.6-7.3%, 4.3-10.1%, and 3.4-9.4%; CVD risk cohort: 3.3-6.8%, 4.6-9.6%, and 3.5-8.9%). CONCLUSIONS: Although use of SGLT-2is and GLP-1 RAs increased over time, overall utilization of these agents in patients with T2D and ASCVD/HF or at risk for ASCVD/HF remained low, especially for those aged ≥ 65 years.

Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are types of glucose-lowering medications for patients with type 2 diabetes (T2D). The American Diabetes Association, the American Association of Clinical Endocrinologists, and American College of Endocrinology have recommended these medications for patients who have been diagnosed with T2D and atherosclerotic cardiovascular disease or heart failure (ASCVD/HF). The purpose of this study was to find out how many patients in a US-based health insurance population with T2D and ASCVD/HF were treated with SGLT-2is, GLP-1 RAs, and other glucose-lowering medications from 2015 to 2019. Using insurance claims data, we identified 50- to 89-year-old patients with T2D and either ASCVD/HF or at least one risk factor for ASCVD/HF. We tracked the number of patients with T2D and either ASCVD/HF or ASCVD/HF risk factors who were using different glucose-lowering medications. Glucose-lowering medications were used in most patients (60­78%), but fewer than 11% of patients aged 50­64 years, and fewer than 5% of patients over 65 years of age were prescribed SGLT-2i and GLP-1 RA medications, despite clinical guidelines recommending their use for the above-mentioned indications. Increasing awareness among healthcare providers may be required to ensure patients with T2D and ASCVD/HF or ASCVD/HF risk factors are prescribed the guideline-recommended cardioprotective glucose-lowering agents.

Examining the evidence for weight management in individuals with type 2 diabetes.

The obesity epidemic has been linked to the worsening diabetes epidemic. Despite this, weight reduction for individuals with obesity is seen as a secondary, or even tertiary, consideration in the treatment of type 2 diabetes (T2D). The aim of this review is to examine the benefits of weight management in individuals with T2D. A literature review of current available published data on the benefits of weight reduction in individuals with T2D was conducted. In individuals with T2D who have obesity or overweight, modest and sustained weight reduction results in improvement in glycaemic control and decreased utilization of glucose-lowering medication. A total body weight loss of 5% or higher reduces HbA1c levels and contributes to mitigating risk factors of cardiovascular disease, such as hyperlipidaemia and hypertension, as well as other disease-related complications of obesity. Progressive improvements in glycaemic control and cardiometabolic risk factors can occur when the total body weight loss increases to 10% or more. In the approach to treating patients with T2D and obesity, prioritizing weight management and the use of therapeutics that offer glycaemic control as well as the additional weight loss should be emphasized given their potential to attenuate the progression and severity of T2D.

HbA1c Reduction in Dulaglutide-Treated Patients Irrespective of Duration of Diabetes, Microvascular Disease, and BMI: A Post Hoc Analysis From the REWIND Trial.

OBJECTIVE: To evaluate participant characteristics and long-term changes in glycated hemoglobin (HbA1c) levels in patients treated with dulaglutide 1.5 mg in a post hoc analysis of the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. RESEARCH DESIGN AND METHODS: Change from baseline in HbA1c was assessed during and up to 72 months of treatment before and after adjustment for duration of diabetes, prior microvascular disease (nephropathy or retinopathy), and BMI. Slope analyses were used to assess the change in HbA1c during 0-12 months and 12-72 months of therapy. RESULTS: HbA1c was significantly reduced in patients treated with dulaglutide compared with placebo during 72 months of treatment (least-squares mean difference = -0.61%, P < 0.001), regardless of diabetes duration, prior microvascular disease, and BMI (all interaction P > 0.07). Significant reductions were apparent at all time points and were independent of these baseline characteristics. Slope analyses revealed that the dulaglutide group experienced a higher rate of HbA1c reduction compared with the placebo group from 0 to 12 months before and after adjustment. The dulaglutide group also experienced a higher rate of HbA1c increase from 12 to 72 months compared with the placebo group that became nonsignificant after adjustment for diabetes duration, prior microvascular disease, and BMI combined. Despite the greater rate of HbA1c increase in the dulaglutide group during this period, mean HbA1c values remained below baseline in the dulaglutide group and below mean HbA1c values in the placebo group. CONCLUSIONS: Dulaglutide 1.5-mg treatment was statistically associated with a long-lasting decrease in HbA1c over 72 months, irrespective of baseline duration of diabetes, microvascular disease, and BMI.

A model-based simulation of glycaemic control and body weight when switching from semaglutide to 3.0- and 4.5-mg doses of once-weekly dulaglutide.

AIM: To evaluate HbA1c and body weight changes when semaglutide 0.5- or 1.0-mg once-weekly (QW) is switched to dulaglutide 3.0- or 4.5-mg QW via exposure-response modelling. METHODS: HbA1c and body weight time-course models were developed and validated with data from the SUSTAIN 1 to 10 trials for semaglutide and the AWARD-11 trial for dulaglutide. Simulations were conducted for HbA1c and body weight over 52 weeks. In the initial 26 weeks, semaglutide was initiated at 0.25-mg and titrated to 0.5- or 1.0-mg QW via 4-weekly stepwise titration, followed by 26 weeks of dulaglutide initiated at 0.75- or 1.5-mg QW and escalated to 3.0- or 4.5-mg QW via 4-weekly stepwise titration. RESULTS: At 26 weeks, model-predicted mean changes from baseline in HbA1c and weight for semaglutide 0.5 mg were up to -1.55% and -3.44 kg, respectively. After switching to dulaglutide 3.0 mg, further reductions were 0.19% and 1.40 kg, respectively, at 52 weeks. Predicted mean HbA1c and weight changes for semaglutide 1.0 mg at 26 weeks were -1.84% and -4.96 kg, respectively; after switching to dulaglutide 4.5 mg, HbA1c was maintained with additional weight reduction of up to 0.57 kg at 52 weeks. Glycaemic control was preserved when switching from semaglutide 1.0 mg to dulaglutide 3.0 mg. CONCLUSION: Switching from semaglutide 0.5 mg to dulaglutide 3.0 or 4.5 mg with dose escalation potentially yields additional HbA1c and weight reductions; switching from semaglutide 1.0 mg to dulaglutide 4.5 mg may enhance weight loss.

Gastrointestinal Tolerability of Once-Weekly Dulaglutide 3.0 mg and 4.5 mg: A Post Hoc Analysis of the Incidence and Prevalence of Nausea, Vomiting, and Diarrhea in AWARD-11.

BACKGROUND: Gastrointestinal (GI) events are the most frequent treatment-emergent adverse events (TEAEs) reported for glucagon-like peptide-1 receptor agonist therapies. This post hoc analysis of the AWARD-11 phase 3 trial assessed the GI tolerability of dulaglutide at once-weekly doses of 1.5, 3.0, and 4.5 mg. METHODS: The AWARD-11 trial randomized patients to once-weekly dulaglutide 1.5 mg (n = 612), 3.0 mg (n = 616), or 4.5 mg (n = 614) for 52 weeks. Patients started on dulaglutide 0.75 mg for 4 weeks before escalating stepwise every 4 weeks until the final randomized dose was reached. This study analyzes the onsets, incidences, prevalences, and severities of nausea, vomiting, and diarrhea events reported through 52 weeks. RESULTS: The highest incidences of nausea (≤ 8%), vomiting (≤ 2%), and diarrhea (≤ 4%) were primarily observed soon after the initiation of dulaglutide treatment at 0.75 mg. Incidence then declined throughout the remainder of the study, even with dose escalation to 1.5, 3.0, and 4.5 mg. Most of these GI TEAEs were mild to moderate in severity, with severe nausea, vomiting, or diarrhea events occurring in ≤ 0.6% of patients. Treatment discontinuation due to nausea was low across treatment groups (≤ 1.5%). CONCLUSIONS: The tolerability profiles of dulaglutide 3.0 mg and 4.5 mg were consistent with that of the 1.5-mg dose. Patients experiencing GI events were most likely to do so within 2 weeks of treatment initiation, and few patients experienced a new GI event after escalating to the 3.0-mg or 4.5-mg dose. Severe events were infrequent, and when they did occur, no relationship with dose at time of event was observed. Supplementary file1 (MP4 33880 kb).

Dulaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) prescribed for the treatment of type 2 diabetes (T2D). The most frequently reported side effects of GLP-1 RAs are nausea, vomiting, or diarrhea. This analysis of a 52-week study in adult patients with T2D details the tolerability of dulaglutide injected once weekly at a dose of 1.5 mg, 3 mg, or 4.5 mg, as assessed by looking at the nausea, vomiting, and diarrhea events reported during the study. All patients started dulaglutide at 0.75 mg before escalating to 1.5 mg after 4 weeks. Depending on the group they were randomly assigned to, the patients then either remained on the 1.5-mg dose, escalated to 3 mg after another 4 weeks and remained on this dose, or escalated further to 4.5 mg after another 4 weeks. The minority of patients who experienced nausea, vomiting, or diarrhea events (less than 16% of patients in each case) generally did so at the beginning of treatment, when all groups were taking the same dose (0.75 mg). Episodes of nausea, vomiting, or diarrhea then became less frequent, even as patients escalated to each of the higher doses. Most of these events were mild to moderate in severity, and most did not cause patients to stop taking the treatment. In general, this analysis shows that, for the minority of patients who experienced nausea, vomiting, or diarrhea, these events were most likely to happen shortly after starting treatment and lessened over time, even as patients escalated to higher dulaglutide doses.

Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND.

BACKGROUND: The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial. METHODS: Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model. RESULTS: Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively). CONCLUSIONS: Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.

Efficacy and safety of dulaglutide 3.0 and 4.5 mg in patients aged younger than 65 and 65 years or older: Post hoc analysis of the AWARD-11 trial.

AIM: To evaluate the efficacy and safety of dulaglutide 3.0 and 4.5 mg versus 1.5 mg when used as an add-on to metformin in subgroups defined by age (<65 and ≥65 years). MATERIALS AND METHODS: Of 1842 patients included in this post hoc analysis, 438 were aged 65 years or older and 1404 were younger than 65 years. The intent-to-treat (ITT) population, while on treatment without rescue medication, was used for all efficacy analyses; the ITT population without rescue medication was used for hypoglycaemia analyses; all other safety analyses used the ITT population. RESULTS: Patients aged 65 years or older and those younger than 65 years had a mean age of 69.5 and 53.2 years, respectively. In each age subgroup, the reduction from baseline in HbA1c and body weight (BW), and the proportion of patients achieving a composite endpoint of HbA1c of less than 7% (<53 mmol/mol) with no weight gain and no documented symptomatic or severe hypoglycaemia, were larger for dulaglutide 3.0 and 4.5 mg compared with dulaglutide 1.5 mg, but the treatment-by-age interactions were not significant. The safety profile for the additional dulaglutide doses was consistent with that of dulaglutide 1.5 mg and was similar between the age subgroups. CONCLUSION: Dulaglutide doses of 3.0 or 4.5 mg provided clinically relevant, dose-related improvements in HbA1c and BW with no significant treatment-by-age interactions, and with a similar safety profile across age subgroups.

Efficacy and Safety of Dulaglutide in Older Patients: A post hoc Analysis of the REWIND trial.

CONTEXT: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed. OBJECTIVE: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years). METHODS: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes). RESULTS: There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant. CONCLUSION: Dulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years.

Clinical Outcomes by Albuminuria Status with Dulaglutide versus Insulin Glargine in Participants with Diabetes and CKD: AWARD-7 Exploratory Analysis.

Background: In the AWARD-7 trial of participants with type 2 diabetes (T2DM) and moderate-to-severe CKD, dulaglutide (DU) treatment slowed decline in eGFR compared with insulin glargine (IG). Treatment with doses of either DU or IG resulted in similar levels of glycemic control and BP. The aim of this analysis was to determine the risk of clinical event outcomes between treatment groups. Methods: Participants with T2DM and CKD categories 3-4 were randomized (1:1:1) to 0.75 or 1.5 mg DU weekly or IG daily as basal therapy, with titrated insulin lispro, for 1 year. The time to occurrence of the composite outcome of ≥40% eGFR decline, ESKD, or death due to kidney disease was compared using a Cox proportional-hazards model. Results: Patients treated with 1.5 mg DU weekly versus IG daily for 1 year had a lower risk of ≥40% eGFR decline or ESKD events in the overall study population (5% versus 11%; hazard ratio, 0.45; 95% CI, 0.20 to 0.97; P=0.04). Most events occurred in the subset of patients with macroalbuminuria, where risk of the composite outcome was substantially lower for 1.5 mg DU versus IG (7% versus 22%; hazard ratio, 0.25; 95% CI, 0.10 to 0.68; P=0.006). No deaths due to kidney disease occurred. Conclusions: Treatment with 1.5 mg DU weekly was associated with a clinically relevant risk reduction of ≥40% eGFR decline or ESKD compared with IG daily, particularly in the macroalbuminuria subgroup of participants with T2DM and moderate-to-severe CKD.

Adherence and persistence among patients with type 2 diabetes initiating dulaglutide compared with semaglutide and exenatide BCise: 6-month follow-up from US real-world data.

AIM: To compare 6-month adherence, persistence and treatment patterns among patients initiating once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs), dulaglutide versus semaglutide, and dulaglutide versus exenatide BCise, using claims from the HealthCore Integrated Research Database. MATERIALS AND METHODS: Patients aged ≥18 years, with type 2 diabetes, ≥1 claim for dulaglutide, semaglutide or exenatide BCise during the index period February 2018 to December 2018 (index date = earliest GLP-1RA fill date), no claim for GLP-1RAs in the 6-month pre-index period, and continuous enrolment 6 months pre- and post-index were included. Dulaglutide users were propensity-matched 1:1 to semaglutide users (3852 pairs) or exenatide BCise users (1879 pairs). The proportions of adherent (proportion of days covered ≥80%) patients were compared using chi-squared tests. Persistence, measured as days to discontinuation, was analysed using a Cox regression model. RESULTS: Matched cohorts (dulaglutide:semaglutide and dulagutide:exenatide BCise) were balanced in baseline characteristics and the mean age was 54 and 55 years, respectively, with approximately 51% and 49% women, respectively. At 6 months, significantly more dulaglutide users were adherent than semaglutide (59.7% vs. 42.7%; P <0.0001) or exenatide BCise users (58.1% vs. 40.3%; P <0.0001). Cox regression showed that dulaglutide users were less likely to discontinue therapy than semaglutide (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.66, 0.76) or exenatide BCise users (HR 0.59, 95% CI 0.53, 0.65; P <0.0001, both). CONCLUSION: At 6-month follow-up, a higher proportion of patients initiating dulaglutide were adherent to and persistent with their treatment, compared to matched patients initiating either semaglutide or exenatide BCise.

Patients' preferences for once-daily oral versus once-weekly injectable diabetes medications: The REVISE study.

AIMS: To understand patient preferences for once-daily oral versus once-weekly injectable type 2 diabetes mellitus (T2DM) medication administration profiles, and reasons for their preferences. MATERIALS AND METHODS: The REVISE study, a cross-sectional online survey of 600 participants with T2DM (United Kingdom, n = 300; United States, n = 300), elicited general preferences for once-daily oral versus once-weekly injectable diabetes medications, and reasons for the preference. Participants then viewed two videos describing the administration procedures for injectable dulaglutide and oral semaglutide, based on the product instructions for use. Thereafter, participants indicated their preference for a once-weekly injectable or a once-daily oral medication based on the video descriptions. Participants who switched preferences were asked to identify the reasons influencing their decision. RESULTS: The participants were predominantly male (n = 349; 58.2%), with a mean (SD) age of 64 (11.3) years. Nearly all (n = 557; 92.8%) were taking an oral T2DM medication, and 158 (26.3%) were using an injectable. Initially, 76.5% (n = 459; 95% confidence interval [CI] 73.1-79.9) preferred a once-daily oral and 23.5% a once-weekly injectable (n = 141; 95% CI 20.1-26.9; P < 0.0001). After viewing the videos describing the product-specific administration, the proportions of participants preferring each option were not statistically different (oral semaglutide administration description (n = 315; 52.5%; 95% CI 48.5-56.5; dulaglutide administration description (n = 285; 47.5%; 95% CI 43.5-51.5; NS, P = 0.2207). The most common reason for switching preferences was the timing and steps of administration. CONCLUSION: Several treatment-related characteristics, including route, frequency and complexity of the treatment, play a role in patients' preferences for T2DM treatments and should be considered during treatment selection.

Cardiovascular outcomes trials with glucagon-like peptide-1 receptor agonists: A comparison of study designs, populations and results.

Despite treatment advances leading to improved outcomes over the past 2 decades, cardiovascular (CV) disease (CVD) remains the leading cause of morbidity and mortality in people with diabetes. People with type 2 diabetes (T2D) have a 2- to 4-fold increased risk of CVD and CV death. Individuals with T2D have not seen the same improvements in CV morbidity and mortality as those without T2D. Given this, it is important to understand the CV impact of drugs used to treat T2D. In patients with T2D, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a reduction in HbA1c and body weight regardless of their differences in chemical structure and pharmacokinetic variables. Glycaemic efficacy, accompanied by the potential for weight reduction and a low risk of hypoglycaemia, has moved GLP-1 RAs to the first treatment of choice following metformin monotherapy in the latest American Diabetes Association treatment guidelines. Additionally, all GLP-1 RAs have shown CV safety and several have proven CV benefit. GLP-1 RAs have been evaluated in cardiovascular outcomes trials (CVOTs) of varying sizes, designs and patient populations with differing reported effects on CV outcomes. The purpose of this article is to review the completed GLP-1 RA CVOTs with special attention to how their design, size, patient populations and conduct may influence the interpretation of results.

Real-World Effectiveness of Dulaglutide in Patients with Type 2 Diabetes Mellitus: A Literature Review.

INTRODUCTION: Randomized controlled trials (RCTs) have demonstrated the efficacy of dulaglutide in adults with type 2 diabetes mellitus (T2DM), but results may not be generalizable in routine practice. This pragmatic literature review aimed to summarize real-world evidence (RWE) for dulaglutide. METHODS: The MEDLINE, EMBASE, NHS Economic Evaluation Database, and Health Technology Assessment databases were searched from January 2014 to July 2019 for studies providing RWE for dulaglutide in adults with T2DM regarding at least one outcome of interest (change in glycated hemoglobin [HbA1c]; weight; adherence; persistence; discontinuation; costs; healthcare resource utilization; health-related quality of life; patient satisfaction; and preference). Relevant congress abstracts were identified from EMBASE. RESULTS: A total of 29 studies (11 articles; 18 abstracts) were included. RWE for dulaglutide was not identified for all outcomes of interest. Dulaglutide reduced HbA1c from baseline to 3-24 months by 0.5-2.2% across studies (n = 20), and 23.4-55.7% of patients achieved HbA1c < 7.0%. Weight was reduced by 2.1-6.4 kg across studies of 3-12 months (n = 15). Based on outcomes from ten studies, 27.2-61.0% of dulaglutide patients were adherent. Mean persistence was 146-152 days and > 250 days in 6- and 12-month studies, respectively. Most studies reported discontinuation rates of 26.2-37.0%. Adherence and persistence were consistently reported to be greater in dulaglutide-treated patients in RW settings compared with other glucagon-like peptide-1 receptor agonists. Dulaglutide was associated with lower costs per 1% reduction in HbA1c compared with exenatide, liraglutide, or basal insulin (n = 3 studies). CONCLUSION: Evidence from RWE studies suggests that dulaglutide may be associated with clinically relevant reductions in HbA1c, with a favorable adherence, persistence, and discontinuation profile in patients with T2DM in routine clinical practice. These findings provide additional insights regarding the potential value of dulaglutide in real-world settings that may assist healthcare decision makers in the delivery of patient-centered care.

Efficacy of Dulaglutide as a First Injectable Option for Patients with Type 2 Diabetes: A Post-Hoc Pooled Analysis.

INTRODUCTION: The ADA-EASD consensus report recommends using glucagon-like peptide-1 receptor agonists (GLP-1RAs) as the first injectable therapy prior to basal insulin in most patients with type 2 diabetes (T2D) not at glycemic goals after oral anti-hyperglycemia medications (OH). The objective of this analysis was to assess the glycemic efficacy of once-weekly dulaglutide 1.5 mg in patients with T2D when added on a background of commonly used OH regimens. METHODS: Patients from seven phase 3 AWARD [Assessment of Weekly AdministRation of LY2189265 (Dulaglutide) in Diabetes] trials, where once-weekly dulaglutide 1.5 mg was added to OHs, were pooled into the following categories based on OH regimens: metformin (MET), sulfonylurea (SU), MET + SU, MET + pioglitazone, and MET + SGLT2i. Change from baseline in glycated hemoglobin A1c (HbA1c), fasting serum glucose and body weight, proportion of patients reaching target HbA1c < 7%, and safety parameters were assessed. RESULTS: A total of 1784 patients treated with once-weekly dulaglutide 1.5 mg were included in this analysis. Baseline characteristics of the overall population were (mean ± standard deviation): age, 55.4 ± 9.8 years, HbA1c: 8.2 ± 1.0%, body mass index: 31.4 ± 5.4 kg/m2, duration of diabetes: 8.0 ± 5.6 years, and 878 (49.2%) were female. At 6 months, the addition of once-weekly dulaglutide 1.5 mg to various OH regimens significantly reduced HbA1c (- 1.3 to - 1.6%) and fasting blood glucose (- 29 to - 45 mg/dl) from baseline in all groups (p < 0.001), with 39-61% and 52-76% of these patients achieving HbA1c targets of ≤ 6.5% and < 7%, respectively. Significant reductions in body weight (- 0.8 to - 2.9 kg) were also observed in all groups (p < 0.001). Nausea, vomiting, and diarrhea were reported by 10-35%, 4-19%, and 6-28% of patients, respectively. Severe hypoglycemia occurred in one patient (MET + SU). CONCLUSION: The addition of a once-weekly GLP-1RA, dulaglutide, demonstrated clinically meaningful HbA1c reduction in patients with T2D on different background OH regimens, making it an effective first injectable option. FUNDING: Eli Lilly and Company.