Luis-Emilio Garcia-Perez

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

BACKGROUND 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. METHODS 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 (≥18 years) with inadequately controlled type 2 diabetes (HbA1c concentration ≥7·0% [53 mmol/mol] and ≤9·5% [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 1·5 mg, dulaglutide 0·75 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 (1·5 mg or 0·75 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. FINDINGS Between Dec 7, 2015, and Feb 3, 2017, 424 patients were randomly assigned to dulaglutide 1·5 mg (n=142), dulaglutide 0·75 mg (n=142), and placebo (n=140). One patient in the dulaglutide 0·75 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 1·5 mg -1·34% [SE 0·06] or -14·7 mmol/mol [0·6]; dulaglutide 0·75 mg -1·21% [0·06] or -13·2 mmol/mol [0·6]) than in patients receiving placebo (-0·54% [0·06] or -5·9 mmol/mol [0·6]; p<0·0001 for both groups vs placebo). The LSM differences were -0·79% (95% CI -0·97 to -0·61) or -8·6 mmol/mol (-10·6 to -6·7) for dulaglutide 1·5 mg and -0·66% (-0·84 to -0·49) or -7·2 mmol/mol (-9·2 to -5·4) for dulaglutide 0·75 mg (p<0·0001 for both). Serious adverse events were reported for five (4%) patients in the dulaglutide 1·5 mg group, three (2%) patients in the dulaglutide 0·75 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 1·5 mg group vs seven [5%] in the dulaglutide 0·75 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 0·75 mg group. Two (1%) patients receiving dulaglutide 1·5 mg died, but these deaths were not considered to be related to study drug; no deaths occurred in the other groups. INTERPRETATION 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. FUNDING Eli Lilly and Company.

Associations between adherence and outcomes among older, type 2 diabetes patients: evidence from a Medicare Supplemental database.

Objective To examine the association between adherence to glucose-lowering agents and patient outcomes, including costs, acute-care resource utilization, and complications, in an older, type 2 diabetic population. Data and methods The study used Truven’s Medicare Supplemental database from July 1, 2009 to June 30, 2014. Patients aged 65 years or older were included if they had at least two type 2 diabetes diagnoses and received a glucose-lowering agent from July 1, 2010 through June 30, 2011. Multivariable analyses examined the relationships among 3-year patient outcomes and levels of adherence, proxied by the proportion of days covered. Outcomes included all-cause medical costs, diabetes-related medical costs, acute-care resource utilization, and acute complications. Results In this study (N=123,235), higher adherence was linked to reduced costs and improved health outcomes. For example, comparing an individual with adherence of proportion of days covered <20% to one with proportion of days covered ≥80% illustrates an average saving of

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers

28,824 in total 3-year costs. Furthermore, a 1% increase in adherence among 1,000 patients was associated with all-cause savings of

Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme

65,464 over 3 years. The probability of a hospitalization, an emergency room (ER) visit, or an acute complication decreased monotonically as adherence levels got higher, as did the number of hospitalizations, ER visits, and days hospitalized (P<0.005). Conclusion Higher adherence was associated with substantially less need for acute care, as indicated by a lowered probability of hospitalization or ER use, a reduced risk of an acute complication, and a decreased number of hospitalizations, ER visits, and days hospitalized. Higher adherence was also generally associated with lower all-cause and diabetes-related total costs, despite higher drug costs. These lower total costs were driven by the diminished acute care and outpatient costs. Results suggest that higher glucose-lowering agent adherence is associated with significant benefits for payers and older patients with type 2 diabetes.

Effect of once weekly dulaglutide by baseline beta-cell function in people with type 2 diabetes in the AWARD programme

ABSTRACT Approximately 90% of T2D patients in the US are diagnosed and treated in the primary care setting, and the majority of the burden of disease management falls to primary care providers. Here, we discuss the clinical data for once weekly dulaglutide, e.g. the results of seven completed Phase 3 trials, patient preference studies, patient reported outcomes (PRO), and clinical data surrounding the dulaglutide administration device. Dulaglutide 1.5 mg once weekly demonstrated superiority to placebo, metformin, sitagliptin, exenatide BID, and insulin glargine (in 2 trials), and non-inferiority to liraglutide in reduction of HbA1c from baseline, with an acceptable safety profile. Dulaglutide-treated patients achieved the composite endpoint of an HbA1c <7.0% with no hypoglycemia, no severe hypoglycemia, and no weight gain significantly more than metformin, sitagliptin, exenatide BID or insulin glargine treated patients. Dulaglutide consistently showed an early onset of glycemic control, lasting up to 104 weeks. Additionally, PRO and patient preference data support the benefit of once weekly dulaglutide for the treatment of T2D.

Changes in lipid concentrations in patients with type 2 diabetes on once-weekly dulaglutide 1.5 mg: Post hoc pooled analysis of the AWARD trials

To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis.

Treatment Effects of Once-Weekly Dulaglutide vs. Insulin Glargine in Patients with Different Baseline Glycemic Patterns (Based on High/Low Fasting or High/Low Postprandial Glucose)—A Post-Hoc Analysis of the AWARD-2 Clinical Trial

Glucagon‐like peptide‐1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose‐dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta‐cell function (as measured by HOMA2‐%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide‐treated patients from AWARD‐1, AWARD‐3 and AWARD‐6 clinical studies were categorised based on their homeostatic model assessment of beta‐cell function (HOMA2‐%B) tertiles. Changes in glycaemic measures in response to treatment with once‐weekly dulaglutide were evaluated in each HOMA2‐%B tertile. Patients with low HOMA2‐%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB‐2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; −1.55% vs. −0.98% [−16.94 vs. −10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; −1.00 vs. −1.18% [−10.93 vs. −12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C‐peptide were observed in the low tertile. Similar increases in HOMA2‐%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta‐cell function.