Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.

Disease and Economic Burden of Poor Metabolic and Weight Control in Type 2 Diabetes in Spain: A Systematic Literature Review.

INTRODUCTION: Poor metabolic control and excess body weight are frequently present in people with type 2 diabetes (PwT2D). METHODS: A systematic literature review was conducted to identify observational studies reporting clinical, economic, and health-related quality of life (HRQoL) outcomes associated with poor metabolic (according to HbA1c, blood pressure [BP] and low density lipoprotein cholesterol [LDL-C] levels) and/or weight control (defined by a body mass index [BMI] ≥ 30 kg/m2) in adults with T2D in Spain, including articles published in either Spanish or English between 2013 and 2022 and conference abstracts from the last 2 years. RESULTS: Nine observational studies were included in the analysis. Poor glycemic control (HbA1c ≥ 7%) was associated with cardiovascular disease (CVD), increased requirements for antidiabetic medications, higher and more frequent weight gain, a greater probability of hypoglycemia and dyslipidemia, and worse health-related quality of life (HRQoL). Uncontrolled BP in PwT2D was related with the presence of CVD, worse metabolic control, and higher BMI and abdominal perimeter values. Poor LDL-C control or dyslipidemia was associated with CVD, hypoglycemia, and elevated HbA1c and triglycerides levels. The presence of a BMI ≥ 30 kg/m2 was related to CVD and hypoglycemia, a higher prevalence of metabolic syndrome and worse BP control. Direct medical costs were found to be higher in PwT2D when coexisting with HbA1c levels ≥ 7%, uncontrolled BP or obesity. Increased total costs, including productivity losses, were also detected in those who presented uncontrolled BP and a BMI ≥ 30 kg/m2, and when poor weight control existed together with HbA1c ≥ 8% and poorly controlled BP. CONCLUSION: Gathered evidence supports the high clinical, economic and HRQoL burden of poor metabolic and/or weight control in PwT2D in Spain and reinforces the importance of prioritizing its control to reduce the associated burden, at both the individual and healthcare system levels.

Glycaemic Control and Weight Reduction: A Narrative Review of New Therapies for Type 2 Diabetes.

Early and intensive treatment of type 2 diabetes (T2D) has been associated with lower risk of diabetes-related complications. Control of overweight and obesity, which are strongly associated with T2D and many of its complications, is also key in the management of the disease. New therapies allow for individualised glycaemic control targets with greater safety. Thus, in patients with a higher cardiovascular and renal risk profile, current guidelines encourage early treatment with metformin together with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors with proven cardiovascular benefit. GLP-1 RAs combine highly efficacious glucose-lowering activity with a reduced risk of hypoglycaemia. Recently, tirzepatide, a first-in-class drug that activates both glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has demonstrated very high efficacy in glycated haemoglobin (HbA1c) and weight reduction in clinical trials. Tirzepatide has the potential to help people with T2D reach recommended glycaemic and weight targets (HbA1c < 7% and > 5% weight reduction) and to allow some patients to reach HbA1c measurements close to normal physiological levels and substantial weight reduction. In 2022, tirzepatide was approved by the US Food and Drug Administration and the European Medicines Agency for treatment of people with T2D and is currently in development for chronic weight management.

In people newly diagnosed with type 2 diabetes, early and intensive treatment of the disease can help control blood sugar and reduce the risk of later complications. The need to control weight in people with obesity and diabetes has also recently become a priority. New drugs developed in recent years allow for better and more individualised management of blood sugar without the risk of blood sugar levels dropping too low. In patients at risk of kidney or heart disease, the current recommendation is early treatment with metformin and drugs with proven cardiovascular benefit. Tirzepatide is a new drug that has also demonstrated very high efficacy in reducing blood glucose and body weight. It has the potential to help people with type 2 diabetes achieve their goals and prevent other diabetes-related complications. It is likely that some patients will even be able to bring their blood glucose to normal levels and lose substantial amounts of weight. The US and European regulatory agencies approved tirzepatide in 2022 for the treatment of type 2 diabetes and it is currently being tested for chronic weight management.

Functional, Physical, and Volatile Characterization of Chitosan/Starch Food Films Functionalized with Mango Leaf Extract.

Active packaging is one of the currently thriving methods to preserve highly perishable foods. Nonetheless, the integration of active substances into the formulation of the packaging may alter their properties-particularly mass transfer properties-and therefore, the active compounds acting. Different formulations of chitosan (CH), starch (ST), and their blends (CH-ST), with the addition of mango leaf extract (MLE) have been polymerized by casting to evaluate their food preservation efficiency. A CH-ST blend with 3% MLE using 7.5 mL of the filmogenic solution proved to be the most effective formulation because of its high bioactivity (ca. 80% and 74% of inhibition growth of S. aureus and E. coli, respectively, and 40% antioxidant capacity). The formulation reduced the water solubility and water vapor permeability while increasing UV protection, properties that provide a better preservation of raspberry fruit after 13 days than the control. Moreover, a novel method of Headspace-Gas Chromatography-Ion Mobility Spectrometry to analyze the volatile profiles of the films is employed, to study the potential modification of the food in contact with the active film. These migrated compounds were shown to be closely related to both the mango extract additions and the film's formulation themselves, showing different fingerprints depending on the film.

GLP-1 RAs in Spain: A Short Narrative Review of Their Use in Real Clinical Practice.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs with potent glucose-lowering activity. Additionally, some GLP-1 RAs have demonstrated cardiovascular and renal benefits. Current guidelines recommend their use in patients with type 2 diabetes (T2D) at high risk of or with established cardiovascular disease (CVD), regardless of glycaemic control, with lifestyle modification and metformin. However, several studies have recently highlighted the limited number of patients with T2D benefiting from these medications worldwide. Given the huge burden of CVD among patients with T2D, efforts should be made to bring clinical practice closer to expert guidelines. This review describes the current situation of GLP-1 RA use in Spain and the reasons behind the gap between guidelines and real-world practice and suggests possible solutions. Administrative issues, lack of awareness of the cardiovascular benefits, clinical inertia, rejection of injectable medication and costs could be some of the reasons for the current situation. Possible strategies that could help to close the gap include encouraging a multidisciplinary approach to the treatment of diabetes which involves cardiologists, endocrinologists, nephrologists, primary care providers and pharmacists; improved awareness of comorbidities and earlier evaluation and treatment or risks; and better education of healthcare providers regarding the cardioprotective benefits of these drugs.

The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs that can be beneficial for patients with type 2 diabetes who are at high risk of cardiovascular complications, such as heart attacks. For this reason, the current clinical guidelines strongly recommend their use in these patients. Unfortunately, many patients with type 2 diabetes and high cardiovascular risk still do not benefit from these drugs. This review analyses the reasons for this situation in Spain, and proposes some possible solutions. The reasons for the low use of GLP-1 RAs could be related to doctors not updating a patient's diabetes medicine as often as they should, lack of awareness about the cardiovascular benefits of these drugs, fear of medicines that involve needles, administrative issues, and costs. Some of the possible strategies to improve the use of GLP-1 RAs among patients with type 2 diabetes with high cardiovascular risk could be to foster greater cooperation among specialists, increase awareness of the need to treat cardiovascular risk in patients with diabetes, and better education of doctors regarding the benefits of these drugs.

A Retrospective Observational Study Examining the Generalizability of Glucagon-Like Peptide 1 Receptor Agonist Cardiovascular Outcome Trials to the Real-World Population with Type 2 Diabetes in Spain: The REPRESENT Study.

INTRODUCTION: The REPRESENT study aims to examine whether participants enrolled in glucagon-like peptide 1 receptor agonist cardiovascular outcome trials (CVOTs) LEADER (liraglutide), REWIND (dulaglutide), and SUSTAIN-6 (injectable semaglutide) are representative of the Spanish population with type 2 diabetes (T2D). METHODS: This retrospective observational study used the IQVIA Electronic Medical Records database in Spain to identify adults aged 18 years and older with T2D diagnosed before/between January 2013 and December 2015. Demographic and clinical characteristics were analyzed descriptively. The proportions of individuals in the Spanish cohort who met the key selection criteria of each CVOT were calculated from individuals with available database entries for estimated glomerular filtration rate and body mass index using proxies. RESULTS: A total of 24,268 adults with T2D were identified from the IQVIA database. The Spanish cohort was predominantly male (55.5%) and had a mean (± SD) age of 66.8 ± 12.5 years and HbA1c of 7.2 ± 1.5%, with 14.0% having established cardiovascular disease and 2.9% having prior myocardial infarction. The characteristics of the Spanish cohort were more similar to that of REWIND than LEADER or SUSTAIN-6. The proportions of subjects in the Spanish cohort who met the CVOTs key selection criteria were 10.1% for LEADER, 53.6% for REWIND, and 10.4% for SUSTAIN-6. CONCLUSIONS: Although none of the CVOTs was fully representative of the Spanish cohort, the REWIND population was found to be more representative of the real-world Spanish population with T2D than those of LEADER and SUSTAIN-6. These findings reinforce the applicability of the results of REWIND in clinical practice.

Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.

Type 2 diabetes mellitus (T2DM) is a common disorder characterized by insulin resistance and dysfunction of insulin-producing beta cells of the pancreas. People living with T2DM have an increased risk of developing complications, including chronic kidney disease (CKD), which itself is associated with increased mortality. Both the American Diabetes Association and Kidney Disease Improving Global Outcomes organization provide updated pharmacological recommendations for treating T2DM in people with CKD that include the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). GLP-1 RAs are effective and safe treatments for controlling blood sugar levels and reducing body weight, and evidence from large clinical trials also suggests that GLP-1 RAs may be renoprotective. Despite the benefits of GLP-1 RAs, they are not commonly prescribed in people living with T2DM and CKD. Healthcare practitioners need to be aware of the most recent information so that they can make informed decisions when selecting treatment options. The objective of this review is to summarize the main renal outcomes from clinical studies while providing practical guidance on the use of GLP-1 RAs.

Glycaemic variability in patients with type 2 diabetes mellitus treated with dulaglutide, with and without concomitant insulin: Post hoc analyses of randomized clinical trials.

AIM: To investigate the association between treatment with dulaglutide and glycaemic variability (GV) in adult patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Post hoc analyses of six randomized, phase 3 studies were conducted to investigate the association between treatment with dulaglutide 1.5 mg once weekly and GV in adult patients with T2D. Using data from seven- and eight-point self-monitored plasma glucose (SMPG) profiles over up to 28 weeks of treatment, GV in within- and between-day SMPG, and between-day fasting glucose from SMPG (FSMPG) was assessed according to standard deviation and coefficient of variation. RESULTS: Pooled data from five studies with dulaglutide as monotherapy or added to oral glucose-lowering medication, without concomitant insulin treatment, revealed clinically meaningful reductions in within- and between-day SMPG, and between-day FSMPG variability from baseline in the dulaglutide group. Comparisons between treatment groups in two studies demonstrated that reductions from baseline in within-day and between-day SMPG, and between-day FSMPG variability were greater for treatment with dulaglutide compared with insulin glargine, as well as for treatment with dulaglutide when added to insulin glargine compared with insulin glargine alone. CONCLUSIONS: In patients with T2D, treatment with dulaglutide as monotherapy or added to oral glucose-lowering medication, without concomitant insulin treatment, was potentially associated with a reduction in GV. Treatment with dulaglutide was associated with a reduction in GV to a greater degree than insulin glargine. When added to insulin glargine, treatment with dulaglutide was associated with greater decreases in GV compared with insulin glargine alone. As reduced GV may be associated with better outcomes, these findings may have clinical relevance.

Sequential Organ Failure Assessment Score and the Need for Organ Support Predict Mortality in Allogeneic Stem Cell Transplant Patients Admitted to the Intensive Care Unit.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy resulting in increased definitive cure rates or extended disease-free survival in various malignant and nonmalignant hematologic diseases. However, because of the high risk of severe complications of this therapy, up to 50% of patients may require being admitted to the intensive care unit (ICU) to manage life-threatening conditions. We aimed to evaluate the in-hospital mortality of allo-HSCT recipients admitted to the ICU and to identify those variables associated with in-hospital mortality. A 10-year (January 2010 to December 2019), single-center, retrospective study was conducted in Vall d´Hebron University Hospital, Barcelona. We included all consecutive allo-HSCT patients who required admission to the ICU. Baseline and disease-related characteristics were registered. Severity scores and the need for organ support were also assessed on days 1, 3, and 5 of ICU admission. In-hospital mortality-associated independent variables were identified using the Cox proportional hazards regression model. Three hundred twenty-three patients underwent allo-HSCT during the study period, of whom 82 (25%) were admitted to the ICU; 53 (65%) male, with a median age of 51 (38-59) years. Most patients received allo-HSCT for the treatment of lymphoma (20 patients [24%]) or acute leukemia (44 patients [54%]). The median Acute Physiology And Chronic Health Evaluation II score was 23 (17-28), and the median Sequential Organ Failure Assessment (SOFA) score on admission was 9 (7-11). Forty-nine (60%) patients died in the ICU, and 11 (13%) died in the hospital after being discharged from the ICU. Disease-related characteristics were not associated with mortality. Yet, SOFA score on day 1 (hazard ratio [HR]: 1.11 [95% confidence interval {CI}: 1.04-1.02]; P = .002), the need for vasopressors on day 3 (HR: 2.35 [95% CI: 1.27-4.36]; P = .007), and a nondecreasing SOFA score on day 5 (HR: 2.13 [95% CI: 1.03-4.39]; P = .04), were independently associated with in-hospital mortality. Mortality in allo-HSCT patients who require ICU admission remains high. In the present study, SOFA score, the need for vasopressors on day 3, and a nondecreasing SOFA score on day 5 predicted in-hospital mortality.

Real-World Use of Insulin Glargine U100 and U300 in Insulin-Naïve Patients with Type 2 Diabetes Mellitus: DosInGlar Study.

INTRODUCTION: In the EDITION clinical trial programme, patients with type 2 diabetes mellitus (T2DM) receiving insulin glargine (IGlar) U300 required 10-15% more insulin than those receiving IGlar U100. This study sought to determine whether this difference was apparent in real-world practice. METHODS: In this observational, retrospective cohort study, electronic medical records in the Big-Pac® database (Real Life Data) relating to adult insulin-naïve patients with T2DM who initiated IGlar U100 or U300 treatment in Spain in 2016-2017 and remained on treatment for 18 months were selected. IGlar U100- and U300-treated patients were matched 1:1 (propensity score matching). The primary analysis compared changes from baseline in mean daily IGlar dose (U and U/kg) at 6 (± 2), 12 (± 2) and 18 (± 2) months between cohorts (paired t tests). Changes in glycated haemoglobin (HbA1c) and weight were analysed descriptively. RESULTS: The IGlar U100 and U300 cohorts included 556 matched pairs (46.9% female) with the following mean (standard deviation) values at baseline, respectively: age 63.6 (12.8) versus 63.7 (11.9) years; years since diagnosis 9.5 (1.4) versus 9.5 (1.3); HbA1c 8.8 (1.3) versus 8.7 (1.5) %; weight 84.6 (16.9) versus 84.7 (17.1) kg. Mean IGlar dose at baseline was 0.19 U/kg/day (both cohorts). Patients receiving IGlar U300 showed a greater increase from baseline in IGlar dose at 6, 12 and 18 months [mean dose (U/kg/day) 5.1%, 10.3% and 12.8% greater, respectively, in IGlar U300-treated patients]. Mean HbA1c was 8.1% in both cohorts at 18 months. Mean (SD) weight at 18 months with IGlar U100 and IGlar300 was 86.8 (17.0) kg and 85.0 (17.1) kg, respectively. CONCLUSION: In real-world practice, insulin dose was significantly higher in IGlar U300-treated than U100-treated patients at 6, 12 and 18 months, with similar reductions in HbA1c. At equal IGlar price/unit in Spain, the increased dose requirements of IGlar U300 would result in higher costs.

Epidemiology and Economic Burden of Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus in Spain: A Systematic Review.

INTRODUCTION: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in people with type 2 diabetes mellitus (T2DM). The objectives of this systematic literature review were to identify and synthesize published data describing the epidemiology and mortality of CVD in the T2DM population and the associated economic burden. METHODS: We conducted a systematic review searching the PubMed and MEDES databases from 2009 to 2019 using predefined selection criteria. Peer-reviewed observational studies reporting primary or secondary data on CVD prevalence, incidence, mortality, resource use and costs in patients with T2DM in Spain, written in English and Spanish, were included. Data were tabulated and summarized descriptively. RESULTS: Of 706 articles identified, 52 were included in the review. Most studies were based on data from hospital discharge databases and registries. The reported prevalence of CVD among patients with T2DM ranged from 6.9 to 40.8%. The prevalence of coronary heart disease ranged from 4.7 to 37%, stroke from 3.5 to 19.6%, peripheral artery disease from 2.5 to 13.0%, and heart failure from 4.3 to 20.1%. In-hospital CVD mortality rates ranged from 5.6 to 10.8%. Direct costs due to CVD in hospitalized patients with T2DM were increased (> 50%) compared with patients without CVD. No studies analysed indirect costs of CVD in patients with T2DM. CONCLUSIONS: The burden of CVD among patients with T2DM, combined with the elevated costs of care, highlights the importance of early prevention as part of integrated management of the disease to improve clinical and economic outcomes.

Glucagon-Like Peptide 1 Receptor Agonists in Type 2 Diabetes Mellitus: Data from a Real-World Study in Spain.

INTRODUCTION: This study aimed to describe utilization patterns, persistence, resource utilization and costs in patients with type 2 diabetes mellitus initiating treatment with glucagon-like peptide 1 receptor agonists in routine clinical practice in Spain. METHODS: This retrospective study of medical records in the Big-Pac database identified adults starting treatment with once-weekly (QW) dulaglutide, exenatide-QW or once-daily liraglutide between 1 November 2015 and 30 June 2017. Patients were followed for up to 18 months from treatment initiation. Data on clinical characteristics of patients, treatment patterns, average daily dose and costs were obtained for the three cohorts. Persistence over the 18-month period was evaluated using Kaplan-Meier curves. All analyses were descriptive. RESULTS: A total of 1402 patients were included in this study (dulaglutide [n = 492], exenatide-QW [n = 438] or liraglutide [n = 472]); 52.8% were men, and the mean (SD) age was 62 (11) years, glycated haemoglobin (HbA1c) was 8.1% (1.2) and body mass index was 35.5 (3.2) kg/m2 at treatment initiation. Persistence at 18 months was 59.1% (95% confidence interval [CI] 54.8-63.4) for dulaglutide, 45.7% (95% CI 41.0-50.4) for exenatide-QW and 46.6% (95% CI 42.1-51.1) for liraglutide. The average (SD) dose was 1.2 (0.4) mg/week for dulaglutide, 1.9 (0.3) mg/week for exenatide-QW and 1.1 (0.3) mg/day for liraglutide. The average reduction in HbA1c levels at 1 year was - 0.68% for patients who initiated dulaglutide, - 0.54% for patients who initiated exenatide-QW and - 0.50% for patients who initiated liraglutide. The mean (SD) total annual health care costs were €4072 (1946) for dulaglutide, €4418 (2382) for exenatide-QW and €4382 (2389) for liraglutide. CONCLUSION: Results suggest that patients who started treatment with dulaglutide had higher persistence over 18 months, presented lower HbA1c levels at 12 months and incurred lower annual total healthcare costs than patients who initiated exenatide-QW or liraglutide.

Type 2 diabetes has a major impact on patients psychologically and socially, as well as on healthcare costs. The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are drugs that help maintain blood sugar at healthy levels. They are often used as the first injectable drugs if oral treatments are no longer effective. This study aimed to analyse the use of GLP-1 RAs, and the costs involved, among patients with type 2 diabetes who started treatment with once-weekly dulaglutide, once-weekly exenatide or liraglutide in routine clinical practice in Spain. An electronic database of medical records was used to obtain data from 1402 patients who started treatment with these drugs and were followed for a 1.5-year period. Results of this study suggest that patients who were prescribed dulaglutide stayed on their treatment longer and could reduce their blood sugar levels more efficiently, and at a lower cost, than those who received once-weekly exenatide or liraglutide. These findings could be helpful to physicians prescribing these drugs when considering how to improve the management of type 2 diabetes.

Resource use and costs in patients with poorly controlled type 2 diabetes mellitus and obesity in routine clinical practice in Spain.

OBJECTIVE: To compare healthcare resource use (HRU) and annual costs in type 2 diabetes mellitus (T2DM) patients with poor glycaemic control and obesity versus good glycaemic control without obesity. METHODS: Observational retrospective study based on the analysis of electronic medical records from the BIG-PAC database, with one year of follow-up. T2DM patients aged ≥30 years who requested medical care during 2013 were included. Annual HRU and costs per patient were compared between a reference group (HbA1c ≥ 8%, BMI ≥30 kg/m2, receiving ≥2 oral antidiabetic drugs [OADs]) and a control group (HbA1c < 7% and BMI <30 kg/m2). Direct and indirect costs (lost productivity) were analysed. Cost comparisons across groups were made using the analysis of covariance (ANCOVA) for each cost component, with age, sex, time from diagnosis, Charlson comorbidity index, OAD number and sex by group interaction as covariates. RESULTS: During the follow-up, patients in the reference group (N = 2709) had a greater HRU than those in the control group (N = 5266), especially in the number of primary care (PC) visits (11.8 vs. 9.8; 95%CI: 11.5-12.1 vs. 9.6-10.0) and days of hospitalization (1.1 vs 0.6; 95%CI: 1.0-1.2 vs. 0.5-0.7). The main components of the total cost were hospital admissions (24.5%), productivity losses (16.3%), complementary tests (14.4%), PC visits (14.2%) and medication (13.6%) in the reference group and medication (19.6%), hospital admissions (18.7%) and PC visits (18.2%) in the control group. The corrected mean annual cost per patient was higher in the reference than in the control group: €1804 vs. €1309; p < .001. CONCLUSIONS: Poor glycaemic control and obesity in T2DM patients were associated with increased HRU and costs in routine clinical practice.

Once-weekly dulaglutide versus insulin glargine in the early control of fasting serum glucose and HbA1c.

AIMS: To determine the early benefit:risk balance of dulaglutide versus insulin glargine in patients with type 2 diabetes mellitus (T2DM). METHODS: This post hoc analysis used data from a randomized, open-label study (AWARD-2; modified intention-to-treat group) in which suboptimally controlled metformin + glimepiride-treated patients received dulaglutide 1.5 mg (n = 273) or insulin glargine (n = 262). Two composite endpoints were used: for weeks 2-20, fasting serum glucose (FSG) <130 mg/dL (<7.2 mmol/L) without hypoglycemia (blood glucose ≤70 mg/dL [≤3.9 mmol/L] or severe hypoglycemia); at week 26, patients with glycated hemoglobin (HbA1c) <7.0% (<53.0 mmol/mol) or reduction from baseline ≥1.0% (≥10.9 mmol/mol), no hypoglycemia (as defined above) and no weight gain. Odds ratios (ORs) were generated using logistic regression analysis. RESULTS: The probability of reaching the FSG target without hypoglycemia was higher with dulaglutide than with insulin glargine at weeks 4 (OR 1.78; 95% confidence interval [CI] 1.22-2.60) and 8 (OR 1.69; 95% CI 1.15-2.48). The proportion of patients achieving the 26-week endpoint was higher with dulaglutide (37.4% vs. 10.3%; OR 5.28; 95% CI 3.28-8.48). CONCLUSIONS: Dulaglutide's balanced efficacy-to-safety profile compares favorably with that of insulin glargine and is apparent soon after treatment initiation and after 6 months of therapy.

Clinical Inertia in Poorly Controlled Type 2 Diabetes Mellitus Patients with Obesity: An Observational Retrospective Study.

INTRODUCTION: To evaluate clinical inertia in patients with type 2 diabetes mellitus (T2DM), obesity and poor glycaemic control in routine clinical practice. METHODS: This was a retrospective, observational study based on the analysis of medical records from the BIG-PAC® database. Subjects who required medical care in 2013 with the following characteristics were enrolled in the study: age ≥ 30 years, diagnosis of T2DM, glycosylated haemoglobin (HbA1c) ≥ 8%, obesity (body mass index [BMI] ≥ 30 kg/m2) and treatment with ≥ 2 oral antidiabetic drugs (OADs). Inertia was evaluated by time (days) to the first intensification during the period while HbA1c levels were ≥ 8% and percentage of patients whose treatment was not intensified at 6 months, 1, 2 and 3 years and the end of follow-up. The minimum length of follow-up was 4 years. Descriptive analyses and Kaplan-Meier survival curves were performed. RESULTS: A total of 13,824 patients with T2DM receiving ≥ 2 OADs were identified; of these 2709 (19.6%) had HbA1c ≥ 8% and BMI ≥ 30 kg/m2, thus fulfilling the inclusion criteria. Of these 2709 patients, the mean age was 65.5 (standard deviation [SD] 12.0) years; 54.9% were male, mean HbA1c level was 9.2% (SD 1.3%); mean BMI was 32.1 (SD 0.9) kg/m2; and mean time from diagnosis was 8.2 (SD 3.0) years. HbA1c remained ≥ 8% for a median of 440 (95% confidence interval [CI] 421-459) days. The median time to first intensification was 456 (95% CI 429-483) days. No intensification had occurred in 77.8, 59.5, 41.5, 28.1 and 22.4% of patients at 6 months, 1, 2, 3 years and the end of follow-up, respectively. CONCLUSIONS: The patients with T2DM analysed in this study had a mean HbA1c of 9.2% at baseline, and this remained at ≥ 8% for > 1 year. The time to the first treatment intensification was longer than that recommended by guidelines. Treatment was not intensified in a large percentage of patients, with almost 60% of patients not receiving intensification at 1 year of follow-up.

Dulaglutide is an effective treatment for lowering HbA1c in patients with type 2 diabetes regardless of body mass index.

AIM: To assess the relationship between baseline body mass index (BMI) and glycaemic control in dulaglutide-treated patients, a post hoc analysis was conducted on HbA1c and baseline BMI data from eight AWARD studies, with a total of 5770 patients. MATERIALS AND METHODS: Changes from baseline in HbA1c data from patients treated with 1.5 mg or 0.75 mg dulaglutide, active comparator or placebo, were analyzed in each study (AWARD-1 to -6, -8 and - 9) at approximately 6 months (26, 24 and 28 weeks, respectively). Within each study, data were analyzed by the following baseline BMI categories: <30, ≥30 to <35, and ≥ 35 kg/m2 . RESULTS: In this post hoc analysis, 1.5 mg or 0.75 mg dulaglutide treatment achieved statistically significant HbA1c reductions from baseline in all BMI categories (least-squares mean change from -0.62 to -1.75%) across the AWARD studies. No statistically significant treatment-by-BMI category interactions were found for reductions in HbA1c. CONCLUSION: This post hoc analysis of eight AWARD studies indicates that baseline BMI does not affect the relative treatment efficacy of dulaglutide as measured by HbA1c change from baseline in any study. Dulaglutide is an effective treatment option for adult patients with type 2 diabetes regardless of their baseline BMI category.

Change in HbA1c Across the Baseline HbA1c Range in Type 2 Diabetes Patients Receiving Once-Weekly Dulaglutide Versus Other Incretin Agents.

INTRODUCTION: This exploratory post hoc analysis investigated the relative changes in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) treated with dulaglutide versus active comparators across a continuous range of baseline HbA1c values using data from three phase III randomised controlled trials. METHODS: Data from patients receiving once-weekly dulaglutide 0.75 and 1.5 mg, once-daily sitagliptin 100 mg, once-daily liraglutide 1.8 mg or twice-daily exenatide 10 µg in the intent-to-treat populations in the AWARD-5, AWARD-6 and AWARD-1 trials were analysed using last observation carried forward analysis of covariance. Starting with the predefined statistical model from each study, the type of association between HbA1c baseline and change at 26 weeks was modelled. Consistency of treatment effect was assessed via treatment-by-baseline HbA1c interaction terms. RESULTS: Improvements in HbA1c occurred in all treatment groups across the entire baseline HbA1c range. The relationship between HbA1c baseline and magnitude of change was linear in all treatment groups, with greater reductions in patients with higher baseline HbA1c values. Across the continuum of baseline HbA1c values, patients treated with dulaglutide 1.5 mg achieved a similar mean HbA1c reduction to patients receiving liraglutide 1.8 mg and a greater reduction than patients receiving twice-daily exenatide or sitagliptin. In AWARD-5, the treatment-by-baseline HbA1c interaction P value (0.001) demonstrated progressively greater HbA1c reduction in dulaglutide-treated compared with sitagliptin-treated patients as baseline HbA1c increased. CONCLUSION: Our results suggest that dulaglutide is an appropriate therapeutic option for patients with T2DM across a wide range of baseline HbA1c values, including those with poor metabolic control. FUNDING: Eli Lilly and Company. Plain language summary available for this article.

A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well established as effective treatments for patients with type 2 diabetes. GLP-1 RAs augment insulin secretion and suppress glucagon release via the stimulation of GLP-1 receptors. Although all GLP-1 RAs share the same underlying mechanism of action, they differ in terms of formulations, administration, injection devices and dosages. With six GLP-1 RAs currently available in Europe (namely, immediate-release exenatide, lixisenatide, liraglutide; prolonged-release exenatide, dulaglutide and semaglutide), each with its own characteristics and administration requirements, physicians caring for patients in their routine practice face the challenge of being cognizant of all this information so they are able to select the agent that is most suitable for their patient and use it in an efficient and optimal way. The objective of this review is to bring together practical information on the use of these GLP-1 RAs that reflects their approved use.Funding: Eli Lilly and Company.Plain Language Summary: Plain language summary available for this article.

A paired trial comparing mononuclear cell collection in two machines for further inactivation through an inline or offline extracorporeal photopheresis procedure.

BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment. However, protocols differ widely, and some questions, such as the number of cells to be collected or the number of ECP treatment days per treatment cycle, are still unsolved. The aim of this study was to compare a multistep (offline) (Spectra Optia and Macogenic G2) against an integrated (inline) ECP system (Therakos Cellex system) with respect to mononuclear cell (MNC) collection. STUDY DESIGN AND METHODS: The number and quality parameters of the MNC products collected were evaluated together with some machine parameters, such as collection time. Comparisons were made through paired sample analysis with the t test. RESULTS: Fourteen patients underwent 15 double-paired procedures using both ECP protocols. The average MNC collected in the multistep procedure was 77.4 × 108 , four times more than in the integrated procedure (18.5 × 108 ). MNC purity (84.4% vs. 63.8%) and enrichment (27.9 vs. 5.9) in the product collected were also higher in the multistep procedure. The whole ECP time was higher in the multistep than in the integrated procedure (272 vs. 106 min), but the calculated time to collect 25 × 108 MNCs in the multistep was shorter compared with the one-step procedure (77.8 vs. 172 min). All these differences between the two protocols were statistically significant. CONCLUSIONS: These two ECP protocols are different with respect to MNC collection and length of procedure. Some unresolved questions, such as the better MNC dose to inactivate or the number of consecutive days that ECP should be performed for optimal clinical efficacy, require further review.

Following the results of the EMPA-REG OUTCOME trial with empagliflozin, is it possible to speak of a class effect?

BACKGROUND: The recently published cardiovascular outcomes data for the first sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, have shown cardiovascular safety and additional benefits in patients with type 2 diabetes and established cardiovascular disease. Empagliflozin showed lower rates of death from cardiovascular causes or from any causes and lower hospitalization rates from heart failure compared with placebo, both in addition to standard care. This commentary discusses the existence of a possible class effect considering the available evidence described for other SGLT2 inhibitors. MAIN TEXT: Empagliflozin, dapagliflozin and canagliflozin share the same mechanism of action, and it is a plausible hypothesis that some of the benefits of empagliflozin treatment could also be expected from other SGLT2 inhibitors. However, the rapid and persistent occurrence of cardiovascular benefits observed with empagliflozin and the different results shown by the three inhibitors in meta-analyses of some of their respective Phase II and III trials might suggest another possible mechanism of action, perhaps related to the different selectivity to inhibit SGLT-2 and other SGLT family members that these compounds present. CONCLUSION: There is still lack of evidence to answer whether the cardiovascular benefits observed with empagliflozin in the EMPA-REG OUTCOME study could be seen as a "class effect", which is also attributable to dapagliflozin and canagliflozin.