Early-Onset Type 2 Diabetes and Tirzepatide Treatment: A Post Hoc Analysis From the SURPASS Clinical Trial Program.

OBJECTIVE: We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers. RESEARCH DESIGN AND METHODS: This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia. RESULTS: At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (-2.6% vs. -2.4%), BW (-14 vs. -13 kg), WC (-10 vs. -10 cm), triglycerides (-26% vs. -24%), HDL (7% vs. 7%), and systolic BP (-6 vs. -7 mmHg) were observed in both subgroups with tirzepatide. CONCLUSIONS: Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D.

Effects of Tirzepatide Versus Basal Insulins in People With Type 2 Diabetes and Different Baseline Glycemic Patterns: Post Hoc Analyses of the SURPASS-3 and SURPASS-4 Trials.

OBJECTIVE: This post hoc analysis assessed change from baseline to week 52 in glycemic parameters for tirzepatide (5, 10, 15 mg) versus insulin degludec (SURPASS-3 trial) and glargine (SURPASS-4 trial) in people with type 2 diabetes and different baseline glycemic patterns, based on fasting serum glucose (FSG) and postprandial glucose (PPG) values. RESEARCH DESIGN AND METHODS: Participant subgroups with low FSG/low PPG, low FSG/high PPG, high FSG/low PPG, and high FSG/high PPG were defined according to the median values of these measures. RESULTS: All tirzepatide doses and basal insulins were associated with decreased HbA1c, FSG, and PPG values from baseline to week 52 in all subgroups (P < 0.05). Within each subgroup, HbA1c and PPG decreases were greater with tirzepatide than insulin (P < 0.05). FSG decreases were generally similar. There were no differential treatment effects by FSG/PPG subgroup. CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with superior glycemic control compared with insulin, irrespective of baseline glycemic pattern.

Dulaglutide and Kidney Function-Related Outcomes in Type 2 Diabetes: A REWIND Post Hoc Analysis.

OBJECTIVE: Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants. RESEARCH DESIGN AND METHODS: Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function-related outcome (≥40% sustained decline in estimated glomerular filtration rate [eGFR], per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2). RESULTS: The post hoc composite kidney function-related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio [HR] 0.75, 95% CI 0.62-0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58-0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (-1.37 vs. -1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups. CONCLUSIONS: The estimated 25% reduced hazard of a kidney function-related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes.

Relationship between body weight change and glycaemic control with tirzepatide treatment in people with type 2 diabetes: A post hoc assessment of the SURPASS clinical trial programme.

AIM: To assess the relationship between HbA1c and body weight reductions with tirzepatide treatment (5, 10 or 15 mg). MATERIALS AND METHODS: HbA1c and body weight data at 40 weeks (SURPASS-1, -2 and -5) and 52 weeks (SURPASS-3 and -4) were analysed by trial. RESULTS: Across the SURPASS clinical trials, HbA1c reductions from baseline were observed in 96%-99%, 98%-99% and 94%-99% of participants treated with tirzepatide 5, 10 and 15 mg, respectively. Moreover, 87%-94%, 88%-95% and 88%-97% of participants, respectively, experienced weight loss associated with HbA1c reductions. Statistically significant associations (correlation coefficients ranging from 0.1438 to 0.3130 across studies; P ≤ .038) between HbA1c and body weight changes were observed with tirzepatide in SURPASS-2, -3, -4 (all doses) and -5 (tirzepatide 5 mg only). CONCLUSIONS: In this post hoc analysis, consistent reductions in both HbA1c and body weight were observed in most participants treated with tirzepatide at doses of 5, 10 or 15 mg. A statistically significant but modest association between HbA1c and body weight change was observed in SURPASS-2, SURPASS-3 and SURPASS-4, suggesting that both weight-independent and weight-dependent mechanisms are responsible for the tirzepatide-induced improvement in glycaemic control.

Weight-dependent and weight-independent effects of dulaglutide on blood pressure in patients with type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D. METHODS: Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo. RESULTS: Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was - 2.6 mmHg (95% CI - 3.8, - 1.5; p < 0.001) and was attributed to both a weight-dependent effect (- 0.9 mmHg; 95% CI: - 1.4, - 0.5; p < 0.001) and a weight-independent effect (- 1.5 mmHg; 95% CI: - 2.6, - 0.3; p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (- 2.5 mmHg; 95% CI: - 3.5, - 1.5; p < 0.001) was 14% weight-dependent and 86% weight-independent. For DBP there was limited impact of dulaglutide treatment, with only a small weight-mediated effect. Dulaglutide 4.5 mg demonstrated an effect on reduction in SBP and pulse pressure beyond that of dulaglutide 1.5 mg which was primarily weight mediated. CONCLUSIONS: Dulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension. Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102.

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.

Efficacy and safety outcomes of dulaglutide by baseline HbA1c: A post hoc analysis of the REWIND trial.

AIM: To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher. MATERIALS AND METHODS: Intention-to-treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures. Subgroup analyses with factors for baseline HbA1c categories and their interaction with treatment group, as well as analyses within the HbA1c subgroups, were conducted. Additionally, sensitivity analyses were performed for baseline HbA1c subgroups of 6.5% or less and more than 6.5%. RESULTS: Of the 9876 eligible participants, 3921 and 5955 had a baseline HbA1c of less than 7% and 7% or higher, respectively. Mean baseline HbA1c was 6.3% and 8.0% and the mean duration of diabetes was 9.0 and 11.6 years in the respective subgroups. The less than 7% subgroup was slightly older and less frequently insulin-treated. There was no evidence of a differential dulaglutide treatment effect on body mass index (BMI) reduction, cardiovascular or safety outcomes of interest between the baseline HbA1c subgroups. Treatment-by-baseline HbA1c group interaction was significant for HbA1c change from baseline (P < .001), with a greater reduction in the subgroup with higher baseline HbA1c values. Sensitivity analyses by baseline HbA1c subgroups of 6.5% or less and more than 6.5% showed similar results. CONCLUSIONS: The reduced incidence of cardiovascular events, and the reduction in BMI in participants treated with once-weekly dulaglutide, were independent of the baseline HbA1c level. Conversely, participants with a higher baseline HbA1c level had greater reductions in HbA1c. Dulaglutide has a positive benefit-risk profile and can be considered in patients with comparatively well-controlled HbA1c levels seeking optimal metabolic control and cardiovascular benefits.

Effect of expanded dulaglutide weekly doses (3.0 mg and 4.5 mg) on cardiovascular disease risk factors in participants with type 2 diabetes at increased cardiovascular disease risk: a post hoc analysis of the AWARD-11 study.

AIMS: This post hoc analysis investigated the effect of dulaglutide on cardiovascular disease (CVD) risk factors in subgroups of participants at increased CVD risk in the AWARD-11 study. METHODS: Participants who received once weekly dulaglutide 1.5, 3.0 or 4.5 mg for 52 weeks were categorized according to their baseline Framingham CVD risk category [low (N = 295), medium (N = 481) and high (N = 1054) risk], as well as their baseline CVD risk according to the REWIND study eligibility criteria (N = 953). Serum lipids and vital signs were assessed at baseline and at 52 weeks. Data were analysed as least squares mean percentage change from baseline for lipids and least squares mean change from baseline for vital signs. RESULTS: Demographic and baseline clinical characteristics were balanced across doses within the CVD risk groups. In the high Framingham CVD risk and REWIND-like groups, dulaglutide resulted in dose-related decreases in total cholesterol (≤6.0%), non-high-density lipoprotein cholesterol (≤8.8%), very-low-density lipoprotein cholesterol (≤19.4%) and triglycerides (≤21.5%), with little change in low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Systolic and diastolic blood pressure decreased up to 5.6 mmHg and 1.6 mmHg, respectively, and heart rate increased up to 2 beats/min. CONCLUSIONS: This post hoc analysis suggests the magnitude of the favourable effects of dulaglutide 3.0 mg and 4.5 mg on several cardiometabolic CVD risk factors was similar to, if not greater than, those of dulaglutide 1.5 mg among participants with type 2 diabetes and increased CVD risk. CLINICALTRIALS: gov Identifier: NCT03495102.

A Network Meta-Analysis to Compare Effectiveness of Baricitinib and Other Treatments in Rheumatoid Arthritis Patients with Inadequate Response to Methotrexate.

BACKGROUND/OBJECTIVES: This article compares the effectiveness of baricitinib (BARI) 4 mg (oral, Janus kinase [JAK] 1/2 inhibitor) versus other targeted synthetic/biologic disease-modifying antirheumatic drugs, in combination with methotrexate (MTX), in moderate-to-severe rheumatoid arthritis patients with inadequate response (IR) to MTX. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of the interventions of interest. Bayesian network meta-analyses (NMA) were used to compare American College of Rheumatology (ACR) responses at 24 weeks. A series of prespecified sensitivity analyses addressed the potential impact of, among others, baseline risk, treatment effect modifiers, and trial design on treatment response. RESULTS: Nineteen RCTs were included in the NMA (primary analysis). For ACR20, BARI 4 mg + MTX was found to be more effective than adalimumab (ADA) 40 mg + MTX (Odds Ratio [OR] 1.33), abatacept (ABA) 10 mg + MTX (IV/4 weeks) (OR 1.45), infliximab (IFX) 3 mg + MTX (IV/8 wks) (OR 1.63), and rituximab (RTX) 1000 mg + MTX (OR 1.63). No differences were found on ACR50. For ACR70, BARI 4 mg + MTX was more effective than ADA 40 mg + MTX (OR 1.37), ABA 10 mg + MTX (OR 1.86), and RTX 1000 mg + MTX (OR 2.26). Sensitivity analysis including 10 additional RCTs with up to 20% of patients with prior biologic use showed BARI 4 mg + MTX to be more effective than tocilizumab (TCZ) 8 mg + MTX on ACR20 (OR 1.44). Results for all sensitivity analyses were consistent with the direction and magnitude of the primary results. Key limitations include the time span in which trials were conducted (1999-2017), during which patient characteristics and treatment approaches might have changed. CONCLUSION: This NMA suggests that BARI 4 mg + MTX is an efficacious treatment option in the MTX-IR population as evidenced by the robustness of results.

New Rheumatoid Arthritis Treatments for 'Old' Patients: Results of a Systematic Review.

INTRODUCTION: In the last 20 years, biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) have become available for treating rheumatoid arthritis (RA), and a treat-to-target strategy has been introduced. We hypothesise that these advances should have resulted in changes to the characteristics of patients with RA participating in clinical trials of the newest therapies. This study determined whether the baseline characteristics of patients with RA enrolled in clinical trials have changed in the past decade versus patients participating in earlier RA studies. METHODS: This secondary analysis was based on randomised controlled trials (RCTs) identified in a systematic literature review. Baseline characteristics of patients with RA with inadequate response to conventional synthetic DMARDs were compared between RCTs published in 1999-2009 and those published in 2010-2017 using random-effects meta-analyses. RESULTS: Forty RCTs were analysed: 22 from 1999-2009 and 18 from 2010-2017. No significant difference between the two timeframes and no obvious trend over time were observed for age, gender, disease duration, rheumatoid factor status, tender and swollen joint counts, physician and patient global assessments of disease activity, and pain scores. Variability between RCTs was high. Similar results were observed for Disease Activity Scores and Health Assessment Questionnaire-Disability Index scores, but with low variability between RCTs. CONCLUSION: The baseline characteristics of patients with RA participating in RCTs do not appear to have changed in the last decade despite the availability of new treatments and a different treatment approach. Further research should determine the impact of baseline patient characteristics on patients' response to RA treatments.

In the last 20 years, new treatments and a new treatment approach (called treat-to-target) have been introduced for rheumatoid arthritis (RA). Consequently, the characteristics of patients with RA participating in clinical trials of the newest therapies should have changed compared with those of patients who participated in clinical trials of older therapies. This is important as patient characteristics may influence patients' response to drug treatment. To determine whether characteristics of patients with RA have changed over time, we compared the baseline characteristics (e.g. age, gender, disease duration, measures of disease activity, and pain scores) of patients with RA between 22 clinical trials published in 1999­2009 and 18 published in 2010­2017. No significant difference between the two timeframes and no obvious trend over time were observed for any baseline characteristic of patients with RA, including physician and patient measures of disease activity, and patient measures of physical function and pain. Thus, the baseline characteristics of patients with RA participating in clinical trials do not appear to have changed in the last decade despite the introduction of new treatments and the treat-to-target approach. Further research is needed to determine the impact of baseline patient characteristics on patients' response to RA treatments.

A modeling framework for the economic evaluation of baricitinib in moderate-to-severe rheumatoid arthritis.

Objectives: The approval in more than 50 countries of baricitinib, an oral Janus Kinase inhibitor for the treatment of Rheumatoid Arthritis (RA), warrants a framework for corresponding economic evaluations. To develop a comprehensive economic model assessing the cost-effectiveness of baricitinib for the treatment of moderately-to-severely active RA patients in comparison to other relevant treatments, considering the natural history of the disease, real world treatment patterns, and clinical evidence from the baricitinib trials.Methods: A systematic literature review of previously developed models in RA was conducted to inform the model structure, key modeling assumptions and data inputs. Consultations with rheumatologists were undertaken to validate the modeling approach and underlying assumptions.Results: A discrete event simulation model was developed to international best practices with flexibility to assess the cost-effectiveness of baricitinib over a lifetime in a variety of markets. The model incorporates treatment sequencing to adequately reflect treatment pathways in clinical practice. Outcomes assessed include cost and quality-adjusted life years, allowing for a full incremental analysis of cost-effectiveness of competing treatments and treatment sequences.Conclusion: The economic model developed provides a robust framework for future analyses assessing the cost-effectiveness of baricitinib for the treatment of RA in specific country settings.

A Budget Impact and Cost Per Additional Responder Analysis for Baricitinib for the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients with an Inadequate Response to Tumor Necrosis Factor Inhibitors in the USA.

BACKGROUND/OBJECTIVE: Baricitinib is a selective and reversible Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor inhibitors (TNFis) and has been shown to improve multiple clinical and patient-reported outcomes. However, it is unclear what the budgetary impact would be for US commercial payers to add baricitinib to their formulary and how the efficacy of baricitinib compares to other disease-modifying antirheumatic drugs (DMARDs) with a similar indication. METHODS: A budget impact model (BIM) was developed for a hypothetical population of 1 million plan members that compared a world without and with baricitinib. A retrospective observational study was carried out to estimate market utilization of advanced therapies. Number needed to treat (NNT) and cost per additional responder were calculated for American College of Rheumatology (ACR) 20%/50%/70% improvement criteria (ACR20/50/70) response outcomes combining cost estimates from the BIM and efficacy values from a network meta-analysis (NMA). The model included costs related to drug acquisition and monitoring costs. RESULTS: Adding baricitinib would save a commercial payer $US169,742 for second-line therapy and $US135,471 for third-line therapy over a 2-year time horizon (all costs correspond to 2019 US dollars). Cost savings were driven by baricitinib drawing market share away from more expensive comparators. The NMA, based on nine studies, found no statistically significant differences in the median treatment difference between baricitinib and comparators except for versus a conventional synthetic DMARD (csDMARD), and thus NNT versus a csDMARD was similar. The cost per additional responder for baricitinib in patients with inadequate response to a TNFi was substantially lower than all other treatments for all three ACR response criteria at 12 weeks (ACR20: $US129,672; ACR50: $US237,732; ACR70: $US475,464), and among the lowest at 24 weeks (ACR20: $US167,811; ACR50: $US259,344; ACR70: $US570,557). CONCLUSIONS: Baricitinib, compared to other DMARDs, was a less expensive option (- $US0.01 incremental cost per member per month in second- and third-line therapy over a 2-year time horizon) with comparable efficacy in patients with inadequate response to TNFi. Adding baricitinib to formulary would likely be cost saving for US payers and expands treatment options for these patients.

Correction to: A Budget Impact and Cost Per Additional Responder Analysis for Baricitinib for the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients with an Inadequate Response to Tumor Necrosis Factor Inhibitors in the USA.

Due to a single error in the annual cost of sarilumab the following needs to be corrected in the article.

Safety of baricitinib in East Asian patients with moderate-to-severe active rheumatoid arthritis: An integrated analysis from clinical trials.

AIM: We evaluated the safety of baricitinib in an East Asian (EA) patient population with moderate-to-severely active rheumatoid arthritis (RA), through an integrated sub-analysis of data from the overall baricitinib RA clinical program. METHODS: Data from EA patients who received any dose of baricitinib from five completed studies (1 Phase 2, 4 Phase 3) and an ongoing long-term extension study were pooled up to 1 September, 2016. Exposure-adjusted incidence rates (EAIR) and incidence rates (IRs), both per 100 patient-years (PY), were calculated. RESULTS: This analysis included 740 EA patients with 1294 PY of total baricitinib exposure (maximum 3.5 years). Overall, 109 patients discontinued baricitinib due to adverse events (AEs); EAIR: 8.4. No deaths were reported in this cohort. Serious AEs were reported by 125 patients (EAIR: 9.7). Serious infections were the most common serious AEs (n = 53, IR: 4.15). IR of herpes zoster infection was 6.2; the majority of events were of mild-to-moderate severity. Three cases (IR: 0.23) of tuberculosis were reported. The IRs of malignancy (excluding non-melanoma skin cancer) was 0.99 and EAIR specifically of lymphoma was 0.1. The IR of major adverse cardiovascular events was 0.26, and deep vein thrombosis was reported in four patients (EAIR: 0.3). Two cases of gastrointestinal perforations (EAIR: 0.2) were reported. CONCLUSION: Integrated data show that baricitinib is well-tolerated in EA patients with moderate-to-severely active RA in the context of demonstrated efficacy, which is generally consistent with safety results of the overall study population.

Long-term clinical, functional, and cost outcomes for early rheumatoid arthritis patients who did or did not achieve early remission in a real-world treat-to-target strategy.

OBJECTIVE: To retrospectively compare the long-term clinical, functional, and cost outcomes for early RA patients (symptoms < 1 year) who did or did not achieve early remission in a treat-to-target strategy. METHOD: Five-year data of 471 patients included in the DREAM remission induction cohort were used. Patients were treated according to a pre-specified 28-joint Disease Activity Score (DAS28) remission driven step-up treatment strategy starting with methotrexate, addition of sulfasalazine, and exchange of sulfasalazine for biological medication in case of failure. Two- and 3-year healthcare costs were available for selected subsamples of patients only. RESULTS: DAS28 remission was achieved in 27.7%, 38.2%, and 51.6% of patients at 2, 3, and 6 months, respectively. Achieving DAS28 remission at 2, 3, or 6 months was consistently associated with significantly lower DAS28 and Health Assessment Questionnaire-Disability scores at 1, 3, and 5 years of follow-up (all P values < 0.02). Patients in remission at 2, 3, or 6 months also had significantly lower medication costs per patient over the first 2 and 3 years of treatment, mainly due to lower biologic use, but differences in total healthcare resource costs (hospital admissions plus consultations) were less pronounced. Mean total medication and total healthcare resource costs at 3 years were €1131 and €1757 for patients in remission at 6 months vs. €7533 (P < 0.01) and €2202 (P = 0.09) for those not in remission. CONCLUSION: Achieving early remission was associated with beneficial clinical outcomes for early RA patients and lower costs in the long term. Key Points • Previous studies in rheumatoid arthritis patients have demonstrated that early good response is associated with sustained remission and better long-term clinical outcomes. • This study extents these findings by examining the long-term benefits of achieving early remission on clinical, patient-reported, and economic outcomes in a real-world cohort of patients with very early rheumatoid arthritis treated according to treat-to-target principles. • The findings of this study clearly demonstrate that aiming for early remission in rheumatoid arthritis patients is beneficial in the long-term in terms of better clinical and functional outcomes and lower healthcare costs.

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.

Weight loss in patients with type 2 diabetes receiving once-weekly dulaglutide plus insulin lispro or insulin glargine plus insulin lispro: A post-hoc analysis of the AWARD-4 study across baseline body mass index subgroups.

AIMS: Insulin-treated patients with type 2 diabetes (T2D) and obesity are challenged in achieving body weight stability or reduction, in addition to glycaemic control. Post-hoc analyses of body weight and insulin dose data from the AWARD-4 trial involved comparison of treatment with once-weekly dulaglutide 1.5 mg (N = 295) or 0.75 mg (N = 293) and treatment with daily insulin glargine (N = 296), each with prandial insulin lispro (± metformin). MATERIALS AND METHODS: Changes in weight and in the proportion of patients without weight gain or with weight loss of at least 3%, 5% or 10% or composites of HbA1c less than 7% without weight gain and weight loss of at least 3% after 52 weeks were compared between the dulaglutide (either dose) groups and the insulin glargine group, overall and by baseline BMI (<30, 30-<35, ≥35 kg/m2 ), using analysis of covariance and logistic regression, including interaction terms. RESULTS: The following parameters were statistically significant (P < 0.01) in favour of the dulaglutide-treated groups, at lower mean total daily insulin doses, vs the insulin glargine group. The achieved targets were more pronounced with dulaglutide 1.5 mg than with insulin glargine: LSM weight change difference, -3.23 kg; proportion of patients without weight gain, 49.0% vs 19.0%; proportion of patients with weight loss ≥3%, 21.7% vs 5.7% or with weight loss ≥5%, 10.5% vs 2.4%; proportion of patients with HbA1c <7% without weight gain, 26.2% vs 7.9%; proportion of patients with HbA1c <7% and weight loss ≥3%, 11.9% vs 1.4%, respectively. Treatment effect for these parameters was not significantly different across BMI categories. CONCLUSIONS: Larger proportions of patients in late-stage T2D needing treatment intensification achieved glycemic control without weight gain or with weight loss at lower insulin doses with once-weekly dulaglutide plus daily prandial insulin than with a basal-bolus insulin regimen, overall and across all three BMI subgroups.

EQ-5D health utilities: exploring ways to improve upon responsiveness in psoriasis.

AIMS: To determine if EuroQoL 5-Dimension Health Questionnaire (EQ-5D) health utility scores were able to discriminate among different levels of improvement in psoriasis severity following therapy. MATERIALS AND METHODS: Data were from three placebo-controlled phase 3 ixekizumab studies (UNCOVER-1, UNCOVER-2, and UNCOVER-3) with patients who had baseline Dermatology Life Quality Index scores >10 (DLQI >10). Psoriasis severity (Psoriasis Area and Severity Index [PASI]), general health utility (EQ-5D), and psoriasis-specific utility (EQ-PSO, UNCOVER-3 only) were assessed. EQ-5D-5L utility scores were generated using the England EQ-5D-5L value set, a crosswalk applied to the EQ-5D-3L United States (US) and United Kingdom (UK) value sets, and a regression-based exploratory scoring function for the EQ-PSO (UK). Analysis of variance was used to estimate change in EQ-5D-5L from baseline to Week 12 per PASI improvement level: PASI <50, PASI 50 to <75, PASI 75 to <90, PASI 90 to <100, and PASI 100. Missing data were imputed using the last observation carried forward method. Value sets for the UK, England, and the US were applied. RESULTS: In total, 2085 patients across UNCOVER-1, UNCOVER-2, and UNCOVER-3 had baseline DLQI >10 and available utility scores. At Week 12, mean EQ-5D utility scores increased with increasing PASI improvement levels (p < 0.001, all analyses). Mean health utilities for PASI 90 to <100 and PASI 100 were similar when based on the generic classifier, whereas a clear differentiation between PASI 90 to <100 and PASI 100 was observed for EQ-PSO mean scores (UNCOVER-3 only, n = 645; PASI 90 to <100: 0.141, PASI 100: 0.200; adjusted p = 0.043). LIMITATIONS: EQ-5D-5L index-based scores have limited ability to differentiate among psoriasis patients at the highest PASI improvement levels. ConclusionsL Adding psoriasis-specific EQ-PSO dimensions to the EQ-5D may enhance responsiveness to improvement in skin clarity at the highest PASI levels, and, therefore, generate utility scores that better reflect treatment benefit in cost-utility models.

Risk of severe hypoglycemia in sulfonylurea-treated patients from diabetes centers in Germany/Austria: How big is the problem? Which patients are at risk?

BACKGROUND: We investigated the rate of severe hypoglycemic events and confounding factors in patients with type 2 diabetes treated with sulfonylurea at specialized diabetes centers, documented in the German/Austrian DPV-Wiss database. METHODS: Data from 29 485 sulfonylurea-treated patients were analyzed (median[IQR] age 70.8[62.2-77.8] years, diabetes duration 8.2[4.3-12.8] years). The primary objective was to estimate the event rate of severe hypoglycemia (requiring external help, causing unconsciousness/coma/convulsion and/or emergency hospitalization). Secondary objectives included exploration of confounding risk factors through group comparison and Poisson regression. RESULTS: Severe hypoglycemic events were reported in 826(2.8%) of all patients during their most recent year of sulfonylurea treatment. Of these, n = 531(1.8%) had coma, n = 501(1.7%) were hospitalized at least once. The adjusted event rate of severe hypoglycemia [95%CI] was 3.9[3.7-4.2] events/100 patient-years (coma: 1.9[1.8-2.1]; hospitalization: 1.6[1.5-1.8]). Adjusted event rates by diabetes treatment were 6.7 (sulfonylurea + insulin), 4.9 (sulfonylurea + insulin + other OAD), 3.1 (sulfonylurea + other OAD) and 3.8 (sulfonylurea only). Patients with ≥1 severe event were older (p < 0.001) and had longer diabetes duration (p = 0.020) than patients without severe events. Participation in educational diabetes-programs and indirect measures of insulin-resistance (increased BMI, plasma-triglycerides) were associated with fewer events (all p < 0.001). Impaired renal function was common (n = 3113 eGFR; ≤30 mL/min) and associated with an increased rate of severe events (≤30 mL/min: 7.7; 30-60 mL/min: 4.8; >60 mL/min: 3.9). CONCLUSIONS: These real-life data showed a rate of severe hypoglycemia of 3.9/100 patient-years in sulfonylurea-treated patients from specialized diabetes centers. Higher risk was associated with known risk factors including lack of diabetes education, older age and decreased eGFR but also with lower BMI and lower triglyceride levels, suggesting that sulfonylurea treatment in those patients should be considered with caution.

Estimating the real world daily usage and cost for exenatide twice daily and liraglutide in Germany, the Netherlands, and the UK based on volumes dispensed by pharmacies.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for improvement of glycemic control in adults with type 2 diabetes. Cost is one aspect of treatment to be considered, in addition to clinical benefits, when selecting optimal therapy for a patient. The objective of this study was to estimate the average dose usage and real world daily cost of the GLP-1 receptor agonists, exenatide twice daily and liraglutide once daily, in Germany, the Netherlands, and the UK. METHODS: Administrative databases were used to source the data from longitudinal records of dispensed prescriptions. Data were extracted from the IMS Longitudinal Prescription database which captures details of prescriptions dispensed in pharmacies. Information on the dispensed quantity of each product was used to estimate average daily usage per patient. Daily dose usage was multiplied by the public price per unit to estimate daily cost. RESULTS: The dispensed volume in Germany corresponded to a mean dispensed daily dose of 16.81 µg for exenatide twice daily and 1.37 mg for liraglutide (mean daily cost €4.02 and €4.54, respectively). In the Netherlands, average dispensed daily doses of 17.07 µg and 1.49 mg were observed for exenatide twice daily and liraglutide (mean daily cost €3.05 and €3.97, respectively). In the UK, the mean dispensed volume corresponded to a daily usage of 20.49 µg for exenatide twice daily and 1.50 mg for liraglutide (mean daily cost £2.53 and £3.28, respectively). CONCLUSION: Estimates of average daily dispensed doses of GLP-1 receptor agonists derived from pharmacy data in real world settings corresponded to the dosing recommendation of the summaries of product characteristics. Nevertheless, the mean daily cost of exenatide twice daily was lower than that of liraglutide in Germany, the Netherlands, and the UK. Such estimates can be used to inform health care decision-makers on the real world usage and cost of medications effective in achieving glycemic control in patients with type 2 diabetes.