Ultra rapid lispro improves postprandial glucose control compared with lispro in patients with type 1 diabetes: Results from the 26-week PRONTO-T1D study.

AIMS: To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes in a 26-week, treat-to-target, phase 3 trial. MATERIALS AND METHODS: After an 8-week lead-in to optimize basal insulin glargine or degludec, patients were randomized to double-blind mealtime URLi (n = 451) or lispro (n = 442), or open-label post-meal URLi (n = 329). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) to 26 weeks (non-inferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions after a meal test. RESULTS: Both mealtime and post-meal URLi demonstrated non-inferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi -0.08% [95% confidence interval (CI) -0.16, 0.00] and for post-meal URLi +0.13% (95% CI 0.04, 0.22), with a significantly higher endpoint HbA1c for post-meal URLi versus lispro (P = 0.003). Mealtime URLi was superior to lispro in reducing 1- and 2-hour PPG excursions during the meal test: ETD -1.55 mmol/L (95% CI -1.96, -1.14) at 1 hour and - 1.73 mmol/L (95% CI -2.28, -1.18) at 2 hours (both P < 0.001). The rate and incidence of severe, documented and postprandial hypoglycaemia (<3.0 mmol/L) was similar between treatments, but mealtime URLi demonstrated a 37% lower rate in the period >4 hours after meals (P = 0.013). Injection site reactions were reported by 2.9% of patients on mealtime URLi, 2.4% on post-meal URLi, and 0.2% on lispro. Overall, the incidence of treatment-emergent adverse events was similar between treatments. CONCLUSIONS: The results showed that URLi provided good glycaemic control, with non-inferiority to lispro confirmed for both mealtime and post-meal URLi, while superior PPG control was demonstrated with mealtime dosing.

Key Strategies for Overcoming Psychological Insulin Resistance in Adults with Type 2 Diabetes: The UK Subgroup in the EMOTION Study.

INTRODUCTION: Many patients with type 2 diabetes mellitus (T2DM) delay initiation of insulin therapy despite healthcare professional (HCP) advice. This phenomenon has been referred to as 'psychological insulin resistance' (PIR), and various contributing factors have been identified. Studies discussing approaches to overcoming PIR are lacking. Our aim was to identify the key strategies used by HCPs that most helped adults with T2DM and PIR in the UK to initiate insulin. METHODS: As part of a global study, UK adults with T2DM and PIR were recruited (N = 125) to take a survey that included 38 HCP statements and actions about insulin initiation. Data assessed were perceived occurrence and helpfulness of these strategies in facilitating insulin initiation. RESULTS: The most helpful strategies involved demonstrating the injection process (e.g. HCP talked patient through the process of taking insulin [83.6%]) and adopting a collaborative approach (HCP encouraged patient to contact the clinic immediately in case of any problems/questions [80.5%]). Additionally, HCPs highlighting the benefits of insulin (HCP explained that insulin was a natural substance needed by patient's body [81.2%]) and allaying patients' concerns (HCP explained that patient might not have to take insulin forever [78.0%]) helped patients initiate insulin. The least helpful action was HCPs repeatedly persuading patients to initiate insulin (40.9%). CONCLUSIONS: The study recommends key strategies that HCPs can adopt to help adults with T2DM overcome PIR in the UK.

Many patients with type 2 diabetes (T2DM) are reluctant to start insulin therapy despite it being recommended by their doctor. This can lead to a delay in receiving effective treatment to control blood sugar. There are many reasons to explain this reluctance­which is also referred to as psychological insulin resistance (PIR)­including fear of injections and lack of understanding. EMOTION was a global study which set out to identify strategies to overcome PIR. It looked at 38 things, identified by people with diabetes, that doctors/nurses can do or say to encourage a patient to try insulin. Analysis of results for the 125 UK patients with T2DM who were reluctant to start insulin showed that the most helpful approach was demonstrating the injection procedure. Actually talking a patient through how to inject insulin and demonstrating how the pen works can help reduce their fears about the injection process. Adopting a collaborative approach was found to be important, encouraging patients to get in touch with any problems or questions. Other helpful strategies included highlighting the benefits of insulin­explaining that it is a natural substance the body needs­and addressing any specific concerns a patient may have about insulin. The least helpful strategy was taking an authoritarian approach and repeatedly trying to persuade a patient to start insulin. This is the first study which provides evidence-based clinical strategies that UK healthcare professionals can use to help overcome PIR in their patients with T2DM.

Ultra-Rapid Lispro Improves Postprandial Glucose Control and Time in Range in Type 1 Diabetes Compared to Lispro: PRONTO-T1D Continuous Glucose Monitoring Substudy.

Background: This study evaluated glucose control by continuous glucose monitoring (CGM) during treatment with ultra-rapid lispro (URLi) or lispro used in combination with insulin glargine or degludec in adults with type 1 diabetes in a substudy of the PRONTO-T1D study. Methods: Ambulatory glucose profiles were evaluated in 269 patients from PRONTO-T1D assigned to double-blind URLi (n = 97) or lispro (n = 99) given 0-2 min before the start of the meal (mealtime), or open-label URLi (n = 73) given 20 min after the meal (postmeal URLi). Blinded CGM was used for up to 14 days before baseline and the 26-week primary endpoint. The primary objective was to compare mealtime URLi and lispro with respect to incremental area under the serum glucose concentration versus time curve from 0 to 2 h (iAUC0-2h) after breakfast. Results: Mealtime URLi was superior in reducing the iAUC0-2h when compared to lispro for breakfast (least squares mean [LSM] difference -28.1 mg·h/L, P = 0.048) and for all meals combined. iAUC0-3h and iAUC0-4h were also reduced. Postmeal URLi resulted in similar postprandial glucose (PPG) control to mealtime lispro, but less optimal PPG control compared to mealtime URLi. Mealtime URLi increased daytime time in range (71-180 mg/dL [3.9-10.0 mmo/L]) (LSM difference = +43.6 min, P = 0.020) and decreased nighttime time in hypoglycemia (LSM difference ≤70 mg/dL [3.9 mmol/L] = -11.5 min, P = 0.009) compared to mealtime lispro. Conclusions: Results of this CGM substudy support the improved PPG control seen with mealtime URLi in the PRONTO-T1D study and show that mealtime URLi resulted in improved daytime time in target range.

Basal insulin persistence in Brazilian participants with T2DM.

OBJECTIVE: Real-world effectiveness of basal insulin therapy is affected by poor treatment persistence, often occurring soon after initiation. This analysis is part of an international cross-sectional study conducted in T2DM patients and is intended to describe the reasons behind non-persistence to insulin therapy in Brasil. METHODS: Responders to an online survey in seven countries were classified as continuers (no gap of ≥7 days), interrupters (interrupted therapy for ≥7 days within first 6 months, then restarted), and discontinuers (terminated therapy for ≥7 days within first 6 months, and did not start it again before the survey). We present the results from the Brazilian cohort. RESULTS: Of 942 global respondents, 156 were from Brasil, with a mean age of 34 years and a mean of 5.8 years since T2DM diagnosis. Reasons contributing to insulin continuation (n=50) were improved glycemic control (82%) and improved physical feeling (50%). Common reasons for interruption (n=51) or discontinuation (n=55) were, respectively, weight gain (47.1%, 43.6%), hypoglycemia (45.1%, 38.2%), and pain from injections (39.2%, 49.1%). However, not all patients who reported weight gain and hypoglycemia as a reason for interruption or discontinuation experienced these: 16/24 (66.7%) and 22/24 (91.7%) participants had weight gain, and 13/23 (56.5%) and 15/21 (71.4%) had hypoglycemia, respectively. The most important reason for possible re-initiation for interrupters and discontinuers, respectively, was persuasion by the physician/HCP (80.4%, 72.7%). CONCLUSION: The benefits of basal insulin therapy motivated continuers to persist with the treatment; experienced or anticipated side effects contributed to interruption and discontinuation. Physician and patient training is key in the treatment of diabetes.

Basal insulin persistence in Brazilian participants with T2DM

SUMMARY OBJECTIVE Real-world effectiveness of basal insulin therapy is affected by poor treatment persistence, often occurring soon after initiation. This analysis is part of an international cross-sectional study conducted in T2DM patients and is intended to describe the reasons behind non-persistence to insulin therapy in Brasil. METHODS Responders to an online survey in seven countries were classified as continuers (no gap of ≥7 days), interrupters (interrupted therapy for ≥7 days within first 6 months, then restarted), and discontinuers (terminated therapy for ≥7 days within first 6 months, and did not start it again before the survey). We present the results from the Brazilian cohort. RESULTS Of 942 global respondents, 156 were from Brasil, with a mean age of 34 years and a mean of 5.8 years since T2DM diagnosis. Reasons contributing to insulin continuation (n=50) were improved glycemic control (82%) and improved physical feeling (50%). Common reasons for interruption (n=51) or discontinuation (n=55) were, respectively, weight gain (47.1%, 43.6%), hypoglycemia (45.1%, 38.2%), and pain from injections (39.2%, 49.1%). However, not all patients who reported weight gain and hypoglycemia as a reason for interruption or discontinuation experienced these: 16/24 (66.7%) and 22/24 (91.7%) participants had weight gain, and 13/23 (56.5%) and 15/21 (71.4%) had hypoglycemia, respectively. The most important reason for possible re-initiation for interrupters and discontinuers, respectively, was persuasion by the physician/HCP (80.4%, 72.7%). CONCLUSION The benefits of basal insulin therapy motivated continuers to persist with the treatment; experienced or anticipated side effects contributed to interruption and discontinuation. Physician and patient training is key in the treatment of diabetes.

RESUMO OBJETIVO Dados de vida real sobre como a eficácia da terapia com insulina é afetada pela baixa persistência ao tratamento que ocorre logo após o início da terapia. Esta análise é a parte brasileira de um estudo transversal internacional conduzido em pacientes com DM2 que teve como objetivo descrever as razões relacionadas à não persistência ao tratamento com insulina. METODOLOGIA O estudo realizado em sete países por meio de questionários on-line classificou como pacientes continuadores (aqueles que não apresentaram intervalo ≥7 dias sem uso da insulina), interrompedores (interromperam a terapia por ≥7 dias nos primeiros seis meses de uso, depois recomeçaram) e descontinuadores (interromperam a terapia por ≥7 dias nos primeiros seis meses de uso e não retornaram). Nesta análise descrevemos os dados da coorte brasileira. RESULTADOS Dos 942 pacientes incluídos, 156 eram do Brasil, com idade média de 34 anos e média de seis anos desde o diagnóstico de DM2. Razões que contribuíram para o uso contínuo da insulina (n=50) foram a melhora do controle glicêmico (82%) e a melhora no estado geral (50%). Razões para a interrupção (n=51) ou para a descontinuação (n=55) foram, respectivamente, ganho de peso (41,7%, 43,6%), hipoglicemia (45,1%, 38,2%) e dor à aplicação (39,2%, 49,1%). Entretanto, nem todos os pacientes que reportaram ganho de peso e hipoglicemia como possível razão para interrupção ou descontinuação realmente apresentaram esses eventos: 16/24 (66,7%) e 22/24 (91,4%) dos participantes apresentaram ganho de peso e 13/23 (56,6%) e 15/21 (71,4%) apresentaram hipoglicemia, respectivamente. A razão mais importante para o possível recomeço entre os interrompedores e descontinuadores foi a persuasão de médicos/profissionais de saúde (80,4% e 72,7%, respectivamente). CONCLUSÕES Os benefícios do tratamento com insulina basal motivaram continuadores a persistir com a terapia; a experiência ou a antecipação de eventos adversos contribuíram para a interrupção e descontinuação. O treinamento de médicos e pacientes é um dos pilares fundamentais do tratamento do diabetes.

Identifying solutions to psychological insulin resistance: An international study.

AIMS: To identify actions of healthcare professionals (HCPs) that facilitate the transition to insulin therapy (IT) in type 2 diabetes (T2D) adults. METHODS: Included were T2Ds in seven countries (n = 594) who reported initial IT reluctance but eventually began IT. An online survey included 38 possible HCP actions: T2Ds indicated which may have occurred and their helpfulness. Also reported were delays in IT start after initial recommendation and any period of IT discontinuation. RESULTS: Exploratory factor analysis of HCP actions yielded five factors: "Explained Insulin Benefits" (EIB), "Dispelled Insulin Myths" (DIM), "Demonstrated the Injection Process" (DIP), "Collaborative Style" (CS) and "Authoritarian Style" (AS). Highest levels of helpfulness occurred for DIP, EIB and CS; lowest for AS. Participants who rated DIP as helpful were less likely to delay IT than those who rated DIP as less helpful (OR = 0.75, p = 0.01); participants who rated CS and EIB as helpful were less likely to interrupt IT than those who rated these as less helpful (OR = 0.55, p < 0.01; OR = 0.51, p = 0.01, respectively). CONCLUSIONS: Three key HCP actions to facilitate IT initiation were identified as helpful and were associated with more successful initiation and persistence. These findings may aid the development of interventions to address reluctance to initiating IT.

Key factors for overcoming psychological insulin resistance: an examination of patient perspectives through content analysis.

Objective: To understand participant perceptions about insulin and identify key behaviors of healthcare professionals (HCPs) that motivated initially reluctant adults from seven countries (n=40) who had type 2 diabetes (T2D) to start insulin treatment. Research design and methods: Telephone interviews were conducted with a subset of participants from an international investigation of adults with T2D who were reluctant to start insulin (EMOTION). Questions related to: (a) participants' thoughts about insulin before and after initiation; (b) reasons behind responses on the survey that were either 'not helpful at all' or 'helped a lot'; (c) actions their HCP may have taken to help start insulin treatment; and (d) advice they would give to others in a similar situation of starting insulin. Responses were coded by two independent reviewers (kappa 0.992). Results: Starting insulin treatment was perceived as a negative experience that would be painful and would lead down a 'slippery slope' to complications. HCPs engaged in four primary behaviors that helped with insulin acceptance: (1) showed the insulin pen/needle and demonstrated the injection process; (2) explained how insulin could help with diabetes control and reduce risk of complications; (3) used collaborative communication style; and (4) offered support and willingness to answer questions so that participants would not be 'on their own'. Following initiation, most participants noted that insulin was not 'as bad as they thought' and recommended insulin to other adults with T2D. Conclusions: Based on these themes, two actionable strategies are suggested for HCPs to help people with psychological insulin resistance: (1) demonstrate the injection process and discuss negative perceptions of insulin as well as potential benefits; (2) offer autonomy in a person-centred collaborative approach, but provide support and accessibility to address concerns. These findings help HCPs to better understand ways in which they can engage reluctant people with T2D with specific strategies.

Associated factors that influenced persistence with basal analog insulin therapy among people with type 2 diabetes: An exploratory analysis from a UK real-world sample.

AIM: Real-world effectiveness of insulin therapy is affected by poor treatment persistence, often occurring soon after initiation. An international cross-sectional survey of people with type 2 diabetes mellitus (T2DM) has been conducted to describe reasons for non-persistence with insulin therapy. METHODS: Responders to an online survey in 7 countries were classified as continuers (no gap of ≥7days), interrupters (interrupted therapy for ≥7days within first 6 months, then restarted), and discontinuers (terminated therapy for ≥7days within first 6 months, no restart before survey). We present the results from the United Kingdom (UK) cohort. RESULTS: Of 942 global respondents, 131 were from the UK, having a mean age of 37years and a mean of 7years since first T2DM diagnosis. Reasons contributing to insulin continuation (n=50) were improved physical feeling (52.0%) and improved glycemic control (48.0%). Common reasons for interruption (n=50) or discontinuation (n=31), respectively were weight gain (50.0%, 48.4%) and hypoglycemia (38.0%, 25.8%). Most important reason for possible re-initiation for interrupters and discontinuers, respectively was persuasion by physician/healthcare professional (74.0%, 64.5%). CONCLUSION: The benefits of basal insulin therapy motivated continuers to persist with the treatment; experienced or anticipated side effects contributed to interruption and discontinuation.

Insulin non-persistence among people with type 2 diabetes: how to get your patients to stay on insulin therapy.

Continuing use of medication is key to effective treatment and positive health outcomes, particularly in chronic conditions such as diabetes. However, in primary care, non-persistence (i.e. discontinuing or interrupting treatment) with insulin therapy is a common problem among patients with type 2 diabetes. To help primary care physicians manage patients who are non-persistent or likely not to be persistent, this review aimed to provide an overview of modifiable and non-modifiable factors associated with insulin non-persistence as well as practical strategies to address them. Data were extracted from published studies evaluating factors associated with non-persistence among patients with type 2 diabetes. A targeted literature review was performed using PubMed to identify recent studies (2000-2016) reporting measures of non-persistence with insulin therapy. Practical strategies to identify and prevent non-persistence were based on the authors' direct experience in primary care. Non-modifiable factors associated with non-persistence included gender, age, prior treatments, and cost of therapy. Before/at insulin initiation, modifiable factors included patients' perception of diabetes, preference for oral medication, and concerns/expectations about treatment complexity, inconvenience, or side effects. After initiation, modifiable factors included syringe use, difficulties during the first week of therapy, side effects, and insufficient glycemic control. Open-ended and patient-centered questions and a blame-free environment can help physicians identify, prevent, and reduce non-persistence behaviors. Possible questions to start a conversation with patients are provided. Effective physician-patient communication is essential to the management of diabetes. Primary care physicians should be familiar with the most common reasons for insulin non-persistence.

Initiation of Basal Insulin Analog Treatment for Type 2 Diabetes and Reasons Behind Patients' Treatment Persistence Behavior: Real-World Data from Germany.

BACKGROUND: Poor treatment persistence can affect the real-world effectiveness of insulin therapy. A cross-sectional online survey in 942 patients with type 2 diabetes from 7 different countries evaluated patient experience when initiating basal insulin and the reasons behind insulin persistence patterns. Here, we report the quantitative results for the subset of patients from Germany. METHODS: Adults with type 2 diabetes who had initiated basal insulin during the last 3-24 months, identified from market-research panels, participated in the survey. Patients were asked if they had ≥7-day gaps in basal insulin treatment, and were then classified as "continuers" (no gap since starting insulin), "interrupters" (≥1 gap within the first 6 months after starting insulin and subsequently restarted insulin), or "discontinuers" (stopped insulin within the first 6 months after starting and had not restarted at the time of the survey). For each country, 50 participants were planned per persistence category. Enrollment ended if the target quota was reached or enrollment plateaued. Data were analyzed overall and separately for each persistence cohort. RESULTS: The 131 participants from Germany included 55 (42.0%) continuers, 50 (38.2%) interrupters and 26 (19.9%) discontinuers. The most common motivations to initiate basal insulin therapy were encouragement by physician or other healthcare provider (HCP; 54.2%) and expectation to improve glycemic control (42.0%). More than 95% of participants received training before and during insulin initiation (considered as helpful by 81.7%); most (67.2%) preferred in-person training. Continuers more frequently felt that insulin would help to manage diabetes and that their own views were considered when initiating insulin, they reported less concerns and challenges before and during insulin initiation than interrupters or discontinuers. The most common motivations to continue basal insulin were improved glycemic control (72.7%), improved physical well-being (49.1%), and instruction by physician or other HCP (45.5%). The most common reasons contributing to interruption/discontinuation were perceived weight gain (52.0%/50.0%), hypoglycemia (22.0%/38.5%), and potential adverse effects (30.0%/26.9%). CONCLUSIONS: Quality interactions between physicians or other HCPs and their patients before and during the initiation of basal insulin may help to manage patient expectations and to improve persistence to insulin therapy.

Identifying insulin treatment responders with a composite measure: beyond Hba1c < 7% in patients with type 2 diabetes.

OBJECTIVES: Many insulin-treated patients with type 2 diabetes (T2D) do not reach hemoglobin A1c (HbA1c) < 7%, but have clinically relevant HbA1c reductions. Using an integrated database (IDB) of 53 insulin lispro clinical trials and a real-world evidence (RWE) database of T2D patients initiating insulin therapy, an expanded HbA1c measure was used to identify responders to insulin therapy. METHODS: Analysis included 4,908 patients (IDB) and 1,134 patients (RWE) with T2D treated with any insulin regimen with a baseline and ≥1 post-baseline HbA1c. Responders were defined as patients with endpoint HbA1c < 7% (cut point [CP]) and/or either ≥1% absolute (ABS) decrease, and/or ≥10% relative (REL) decrease in HbA1c from baseline. The percentage of responders with CP vs ABS and concordance between ABS and REL were calculated. As the ABS and REL measures were highly correlated (94%), the ABS measure was used to compare characteristics of responders and non-responders by age, diabetes duration, race/ethnicity, baseline HbA1c, and insulin regimen at 24 weeks. RESULTS: In both databases, more responders were identified with ABS or REL (>62%) than CP (<41%). More ABS responders had a baseline HbA1c ≥ 9% and a shorter diabetes duration than non-responders. Basal insulin-treated patients in the IDB had 78.2% responders at 24 weeks, compared to 69.7% with basal/bolus or pre-mixed insulin (75.4%). Results were similar in the IDB and RWE. CONCLUSION: Composite HbA1c measures identified more patients with clinically meaningful responses to therapy than the broadly accepted HbA1c < 7% and may be useful in assessing clinical trials, clinical care, and quality measures.

Basal insulin initiation use and experience among people with type 2 diabetes mellitus with different patterns of persistence: results from a multi-national survey.

BACKGROUND AND OBJECTIVE: People with type 2 diabetes mellitus (T2DM) often interrupt basal insulin treatment soon after initiation. This study aimed to describe the experiences during and after basal insulin initiation among people with T2DM with different persistence patterns. METHODS: Adults with T2DM from France, Germany, Spain, UK, US, Brazil, and Japan were identified from consumer panels for an online survey. Respondents who initiated basal insulin 3-24 months prior to survey date were categorized as continuers (no gaps of ≥7 days in insulin treatment); interrupters (first gap ≥7 days within 6 months of initiation and restarted insulin); and discontinuers (stopped insulin for ≥7 days within 6 months of initiation without restarting). RESULTS: Among 942 participants, continuers were older than interrupters and discontinuers (46, 37, and 38 years, respectively, p < .01). Continuers reported having fewer concerns before and after insulin initiation than interrupters and discontinuers, while interrupters had the most concerns. Continuers also reported fewer challenges during the first week of insulin use. Continuers were more likely to respond that insulin use had a positive impact on specific aspects of life than interrupters and discontinuers, for example on glycemic control (73.0%, 63.0%, and 61.8%, respectively; p < .01 vs. continuers). CONCLUSION: Among people with T2DM with different persistence patterns after basal insulin initiation there were significant differences in patient characteristics and experience during and after insulin initiation. Interrupters and discontinuers more frequently reported having concerns and challenges during the initiation process, negative impacts after initiation, and less improvement in glycemic control than continuers.

Correlates of basal insulin persistence among insulin-naïve people with type 2 diabetes: results from a multinational survey.

BACKGROUND AND OBJECTIVE: People with T2DM who initiate basal insulin therapy often stop therapy temporarily or permanently soon after initiation. This study analyzes the reasons for and correlates of stopping and restarting basal insulin therapy among people with T2DM. METHODS: An online survey was completed by 942 insulin-naïve adults with self-reported T2DM from Brazil, France, Germany, Japan, Spain, UK, and US. Respondents had initiated basal insulin therapy within the 3-24 months before survey participation and met criteria for one of three persistence groups: continuers had no gaps of ≥7 days in basal insulin treatment; interrupters had at least one gap in insulin therapy of ≥7 days within the first 6 months after initiation and had since restarted basal insulin; and discontinuers stopped using basal insulin within the first 6 months after initiation and had not restarted. RESULTS: Physician recommendations and cost were strongly implicated in patients stopping and not resuming insulin therapy. Continuous persistence was lower for patients with more worries about insulin initiation, greater difficulties and weight gain while using insulin, and higher for those using pens and perceiving their diabetes as severe. Repeated interruption of insulin therapy was associated with hyperglycemia and treatment burden while using insulin. Resumption and perceived likelihood of resumption were associated with hyperglycemia upon insulin cessation. Perceived likelihood of resumption among discontinuers was associated with perceived benefits of insulin. CONCLUSION: Better understanding of the risk factors for patient cessation and resumption of basal insulin therapy may help healthcare providers improve persistence with therapy.

Basal Insulin Persistence, Associated Factors, and Outcomes After Treatment Initiation: A Retrospective Database Study Among People with Type 2 Diabetes Mellitus in Japan.

INTRODUCTION: The objective of this study was to assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in Japan. METHODS: People aged at least 18 years with T2DM with first claim for basal insulin between May 2006 and April 2013 (index date), no insulin use before index date, and continuous insurance coverage for 6 months before (baseline) and 12 months after index date were selected from the Japan Medical Center Database. On the basis of whether there were at least 30-day gaps in basal insulin treatment, patients were classified as continuers (no gap), interrupters (at least one prescription after gap), and discontinuers (no prescription after gap). A multinomial logistic regression model identified factors associated with persistence. Annual healthcare resource use and costs in the year after initiation were compared between continuers and interrupters and between continuers and discontinuers using propensity score-based inverse probability weighting to adjust for baseline differences. RESULTS: Of the 827 people included (mean age 50 years, ca. 71% male), 36% continued, 42% interrupted, and 22% discontinued basal insulin therapy in the year after initiation. Having at least one inpatient visit and using fewer classes of non-insulin antihyperglycemic medications during baseline were associated with lower likelihoods of continuing therapy. Relative to interrupters and discontinuers, continuers had lower hospitalization rates [continuers, 12.7%; interrupters, 25.4% (p < 0.001); discontinuers, 28.4% (p < 0.001)] and lower inpatient costs [continuers, ¥132,013; interrupters, ¥225,745 (p = 0.054); discontinuers, ¥320,582 (p = 0.036)], but higher pharmacy costs [continuers, ¥158,403; interrupters, ¥134,301 (p = 0.039); discontinuers, ¥121,593 (p = 0.002)] in the year after insulin initiation. Total healthcare costs were similar for the three cohorts. CONCLUSIONS: Substantial proportions of people with T2DM in Japan interrupt or discontinue basal insulin within the year after initiation, and they have higher rates and costs of hospitalizations than patients who continue with their insulin therapy. Further research is needed to understand reasons behind basal insulin persistence and the implications thereof to help clinicians manage T2DM more effectively. FUNDING: Eli Lilly and Company, Boehringer Ingelheim.

Basal insulin persistence, associated factors, and outcomes after treatment initiation among people with type 2 diabetes mellitus in the US.

OBJECTIVE: To assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in the US. RESEARCH DESIGN AND METHODS: People aged ≥18 years diagnosed with T2DM initiating basal insulin between April 2006 and March 2012 (index date), no prior insulin use, and continuous insurance coverage for 6 months before (baseline) and 24 months after index date (follow-up period) were selected using de-identified administrative claims data in the US. Based on whether there were ≥30 day gaps in basal insulin use in the first year post-index, patients were classified as continuers (no gap), interrupters (≥1 prescription after gap), and discontinuers (no prescription after gap). MAIN OUTCOME MEASURES: Factors associated with persistence - assessed using multinomial logistic regression model; annual healthcare resource use and costs during follow-up period - compared separately between continuers and interrupters, and continuers and discontinuers. RESULTS: Of the 19,110 people included in the sample (mean age: 59 years, ∼60% male), 20% continued to use basal insulin, 62% had ≥1 interruption, and 18% discontinued therapy in the year after initiation. Older age, multiple antihyperglycemic drug use, and injectable antihyperglycemic use during baseline were associated with significantly higher likelihoods of continuing basal insulin. Relative to interrupters and discontinuers, continuers had fewer emergency department visits, shorter hospital stays, and lower medical costs (continuers: $10,890, interrupters: $13,674, discontinuers: $13,021), but higher pharmacy costs (continuers: $7449, interrupters: $5239, discontinuers: $4857) in the first year post-index (p < 0.05 for all comparisons). Total healthcare costs were similar across the three cohorts. Findings for the second year post-index were similar. CONCLUSIONS: The majority of people in this study interrupted or discontinued basal insulin treatment in the year after initiation; and incurred higher medical resource use and costs than continuers. The findings are limited to the commercially insured population in the US. In addition, persistence patterns were assessed using administrative claims as opposed to actual medication-taking behavior and did not account for measures of glycemic control. Further research is needed to understand the reasons behind basal insulin persistence and the implications thereof, to help clinicians manage care for T2DM more effectively.

Early Glycemic Response Predicts Achievement of Subsequent Treatment Targets in the Treatment of Type 2 Diabetes: A Post hoc Analysis.

INTRODUCTION: American Diabetes Association consensus guidelines emphasize individualized treatment in the management of type 2 diabetes mellitus (T2DM). Early glycemic response is a clinical marker that may predict longer term efficacy for individual patients and provide a clinical tool to enhance personalized treatment. This analysis evaluated whether glycemic response measured at week 12 ("early") could serve as a reliable predictor of glycemic control at weeks 24 and 52 of therapy in patients with T2DM. METHODS: We used data from 3 randomized, controlled clinical trials that evaluated patients with T2DM treated with 3 commonly prescribed glucose-lowering medications: metformin (n = 597), sulfonylurea (n = 626), and insulin glargine (n = 1046). The gradient boosting method was used to identify predictors of subsequent response; predictive accuracy was represented by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Treatment success at weeks 24 and 52 was assessed for each patient and defined as achieving a glycated hemoglobin (HbA1c) level of <7.0% or a reduction from baseline of ≥1.0%. RESULTS: The predictive parameters (sensitivity, specificity, PPV, and NPV) for improvements in HbA1c at week 24 for metformin were 0.83, 0.81, 0.44, and 0.96; for sulfonylurea, 0.79, 0.94, 0.71, and 0.96; and for insulin glargine, 0.67, 0.89, 0.65, and 0.90. The predictive parameters for improvements in HbA1c at week 52 for metformin were 0.73, 0.84, 0.56, and 0.92 and for sulfonylurea, 0.45, 0.94, 0.74, and 0.82. CONCLUSION: High predictive values identified in this analysis support "early" response as an appropriate tool for predicting treatment success at weeks 24 and 52. The high NPV (lack of early glycemic response) appears to be an effective indicator of the likely need for change in (or intensification of) therapy. These data support the current guideline recommendations that clinicians evaluate therapeutic responses to pharmacologic interventions with metformin, sulfonylureas, or insulin glargine as early as week 12.

Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non-small cell lung cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in non-small cell lung cancer (NSCLC). Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2. This phase 2 study investigated ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC. METHODS: Eligible stage IV nonsquamous NSCLC patients with no prior chemotherapy for metastatic disease were randomized 1:1 to pemetrexed and carboplatin (or cisplatin) or ramucirumab (10 mg/kg) plus pemetrexed and carboplatin (or cisplatin) once every 3 weeks. Treatment was given for 4 to 6 cycles, and this was followed by a maintenance phase with pemetrexed or ramucirumab and pemetrexed. The primary endpoint was progression-free survival (PFS) with a sample size of sufficient power to detect an increase from 7 to 10.4 months. RESULTS: From October 2010 to October 2011, 140 patients were randomized (pemetrexed-platinum arm, 71; ramucirumab-pemetrexed-platinum arm, 69), and most baseline characteristics were similar for the 2 treatment arms. The median PFS was 5.6 months for the pemetrexed-platinum arm and 7.2 months for the ramucirumab-pemetrexed-platinum arm (hazard ratio, 0.75; P = .132). The objective response rates were 38.0% and 49.3% for the pemetrexed-platinum and ramucirumab-pemetrexed-platinum arms, respectively (P = .180). The disease control rate was 70.4% for the pemetrexed-platinum arm and 85.5% for the ramucirumab-pemetrexed-platinum arm (P = .032). The grade 3 or higher adverse events occurring in 10% or more of patients were thrombocytopenia, neutropenia, fatigue, anemia, nausea, back pain, and hypertension. CONCLUSIONS: The primary endpoint of significant prolongation of PFS was not met; however, ramucirumab showed evidence of clinical activity in combination with pemetrexed and platinum in nonsquamous NSCLC patients. The addition of ramucirumab to pemetrexed and platinum did not result in new or unexpected safety findings.

A randomized, double-blind, phase III study of Docetaxel and Ramucirumab versus Docetaxel and placebo in the treatment of stage IV non-small-cell lung cancer after disease progression after 1 previous platinum-based therapy (REVEL): treatment rationale and study design.

This article describes the treatment rationale and study-related procedures for the A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small-Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL) study (I4T-MC-JVBA; ClinicalTrials.govNCT01168973). This international, randomized, placebo-controlled, double-blinded phase III trial examines the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV non-small-cell lung cancer (NSCLC) whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end point is overall survival; secondary end points include progression-free survival, objective response rate, disease control rate, patient-reported outcomes, and assessment of safety and tolerability of ramucirumab. Eligible patients (enrollment N = 1242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m(2)) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m(2)) plus placebo (Arm B). Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, noncompliance, or patient's consent withdrawal. Efficacy and safety will be compared between the study arms and in patient subgroups including patients with nonsquamous versus squamous tumor histology and patients who received prior bevacizumab treatment. Multiple blood and tumor tissue biomarker samples are collected during the study. The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves overall survival of patients with NSCLC with progressive disease after first-line therapy, and to advance our knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis.

Growth hormone plus childhood low-dose estrogen in Turner's syndrome.

BACKGROUND: Short stature and ovarian failure are characteristic features of Turner's syndrome. Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome, a randomized, placebo-controlled trial is needed to document whether such treatment increases adult height. Furthermore, it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit. We examined the independent and combined effects of growth hormone and early, ultra-low-dose estrogen on adult height in girls with Turner's syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 149 girls, 5.0 to 12.5 years of age, to four groups: double placebo (placebo injection plus childhood oral placebo, 39 patients), estrogen alone (placebo injection plus childhood oral low-dose estrogen, 40), growth hormone alone (growth hormone injection plus childhood oral placebo, 35), and growth hormone-estrogen (growth hormone injection plus childhood oral low-dose estrogen, 35). The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week. The doses of ethinyl estradiol (or placebo) were adjusted for chronologic age and pubertal status. At the first visit after the age of 12.0 years, patients in all treatment groups received escalating doses of ethinyl estradiol. Growth hormone injections were terminated when adult height was reached. RESULTS: The mean standard-deviation scores for adult height, attained at an average age of 17.0±1.0 years, after an average study period of 7.2±2.5 years were -2.81±0.85, -3.39±0.74, -2.29±1.10, and -2.10±1.02 for the double-placebo, estrogen-alone, growth hormone-alone, and growth hormone-estrogen groups, respectively (P<0.001). The overall effect of growth hormone treatment (vs. placebo) on adult height was a 0.78±0.13 increase in the height standard-deviation score (5.0 cm) (P<0.001); adult height was greater in the growth hormone-estrogen group than in the growth hormone-alone group, by 0.32±0.17 standard-deviation score (2.1 cm) (P=0.059), suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone. CONCLUSIONS: Our study shows that growth hormone treatment increases adult height in patients with Turner's syndrome. In addition, the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement. (Funded by the National Institute of Child Health and Human Development and Eli Lilly; ClinicalTrials.gov number, NCT00001221.).