The Relationship Between Health-Related Quality of Life and Overall Survival in Patients With Advanced Renal Cell Carcinoma in CheckMate 214.

BACKGROUND: In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. PATIENTS AND METHODS: CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic score ≥ 1; n = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. RESULTS: Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR ≤ 0.834; P < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR ≤ 0.69; P < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. CONCLUSION: In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. CLINICALTRIALS.GOV IDENTIFIER: NCT02231749; https://clinicaltrials.gov/ct2/show/NCT02231749.

Challenges in conducting fractional polynomial and standard parametric network meta-analyses of immune checkpoint inhibitors for first-line advanced renal cell carcinoma.

Aim: Network meta-analyses (NMAs) increasingly feature time-varying hazards to account for non-proportional hazards between different drug classes. This paper outlines an algorithm for selecting clinically plausible fractional polynomial NMA models. Methods: The NMA of four immune checkpoint inhibitors (ICIs) + tyrosine kinase inhibitors (TKIs) and one TKI therapy for renal cell carcinoma (RCC) served as case study. Overall survival (OS) and progression free survival (PFS) data were reconstructed from the literature, 46 models were fitted. The algorithm entailed a-priori face validity criteria for survival and hazards, based on clinical expert input, and predictive accuracy against trial data. Selected models were compared with statistically best-fitting models. Results: Three valid PFS and two OS models were identified. All models overestimated PFS, the OS model featured crossing ICI + TKI versus TKI curves as per expert opinion. Conventionally selected models showed implausible survival. Conclusion: The selection algorithm considering face validity, predictive accuracy, and expert opinion improved the clinical plausibility of first-line RCC survival models.

A Matching-adjusted Indirect Comparison of Nivolumab Plus Cabozantinib Versus Pembrolizumab Plus Axitinib in Patients with Advanced Renal Cell Carcinoma.

BACKGROUND: The comparative efficacy and health-related quality of life (HRQoL) outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib as first-line treatments for advanced renal cell carcinoma (aRCC) have not been assessed in head-to-head trials. OBJECTIVE: To assess the efficacy and HRQoL outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib. DESIGN, SETTING, AND PARTICIPANTS: Patient-level data for nivolumab plus cabozantinib from the CheckMate 9ER trial and published data for pembrolizumab plus axitinib from the KEYNOTE-426 trial were used. CheckMate 9ER data were reweighted to match the key baseline characteristics as reported in KEYNOTE-426. INTERVENTION: Nivolumab (240 mg every 2 wk) plus cabozantinib (40 mg once daily) and pembrolizumab (200 mg every 3 wk) plus axitinib (5 mg twice daily, initially). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hazard ratios (HRs) for progression-free survival (PFS), duration of response, overall survival (OS), and deterioration in HRQoL were assessed using weighted Cox proportional-hazard models, with sunitinib as a common anchor. Objective response rates (ORRs) and changes in HRQoL scores from baseline were assessed as difference-in-differences for the two treatments relative to sunitinib. RESULTS AND LIMITATIONS: After balancing patient characteristics between the trials, nivolumab plus cabozantinib was associated with significantly improved PFS (HR [95% confidence interval {CI}] 0.70 [0.53-0.93]; p = 0.01) and a significantly decreased risk of confirmed deterioration in HRQoL (Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms: HR [95% CI] 0.48 [0.34-0.69]) versus pembrolizumab plus axitinib. OS was similar between treatments (HR [95% CI] 0.99 [0.67-1.44]; p = 0.94). Nivolumab plus cabozantinib was associated with numerically greater ORRs (difference-in-difference [95% CI] 8.4% [-1.7 to 18.4]; p = 0.10) and longer duration of response (HR [95% CI] 0.79 [0.47-1.31]; p = 0.36) than pembrolizumab plus axitinib. Comparative studies using data with a longer duration of follow-up are warranted. CONCLUSIONS: Nivolumab plus cabozantinib significantly improved PFS and HRQoL compared with pembrolizumab plus axitinib as first-line treatment for aRCC. PATIENT SUMMARY: This study was conducted to indirectly compare the results of two immunotherapy-based combinations-nivolumab plus cabozantinib versus pembrolizumab plus axitinib-for patients who have not received any treatment for advanced renal cell carcinoma. Patients who received nivolumab plus cabozantinib had a significant improvement in the length of time without worsening of their disease and in their perceived physical and mental health compared with pembrolizumab plus axitinib; patients remained alive for a similar length of time from the start of either treatment. This analysis further adds to our current knowledge of the relative benefits of these two treatment regimens and will help with physician and patient treatment decisions.

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. METHODS: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. RESULTS: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. CONCLUSIONS: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial.

BACKGROUND: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER. METHODS: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment. FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23·5 months (IQR 21·0-26·5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30·24 [SD 5·19] for the nivolumab plus cabozantinib group and 30·06 [5·03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2·38 [95% CI 1·20-3·56], nominal p<0·0001, effect size 0·33 [95% CI 0·17-0·50] for FKSI-19 total score; 1·33 [0·84-1·83], nominal p<0·0001, 0·45 [0·28-0·61] for FKSI-19 disease-related symptoms version 1; 3·48 [1·58-5·39], nominal p=0·0004, 0·30 [0·14-0·47] for EQ-5D-3L VAS; and 0·04 [0·01-0·07], nominal p=0·0036, 0·25 [0·08-0·41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0·70 [95% CI 0·56-0·86], nominal p=0·0007; confirmed deterioration event 0·63 [0·50-0·80], nominal p=0·0001). INTERPRETATION: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma. FUNDING: Bristol Myers Squibb.

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Cost-effectiveness of pembrolizumab versus chemotherapy as first-line treatment in PD-L1-positive advanced non-small-cell lung cancer in the USA.

Aim: This analysis aimed to evaluate the cost-effectiveness of pembrolizumab monotherapy as first-line treatment in advanced non-small-cell lung cancer patients with a programmed death ligand 1 (PD-L1) tumor proportion score ≥1% from a US payer perspective. Materials & methods: A partitioned survival model was developed using efficacy and safety data from the KEYNOTE-042 trial and projected over 20 years. Costs accounted for treatment, toxicity and disease management. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were reported. Results: Pembrolizumab resulted in an expected gain of 0.60 life years and 0.49 QALYs compared with platinum-based chemotherapy. The incremental cost-effectiveness ratio was US$130,155/QALY. Conclusion: Pembrolizumab is projected to be cost-effective compared with platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer with PD-L1 tumor proportion score ≥1%.

Ertugliflozin Compared to Other Anti-hyperglycemic Agents as Monotherapy and Add-on Therapy in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: Ertugliflozin is a new sodium-glucose co-transporter-2 inhibitor (SGLT2i) for the treatment of type 2 diabetes mellitus. As there are no head-to-head trials comparing the efficacy of SGLT2is, the primary objective of this analysis was to indirectly compare ertugliflozin to other SGLT2i in patient populations with inadequately controlled glycated hemoglobin (HbA1c > 7.0%) and previously treated with either diet/exercise, metformin alone or metformin plus a dipeptidyl peptidase-4 inhibitor (DPP4i). METHODS: A systematic literature review (SLR) identified randomized controlled trials (RCTs) reporting outcomes at 24-26 weeks of treatment. Comparators to ertugliflozin were the SGLT2is canagliflozin, dapagliflozin and empagliflozin, with non-SGLT2i comparators also evaluated third-line [insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)]. Outcomes were change from baseline in HbA1c, weight and systolic blood pressure (SBP) as well as HbA1c < 7% and key safety events. Bayesian network meta-analysis was used to synthesize evidence. Results are presented as the median of the mean difference (MD) or as odds ratios with 95% credible intervals (CrI). RESULTS: In patients uncontrolled on diet/exercise, the efficacy of ertugliflozin 5 mg monotherapy was not significantly different from that of other low-dose SGLT2is in terms of HbA1c reduction, while ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD - 0.36%, CrI - 0.65, - 0.08) and empagliflozin 25 mg (MD - 0.31%, CrI - 0.58, - 0.04). As add-on therapy to metformin, ertugliflozin 5 mg was more effective in lowering HbA1c than dapagliflozin 5 mg (MD - 0.22%, CrI - 0.42, - 0.02), and ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD - 0.26%, CrI - 0.46, - 0.06) and empagliflozin 25 mg (MD - 0.23%, CrI - 0.44, - 0.03). Among patients uncontrolled on combination therapy metformin plus a DPP4i, no relevant RCTs with insulin were identified from the SLR. One study with a GLP-1 RA was included in a sensitivity analysis due to limited data. There were no differences between ertugliflozin 5 or 15 mg and other SGLT2is, with the exception of dapagliflozin 10 mg, which was significantly less effective when added to sitagliptin and metformin. Overall, there were no other significant differences for remaining efficacy and safety outcomes except for a lower SBP for canagliflozin 300 mg compared to ertugliflozin 15 mg in the diet/exercise population. CONCLUSIONS: Indirect comparisons for HbA1c reduction found that ertugliflozin 5 mg was more effective than dapagliflozin 5 mg when added to metformin monotherapy, whereas ertugliflozin 15 mg was more effective than dapagliflozin 10 mg and empagliflozin 25 mg when added to diet/exercise and to metformin monotherapy. The HbA1c reduction associated with ertugliflozin was no different than that associated with canagliflozin across all populations. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Cost-effectiveness of pembrolizumab in combination with chemotherapy versus chemotherapy and pembrolizumab monotherapy in the first-line treatment of squamous non-small-cell lung cancer in the US.

Objective: To describe the cost-effectiveness of pembrolizumab plus chemotherapy (carboplatin and paclitaxel or nab-paclitaxel; P + C) in metastatic, squamous, non-small-cell lung cancer (NSCLC) patients in the US. Methods: A model comparing P + C versus C alone is developed utilizing partitioned survival analysis. Primary clinical efficacy, treatment utilization, health utility and safety data are derived from the KEYNOTE-407 trial and projected over 20 years. Costs for drugs and non-drug disease management are also incorporated. Additionally, the cost-effectiveness of P + C vs. pembrolizumab monotherapy (P) is evaluated via an indirect treatment comparison, for patient subgroups with PD-L1 Tumor Proportion Score (TPS) ≥ 50% and 1-49%. Results: Overall, P + C is projected to increase life expectancy by 1.95 years vs. C (3.86 versus 1.91). The resultant ICER is $86,293/QALY. In patients with PD-L1 ≥ 50%, 1-49% and <1 the corresponding incremental cost-effectiveness ratios (ICERs) are $99,777/QALY, $85,986/QALY and $87,507/QALY, respectively. Versus P, in the PD-L1 ≥ 50% subgroup, P + C appears cost saving; however, this result should be interpreted with caution as there is considerable uncertainty in the relative efficacy of these comparators. Conclusions: Across all eligible patients, the addition of pembrolizumab to chemotherapy is projected to approximately double life expectancy, yielding an extension to a point not previously seen in metastatic squamous NSCLC. Overall, and within all relevant PD-L1 subgroups, use of P + C yields an ICER below $100,000/QALY, and can be a cost-effective first-line treatment for eligible metastatic squamous NSCLC patients for whom chemotherapy is currently administered. In the PD-L1 ≥ 50% subgroup, additional follow-up within trials of pembrolizumab plus chemotherapy and pembrolizumab monotherapy are needed to better define cost-effectiveness between these comparators.

Prevalence of hypoglycemia among a sample of sulfonylurea-treated patients with Type 2 diabetes mellitus in Argentina: The real-life effectiveness and care patterns of diabetes management (RECAP-DM) study / Prevalencia de hipoglucemia en un grupo de pacientes con Diabetes Tipo 2 tratados con Sulfonilureas en Argentina: estudio RECAP-DM en Argentina

Aim: Strict blood glucose control in the treatment of diabetes can sometimes lead to hypoglycemia. The main aim of this study was to assess the prevalence of hypoglycemia among patients receiving sulfonylureas alone, or in combination with metformin, for the treatment of Type 2 Diabetes Mellitus (T2DM) in Argentina. Methods: This is a real life, multi-center, retrospective, and cross-sectional study based on clinical chart reviews including cross-sectional data, and evaluation of patient questionnaires of T2DM patients (>30 years), treated with sulfonylureas alone or in combination with metformin, during a routine clinic visit in 16 medical centers across Argentina. Socio-demographic and clinical parameters were collected from medical records, as well as hypoglycemic events from both the medical records and the patient questionnaires. The glycated hemoglobin (HbA1c) levels were obtained from medical records as well as a blood test. Results: The study included a total of 397 patients with a mean age of 62.5 years, diagnosed for 9.9 years, and 54.2% male. Mean HbA1c levels were 8.1%, (65mmol/mol) at enrolment, with 36.4% being in control (HbA1c<7%, (53mmol/mol). Patients with HbA1c<7%, (53mmol/mol) were significantly older, diagnosed at older age, and had lower triglyceride levels. Almost 50% reported hypoglycemic episodes that were mostly mild, and with women more likely to report them. The large majority (86%) were on combined metformin and sulfonylureas, most commonly Glibenclamide (48.6%). Patients on combined therapy were significantly younger and more likely to have uncontrolled diabetes. Conclusions: This study demonstrated that out of a sample of 397 patients with T2DM treated with sulfonylureas alone or in combination with metformin in Argentina, around 50% of them reported symptoms of hypoglycemia induced by sulfonylureas, and one third of them achieved target HbA1c<7% levels

Objetivo: El control estricto de la glucemia en el tratamiento de la diabetes puede provocar hipoglucemia. El objetivo principal de este estudio fue evaluar la prevalencia de hipoglucemia en pacientes que reciben sulfonilureas (SU) solas o en combinación con metformina para el tratamiento de la diabetes tipo 2 en Argentina. Métodos: Este es un estudio multicéntrico, retrospectivo y transversal de la vida real basado en la revisión de historias clínicas que incluyen datos transversales y evaluación de cuestionarios de pacientes con diabetes mellitus tipo 2 (>30 años) tratados con SU solas o en combinación con metformina, durante una consulta de rutina en 16 centros médicos en toda Argentina. Se recogieron los parámetros sociodemográficos y clínicos de los registros médicos y los eventos hipoglucémicos de los registros médicos y los cuestionarios de los pacientes. Los niveles de hemoglobina glucosilada (HbA1c) se obtuvieron a partir de registros médicos y un análisis de sangre. Resultados: Se incluyeron 397 pacientes. La edad media fue de 62,5 años, con diagnóstico realizado hace 9,9 años y donde el 54,2% de los pacientes fueron varones. Los niveles de HbA1c fueron del 8,1% (65mmol/mol) al momento del enrolamiento y del 36,4% estaban en meta terapéutica (HbA1c<7%, 53mmol/mol). Dichos pacientes tenían una edad avanzada y los niveles de triglicéridos más bajos. Cerca del 50% informó de episodios de hipoglucemia, en su mayoría leves, y las mujeres eran más propensas a informar dichos episodios. El 86% estaban con metformina combinada con SU, más comúnmente glibenclamida (48,6%). Dichos pacientes eran significativamente más jóvenes y más propensos a tener diabetes no controlada. Conclusiones: Este estudio demostró que de una muestra de 397 pacientes con diabetes mellitus tipo 2 tratados con SU solas o en combinación con metformina en Argentina, alrededor del 50% de ellos informaron síntomas de hipoglucemia inducida por SU y un tercio de ellos alcanzaron el objetivo HbA1c<7%

Prevalence of hypoglycemia among a sample of sulfonylurea-treated patients with Type 2 diabetes mellitus in Argentina: The real-life effectiveness and care patterns of diabetes management (RECAP-DM) study.

AIM: Strict blood glucose control in the treatment of diabetes can sometimes lead to hypoglycemia. The main aim of this study was to assess the prevalence of hypoglycemia among patients receiving sulfonylureas alone, or in combination with metformin, for the treatment of Type 2 Diabetes Mellitus (T2DM) in Argentina. METHODS: This is a real life, multi-center, retrospective, and cross-sectional study based on clinical chart reviews including cross-sectional data, and evaluation of patient questionnaires of T2DM patients (>30 years), treated with sulfonylureas alone or in combination with metformin, during a routine clinic visit in 16 medical centers across Argentina. Socio-demographic and clinical parameters were collected from medical records, as well as hypoglycemic events from both the medical records and the patient questionnaires. The glycated hemoglobin (HbA1c) levels were obtained from medical records as well as a blood test. RESULTS: The study included a total of 397 patients with a mean age of 62.5 years, diagnosed for 9.9 years, and 54.2% male. Mean HbA1c levels were 8.1%, (65mmol/mol) at enrolment, with 36.4% being in control (HbA1c<7%, (53mmol/mol). Patients with HbA1c<7%, (53mmol/mol) were significantly older, diagnosed at older age, and had lower triglyceride levels. Almost 50% reported hypoglycemic episodes that were mostly mild, and with women more likely to report them. The large majority (86%) were on combined metformin and sulfonylureas, most commonly Glibenclamide (48.6%). Patients on combined therapy were significantly younger and more likely to have uncontrolled diabetes. CONCLUSIONS: This study demonstrated that out of a sample of 397 patients with T2DM treated with sulfonylureas alone or in combination with metformin in Argentina, around 50% of them reported symptoms of hypoglycemia induced by sulfonylureas, and one third of them achieved target HbA1c<7% levels.

Impact of Timely Treatment Intensification on Glycemic Goal Achievement in Patients With Type 2 Diabetes Failing Metformin Monotherapy.

Purpose The purpose of the study was to examine the association between timely treatment intensification (TTI) and glycemic goal achievement in patients with type 2 diabetes (T2D) failing metformin monotherapy (MM). Methods This study was set at a large integrated health care system in the United States. The study cohort included T2D patients aged 18 to 85 years who were on MM between January 2009 and September 2013 and had an uncontrolled glycated hemoglobin (A1C) reading (≥8%) after at least 3 months of MM (corresponding date was index date). Secondary analyses were performed using A1C <7% as T2D control. TTI was defined as receipt of an add-on therapy within 180 days after the index date. Impact of TTI on glycemic goal achievement was determined using multivariate Cox proportional hazards regression. Patients were censored at their last A1C reading or health care visit during 2 years after the index date. Results The study cohort consisted of 996 patients, ~58% male and ~59% Caucasian, with a mean age of ~54 (±12) years. TTI was observed in 50.2% of the patients. The rate of glycemic goal achievement was higher in patients with TTI compared with patients without TTI (hazards ratio = 1.632, 95% confidence interval = 1.328-2.006). The results for the secondary analyses were largely consistent with the primary findings. Conclusions TTI positively affected glycemic goal achievement among T2D patients failing MM and could be a useful strategy to increase the currently low proportion of patients with their T2D controlled in the United States.

Patient and Provider Factors Affecting Clinical Inertia in Patients With Type 2 Diabetes on Metformin Monotherapy.

PURPOSE: Our aim was to determine the extent of clinical inertia and the associated patient and provider factors in patients with type 2 diabetes on metformin monotherapy (MM) at a large integrated health care system in the United States. METHODS: The study cohort included patients with type 2 diabetes aged 18 to 85 years, on MM between January 2009 and September 2013, who experienced MM failure (had an uncontrolled glycosylated hemoglobin [HbA1c] reading (≥8.0% [64 mmol/mol]) after at least 90 days of MM). Clinical inertia was defined as absence of treatment intensification with an add-on therapy within 180 days after the MM failure (index date). The impact of patient and provider factors on clinical inertia was determined using generalized estimating equations. FINDINGS: The study cohort consisted of 996 patients; 58% were men and 59% were white, with a mean age of 53 (11.8) years. Of these, 49.8% experienced clinical inertia. Lower HbA1c at index date, absence of liver diseases, absence of renal diseases, and greater provider age were associated with clinical inertia. The clinical inertia rate in a secondary analysis considering HbA1c <7.0% (53 mmol/mol) as glycemic control was 67.9%. Greater patient age, lower HbA1c at index date, greater provider age, and being a primary care physician were associated with clinical inertia. IMPLICATIONS: Considerable clinical inertia rates were observed in our real-world patient population, suggesting the need of interventions to reduce clinical inertia in clinical practice. Information about patient and provider factors affecting clinical inertia provided by this study could help healthcare policymakers plan and implement such interventions.

Intensification of Diabetes Therapy and Time Until A1C Goal Attainment Among Patients With Newly Diagnosed Type 2 Diabetes Who Fail Metformin Monotherapy Within a Large Integrated Health System.

OBJECTIVE: "Clinical inertia" has been used to describe the delay in the intensification of type 2 diabetes treatment among patients with poor glycemic control. Previous studies may have exaggerated the prevalence of clinical inertia by failing to adequately monitor drug dose changes and nonmedication interventions. This project evaluated the intensification of diabetes therapy and hemoglobin A1c (A1C) goal attainment among patients with newly diagnosed type 2 diabetes when metformin monotherapy failed. RESEARCH DESIGN AND METHODS: The electronic health record at Cleveland Clinic was used to identify patients with newly diagnosed type 2 diabetes between 2005 and 2013 who failed to reach the A1C goal after 3 months of metformin monotherapy. A time-dependent survival analysis was used to compare the time until A1C goal attainment in patients who received early intensification of therapy (within 6 months of metformin failure) or late intensification. The analysis was performed for A1C goals of 7% (n = 1,168), 7.5% (n = 679), and 8% (n = 429). RESULTS: Treatment was intensified early in 62%, 69%, and 72% of patients when poor glycemic control was defined as an A1C >7%, >7.5%, and >8%, respectively. The probability of undergoing an early intensification was greater the higher the A1C category. Time until A1C goal attainment was shorter among patients who received early intensification regardless of the A1C goal (all P < 0.05). CONCLUSIONS: A substantial number of patients with newly diagnosed type 2 diabetes fail to undergo intensification of therapy within 6 months of metformin monotherapy failure. Early intervention in patients when metformin monotherapy failed resulted in more rapid attainment of A1C goals.

Cost-effectiveness of adding ezetimibe to atorvastatin vs switching to rosuvastatin therapy in Portugal.

BACKGROUND: Statin monotherapy is the mainstay of low-density lipoprotein cholesterol (LDL-C) management for high cardiovascular risk patients in Portugal; however, several therapeutic options are available and predicted to have different clinical and economic impacts. The aim of this study was to evaluate the cost-effectiveness of adding ezetimibe 10 mg (EZ10) to atorvastatin 10 or 20 mg (A10/20) vs switching to rosuvastatin 10 or 20 mg (R10/20) in Portuguese patients with coronary heart disease (CHD) and/or diabetes who are currently above the LDL-C goal. METHODS: A Markov model was used to describe CHD disease progression and the lifetime costs and utilities associated with each disease state were used to estimate the gains in life-years and quality-adjusted life-years (QALYs), as well as the incremental cost-effectiveness ratio (ICER), of the two treatment regimens. Model inputs, such as age, gender, and prevalence of cardiovascular risk factors of the dyslipidemic Portuguese patients were obtained from the Portuguese cohort of the Dyslipidemia International Study (DYSIS). The efficacy of each treatment regimen, the cost of drugs and of treating CHD events, and the utilities for each disease state were derived from published sources. RESULTS: The estimated lifetime discounted number of QALYs gained by patients treated with A10/20 was 8.70, while in those switching to R10/20 it was 8.81 and in those adding EZ10 it was 8.93. Discounted total health costs were estimated to be €11,131 for A10/20, but €14,511 and €16,571 for R10/20 and A10/20 + EZ10, respectively. The ICER of adding ezetimibe vs switching to rosuvastatin was €16,465/QALY. Based on the Portuguese cost-effectiveness willingness-to-pay threshold of €30,000/QALY, adding ezetimibe vs switching to rosuvastatin would be a cost-effective use of resources in Portugal. Sensitivity analyses in patients with differing clinical histories (CHD or diabetes or both) yielded similar values, with no ICER over €30,000/QALY. CONCLUSIONS: From the perspective of the National Health Service, prescribing ezetimibe to high cardiovascular risk patients being treated with atorvastatin vs switching them to rosuvastatin is projected to be a cost-effective use of resources in Portugal.

Impact of Switching From High-Efficacy Lipid-Lowering Therapies to Generic Simvastatin on LDL-C Levels and LDL-C Goal Attainment Among High-Risk Primary and Secondary Prevention Populations in the United Kingdom.

PURPOSE: High cholesterol, especially high low-density lipoprotein cholesterol (LDL-C), is an important risk factor for cardiovascular disease (CVD) morbidity/mortality. Switching from high-efficacy lipid-lowering therapies (HETs) to simvastatin might lead to sub-optimal control of LDL-C. Our objective was to evaluate the impact of switching from HETs to generic simvastatin on LDL-C levels and LDL-C goal attainment among the high-risk primary and secondary prevention populations in the United Kingdom. METHODS: This retrospective cohort study was conducted using Clinical Practice Research Datalink database. Included were individuals with more than 2 months of prescriptions of the following HETs between August 1, 2004 and December 31, 2008: simvastatin/ezetimibe fixed dose (S/E), simvastatin and ezetimibe co-administration (S+E), atorvastatin and ezetimibe co-administration (A+E), rosuvastatin and ezetimibe co-administration (R+E), rosuvastatin monotherapy, and atorvastatin monotherapy. For each baseline HET, we used analysis of covariance (ANCOVA) to estimate the least squares mean (LSM) difference in the percentage change from baseline in LDL-C between switchers and non-switchers, and logistic regression to estimate the odds ratio of attaining the LDL-C goal (<3 mmol/L for primary prevention and <2 mmol/L for secondary prevention, by JBS2) at follow-up. Propensity score adjusted analyses were conducted to reduce selection bias. FINDINGS: 30,148 patients met the eligibility criteria with 83.8% received atorvastatin, 9.5% rosuvastatin and 2.6% S/E and S+E combined. 89.1% of patients switching from atorvastatin switched to an equivalent or higher dose of simvastatin (dose equivalency was determined by relative efficacy of one statin to other statins), while 100% of those switching from simvastatin/ezetimibe and 96.8% of those switching from rosuvastatin switched to lower than equivalent dose of simvastatin. Compared to non-switchers, the adjusted least squares mean differences in the percentage change in LDL-C levels from baseline were 18.74% (p = 0.0003), 16.73% (p < 0.0001), and -0.11% (p = 0.9044) when switching from simvastatin/ezetimibe, rosuvastatin, and atorvastatin, respectively. The odds of LDL-C goal attainment at follow-up among switchers from simvastatin/ezetimibe, rosuvastatin, and atorvastatin were 0.40 (95% CI: 0.23-0.70), 0.36 (95% CI: 0.26-0.51) and 1.03 (95% CI: 0.92-1.15) relative to non-switchers respectively. IMPLICATIONS: Among the high risk CVD population in UK, switching to simvastatin from HET, especially rosuvastatin and simvastatin/ezetimibe, resulted in an increase in LDL-C levels and lower goal attainment. These historical data reinforce the appropriateness of the changes in the new Joint British Guideline (JBS3) which no longer recommends starting simvastatin 40 mg.

Risk of all-cause hospitalization in COPD patients initiating long-acting or short-acting beta agonist therapy.

OBJECTIVE: This retrospective claims study investigated the rates of all-cause hospitalization among chronic obstructive pulmonary disease (COPD) patients initiating treatment with short-acting beta agonists (SABA) or long-acting beta agonists (LABA). METHODS: Data from the 5% national sample of Medicare enrollees for 2006-2008 were used. Patients initiating COPD therapy were identified as those with no COPD therapy for ≥ 6-months prior to initiating SABA or LABA (administered via dry-powder inhalers, metered-dose inhalers, or nebulizer) treatment. All patients were continuously eligible for Medicare Parts A, B, and D for 18 months. Those enrolled in Medicare Advantage, who had asthma, or were < 65 years old were excluded. Differences in the rates of all-cause hospitalizations and time to all-cause hospitalization during the 6-month follow-up period were examined, while adjusting for demographics, clinical indicators, and health service use. RESULTS: Among 3017 COPD patients who met the inclusion criteria, 883 (30%) were LABA users and 2134 (70%) were SABA users. Overall, 21% of patients (16% [144/883] of LABA and 23% [492/2134] of SABA) had a hospitalization during the follow-up period. Mean time to hospitalization was 86 days for LABA vs 64 days for SABA patients (p < 0.05). The adjusted hazard ratio for hospitalization in a Cox proportional hazards model was 0.74 (95% CI = 0.62-0.90) for patients treated with LABA vs. SABA. LIMITATIONS: The analysis was adjusted for multiple background characteristics, but important measures of severity in COPD, such as measures of lung functioning, were not available and may have differed between patients treated with LABA or SABA. CONCLUSIONS: The results of this analysis indicate COPD patients initiating LABA treatment had a longer time to all-cause hospitalization and a 26% lower risk of hospitalization during the 6-months follow-up period compared to those initiating SABA therapy.