[89Zr]-immuno-PET prediction of response to rituximab treatment in patients with therapy refractory interstitial pneumonitis: a phase 2 trial.

INTRODUCTION: Immune-mediated interstitial pneumonitis may be treated with anti-CD20 therapy after failure of conventional therapies. However, clinical response is variable. It was hypothesized that autoreactive CD20-positive cells may play an important role in this variability. This prospective study aims to elucidate if imaging of CD20-positive cells in the lungs allows prediction of the response to anti-CD20 treatment. METHODS: Twenty-one patients with immune-mediated interstitial lung disease (ILD) with deteriorated pulmonary function received a dose of 1000 mg rituximab on day 1 and day 14 spiked with a tracer dose of radiolabeled [89Zr]-rituximab. PET/CT was performed on days 3 and 6. Standardized uptake values (SUV) were calculated as a measure for pulmonary CD20 expression. Based on pulmonary function tests (PFT), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), prior to and 6 months after treatment, patients were classified as responder (stable disease or improvement) or non-responder. RESULTS: Fifteen patients (71%) were classified as responder. Pulmonary [89Zr]-rituximab PET SUVmean was significantly correlated with the change in FVC and DLCO (K = 0.49 and 0.56, respectively) when using target-to-background ratios, but not when using SUVmean alone. [89Zr]-rituximab SUVmean was significantly higher in responders than in non-responders (0.35 SD 0.09 vs. 0.23 SD 0.06; P = 0.02). CONCLUSION: Rituximab treatment was effective in the majority of patients. As a higher pulmonary uptake of [89Zr]-rituximab correlated with improvement of PFT and treatment outcome, [89Zr]-rituximab PET imaging may serve as a potential predictive biomarker for anti-CD20 therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02251964.

Individual patient data to allow a more elaborated comparison of trial results with real-world outcomes from first-line immunotherapy in NSCLC.

BACKGROUND: Many studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials. However, any differences observed could be only limitedly explored further for causation because of the unavailability of individual patient data (IPD) from trial participants. The present study aims to explore the additional benefit of comparison with IPD. METHODS: This study compares progression free survival (PFS) and overall survival (OS) of metastatic NSCLC patients treated with second line nivolumab in real-world clinical practice (n = 141) with IPD from participants in the Checkmate-057 clinical trial (n = 292). Univariate and multivariate Cox proportional hazards models were used to construct HRs for real-world practice versus clinical trial. RESULTS: Real-world patients were older (64 vs. 61 years), had more often ECOG PS ≥ 2 (5 vs. 0%) and were less often treated with subsequent anti-cancer treatment (28.4 vs. 42.5%) compared to trial patients. The median PFS in real-world patients was longer (3.84 (95%CI: 3.19-5.49) vs 2.30 (2.20-3.50) months) and the OS shorter than in trial participants (8.25 (6.93-13.2) vs. 12.2 (9.90-15.1) months). Adjustment with available patient characteristics, led to a shift in the hazard ratio (HR) for OS, but not for PFS (HRs from 1.13 (0.88-1.44) to 1.07 (0.83-1.38), and from 0.82 (0.66-1.03) to 0.79 (0.63-1.00), respectively). CONCLUSIONS: This study is an example how IPD from both real-world and trial patients can be applied to search for factors that could explain an efficacy-effectiveness gap. Making IPD from clinical trials available to the international research community allows this.

Chloroquine-induced QTc prolongation in COVID-19 patients.

BACKGROUND: In the battle against the SARS-CoV­2 pandemic, chloroquine has emerged as a new potential therapeutic option for the treatment of infected patients. A safety consideration for the application of chloroquine is its QTc-prolonging potential. Thus far, no data are available on the QTc-prolonging potential of chloroquine in COVID-19 patients. OBJECTIVE: To assess the degree of chloroquine-induced QTc prolongation in hospitalised COVID-19 patients. METHODS: A baseline electrocardiogram (ECG) and ECGs recorded during chloroquine treatment were retrospectively collected in patients suspected of having COVID-19. The QTc interval was calculated by computerised and manual interpretation. Baseline and follow-up QTc intervals were compared using the paired samples t-test. RESULTS: A total of 95 patients had a baseline ECG recording and at least one ECG recording during chloroquine therapy. Chloroquine treatment resulted in a mean QTc prolongation of 35 ms (95% CI 28-43 ms) using computerised interpretation and 34 ms (95% CI 25-43 ms) using manual interpretation. No torsade de pointes was observed during chloroquine treatment. After manual review, 22 patients (23%) had a QTc interval exceeding 500 ms during chloroquine treatment. None of these patients had a prolonged QTc interval prior to the initiation of chloroquine treatment. CONCLUSIONS: Chloroquine significantly prolongs the QTc interval in a clinically relevant matter. This highlights the need for ECG monitoring when prescribing chloroquine to COVID-19 patients.

Decision support systems for incurable non-small cell lung cancer: a systematic review.

BACKGROUND: Individually tailored cancer treatment is essential to ensure optimal treatment and resource use. Treatments for incurable metastatic non-small cell lung cancer (NSCLC) are evolving rapidly, and decision support systems (DSS) for this patient population have been developed to balance benefits and harms for decision-making. The aim of this systematic review was to inventory DSS for stage IIIB/IV NSCLC patients. METHODS: A systematic literature search was performed in Pubmed, Embase and the Cochrane Library. DSS were described extensively, including their predictors, model performances (i.e., discriminative ability and calibration), levels of validation and user friendliness. RESULTS: The systematic search yielded 3531 articles. In total, 67 articles were included after additional reference tracking. The 39 identified DSS aim to predict overall survival and/or progression-free survival, but give no information about toxicity or cost-effectiveness. Various predictors were incorporated, such as performance status, serum and inflammatory markers, and patient and tumor characteristics. Some DSS were developed for the entire incurable NSCLC population, whereas others were specifically for patients with brain or spinal metastases. Few DSS had been validated externally using recent clinical data, and the discrimination and calibration were often poor. CONCLUSIONS: Many DSS have been developed for incurable NSCLC patients, but DSS are still lacking that are up-to-date with a good model performance, while covering the entire treatment spectrum. Future DSS should incorporate genetic and biological markers based on state-of-the-art evidence, and compare multiple treatment options to estimate survival, toxicity and cost-effectiveness.

High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery.

BACKGROUND: Postoperative non-cardiac complication rates are as high as 11-28% after high-risk abdominal procedures. Emerging evidence indicates that postoperative cardiac troponin T elevations are associated with adverse outcome in non-cardiac surgery. The aim of this study was to determine the relationship between postoperative high-sensitive cardiac troponin T elevations and non-cardiac complications in patients after major abdominal surgery. METHODS: This prospective observational single-centre cohort study included patients at risk for coronary artery disease undergoing elective major abdominal surgery. Cardiac troponin was measured before surgery and at day 1, 3, and 7. Multivariable logistic regression analysis was performed to examine the adjusted association for different cut-off concentrations of postoperative myocardial injury and non-cardiac outcome. RESULTS: In 203 patients, 690 high-sensitive cardiac troponin T measurements were performed. Fifty-three patients (26%) had a non-cardiac complication within 30 days after surgery. Hospital mortality was 4% (8/203). An increase in cardiac troponin T concentration ≥100% compared with baseline was a superior independent predictor of non-cardiac postoperative clinical complications (adjusted odds ratio 4.3, 95% confidence interval 1.8-10.1, P<0.001) and was associated with increased length of stay (9 days, 95% confidence interval 7-11 vs 7 days, 95% confidence interval 6-8, P=0.004) and increased hospital mortality (12 vs 2%, P=0.028). CONCLUSIONS: A postoperative high-sensitive cardiac troponin T increase ≥100% is a strong predictor of non-cardiac 30 day complications, increased hospital stay and hospital mortality in patients undergoing major abdominal surgery. CLINICALTRIALSGOV IDENTIFIER: NCT02150486.

Preoperative statin therapy and infectious complications in cardiac surgery.

AIM: To assess whether preoperative statin therapy is associated with the risk of postoperative infection in patients undergoing cardiac surgery. METHODS: 520 patients undergoing cardiac surgery in 2010 were retrospectively examined. Data regarding statin and antibiotic use prior to and after surgery were available from the hospital pharmacy information system. Cultures and clinical data of patients on postoperative antibiotics other than standard prophylactic therapy were studied to identify postoperative infections up to 30 days from day of surgery. RESULTS: 370 (71.2 %) patients were on preoperative statin therapy. Overall, 82 patients (15.8 %) suffered from postoperative infection of which 11 were surgical site infections. In multivariable regression analysis, statin therapy was associated with a reduced risk of postoperative infection (adjusted odds ratio: 0.329, 95 %: CI 0.19-0.57; P < 0.001). CONCLUSIONS: Preoperative statin use was associated with a considerable reduced risk of postoperative infections following cardiac surgery. Randomised controlled trials are required to clarify the role of statin therapy in the prevention of postoperative infections.

The association of body mass index with safety and effectiveness of first-line carboplatin-based chemotherapy in patients with metastatic non-small cell lung cancer.

INTRODUCTION: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations. MATERIALS AND METHODS: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m2 (normal weight and reference), 25.0-29.9 kg/m2 (overweight) or ≥30.0 kg/m2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR]. RESULTS: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90). CONCLUSION: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m2, and to verify calculated dosing of carboplatin for appropriateness.

Development of an international, multidisciplinary, patient-centered Standard Outcome Set for Multiple Sclerosis: The S.O.S.MS project.

BACKGROUND: Currently, outcomes of Multiple Sclerosis (MS) are not standardized and it is unclear which outcomes matter most to people living with MS. A consensus between patients and healthcare professionals on which outcomes to measure and how, would facilitate a move towards value-based MS care. OBJECTIVE: to develop an internationally accepted, patient-relevant Standard Outcome Set for MS (S.O.S.MS). METHODS: A mixed-method design was used, including a systematic literature review, four patient focus groups (n=30) and a RAND-modified Delphi process with seventeen MS experts of five disciplines from seven countries (the Netherlands, United States of America, Portugal, Ireland, India, New Zealand, Switzerland and Turkey). RESULTS: A standard outcome set for MS was defined, consisting of fourteen outcomes divided in four domains: disease activity (n=3), symptoms (n=4), functional status (n=6), and quality of life (n=1). For each outcome, an outcome measure was selected and the measurement protocol was defined. In addition, seven case-mix variables were selected. CONCLUSION: This standard outcome set provides a guideline for measuring outcomes of MS in clinical practice and research. Using this set to monitor and (inter)nationally benchmark real-world outcomes of MS can support improvement of patient value and ultimately guide the transition towards value-based MS care.

Treatment with anti-inflammatory drugs in community-acquired pneumonia.

Pneumonia exhibits a broad range of severity, from mildly symptomatic at one end to fulminant septic shock and death at the other. Although an adequate inflammatory response is necessary for the clearance of microorganisms, excessive inflammation can lead to ongoing local and systemic damage. Because of this extended inflammatory response despite appropriate antibiotic therapy, as well as increasing antibiotic resistance, adjuvant therapy for pneumonia that can favourably modify the immune response has become an increasingly relevant approach to improve prognosis. Different adjuvant treatment options for pneumonia have recently been proposed. Promising treatment options include corticosteroids, statins, macrolides and Toll-like receptor antagonists. The aim of this review is to summarize the inflammatory response during pneumonia and discuss the current knowledge and future perspectives regarding the anti-inflammatory treatment options for patients with pneumonia.

Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy.

BACKGROUND: Chronic thoracic pain after cardiac surgery is a serious condition affecting many patients. The aim of this study was to identify predictors for chronic thoracic pain after sternotomy in cardiac surgery patients by analysing patient and perioperative characteristics. METHODS: A follow-up study was performed in 120 patients who participated in a clinical trial on pain levels in the early postoperative period after cardiac surgery. The presence of chronic thoracic pain was evaluated by a questionnaire 1 yr after surgery. Patients with and without chronic thoracic pain were compared. Associations were studied using multivariable logistic regression analysis. RESULTS: Questionnaires of 90 patients were analysed. Chronic thoracic pain was reported by 18 patients (20%). In the multivariable regression model, remifentanil during cardiac surgery, age below 69 yr, and a body mass index above 28 kg m(-2) were independent predictors for chronic thoracic pain {odds ratios 8.9 [95% confidence interval (CI) 1.6-49.0], 7.0 (95% CI 1.6-31.7), 9.1 (95% CI 2.1-39.1), respectively}. No differences were observed in patient and perioperative characteristics between patients receiving remifentanil (58%, n=52) compared with patients not receiving remifentanil (42%, n=38). The association between remifentanil and chronic thoracic pain appeared dose-dependent, both for total dose and for dose corrected for kilogram lean body mass and duration of surgery (P-value for trend: <0.01 and <0.005, respectively). CONCLUSIONS: In this follow-up study in cardiac surgery patients, intraoperative remifentanil was predictive for chronic thoracic pain in a dose-dependent manner. Randomized studies designed to evaluate the influence of intraoperative remifentanil on chronic thoracic pain are needed to confirm these results.

Microbial evaluation of proton-pump inhibitors and the risk of pneumonia.

Recent initiation of proton-pump inhibitor (PPI) treatment may increase the risk of community-acquired pneumonia (CAP), hypothetically by allowing colonisation of the oropharynx by gastrointestinal bacteria. The aim of this study was to assess the causal pathway by considering microbial aetiology of pneumonia and indications for initiation of PPI treatment. This was a population-based, case-control study with 430 cases with pneumonia and 1,720 matched controls. An elaborate diagnostic protocol was used to identify the causative microorganism of pneumonia. For patients recently starting PPI treatment, indications for treatment were assessed. Recent initiation of PPI treatment (<30 days) was associated with an increased risk of CAP (adjusted OR 3.1, 95% CI 1.4-7.1). Oropharyngeal bacteria were evenly distributed among current users, past users and nonusers of PPIs (p=0.41). Gastrointestinal bacteria were identified in only five (1.2%) patients with pneumonia (two current users and three nonusers). Excluding patients who were possibly prescribed PPI treatment for early symptoms of pneumonia (protopathic bias) did not alter the study findings. This study reaffirmed that use of PPIs is associated with an increased risk of CAP, especially when treatment has recently been started. Neither protopathic bias nor shifts in microbial aetiology seem to explain the association.

Maintenance of anesthesia in morbidly obese patients using propofol with continuous BIS-monitoring: a comparison of propofol-remifentanil and propofol-epidural anesthesia.

PURPOSE: Aim of this study was to evaluate maintenance of anesthesia using propofol with continuous Bispectral Index (BIS)-monitoring in morbidly obese patients receiving propofol-remifentanil and propofol-epidural anesthesia. METHODS: In the first group in ten morbidly obese patients receiving remifentanil analgesia, a propofol infusion was started at 10 mg/kg/hr and modified by aiming at BIS values between 40-60 together with predefined hemodynamic parameters. In the second group, the propofol dose resulting from the first group was prospectively evaluated in a matched cohort of six morbidly obese patients receiving propofol-epidural analgesia aiming for the same BIS and hemodynamic parameters. In both groups, propofol concentration and infusion rates, BIS and hemodynamic values were collected. RESULTS: In the propofol-remifentanil group (Body Mass Index (BMI) 39-60 kg/m2), the mean propofol infusion rate that corresponded to the predefined BIS and hemodynamic parameters was 4.8 mg/kg/hr (SD 1.5). On this basis, a maintenance dose of 5 mg/kg/hr was started in the propofol-epidural group (BMI 38-58 kg/m2). In this second group, the mean propofol infusion rate that corresponded to predefined BIS and hemodynamic parameters was 5.0 mg/kg/hr (SD 0.6). Between the two groups, there was no difference in the propofol concentration-BIS relation. CONCLUSION: Using both BIS and hemodynamic parameters as an endpoint, a maintenance dose of propofol of 4-6 mg/kg/hr is proposed for maintenance of anesthesia in morbidly obese patients undergoing bariatric surgery either in combination with remifentanil or epidural analgesia. There was no difference in propofol concentration-BIS relation in morbidly obese patients receiving propofol-remifentanil or propofol-epidural anesthesia.

The association between gut microbiome affecting concomitant medication and the effectiveness of immunotherapy in patients with stage IV NSCLC.

Several observational studies suggested that gut microbiome-affecting-medication impairs the effectiveness of immunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We postulated that if the effectiveness of immunotherapy is affected by drug-related changes of the microbiome, a stronger association between the use of co-medication and overall survival (OS) will be observed in patients treated with immunotherapy as compared to patients treated with chemotherapy. In a retrospective matched cohort study, immunotherapy patients were matched (1:1) to patients treated with chemotherapy in the pre immunotherapy era. The association between the use of antibiotics, opioids, proton pump inhibitors, metformin and other antidiabetics on OS was assessed with multivariable cox-regression analyses. Interaction tests were applied to investigate whether the association differs between patients treated with immuno- or chemotherapy. A total of 442 patients were studied. The use of antibiotics was associated with worse OS (adjusted Hazard Ratio (aHR) 1.39, p = 0.02) independent of the type of therapy (chemotherapy or immunotherapy). The use of opioids was also associated with worse OS (aHR 1.33, p = 0.01). The other drugs studied showed no association with OS. Interaction term testing showed no effect modification by immuno- or chemotherapy for the association of antibiotics and opioids with OS. The use of antibiotics and opioids is similarly associated with worse outcomes in both chemotherapy and immunotherapy treated NSCLC patients. This suggests that the association is likely to be a consequence of confounding rather than disturbing the composition of the microbiome.

Real-World Results of Ocrelizumab Treatment for Primary Progressive Multiple Sclerosis.

BACKGROUND: Recently, ocrelizumab (Ocrevus®) was approved for the treatment of primary progressive multiple sclerosis (PPMS) based on data from the ORATORIO clinical trial. Real-world data about the clinical effectiveness of ocrelizumab has yet to be gathered. OBJECTIVE: The aim of this study was to provide data about the clinical effectiveness of ocrelizumab for patients diagnosed with PPMS in a real-world setting. METHODS: We conducted a retrospective cohort study of all patients with PPMS who started ocrelizumab treatment (n = 21) in St. Antonius Hospital (Utrecht/Nieuwegein, the Netherlands) between April 2018 and December 31, 2018. Primary outcome was pre- versus post-ocrelizumab disability worsening rate (from 96 weeks prior to first ocrelizumab administration up to 24 weeks post first ocrelizumab administration). RESULTS: Disability worsening rate while on treatment significantly differed (lower) from disability worsening rate in pre-treatment period (Z = -2.81, p ≤ .01). Three out of 17 patients showed a clinically relevant improvement in disability status after treatment start. CONCLUSION: Ocrelizumab can stabilize disability progression in patients with PPMS. Some patients even showed a clinically relevant improvement in disability status. Further research should help to identify which patients benefit most from ocrelizumab.

Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT).

The Dutch Working Party on Antibiotic Policy in collaboration with the Dutch Association of Chest Physicians, the Dutch Society for Intensive Care and the Dutch College of General Practitioners have updated their evidence-based guidelines on the diagnosis and treatment of community-acquired pneumonia (CAP) in adults who present to the hospital. This 2016 update focuses on new data on the aetiological and radiological diagnosis of CAP, severity classification methods, initial antibiotic treatment in patients with severe CAP and the role of adjunctive corticosteroids. Other parts overlap with the 2011 guideline. Apart from the Q fever outbreak in the Netherlands (2007-2010) no other shifts in the most common causative agents of CAP or in their resistance patterns were observed in the last five years. Low-dose CT scanning may ultimately replace the conventional chest X-ray; however, at present, there is insufficient evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. A pneumococcal urine antigen test is now recommended for all patients presenting with severe CAP; a positive test result can help streamline therapy once clinical stability has been reached and no other pathogens have been detected. Coverage for atypical microorganisms is no longer recommended in empirical treatment of severe CAP in the non-intensive care setting. For these patients (with CURB-65 score >2 or Pneumonia Severity Index score of 5) empirical therapy with a 2nd/3rd generation cephalosporin is recommended, because of the relatively high incidence of Gram-negative bacteria, and to a lesser extent S. aureus. Corticosteroids are not recommended as adjunctive therapy for CAP.

Health literacy of patients admitted for elective surgery.

AIM: Patients with limited health literacy have poorer surgical outcomes. However, current studies assessing the prevalence of limited health literacy in patients expecting surgery are small scale. We aimed to provide insight into the health literacy level of patients undergoing planned surgery. SUBJECT AND METHODS: Patients aged ≥18 years visiting the preoperative screening department were approached in the waiting area and invited to participate in a brief interview including the Functional Communicative Critical Health Literacy (FCCHL). RESULTS: In total, 225 patients (84.9% response) were studied. Based on the FCCHL, 37.3% of the patients were classified as having limited health literacy. The mean score in the critical domain (2.7 ± 0.9) was lower than scores in the functional (3.3 ± 0.6) and communicative (3.3 ± 0.6) domains. CONCLUSION: More than one third of the patients admitted to the hospital for surgery had limited health literacy. Healthcare professionals should be aware of the different health literacy levels and tailor their information provision strategies accordingly.

Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial.

BACKGROUND: As adolescents with obesity and insulin resistance may be refractory to lifestyle intervention therapy alone, additional off-label metformin therapy is often used. In this study, the long-term efficacy and safety of metformin versus placebo in adolescents with obesity and insulin resistance is studied. METHODS: In a randomized placebo-controlled double-blinded trial, 62 adolescents with obesity aged 10-16 years old with insulin resistance received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months. Primary end points were change in body mass index (BMI) and insulin resistance measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary end points were safety and tolerability of metformin. Other end points were body fat percentage and HbA1c. RESULTS: Forty-two participants completed the 18-month study (66% girls, median age 13 (12-15) years, BMI 30.0 (28.3 to 35.0) kg m(-2) and HOMA-IR 4.08 (2.40 to 5.88)). Median ΔBMI was +0.2 (-2.9 to 1.3) kg m(-2) (metformin) versus +1.2 (-0.3 to 2.4) kg m(-2) (placebo) (P=0.015). No significant difference was observed for HOMA-IR. No serious adverse events were reported. Median change in fat percentage was -3.1 (-4.8 to 0.3) versus -0.8 (-3.2 to 1.6)% (P=0.150), in fat mass -0.2 (-5.2 to 2.1) versus +2.0 (1.2-6.4) kg (P=0.007), in fat-free mass +2.0 (-0.1 to 4.0) versus +4.5 (1.3 to 11.6) kg (P=0.047) and in ΔHbA1c +1.0 (-1.0 to 2.3) versus +3.0 (0.0 to 5.0) mmol mol(-1) (P=0.020) (metformin versus placebo). CONCLUSIONS: Long-term treatment with metformin in adolescents with obesity and insulin resistance results in stabilization of BMI and improved body composition compared with placebo. Therefore, metformin may be useful as an additional therapy in combination with lifestyle intervention in adolescents with obesity and insulin resistance.