The i-ACT™ in Obesity educational intervention: a pilot study on improving Canadian family physician care in obesity medicine.

BACKGROUND: Obesity is a chronic problem in Canada and although the Canadian Medical Association recognizes obesity as a disease, health care professionals (HCPs) are not necessarily proactively managing it as one. This study aimed to assess current obesity management knowledge and practices of Canadian family physicians (FPs) and evaluate the feasibility of an online self-directed learning platform, i-ACT™ in Obesity, in delivering learning and changing practice intentions to advance obesity management. METHODS: i-ACT™ in Obesity is an online self-directed learning program designed by Canadian obesity medicine experts to provide individualized learning curricula to participants. One hundred FPs, with an interest in weight management and managing patients with obesity, were recruited across Canada to participate in a pilot study. FP education was delivered in a stepwise manner. Each participant completed a practice profile assessment to determine knowledge gaps and educational needs. Learners then watched didactic videos across disciplines on topics assigned to their curriculum by the program algorithm based on the relative difference between indicated and desired current knowledge. FPs also completed 10 retrospective patient assessments to assess clinical management practices and planned behaviour change. Feasibility, acceptability, and satisfaction of the learning program were assessed to formulate the rationale for a more widespread deployment in the future. Survey responses and related data were analyzed using comparative measures and descriptive statistics. RESULTS: The program was piloted by ninety-one Canadian FPs, where 900 patients were assessed. FPs showed distinct differences between their current and desired levels of comfort in a variety of obesity-related topics. Participation was associated with an intention to use more obesity treatment interventions moving forward. The program received an overall satisfaction rating of 8.6 out of 10 and 100% of the evaluators indicated that they would recommend it to their colleagues. CONCLUSION: The program was overall well received and successfully changed obesity management intentions among participating FPs, thus setting the stage for a larger more comprehensive study to examine the efficacy of i-ACT™ in Obesity in addressing knowledge gaps and advancing evidence-based, guidelines-aligned approach to obesity treatment.

Extended-release naltrexone/bupropion is safe and effective among subjects with type 2 diabetes already taking incretin agents: a post-hoc analysis of the LIGHT trial.

BACKGROUND: Extended-release naltrexone/bupropion (NB) is indicated for chronic weight management. Incretin agents are recommended for patients with type 2 diabetes. This analysis looked at the add-on of NB to incretins to see if weight loss could occur in patients already stabilized on incretin agents. METHODS: This was a post-hoc analysis of NB vs. placebo (PL) among subjects with type 2 diabetes stable on an incretin agent prior to randomization in a double-blind, PL-controlled cardiovascular outcome trial (N = 1317). RESULTS: Over 1 year, mean weight loss was significantly greater among NB patients vs. PL among those taking DPP-4i (mean absolute difference 4.6% [p < 0.0001]) and those taking GLP-1RAs (mean absolute difference 5.2%, p < 0.0001). Proportions of subjects achieving 5% weight loss were significantly greater for NB vs. PL at weeks 26 and 52 among those taking DPP-4is or GLP-1RAs. There were no significant differences in effectiveness observed between NB + DPP-4i and NB + GLP-1RA or between PL + DPP-4i and PL + GLP-1RA in any of the analyses. Serious adverse events were reported by 9.1% and 11.1% for PL + DPP-4i and PL + GLP-1RA, respectively, and 13.3% and 12.4% of NB + DPP-4i and NB + GLP-1RA, respectively. CONCLUSION: NB appears to be effective in reducing weight in patients with T2DM and obesity/overweight who are taking DPP-4ihibitors or GLP-1RA. The SAE rates in all arms of this analysis were lower than have been reported in other cardiovascular outcome trials in type 2 diabetes.

Psychiatric Safety and Weight Loss Efficacy of Naltrexone/bupropion as Add-on to Antidepressant Therapy in Patients with Obesity or Overweight.

There is significant association between obesity and depression. Naltrexone/Bupropion (NB) is indicated for treatment of overweight and obesity (BMI ≥27 kg/m2 with a comorbidity or ≥30 kg/m2). This post-hoc analysis examines safety and efficacy of NB and placebo among individuals with overweight or obesity who were also taking antidepressant therapy during the LIGHT trial (N=8910). Subjects were divided into four subgroups: NB + antidepressants (n=1150), NB without antidepressants (n=3300), placebo + antidepressants (n=1127) and placebo without antidepressants (n=3317). Among subjects taking NB, the combined incidence of serious adverse events (AEs) and AEs leading to treatment discontinuation was not significantly different between those on antidepressants and those who were not. The key weight-loss efficacy analyses were performed on NB or placebo-treated subjects who remained on study therapy through 104 weeks and who did or did not have documented antidepressant use at each of the baseline, week 52 and week 104 visits (Completers: N=1811; 47.0% female, 86.9% white, mean age of 61 years, mean baseline BMI 37.4 kg/m2). The mean adjusted weight change in subjects taking antidepressants was numerically, but not significantly greater for NB vs. placebo (-6.3% vs. -4.3%). For those subjects not on antidepressants, weight loss was significantly greater for NB vs. PL (-6.8% vs. -3.6%). NB is generally well tolerated in patients with overweight or obesity who are on antidepressants and is effective in promoting weight loss regardless of antidepressant use. These results show that for patients on antidepressant therapy, NB may be an effective option for obesity management.

Extended-release naltrexone/bupropion and liver health: Pooled, post hoc analysis from four randomized controlled trials.

Sustained weight loss improves liver histology in non-alcoholic fatty liver disease. This post hoc analysis of four phase III, 56-week, randomized controlled trials investigated if extended-release naltrexone and bupropion (NB) affects alanine aminotransferase (ALT) and Fibrosis-4 (FIB-4) index in adults with overweight or obesity. Two thousand and seventy-three subjects (NB = 1310; placebo = 763; 79.0% female; 81.6% Caucasian) had baseline mean weight 101 kg, body mass index 36.2 kg/m2 , ALT 26.9 IU/L and FIB-4 0.79. At 56 weeks, NB-treated subjects experienced more weight loss than placebo (8.7 vs. 3.2 kg, respectively, P < .0001). Weight loss, independent of treatment, was associated with improved ALT and FIB-4 (P < .0001). There was a significant independent effect of NB on change from baseline for FIB-4 (P < .0001), but not for ALT (P = .54). Categorical ALT response (from above to within normal ranges: 10-40 IU/L for men; 7-35 IU/L for women) and achievement of 25% and 50% reduction in ALT were greater for NB versus placebo, and independently affected by weight loss (P < .0001), but not treatment. NB-associated weight loss may improve liver health by normalizing ALT values for those with high baseline levels.

Real-world effectiveness of treatments for type 2 diabetes, hypercholesterolemia, and hypertension in Canadian routine care - Results from the CardioVascular and metabolic treatment in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry, 12-months results.

AIMS: The CV-CARE registry provides RWE in Canadian routine clinical practice. METHODS: CV-CARE is a multi-site, observational, prospective Canadian registry enrolling patients initiating treatment with metformin hydrochloride extended-release (MetER) for T2D; colesevelam (C) for HCh; and azilsartan (AZI), azilsartan/chlorthalidone (AZI/CHL) or diltiazem extended-release (TXC) for HTN. Patient characteristics/assessment were performed at baseline and 12 ± 6 months. Primary outcome was absolute change in HbA1c and FPG (MetER); % change in LDL-C (C); and absolute change in BP (AZI-AZI/CHL-TXC). RESULTS: Of the 4194 patients in the primary analysis population, 24% were taking MetER, 39% were taking C, 33% were taking AZI, 12% were taking AZI/CHL, and 3% were taking TXC. At 12 months, MetER-treated patients had an absolute mean (95% CI) change in HbA1c of -0.3% [-0.4; -0.2] and in FPG of 0.7 mmol/L [-1.0; -0.4]. C-treated patients had a mean (95% CI) % change in LDL-C of -13.0% [-14.6; -11.4]. Absolute mean (95% CI) changes in SBP were -18.7 mmHg [-19.7; -17.7](AZI), -21.3 mmHg [-23.1; -19.5](AZI/CHL), and -12.3 mmHg [-15.1; -9.6](TXC). CONCLUSION: In a real-world Canadian setting, MetER, C, AZI, AZI/CHL, and TXC show improvement of the cardiometabolic profile of T2D, HCh, and HTN patients.

Regional variability in Canadian routine care of type 2 diabetes, hypercholesterolemia, and hypertension: Results from the The Cardio-Vascular and metabolic treatments in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry.

BACKGROUND: Regional differences in the profile and treatment strategies of patients with cardiometabolic diseases have been studied in several different countries. The Cardio-Vascular and metabolic treatments in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry was designed to evaluate patient profiles and medical management of cardiometabolic diseases in routine clinical care settings across Canada. Primary objectives were to (1) evaluate regional variability of patient profiles with cardiometabolic disease(s) and (2) assess treatment differences of patients treated for type 2 diabetes (T2D), hypercholesterolemia (HCh), and hypertension (HTN) across Canada. METHODS: CV-CARE is a multi-center, observational, prospective registry that enrolled Canadian patients treated with metformin-extended release (MetER) for T2D, colesevelam (C) for HCh, azilsartan (AZI) for mild-to-moderate essential HTN and azilsartan/chlorthalidone (AZI/CHL) for severe, essential HTN. Patient characteristics and treatments were assessed at baseline. RESULTS: The registry enrolled 6960 patients, with a total of 4194 patients making up the primary analysis population [MetER (n=995); C (n=1639); AZI (n=1364); AZI/CHL (n=498)]. First-line use of MetER was more common in British Columbia (BC; 45.5%) compared to Ontario (ON; 29.8%), and Quebec (QC; 12.9%). C treatment for HCh was used as monotherapy most readily in BC (68.7%) compared with QC (59.7%) and ON (35.8%). Dual action of low-density lipoprotein cholesterol and hemoglobin A1c reduction was the predominant reason for C add-on therapy (46.8%), with highest usage seen in ON (62.9%). AZI treatment for HTN was most frequently used in BC (43.8%), and AZI/CHL was most commonly used in ON (12.0%). First-line use of AZI was more common in QC (50%) vs. ON (34.9%) and BC (24.1%). The primary reason for switching to AZI and AZI/CHL from prior treatment was lack of efficacy across provinces. CONCLUSION: This is the first regional description of the CV-CARE cohort. Significant variations in both baseline profile and treatments were observed which could have an impact on long-term outcomes.

Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with reduced platelet counts and a unique gain-of-function defect in fibrinolysis due to increased expression and storage of urokinase plasminogen activator (uPA) by megakaryocytes. QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors. The genetic cause of the disorder is a tandem duplication mutation of the uPA gene, PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism. The increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins. The gain-of-function defect in fibrinolysis is thought to be central to the pathogenesis of QPD bleeding as the activation of QPD platelets leads to release of uPA from α-granules and accelerated clot lysis. The purpose of this review is to summarize current knowledge on QPD pathogenesis and the recommended approaches to QPD diagnosis and treatment.

Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder linked to a region on chromosome 10 that includes PLAU, the urokinase plasminogen activator gene. QPD increases urokinase plasminogen activator mRNA levels, particularly during megakaryocyte differentiation, without altering expression of flanking genes. Because PLAU sequence changes were excluded as the cause of this bleeding disorder, we investigated whether the QPD mutation involved PLAU copy number variation. All 38 subjects with QPD had a direct tandem duplication of a 78-kb genomic segment that includes PLAU. This mutation was specific to QPD as it was not present in any unaffected family members (n = 114), unrelated French Canadians (n = 221), or other persons tested (n = 90). This new information on the genetic mutation will facilitate diagnostic testing for QPD and studies of its pathogenesis and prevalence. QPD is the first bleeding disorder to be associated with a gene duplication event and a PLAU mutation.

Increased expression of urokinase plasminogen activator in Quebec platelet disorder is linked to megakaryocyte differentiation.

Quebec platelet disorder (QPD) is an inherited bleeding disorder associated with increased urokinase plasminogen activator (uPA) in platelets but not in plasma, intraplatelet plasmin generation, and alpha-granule protein degradation. These abnormalities led us to investigate uPA expression by QPD CD34(+) progenitors, cultured megakaryocytes, and platelets, and whether uPA was stored in QPD alpha-granules. Although QPD CD34(+) progenitors expressed normal amounts of uPA, their differentiation into megakaryocytes abnormally increased expression of the uPA gene but not the flanking genes for vinculin or calcium/calmodulin-dependent protein kinase IIgamma on chromosome 10. The increased uPA production by cultured QPD megakaryocytes mirrored their production of alpha-granule proteins, which was normal. uPA was localized to QPD alpha-granules and it showed extensive colocalization with alpha-granule proteins in both cultured QPD megakaryocytes and platelets, and with plasminogen in QPD platelets. In QPD megakaryocytes, cultured without or with plasma as a source of plasminogen, alpha-granule proteins were stored undegraded and this was associated with much less uPA-plasminogen colocalization than in QPD platelets. Our studies indicate that the overexpression of uPA in QPD emerges with megakaryocyte differentiation, without altering the expression of flanking genes, and that uPA is costored with alpha-granule proteins prior to their proteolysis in QPD.

Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes.

Quebec platelet disorder (QPD) is an autosomal dominant disorder with high penetrance that is associated with increased risks for bleeding. The hallmark of QPD is a gain-of-function defect in fibrinolysis due to increased platelet content of urokinase plasminogen activator (uPA) without systemic fibrinolysis. We hypothesized that increased expression of uPA by differentiating QPD megakaryocytes is linked to PLAU. Genetic marker analyses indicated that QPD was significantly linked to a 2-Mb region on chromosome 10q containing PLAU with a maximum multipoint logarithm of the odds (LOD) score of +11 between markers D10S1432 and D10S1136. Analysis of PLAU by sequencing and Southern blotting excluded mutations within PLAU and its known regulatory elements as the cause of QPD. Analyses of uPA mRNA indicated that QPD distinctly increased transcript levels of the linked PLAU allele with megakaryocyte differentiation. These findings implicate a mutation in an uncharacterized cis element near PLAU as the cause of QPD.