Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high-dose GLP-1 receptor agonists and GLP-1 receptor-based co-agonists.

Type 2 diabetes (T2D), obesity, and nonalcoholic fatty liver disease/nonalacoholic steatohepatitis (NAFLD/NASH) share mutual causalities. Medications that may offer clinical benefits to all three conditions are being developed. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for the management of T2D and obesity and there is great interest in evaluating higher doses of available GLP-1RAs and developing novel GLP-1RA-based co-agonists to provide greater reductions in glycated hemoglobin (HbA1c) and body weight as well as modifying NAFLD/NASH complications in clinically meaningful ways. High-dose GLP-1RAs and multi-hormonal strategies including GLP-1R agonism have either already been approved or are in development for managing T2D, obesity, or NASH. We provide a mechanistic outline with a detailed summary of the available clinical data and ongoing trials that are adjudicating the impact of high-dose GLP-1RAs, unimolecular, and multimolecular GLP-1R-based co-agonists in populations living with T2D, obesity, or NASH. The available trial findings are aligned with preclinical observations, showing clinical efficacy and safety thus providing optimism for the expansion of GLP-1R-based drug classes for managing the triad of T2D, obesity and NASH. Development, access, and wide-spread utilization of these new therapeutic approaches will offer important opportunities to markedly improve the collective global burden of T2D, obesity, and NASH.

Pharmacotherapy for obesity management

Pharmacological treatments are an effective and scalable approach to treating obesity. As with any chronic disease, such as type 2 diabetes (T2DM) or hypertension, pharmacotherapy is an important pillar in the management of obesity. The focus of obesity management should be the improvement of health parameters (metabolic, mechanical, mental, and/or quality of life [QoL]), not solely weight reduction, and should include outcomes that the patient identifies as important. Obesity is defined by body mass index (BMI) in clinical trials, which itself does not adequately reflect the burden of adiposity-related disease. There are four medications indicated for long-term obesity management in Canada as adjuncts to health-behaviour changes: liraglutide (Saxenda®), naltrexone/bupropion (Contrave®) in a combination tablet, orlistat (Xenical®) and semaglutide (Wegovy®). All four medications are effective in producing clinically significant weight loss and health benefits greater than placebo over a duration of at least one year. The individual response to pharmacotherapy for obesity management is heterogeneous. Efficacy (both for weight and management of obesity-related health issues), mechanism of action, safety, potential side effects/tolerability, contraindications, medication interactions, mode of administration and cost are important considerations in choosing the most appropriate obesity pharmacotherapy. Obesity medications are intended as part of a long-term treatment strategy. Clinical trials of pharmacotherapy for obesity management consistently demonstrate regain of weight when treatment is stopped. Medications that are not approved as pharmacotherapy for obesity management should not be used for this purpose.

Real-World Insights Into Evolocumab Use in Patients With Hyperlipidemia: Canadian Analysis From the ZERBINI Study.

Background: The 2021 Canadian Cardiovascular Society guidelines recommend proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy in patients with atherosclerotic cardiovascular disease whose low-density lipoprotein cholesterol (LDL-C) concentration remains ≥ 1.8 mmol/L despite maximally tolerated statin therapy. This retrospective and prospective observational study characterizes Canadian patients treated with evolocumab and describes its effectiveness and safety. Methods: Between August 2017 and July 2019, a total of 131 patients initiated on evolocumab therapy were enrolled at 15 sites in Canada. Data were extracted from medical records every 3 months between 6 months prior to, and for 12 months following evolocumab therapy initiation, until July 6, 2020. Baseline and prospectively collected data are reported as available. Results: A total of 131 patients were enrolled (59.5% male; mean age [standard deviation (SD)] 64.7 ± 10.6 years), most with a diagnosis of atherosclerotic cardiovascular disease and/or familial hypercholesterolemia (93.4%). Mean (± SD) LDL-C concentration at baseline was 3.7 (± 1.7) mmol/L (n = 119), with 58.0% of patients receiving a statin (36.6% high intensity). Mean (± SD) LDL-C concentration after evolocumab treatment was 1.6 (± 1.0) mmol/L (n = 120), representing a 58.7% decrease from baseline (n = 109). This level remained stable over 12 months. An LDL-C concentration < 1.8 mmol/L was achieved by 77.5% of patients. Persistence was 92%, and no serious treatment-emergent adverse events were reported. Conclusions: These findings provide real-world evidence of guideline-recommended initiation of evolocumab therapy, as well as confirmation of its effectiveness and safety in a Canadian population. Evolocumab therapy can address a healthcare gap in the management of dyslipidemia, by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk.

Introduction: Les lignes directrices de la Société canadienne de cardiologie de 2021 recommandent un traitement par les inhibiteurs de proprotéine convertase subtilisine-kexine de type 9 (PCSK9) aux patients atteints de la maladie cardiovasculaire athérosclérotique chez lesquels les concentrations de cholestérol à lipoprotéines de faible densité (cholestérol LDL) demeurent ≥ 1,8 mmol/l malgré le traitement maximalement toléré par statines. La présente étude observationnelle rétrospective et prospective donne les caractéristiques des patients canadiens traités par évolocumab, et décrit l'efficacité et l'innocuité de ce médicament. Méthodes: Entre août 2017 et juillet 2019, nous avons inscrit un total de 131 patients qui avaient amorcé le traitement d'évolocumab dans 15 établissements du Canada. Nous avons extrait les données des dossiers médicaux tous les trois mois de six mois avant et jusqu'à 12 mois après le début du traitement par évolocumab, et ce, jusqu'au 6 juillet 2020. Les données initiales et les données collectées de façon prospective sont déclarées selon leur disponibilité. Résultats: Nous avons inscrit un total de 131 patients (59,5 % d'hommes; âge moyen [écart type (ET)] 64,7 ± 10,6 ans); la plupart avaient un diagnostic de maladie cardiovasculaire athérosclérotique et/ou d'hypercholestérolémie familiale (93,4 %). Les concentrations initiales moyennes (± ET) de cholestérol LDL étaient de 3,7 (± 1,7) mmol/l (n = 119), et 58,0 % des patients recevaient une statine (36,6 % d'intensité élevée). Les concentrations moyennes (± ET) de cholestérol LDL après le traitement par évolocumab étaient de 1,6 (± 1,0) mmol/l (n = 120), soit une diminution de 58,7 % par rapport aux concentrations initiales (n = 109). Ces concentrations sont demeurées stables durant 12 mois. Des concentrations de cholestérol LDL < 1,8 mmol/l ont été atteintes par 77,5 % des patients. La persistance a été de 92 %, et aucun événement défavorable sérieux associé au traitement n'a été déclaré. Conclusions: Ces résultats fournissent des données probantes du monde réel sur l'amorce du traitement par évolocumab conformément aux recommandations des lignes directrices, ainsi qu'une confirmation de son efficacité et de son innocuité au sein d'une population canadienne. Le traitement par évolocumab peut permettre de remédier aux lacunes des soins de santé dans la prise en charge de la dyslipidémie par l'augmentation de la proportion de patients atteignant les objectifs recommandés en matière de cholestérol LDL pour réduire le risque de maladies cardiovasculaires.

2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.

The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment.

Effect of a functional fibre supplement on glycemic control when added to a year-long medically supervised weight management program in adults with type 2 diabetes.

PURPOSE: Soluble fibre beneficially affects metabolism but whether it can augment the reductions in glycemia induced through intensive weight management has not been extensively studied. Our objective was to examine the adjunct effect of the soluble viscous fibre PGX® on glycemic control in adults with type 2 diabetes (T2D) enrolled in a year-long medically supervised weight management program. METHODS: In a placebo-controlled, double-blind study, 290 adults with overweight/obesity and T2D were randomized to receive PGX (15-20 g/day) or isocaloric placebo (rice flour, 6.4-8.6 g/day) as an adjunct to intensive weight management for 52 weeks. The primary outcome was change in glycemic control (HbA1c). Other outcome measures included weight loss, blood lipids, blood pressure, cytokines and fecal microbiota. RESULTS: Compared to baseline HbA1c in PGX (7.2 ± 1.1%) and placebo (7.0 ± 0.9%) groups, there was a significant reduction at 16 and 26 weeks, however, only PGX showed a significant absolute reduction of 0.23% at 52 weeks; there were no between-group differences in HbA1c. At 52 weeks, only PGX significantly decreased body weight compared to baseline and reduced waist circumference at all time points. Compared to baseline, only PGX showed a significant reduction in LDL cholesterol at 16 and 26 weeks. PGX significantly increased the relative abundance of Collinsella, Parabacteroides and Roseburia. CONCLUSION: Adding PGX to a weight management program for individuals with T2D provides a sustained reduction in HbA1c compared to placebo. Improvements in other metabolic outcomes suggest that PGX may be a promising adjunct to weight loss programs in patients with T2D. CLINICAL TRIAL: This trial was registered at ClinicalTrials.gov as NCT01644201.

Obesity in adults: a clinical practice guideline

Obesity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan.1 Epidemiologic studies define obesity using the body mass index (BMI; weight/height2), which can stratify obesity-related health risks at the population level. Obesity is operationally defined as a BMI exceeding 30 kg/m2 and is subclassified into class 1 (30­34.9), class 2 (35­39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases.2 At the individual level, complications occur because of excess adiposity, location and distribution of adiposity and many other factors, including environmental, genetic, biologic and socioeconomic factors.

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

Hormone Replacement Therapy and Opioid Tapering for Opioid-Induced Hypogonadism Among Patients with Chronic Noncancer Pain: A Systematic Review.

OBJECTIVE: To systematically review evidence addressing the efficacy of testosterone replacement therapy (TRT) and opioid tapering for opioid-induced hypogonadism among patients with chronic noncancer pain. STUDY DESIGN: Systematic review of randomized controlled trials (RCTs) and observational studies. METHODS: We searched MEDLINE, CINAHL, AMED, CENTRAL, CINAHL, DARE, EMBASE, and PsycINFO through August 2017. Eligible studies enrolled ≥10 patients with chronic noncancer pain and opioid-induced hypogonadism and reported the effect of TRT or opioid tapering on a patient-important outcome collected ≥14 days after treatment. Pairs of reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. We used the GRADE approach to rate quality of evidence. RESULTS: Of 666 abstracts reviewed, five studies including one RCT (N = 84) and four observational studies (N = 157) were eligible. No studies explored the effect of opioid tapering for opioid-induced hypogonadism. Very low-quality evidence found that TRT was associated with improvements in pain (median reduction of 2 points on the 11-point numerical rating scale for pain; 95% confidence interval [CI] = -1.4 to -2.6; minimally important difference [MID] = 2 points), and emotional functioning (mean increase of 9 points on the 100-point SF-36 Mental Component Summary score; 95% CI = 4.40 to 13.60; MID = 5 points). Low-quality evidence suggested that TRT had no effect on sleep quality, sexual function, physical functioning, role functioning, or social functioning; very low-quality evidence suggested no association with depressive symptoms. CONCLUSIONS: Low-quality to very low-quality evidence suggests that TRT may improve pain and emotional functioning, but not other outcomes, in chronic noncancer pain patients with opioid-induced hypogonadism.

Utility of current obesity thresholds in signaling diabetes risk in the James Bay Cree of Eeyou Istchee.

OBJECTIVE: The anthropometric thresholds signaling type 2 diabetes risk have not been well defined for Aboriginal communities. This study examined current thresholds in terms of ability to capture diabetes risk in the Cree of Eeyou Istchee in northern Quebec, Canada. RESEARCH DESIGN AND METHODS: The study cohort for this analysis included adult participants from the Nituuchischaayihtitaau Aschii Multi-Community Environment and Health Study with complete data on anthropometric measures, fasting glucose, and insulin. Diabetes risk was defined as Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) value >2. Positive and negative likelihood ratios (PLR, NLR) of existing obesity thresholds were evaluated (WHO; International Diabetes Federation, IDF; Adult Treatment Panel III, ATP III). Receiver operating curves were examined to estimate optimal thresholds. In a sensitivity analysis, diabetes risk was defined as HOMA-IR >2.7. RESULTS: The WHO 30 kg/m(2) body mass index (BMI) threshold performed well in women (PLR 5.56, 95% CI 1.95 to 15.9; NLR 0.24, 95% CI 0.19 to 0.31) and men (PLR 7.51, 95% CI 2.94 to 19.2; NLR 0.33, 95% CI 0.27 to 0.41). It was close to the estimated optimal threshold (28.5 kg/m(2)). The ATP III waist circumference threshold (102 cm) performed well in men (PLR 4.64, 95% CI 2.47 to 8.71; NLR 0.21, 95% CI 0.16 to 0.28) and was close to the estimated optimal threshold (101 cm). With diabetes risk defined at HOMA-IR >2.7, PLR values were slightly lower with narrower 95% CIs and optimal thresholds were slightly higher; PLR values remained above 3. For other current thresholds, estimated optimal values were higher and none had a PLR above 2. CONCLUSIONS: A BMI of 30 kg/m(2) in women and men, and a 102 cm waist circumference in men, are meaningful obesity thresholds in this Aboriginal population. Other thresholds require a further evaluation.

Decreasing cardiovascular risk factors in obese individuals using a combination of PGX® meal replacements and PGX® granules in a 12-week clinical weight modification program.

In this open, clinically based, weight modification program, we determined in six sedentary obese adults (five women; one male; age range 30-62 years) that the combination of a modified calorie diet plus PGX® meal replacement and PGX® supplementation resulted in a significant reduction in several cardiovascular risk factors over a 12-week time period. This included a significant improvement in lipids (-0.98 mmol/l LDL-C), reduction in average weight (-9.2 kg), mean reduction in fat (-4.1%) and an increase in fat-free mass (2.8%).

Sex differences in step count-blood pressure association: a preliminary study in type 2 diabetes.

BACKGROUND: Walking and cardiovascular mortality are inversely associated in type 2 diabetes, but few studies have objectively measured associations of walking with individual cardiovascular risk factors. Such information would be useful for "dosing" daily steps in clinical practice. This study aimed to quantify decrements in blood pressure and glycated hemoglobin (A1C) per 1,000 daily step increments. METHODOLOGY/PRINCIPAL FINDINGS: Two hundred and one subjects with type 2 diabetes underwent assessments of step counts (pedometer-measured), blood pressure, A1C and anthropometric parameters. Due to missing data, the final analysis was conducted on 83 women and 102 men, with a mean age of 60 years. Associations of daily steps with blood pressure and A1C were evaluated using sex-specific multivariate linear regression models (adjusted for age, ethnicity, and BMI). Potential sex differences were confirmed in a combined model (women and men) with interaction terms. Mean values for daily steps, blood pressure, A1C and BMI were 5,357 steps/day; 137/80 mm Hg; 7.7% and 30.4 kg/m(2) respectively. A 1,000 daily step increment among women was associated with a -2.6 (95% CI: -4.1 to -1.1) mm Hg change in systolic and a -1.4 (95% CI: -2.2 to -0.6) mm Hg change in diastolic blood pressure. Among men, corresponding changes were -0.7 (95% CI: -2.1 to 0.7) and -0.6 (95% CI: -1.4 to 0.3) mm Hg, respectively. Sex differences were confirmed in combined models. Step counts and A1C did not demonstrate clinically important associations. CONCLUSIONS/SIGNIFICANCE: A 1,000 steps/day increment is associated with important blood pressure decrements among women with type 2 diabetes but the data were inconclusive among men. Targeted "dose increments" of 1,000 steps/day in women may lead to measurable blood pressure reductions. This information may be of potential use in the titration or "dosing" of daily steps. No associations were found between step count increments and A1C.