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.

Review of an international pilot project to adapt the Canadian Adult Obesity Clinical Practice Guideline.

Background: The evidence-based Canadian Adult Obesity Clinical Practice Guideline (CPG) released in August 2020 were developed through a systematic literature review and patient-oriented research process. This CPG is considered a paradigm shift for obesity care as it introduced a new obesity definition that is based on health not body size, incorporates lived experiences of people affected by obesity, and addresses the pervasive weight bias and stigma that patients face in healthcare systems. The purpose of this pilot project was to assess the feasibility of adapting the Canadian CPG in Chile and Ireland. Methods: An International Clinical Practice Guideline Adaptation Committee was established to oversee the project. The project was conducted through four interrelated phases: 1) planning and preparation; 2) pilot project application process; 3) adaptation; and 4) launch, dissemination, and implementation. Ireland used the GRADE-ADAPTE framework and Chile used the GRADE-ADOLOPMENT approach. Results: Chile and Ireland developed their adapted guidelines in one third of the time it took to develop the Canadian guidelines. In Ireland, 18 chapters, which underpin the 80 key recommendations, were contextually adapted. Chile adopted 18 chapters and 76 recommendations, adapted one recommendation, and developed 12 new recommendations.. Conclusion: The pilot project demonstrated it is feasible to adapt the Canadian CPG for use in other countries with different healthcare systems, languages, and cultural contexts, while retaining the Canadian CPG's key principles and values such as the treatment of obesity as a chronic disease, adoption of new clinical assessment approaches that go beyond anthropometric measurements, elimination of weight bias and stigma, shifting obesity care outcomes to improved health and well-being rather than weight loss alone, and the use of patient-centred, collaborative and shared-decision clinical care approaches.

Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial.

BACKGROUND: Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA1c) is unknown. This trial assessed the efficacy and safety of co-administered semaglutide with cagrilintide (CagriSema) in participants with type 2 diabetes. METHODS: This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m2 or higher on metformin with or without an SGLT2 inhibitor were randomly assigned (1:1:1) to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide (all escalated to 2·4 mg). Randomisation was done centrally using an interactive web response system and was stratified according to use of SGLT2 inhibitor treatment (yes vs no). The trial participants, investigators, and trial sponsor staff were masked to treatment assignment throughout the trial. The primary endpoint was change from baseline in HbA1c; secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Efficacy analyses were performed in all participants who had undergone randomisation, and safety analyses in all participants who had undergone randomisation and received at least one dose of the trial medication. This trial is registered on ClinicalTrials.gov (NCT04982575) and is complete. FINDINGS: Between Aug 2 and Oct 18, 2021, 92 participants were randomly assigned to CagriSema (n=31), semaglutide (n=31), or cagrilintide (n=30). 59 (64%) participants were male; the mean age of participants was 58 years (SD 9). The mean change in HbA1c from baseline to week 32 (CagriSema: -2·2 percentage points [SE 0·15]; semaglutide: -1·8 percentage points [0·16]; cagrilintide: -0·9 percentage points [0·15]) was greater with CagriSema versus cagrilintide (estimated treatment difference -1·3 percentage points [95% CI -1·7 to -0·8]; p<0·0001), but not versus semaglutide (-0·4 percentage points [-0·8 to 0·0]; p=0·075). The mean change in bodyweight from baseline to week 32 (CagriSema: -15·6% [SE 1·26]; semaglutide: -5·1% [1·26]; cagrilintide: -8·1% [1·23]) was greater with CagriSema versus both semaglutide (p<0·0001) and cagrilintide (p<0·0001). The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3·3 mmol/L [SE 0·3]; semaglutide: -2·5 mmol/L [0·4]; cagrilintide: -1·7 mmol/L [0·3]) was greater with CagriSema versus cagrilintide (p=0·0010) but not versus semaglutide (p=0·10). Time in range (3·9-10·0 mmol/L) was 45·9%, 32·6%, and 56·9% at baseline and 88·9%, 76·2%, and 71·7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively. Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported. INTERPRETATION: In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA1c with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. FUNDING: Novo Nordisk.

Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial.

BACKGROUND: Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes. METHODS: This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0-10·5% (64-91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete. FINDINGS: Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were -1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, -1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] -0·27, 95% CI -0·42 to -0·12; p=0·0006), and -2·0 percentage points (0·06) with 50 mg (ETD -0·53, -0·68 to -0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related. INTERPRETATION: Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified. FUNDING: Novo Nordisk.

Relationship between body weight change and glycaemic control with tirzepatide treatment in people with type 2 diabetes: A post hoc assessment of the SURPASS clinical trial programme.

AIM: To assess the relationship between HbA1c and body weight reductions with tirzepatide treatment (5, 10 or 15 mg). MATERIALS AND METHODS: HbA1c and body weight data at 40 weeks (SURPASS-1, -2 and -5) and 52 weeks (SURPASS-3 and -4) were analysed by trial. RESULTS: Across the SURPASS clinical trials, HbA1c reductions from baseline were observed in 96%-99%, 98%-99% and 94%-99% of participants treated with tirzepatide 5, 10 and 15 mg, respectively. Moreover, 87%-94%, 88%-95% and 88%-97% of participants, respectively, experienced weight loss associated with HbA1c reductions. Statistically significant associations (correlation coefficients ranging from 0.1438 to 0.3130 across studies; P ≤ .038) between HbA1c and body weight changes were observed with tirzepatide in SURPASS-2, -3, -4 (all doses) and -5 (tirzepatide 5 mg only). CONCLUSIONS: In this post hoc analysis, consistent reductions in both HbA1c and body weight were observed in most participants treated with tirzepatide at doses of 5, 10 or 15 mg. A statistically significant but modest association between HbA1c and body weight change was observed in SURPASS-2, SURPASS-3 and SURPASS-4, suggesting that both weight-independent and weight-dependent mechanisms are responsible for the tirzepatide-induced improvement in glycaemic control.

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.

A Cross-sectional Survey to Assess Reasons for Therapeutic Inertia in People With Type 2 Diabetes Mellitus and Preferred Strategies to Overcome It From the Perspectives of Persons With Diabetes and General/Family Practitioners: Results From the MOTION Study.

OBJECTIVES: Although multiple causes of therapeutic inertia in type 2 diabetes mellitus (T2DM) have been identified, few studies have addressed the behavioural aspects of treatment-intensification decisions among persons with type 2 diabetes (PwT2DM) and general practitioners/family practitioners (GPFPs). METHODS: A quantitative online survey was developed to capture from 300 PwT2DM and 100 GPFPs the following information: 1) perspectives on shared decision-making (SDM) related to treatment intensification, using the 9-item Shared Decision Making Questionnaire and the Shared Decision Making Questionnaire---physician version; 2) intentions to intensify treatments, using the Theory of Planned Behaviour (TPB); and 3) preferred strategies to overcome causes of therapeutic inertia in T2DM. Regression methods were applied post hoc to examine correlations with SDM scores, behavioural intentions and behaviours. RESULTS: SDM scores showed a significantly lower level of perceived involvement in decision-making related to treatment intensification among PwT2DM compared with GPFPs. The TPB identified that, for PwT2DM, attitudes, perceived behavioural control and age were associated with variation in intention to intensify treatment and, for GPFPs, perceived behavioural control and not being in a shared/group practice were associated with intentions to intensify treatment. PwT2DM behaviour, measured as hesitancy to intensify treatment, was associated with age. PwT2DM want more information to become more comfortable with the treatment decision-making process, whereas GPFPs desired support from other health professionals, and more time to address issues among PwT2DM. CONCLUSIONS: Strategies directed at providing GPFPs with tools/approaches to increase PwT2DM involvement in the decision-making process, such as behavioural coaching, decision aids and goal setting, may increase acceptance of treatment intensification, leading to a reduction in therapeutic inertia in T2DM.

Persons With Diabetes and General/Family Practitioner Perspectives Related to Therapeutic Inertia in Type 2 Diabetes Mellitus Using Qualitative Focus Groups and the Theoretical Domains Framework: Results From the MOTION Study.

OBJECTIVES: Therapeutic inertia in type 2 diabetes (T2DM) is the failure to receive timely treatment intensification as indicated according to T2DM treatment guidelines. Multifactorial causes of therapeutic inertia in T2DM have been documented at the level of persons with diabetes (PwD), health-care providers and health-care systems. METHODS: We developed a 3-part mixed-methods research program, called the Moving to Overcome Therapeutic Inertia Obstacles Now in T2DM (MOTION) study, to inform the development of strategies to address therapeutic inertia in T2DM. We present the results from focus groups with the following objectives: 1) understanding PwD and general practitioner/family practitioner (GPFP) determinants of behaviour related to treatment intensification using the Theoretical Domains Framework (TDF); and 2) identifying the sources of behaviours contributing to therapeutic inertia in T2DM, as proposed by the Behaviour Change Wheel (BCW). Two focus groups with PwD and 4 with GPFPs were conducted. Transcripts from the focus groups were coded independently by 2 investigators to identify themes, then mapped to TDF domains and linked using the BCW. RESULTS: For PwD, the most commonly coded TDF domains were intentions, goals, knowledge, beliefs about consequences and social influences. For GPFPs, the most common domains were intentions, environmental context and resources and social/professional role and identity. The BCW identified that PwD interventions should include reflective motivation, psychological capability and social opportunity; GPFP interventions should include physical opportunity, social opportunity and reflective motivation. CONCLUSIONS: Comprehensive strategies that target both PwD and GPFP barriers would encourage a more collaborative approach toward treatment intensification decisions and reducing therapeutic inertia.

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss.

AIM: We evaluated gastrointestinal (GI) adverse events (AEs) with once-weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL). MATERIALS AND METHODS: AE analyses pooled data from the Semaglutide Treatment Effect in People With Obesity (STEP) 1-3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run-in. RESULTS: GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non-serious (99.5% of AEs), mild-to-moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation. Few semaglutide-treated participants (4.3%) permanently discontinued treatment for GI AEs. In STEP 1-3, mean WL with semaglutide 2.4 mg was similar in participants without (9.6%-17.1%) versus with GI AEs (11.4%-17.7%). Consistent with this observation, mediation analysis found that GI AEs contributed little to semaglutide-induced WL: of the additional 7.6%-14.4% WL with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. In STEP 4, semaglutide 2.4 mg maintenance was well tolerated. CONCLUSIONS: GI AEs were more common with semaglutide 2.4 mg than placebo, but typically mild-to-moderate and transient. Semaglutide-induced WL was largely independent of GI AEs.

Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well established in clinical practice for the treatment of type 2 diabetes, and are approved and recommended for weight management in overweight or obesity. Gastrointestinal side effects are well known as the most common adverse effects of these agents and represent a potential barrier for use, particularly at higher doses. Drawing on both published evidence and our collective clinical experience, we aim to guide practitioners through managing these side effects with a view to optimizing therapeutic outcomes with GLP-1RAs.

Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial.

BACKGROUND: Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose-response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m2 or at least 27 kg/m2 with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants. FINDINGS: Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3-4·5 mg (100-102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3-4·5 mg, 6·0%-10·8% [6·4-11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%-7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3-4·5 mg had gastrointestinal adverse events compared with placebo (41%-63% vs 32%), primarily nausea (20%-47% vs 18%). INTERPRETATION: Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. FUNDING: Novo Nordisk A/S.

The role of icosapent ethyl in cardiovascular risk reduction.

PURPOSE OF REVIEW: Elevated levels of triglycerides, independent of low-density lipoprotein cholesterol (LDL-C) levels and statin therapy, are associated with heightened cardiovascular risk. RECENT FINDINGS: Mixed omega-3 fatty acid formulations, which contain varying amounts of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), lower triglycerides levels but trial results with omega-3 fatty acids combinations have generally been neutral for cardiovascular outcomes. In contrast, the REDUCE-IT trial with icosapent ethyl (IPE), a highly purified ethyl ester of EPA, demonstrated reduced cardiovascular risk in individuals with established atherosclerotic cardiovascular disease or diabetes with at least one additional risk factor, despite having relatively well controlled LDL-C levels but triglycerides at least 135 mg/dl while on statin therapy. IPE offers an important new avenue for cardiovascular risk management in statin-treated individuals with elevated triglycerides. SUMMARY: This review summarizes the results from outcome trials conducted with omega-3 fatty acids, differentiating between those with combinations of EPA/DHA and those with pure EPA, as well as imaging and preclinical data that help explain the different cardiovascular efficacy observed. A list of frequently asked questions with evidence-based responses is provided to assist our colleagues and their patients in the shared-decision process when considering if IPE is appropriate for cardiovascular risk reduction.

Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.

BACKGROUND: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. METHODS: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7-10% (53-86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. FINDINGS: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was -9·6% (SE 0·4) with semaglutide 2·4 mg vs -3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was -6·2 percentage points (95% CI -7·3 to -5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. INTERPRETATION: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. FUNDING: Novo Nordisk.

Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial.

OBJECTIVE: Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population. RESEARCH DESIGN AND METHODS: Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs. RESULTS: Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; P < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA1c and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed. CONCLUSIONS: In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.

Perceptions of barriers to effective obesity management in Canada: Results from the ACTION study.

Obesity is a chronic disease with a significant and growing impact on Canadians. The "Awareness, Care and Treatment In Obesity MaNagement" (ACTION) Study investigated perceptions, attitudes and perceived barriers to obesity management among Canadian people with obesity (PwO), healthcare providers (HCPs) and employers. In this study adult PwO (body mass index ≥30 kg/m2 , based on self-reported height/weight), HCPs (physicians and allied HCPs managing PwO) and employers (≥20 employees; offering health insurance), completed online surveys between 3 August and 11 October 2017 in a cross-sectional design. Survey respondents (N = 2545) included 2000 PwO, 395 HCPs and 150 employers. Obesity was viewed as a "chronic medical condition" by most PwO (60%), HCPs (94%) and employers (71%) and deemed to have a large impact on overall health (74%, 78%, 81%, respectively). Many PwO (74%) believed weight management was their own responsibility. While PwO (55%) reportedly knew how to manage their weight, only 10% reported maintaining ≥10% weight reduction for >1 year. Despite low success rates, the most commonly reported effective long-term weight loss methods tried and/or recommended were "improvements in eating habits" (PwO 38%; HCP 63%) and "being more active" (PwO 39%; HCP 54%). PwO and HCPs reported very different perceptions of the quality and content of their interaction during obesity management discussions. These findings highlight the communication gaps and misunderstanding between PwO, HCPs and employers. This underscores the importance of, and need for, evidence-based management of obesity and a collaborative approach and understanding of the complex nature of this chronic disease.

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

AIMS: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon-like peptide-1 receptor agonist. MATERIALS AND METHODS: PIONEER 6 is a multinational, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once-daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non-fatal myocardial infarction or non-fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non-inferiority versus placebo for the primary endpoint (non-inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event-driven, with follow-up continuing until accrual of at least 122 primary outcome events. There is no pre-defined minimal duration. RESULTS: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. CONCLUSIONS: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.

BACKGROUND: Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss. METHODS: We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide [0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks] or liraglutide [3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week]) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711. FINDINGS: Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102-103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was -2·3% for the placebo group versus -6·0% (0·05 mg), -8·6% (0·1 mg), -11·6% (0·2 mg), -11·2% (0·3 mg), and -13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p≤0·0010), and remained significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all significant (-13·8% to -11·2% vs -7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37-65% receiving 0·1 mg or more of semaglutide (p<0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists. INTERPRETATION: In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses. FUNDING: Novo Nordisk A/S.

Family Intervention for Obese/Overweight Children Using Portion Control Strategy (FOCUS) for Weight Control: A Randomized Controlled Trial.

Nutritional counseling for children with obesity is an important component of management. This randomized controlled trial was conducted to compare change in body mass index (BMI) z score after 6 months. Children 8 to 16 years with a BMI greater than the 85th percentile were randomized to standard of care nutrition counseling versus intervention with standard nutrition counseling including portion control tool training for the family. Measures were completed at baseline, 3 months, and 6 months. Fifty-one children were randomized to control and 48 to intervention. Mean age was 11 years (SD = 2.2). Mean BMI z score was 2.7 (SD = 0.4). Forty-five percent were male (n = 45). Follow-up at 6 months was 73.7% (73/99). Although no differences were seen between the groups, there was a significant decrease in BMI z score between baseline and 6 months within each group.