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Introduction: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m ® (Mifepri st one) (CATALYST) trial., Methods and Analysis: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym ® ). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life., Ethics and Dissemination: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals., Trial Registration Number: NCT05772169., Competing Interests: Competing interests: RAF reports: advisory board with AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Renalytix, Corcept Therapeutics; research support from Boehringer Ingelheim, AstraZeneca; speaker's bureau with AstraZeneca. RJA reports: research support from Neurocrine Biosciences and Diurnal, Spruce Biosciences, Corcept Therapeutics, Sparrow Pharmaceuticals; consulting fees from Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Adrenas Therapeutics, PhaseBio Pharmaceuticals, Novo Nordisk, Recordati Rare Diseases, H Lundbeck A/S, OMass Therapeutics, Sparrow Pharmaceuticals. IB reports: consulting and/or advisory board with Corcept, HRA Pharma, Recordati, Sparrow, Neurocrine, Diurnal, Spruce; data safety monitoring board with Adrenas; funding for investigator initiated award from Recordati. LB reports: contracted fees paid to the Ochsner Clinic Foundation by Novo Nordisk for consulting work, and to Corcept Therapeutics for both speaking and consulting services. RSB reports: grant funding from Corcept pharmaceuticals; research funding from Novo, Lilly and Novartis; and speaker bureaus for Novo, Lilly, AstraZeneca, Amgen,and Bayer. JBB reports: contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support from Dexcom, Insulet, NovaTarg, Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion, Boehringer Ingelheim, CeQur, Cirius Therapeutics, Corcept Therapeutics, Eli Lilly, Fortress Biotech, GentiBio, Glycadia, Glyscend, Janssen, MannKind, Medtronic, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Terns, Valo and Zealand Pharma; stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. JWF reports: consultant and investigator for Corcept, Recordati. VAF reports: research support (to Tulane): grants from Fractyl, Jaguar Gene Therapy, Corcept; honoraria for consulting and lectures from Asahi, Bayer, Abbott, Boehringer Ingelheim, Corcept; stock options in Mellitus Health, BRAVO4Health; stock in Amgen, Abbott; patents pending for 1) BRAVO risk engine for predicting diabetes complications, 2) PAX4 gene therapy for type 1 diabetes. JPF reports: research support from Akero, Altimmune, Boehringer Ingelheim, 89bio, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Sanofi, Shionogi, Corcept Therapeutics; advisory boards and consulting with Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, Sanofi, Sun Pharma; speaker’s bureau with Eli Lilly; employment and stock ownership in Biomea Fusion. OH reports: scientific advisory board participation with Corcept Therapeutics, Strongbridge Pharma, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Lantheus, Xeris. YH reports: research grant from Amgen, Applied Therapeutic, Corcept, Ionis, Lilly, Merck, Regor; advisory/consultant role with Amgen, Applied Therapeutic, AZ, Bayer, BI, Corcept, Esperion, Mankind Pharma, Merck, Merck-Pfizer, Novartis, Novo Nordisk, Sanofi; speaker’s bureau with Bayer, Esperion, Novo Nordisk. REP reports: consulting fees from Bayer AG, Corcept Therapeutics Incorporated, Dexcom, Hanmi Pharmaceutical Co., Merck, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma, Sun Pharmaceutical Industries; grants/research support from Hanmi Pharmaceutical Co., Janssen, Metavention, Novo Nordisk, Poxel SA, Sanofi. All funds are paid directly to REP’s employer, AdventHealth, a non-profit organisation that supports education and research. JR reports: advisory panels with Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma and Zealand; research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, Sanofi. ICT, AGM and DE report: employed by and own stock in Corcept Therapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 ., (© 2024. The Author(s).)

Context: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and β-cell function to a greater extent than comparators., Objective: Explore changes in biomarkers of β-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide., Design: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks)., Setting: Post hoc analysis of 128 sites in 8 countries., Participants: A total of 1879 participants with type 2 diabetes., Interventions: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg., Main Outcomes Measures: Change in homeostatic model assessment indices for pancreatic β-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin., Results: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile., Conclusion: In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline β-cell function and insulin resistance, compared with semaglutide., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background & Aims: In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA., Methods: Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters., Results: Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss., Conclusions: The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin., Clinicaltrials: gov, Number: NCT05039450., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs., Materials and Methods: Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates., Results: Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo., Conclusions: GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages., (© 2023 John Wiley & Sons Ltd.)

Background: Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis., Methods: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing., Findings: Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred., Interpretation: Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials., Funding: Akero Therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need., Aim: To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy-confirmed NASH., Methods: This proof-of-concept, open-label, single-cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21-75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability., Results: Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2-point improvement in NAFLD activity score with ≥1-point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least-squares mean relative change from baseline in MRI-PDFF was -64.7% (95% CI: -71.7, -57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths., Conclusions: Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH., Clinicaltrials: gov: NCT04048135., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aim: To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron., Materials and Methods: This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID., Results: Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m 2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05)., Conclusions: Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses., Clinicaltrials: gov identifier: NCT04617275., (© 2023 John Wiley & Sons Ltd.)

Background: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established., Methods: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed., Results: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea., Conclusions: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA 1c ) 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/m 2 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 HbA 1c ; 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 HbA 1c 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 HbA 1c 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., Competing Interests: Declaration of interests JPF has received research funding (paid to institution) from 89bio, Akero, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Merck, Metacrine, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; is involved with advisory boards and consulting for 89bio, Akero, Altimmune, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Echosens, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and has received payment or honoraria for speaker bureaus for Eli Lilly. They are seated on the board of directors in T1D Exchange (non-compensated position). SD, LE, and SM are employed at Novo Nordisk and are stockholders of Novo Nordisk shares. FKK has received research grants (paid to institution) from AstraZeneca, Gubra, Novo Nordisk, Sanofi, and Zealand Pharma; and received personal honoraria for consulting, participating in advisory boards, and/or speaking for 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara. They are a co-founder and minority shareholder in Antag Therapeutics and co-owner of the medical weight-loss clinic Medicinsk Vægttabsbehandling ApS. IL has received research funding (paid to institution) from Boehringer Ingelheim, Merck, Mylan, Novo Nordisk, Pfizer, and Sanofi. They received advisory/consulting fees and/or other support from AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GI Dynamics, Intarcia, Intercept, Johnson and Johnson, Mannkind, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Shionogi, Structure Therapeutics, TARGETPharma, Valeritas, and Zealand Pharma. CM has received research funding (paid to institution) from the European Commission, FWO, Helmsley Charitable Trust, JDRF, and Novo Nordisk Foundation. They have received honoraria (paid to institution) for consulting, participating in advisory boards, and/or giving lectures/presentations from ActoBio Therapeutics, AstraZeneca, Avotres, Boehringer Ingelheim, Eli Lilly and Company, Imcyse, Insulet, Mannkind, Medtronic, Novartis, Novo Nordisk, Pfizer, Roche, Sandoz, Sanofi, Vertex, and Zealand Pharma; and are Chair of the Board of Hippo and Friends iVZW, Vice President of EUDF, President of EASD, and Chair of the Board of INNODIA iVZW. SDP acted as consultant, advisory board member, and/or speaker for Abbott, AstraZeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi. They are/have been an investigator in clinical trials funded by AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Prometic, and Sanofi. MD has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; an advisory board member for Lexicon, Medtronic, Pfizer, and ShouTi Pharma; and as a speaker for Amgen, AstraZeneca, Napp Pharmaceuticals, and Novartis. MD has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes., Methods: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m 2 or higher and glycated haemoglobin (HbA 1c ) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003., Findings: Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m 2 (SD 6·6), and HbA 1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator., Interpretation: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests WTG has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck, and as a site principal investigator for multicentred clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly and Company, Epitomee, Neurovalens, and Pfizer. JPF has received research funding (paid to his institution) from Akero, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly and Company, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; has received consulting fees from Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly and Company, Merck, Novo Nordisk, Pfizer, and Sanofi; has received speaker bureau honoraria from Eli Lilly and Company and travel support for attending meetings from Eli Lilly and Company, Novo Nordisk, Pfizer, and Sanofi; has served on advisory boards for Altimmune, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and has served on the board of directors for T1D Exchange. AMJ reports grants or contracts (through her institution) from Novo Nordisk, Eli Lilly and Company, Rhythm Pharmaceutical, and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; consults for Amgen and Scholar Rock; has received honoraria or travel support from Eli Lilly and Company, Novo Nordisk, and WeightWatchers, and stock options from Intellihealth; and serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly and Company, Intellihealth, Novo Nordisk, Rhythm Pharmaceuticals, Structure Therapeutics, Terns Pharmaceutics, and WeightWatchers. CWlR reports grants from the Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board. He serves on advisory boards and speakers’ panels of Novo Nordisk, Herbalife, GI Dynamics, Eli Lilly and Company, Johnson & Johnson, Glia, Irish Life Health, and Boehringer Ingelheim; is a member of the Irish Society for Nutrition and Metabolism outside the area of work commented on here; was the chief medical officer and director of the Medical Device Division of Keyron in 2021 (both unremunerated positions); is a previous investor in Keyron; was gifted stock holdings and divested all stock holdings in Keyron in September, 2021; continues to provide scientific advice to Keyron for no remuneration; and provides obesity clinical care in the Beyond BMI clinic and is a shareholder. NS has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; a grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, outside of the submitted work. SZ, HM, NNA, MCB, IB, and XMZ are employees and shareholders of Eli Lilly and Company., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes., Methods: In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA 1c ) of 7·0-10·5%, and stable BMI of 23 kg/m 2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA 1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed., Findings: Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA 1c was 8·1%, BMI was 35·2 kg/m 2 , 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA 1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA 1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment., Interpretation: In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA 1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests JPF reports research funding from Akero, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly, Intercept, Ionis, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; consulting fees from Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Merck, Novo Nordisk, Pfizer, and Sanofi; speaker bureau from Eli Lilly; support for attending meetings or travel from Eli Lilly, Novo Nordisk, Pfizer, and Sanofi; participant advisory boards and consulting for Altimmune, Becton Dickinson, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and is on the board of directors for T1D Exchange. SH reports research funding from Eli Lilly. SE reports funding from Eli Lilly for statistical services provided by employer Tigermed and travel support from Eli Lilly. RL, XM, MK, CK, KJM, AH, and EP are employees and shareholders of Eli Lilly. DR is a shareholder and retired employee of Eli Lilly., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the efficacy and safety of once-weekly (QW) efpeglenatide in people with type 2 diabetes (T2D) suboptimally controlled with oral glucose-lowering drugs and/or basal insulin (BI)., Materials and Methods: Three phase 3, multicentre, randomized controlled trials compared the efficacy and safety of QW efpeglenatide versus dulaglutide when added to metformin (AMPLITUDE-D), efpeglenatide versus placebo when added to BI ± oral glucose-lowering drugs (AMPLITUDE-L) or metformin ± sulphonylurea (AMPLITUDE-S). All trials were terminated early by the sponsor because of funding rather than safety or efficacy concerns., Results: In AMPLITUDE-D, non-inferiority of efpeglenatide to dulaglutide 1.5 mg was shown in HbA1c reduction from baseline to week 56, least squares mean treatment difference (95% CI): 4 mg, -0.03% (-0.20%, 0.14%)/-0.35 mmol/mol (-2.20, 1.49); 6 mg, -0.08% (-0.25%, 0.09%)/-0.90 mmol/mol (-2.76, 0.96). The reductions in body weight (approximately 3 kg) from baseline to week 56 were similar across all treatment groups. In AMPLITUDE-L and AMPLITUDE-S, numerically greater reduction in HbA1c and body weight were observed at all doses of efpeglenatide than placebo. American Diabetes Association level 2 hypoglycaemia (< 54 mg/dL [< 3.0 mmol/L]) was reported in few participants across all treatment groups (AMPLITUDE-D, ≤ 1%; AMPLITUDE-L, ≤ 10%; and AMPLITUDE-S, ≤ 4%). The adverse events profile was consistent with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs); gastrointestinal adverse events were most frequent in all three studies., Conclusions: In people with T2D suboptimally controlled with oral glucose-lowering drugs and/or BI, QW efpeglenatide was non-inferior to dulaglutide in terms of HbA1c reduction and showed numerically greater improvements than placebo in glycaemic control and body weight, with safety consistent with the GLP-1 RA class., (© 2023 John Wiley & Sons Ltd.)

Importance: Currently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration., Objective: To investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks., Design, Setting, and Participants: A phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions., Interventions: Participants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily., Main Outcomes and Measures: Change from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period., Results: Of 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of -2.04 kg (90% CI, -3.01 to -1.07 kg) for the 80-mg twice daily group and -4.17 kg (90% CI, -5.15 to -3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting., Conclusions and Relevance: In adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action., Trial Registration: ClinicalTrials.gov Identifier: NCT03985293.

Objective: Basal insulin Fc (BIF) (insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed the safety and efficacy of BIF versus degludec in insulin-naive patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications., Research Design and Methods: During this randomized, parallel, open-label study, 278 insulin-naive patients with T2D were randomly assigned (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80-100 mg/dL (4.4 to <5.6 mmol/L). The primary end point was HbA1c change from baseline to week 26 (noninferiority margin 0.4%). Secondary end points included fasting blood glucose (FBG), six-point glucose profiles, and rate of hypoglycemia., Results: After 26 weeks of treatment, BIF demonstrated a noninferior HbA1c change from baseline versus degludec, with a treatment difference of 0.06% (90% CI -0.11, 0.24; P = 0.56). Both BIF and degludec treatment led to significant reductions in FBG from baseline. At week 26, the between-treatment difference for BIF versus degludec was 4.7 mg/dL (90% CI 0.1, 9.3; P = 0.09). The rate of level 2 hypoglycemia was low and not significantly different between treatment groups (BIF 0.22 events/patient/year, degludec 0.15 events/patient/year; P = 0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec., Conclusions: Once-weekly BIF achieved excellent glycemic control similar to degludec, with no concerning hypoglycemia or other safety findings., (© 2023 by the American Diabetes Association.)

Aims: To investigate a prebiotic fibre-enriched nutritional formula on health-related quality of life and metabolic control in type 2 diabetes., Materials and Methods: This was a 12-week, double-blind, placebo-controlled study with an unblinded dietary advice only comparator arm. Participants were randomized 2:1:1 to a prebiotic fibre-enriched nutritional formula (Active), a placebo fibre-absent nutritional formula (Placebo), or non-blinded dietary advice alone (Diet). Primary endpoint was change in core Type 2 Diabetes Distress Assessment System (cT2-DDAS) at week 12. Glycated haemoglobin (HbA1c) change was a key secondary endpoint., Results: In total, 192 participants were randomized. Mean age was 54.3 years, HbA1c 7.8%, and body mass index 35.9 kg/m 2 . At week 12, cT2-DDAS reduced significantly in Active versus Placebo (-0.4, p = .03), and HbA1c was reduced significantly in Active vs Placebo (-0.64%, p = .01). Gut microbiome sequencing revealed that the relative abundance of two species of butyrate-producing bacteria (Roseburia faecis and Anaerostipes hadrus) increased significantly in Active vs. Placebo., Conclusions: A microbiome-targeting nutritional formula significantly improved cT2-DDAS and HbA1c, suggesting the potential for prebiotic fibre as a complement to lifestyle and/or pharmaceutical interventions for managing type 2 diabetes., (© 2023 Supergut. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

In type 2 diabetes, therapeutic failure to the oral anti diabetics is frequent, the use of schemes with basal insulin or with multiple doses of insulin (basal insulin and short-acting insulins) are a widely accepted way to intensify therapy. The use of GLP-1 receptor agonists is another intensification strategy. The fixedratio combinations with molecules such as insulin degludec + liraglutide, and insulin glargine + lixisenatide have proven useful in intensifying treatment of individuals with type 2 diabetes. The purpose of this review was to evaluate and analyze the results of pivotal studies with both fixed-ratio combinations in individuals with type 2 diabetes, finding that, they are capable of achieving better glycemic control when compared with each of its components separately (with a lower risk of hypoglycemia vs basal insulin and lower risk of gastrointestinal adverse effects vs GLP-1 receptor agonists) in various clinical scenarios, especially in individuals who do not achieve control with oral antidiabetics or who do not achieve control with basal insulin (associated with oral antidiabetics) or in those under management with GLP-1RA plus oral antidiabetics.

Objective: This study evaluated the effect of once-weekly semaglutide 2.4 mg on 2-year control of eating., Methods: In STEP 5, adults with overweight/obesity were randomized 1:1 to semaglutide 2.4 mg or placebo, plus lifestyle modification, for 104 weeks. A 19-item Control of Eating Questionnaire was administered at weeks 0, 20, 52, and 104 in a subgroup of participants. P values were not controlled for multiplicity., Results: In participants completing the Control of Eating Questionnaire (semaglutide, n = 88; placebo, n = 86), mean body weight changes were -14.8% (semaglutide) and -2.4% (placebo). Scores significantly improved with semaglutide versus placebo for Craving Control and Craving for Savory domains at weeks 20, 52, and 104 (p < 0.01); for Positive Mood and Craving for Sweet domains at weeks 20 and 52 (p < 0.05); and for hunger and fullness at week 20 (p < 0.001). Improvements in craving domain scores were positively correlated with reductions in body weight from baseline to week 104 with semaglutide. At 104 weeks, scores for desire to eat salty and spicy food, cravings for dairy and starchy foods, difficulty in resisting cravings, and control of eating were significantly reduced with semaglutide versus placebo (all p < 0.05)., Conclusions: In adults with overweight/obesity, semaglutide 2.4 mg improved short- and longer-term control of eating associated with substantial weight loss., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: Management strategies for non-alcoholic steatohepatitis (NASH) are based predominantly on lifestyle modification, with no approved disease-modifying drugs yet available. We aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of pegozafermin (BIO89-100), a glycoPEGylated FGF21 analogue, in participants with NASH., Methods: This randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study enrolled adults (aged 21-75 years) who had NASH with stage F1-F3 fibrosis, or non-alcoholic fatty liver disease and a high risk of NASH (referred to in this study as phenotypic NASH) due to central obesity with type 2 diabetes, or central obesity with increased alanine aminotransferase (ALT) or a Fibroscan score of 7 kPa or greater, across 12 specialist centres and clinics in the USA. Patients were centrally randomised by use of an interactive web response system to receive subcutaneously administered pegozafermin (3, 9, 18, or 27 mg once weekly; 18 or 36 mg once every 2 weeks) or placebo for 12 weeks. The primary endpoints were the safety, tolerability, and pharmacokinetics of pegozafermin. This trial is registered with ClinicalTrials.gov (NCT04048135)., Findings: Between July 29, 2019, and Aug 3, 2020, 275 participants were screened and 81 (15 [19%] with biopsy-confirmed NASH) were randomly assigned: 62 to pegozafermin (six to 3 mg once weekly, 12 to 9 mg once weekly, 11 to 18 mg once weekly, ten to 27 mg once weekly, 14 to 18 mg once every 2 weeks, and nine to 36 mg once every 2 weeks) and 19 to placebo; 63 received pegozafermin and 18 received placebo, as one participant in the placebo group inadvertently received 3 mg pegozafermin once weekly. Adverse events were reported in eight (44%) of 18 participants in the pooled placebo group, six (86%) of seven in the 3 mg once weekly pegozafermin group, four (33%) of 12 in the 9 mg once weekly group, seven (64%) of 11 in the 18 mg once weekly group, seven (70%) of ten in the 27 mg once weekly group, eight (57%) of 14 in the 18 mg once every 2 weeks group, and eight (89%) of nine in the 36 mg once every 2 weeks group. The most common treatment-related adverse event was mild increased appetite (in ten [16%] of 63 participants in the pooled pegozafermin group vs none of 18 in the pooled placebo group), which was not associated with bodyweight gain. Two patients discontinued treatment due to an adverse event (one each in the 27 mg once weekly and 18 mg once every 2 weeks groups). No treatment-related serious adverse events or deaths occurred. Dose-proportional pharmacokinetics were observed. Anti-drug antibodies were detected in 41 (65%) of 63 participants treated with pegozafermin. By week 13, pegozafermin significantly reduced the least squares mean (LSM) absolute differences in hepatic fat fraction versus pooled placebo (-8·9% [95% CI -14·8 to -3·1; p=0·0032] for 3 mg once weekly, -11·5% [-16·1 to -6·9; p<0·0001] for 9 mg once weekly, -8·9% [-13·7 to -4·2; p=0·0004] for 18 mg once weekly, -14·9% [-20·1 to -9·7; p<0·0001] for 27 mg once weekly, -10·4% [-14·7 to -6·1; p<0·0001] for 18 mg once every 2 weeks, and -11·1% [-16·2 to -6·0; p<0·0001] for 36 mg once every 2 weeks). At week 13, significant LSM relative reductions versus pooled placebo in ALT were observed for pegozafermin 9 mg once weekly, 18 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. At week 13, significant LSM relative reductions versus pooled placebo in aspartate aminotransferase were observed for pegozafermin 3 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. Significant improvements were also observed with pegozafermin treatment for triglycerides (9 mg once weekly, 27 mg once weekly, and 18 mg once every 2 weeks), LDL-C (9 mg once weekly and 27 mg once weekly), HDL-C (3 mg once weekly and 18 mg once every 2 weeks), non-HDL-C (9 mg once weekly and 27 mg once weekly), adiponectin (all doses except for 36 mg once every 2 weeks), PRO-C3 (27 mg once weekly), and bodyweight (27 mg once weekly). Changes in insulin resistance and HbA 1c were not significant., Interpretation: Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted., Funding: 89bio., Competing Interests: Declaration of interests RL reports consultant fees from Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics; institutional research grant support from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals; and is a co-founder of LipoNexus Inc. EJL reports grants or contracts from 89bio, Akero Therapeutics, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Axcella Health, Boehringer Ingelheim, Bristol Myers Squibb, CytoDyn, Durect Corporation, Eli Lilly and Company, Enanta Pharmaceuticals, Galectin Therapeutics, Galmed Pharmaceuticals, Genentech, Gilead Sciences, Hanmi Pharmaceuticals, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Laboratory for Advanced Medicine, Madrigal Pharmaceuticals, Merck & Co., Metacrine, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Poxel, Roche, Sagimet Biosciences, Terns Pharmaceuticals, Valeant Pharmaceuticals, Viking Therapeutics, and Zydus Pharmaceuticals; and consultant fees from Boehringer Ingelheim, Bristol Myers Squibb, Metacrine, Sagimet Biosciences, and Terns Pharmaceuticals. JPF reports grants or contracts for their institution from 89bio, Akero, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Carmot Therapeutics, Eli Lilly, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; consulting fees from Akero, Altimmune, Axcella Health, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Metacrine, Merck, Novo Nordisk, and Pfizer; payment or honoraria (for lectures, presentations, speakers bureaus, manuscript writing, or educational events) from Eli Lilly, Merck, Sanofi, Echosens, and Novo Nordisk; support for attending meetings or travel, or both, from Eli Lilly and Novo Nordisk; and participation in data safety monitoring boards or advisory boards for, 89bio, Carmot Therapeutics, Eli Lilly, Sanofi, Merck, Pfizer, Gilead, Intercept, and Beckton Dickenson. LJ is an employee of, and has stock or stock options in, Antaros Medical, which received grants or contracts from the study sponsor for services performed in the study. BBF was an employee of ProSciento at the time of the study, which received grants or contracts from the study sponsor for services performed in the study; received support or travel (as a principal investigator), or both, for attending the investigator meeting at the start of the study; and participated in data safety monitoring for the study. LM reports consulting fees from, and has stock or stock options in, ProSciento, which received grants or contracts from the study sponsor for services performed in the study. MR (deceased) was an employee of 89bio at the time of the study. C-YC was an employee of 89bio at the time of the study. RWC is an employee of 89bio; has stock or stock options in 89bio, Gilead, and Ascendis Pharma; and is a volunteer (unpaid) faculty committee member for the Pediatric Endocrine Society Fellow's Retreat. LT is an employee of, and has stock or stock options in, 89bio; and holds a patent for the dosing regimen of the study drug. CH, HM, and MM are employees of, and have stock or stock options in, 89bio. GOL reports no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Obesity is a serious, chronic disease that is associated with a range of adiposity-based comorbidities, including cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver disease. In the United States, obesity is a public health crisis, affecting more than 40% of the population. Obesity disproportionately affects Latinx people, who have a higher prevalence of obesity and related comorbidities (such as cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver disease) compared with the general population. Many factors, including genetic predisposition, environmental factors, traditional calorie-dense Latinx diets, family dynamics, and differences in socioeconomic status, contribute to the increased prevalence and complexity of treating obesity in the Latinx population. Additionally, significant heterogeneity within the Latinx population and disparities in health care access and utilization between Latinx people and the general population add to the challenge of obesity management. Culturally tailored interventions have been successful for managing obesity and related comorbidities in Latinx people. Antiobesity medications and bariatric surgery are also important options for obesity treatment in Latinx people. As highlighted in this review, when managing obesity in the Latinx population, it is critical to consider the impact of genetic, dietary, cultural, and socioeconomic factors, in order to implement an individualized treatment strategy., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Aim: For people with suboptimally controlled type 2 diabetes (T2D) on basal insulin (BI), guidelines recommend several treatment advancement options. This study compared the clinical effectiveness of once-daily iGlarLixi versus a multiple-injection BI + rapid acting insulin (RAI) regimen in adults with T2D advancing from BI therapy in real-world clinical practice., Materials and Methods: Electronic medical records from the Observational Medical Outcomes Partnership (OMOP) database were analysed retrospectively using propensity score matching to compare therapy advancement with iGlarLixi or BI + RAI in US adults ≥18 years with T2D on BI who had ≥1 valid glycated haemoglobin (HbA1c) value at baseline and at the 6-month follow-up. The primary objective was non-inferiority of iGlarLixi to BI + RAI in HbA1c change from baseline to 6 months (margin 0.3%)., Results: Propensity score matching generated cohorts with balanced baseline characteristics (N = 814 in each group). HbA1c reduction from baseline to 6 months with iGlarLixi was non-inferior to BI + RAI [mean difference (95% confidence interval): 0.1 (-0.1, 0.2)%; one-sided p = .0032]. At 6 months, weight gain was significantly lower with iGlarLixi than with BI + RAI [-0.8 (-1.3, -0.2) kg; two-sided p = .0069]. Achievement of HbA1c <7% without hypoglycaemia and weight gain were similar between groups [odds ratio (95% confidence interval): 1.15 (0.81, 1.63); p = .4280]. Hypoglycaemia was low in both groups, probably because of underreporting., Conclusions: In real-world clinical practice, glycaemic outcomes 6 months after treatment advancement from BI are similar for people with T2D using iGlarLixi versus BI + RAI, with iGlarLixi leading to less weight gain., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To compare the effects of bexagliflozin tablets 20 mg, with those of optimally titrated glimepiride when used to treat adults with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin., Methods: Adults with type 2 diabetes (n = 426) taking metformin, and with a glycated haemoglobin (HbA1c) level between 53 and 91 mmol/mol [7.0% and 10.5%], were randomized to receive bexagliflozin tablets 20 mg or titrated glimepiride. The primary endpoint was the intergroup difference in the change from baseline to Week 60 in percent HbA1c. Secondary endpoints included changes from baseline in body mass and systolic blood pressure (SBP), and proportion of subjects experiencing severe or documented symptomatic hypoglycaemia., Results: The intergroup difference in percent HbA1c (bexagliflozin minus glimepiride) from baseline to Week 60 was -0.55 mmol/mol (95% confidence interval [CI] -2.30, 1.20)-[-0.05% (-0.21, 0.11)], establishing noninferiority of bexagliflozin to glimepiride by the prespecified margin of 3.83 mmol/mol [0.35%]. Prespecified tests gave, in order, a difference in body mass of -4.31 kg (95% CI -5.10, -3.52; P < 0.0001), a difference in SBP of -6.53 mm Hg (95% CI -10.56, -2.51; P = 0.0008), and an odds ratio of 0.12 (95% CI 0.05, 0.28; P < 0.0001) for severe or documented symptomatic hypoglycaemia. At the follow-up visit the mean difference in estimated glomerular filtration rate (eGFR) between arms was 6.05 mL min -1 per 1.73 m 2 (95% CI, 3.24, 8.87; P < 0.0001)., Conclusions: Bexagliflozin was noninferior to glimepiride in lowering HbA1c, was superior to glimepiride for decreases in body mass and SBP, and was associated with significantly fewer hypoglycaemic events than glimepiride. A favourable effect on eGFR was observed., (© 2022 John Wiley & Sons Ltd.)

The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m -2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was -15.2% in the semaglutide group (n = 152) versus -2.6% with placebo (n = 152), for an estimated treatment difference of -12.6 %-points (95% confidence interval, -15.3 to -9.8; P < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430., (© 2022. The Author(s).)

Objective: This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes., Research Design and Methods: STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc)., Results: Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01)., Conclusions: STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia., (© 2022 by the American Diabetes Association.)

Objective: CeQur Simplicity™ (CeQur, Marlborough, MA) is a 3-day insulin delivery patch designed to meet mealtime insulin requirements. A recently reported 48-week, randomized, multicenter, interventional trial compared efficacy, safety and self-reported outcomes in 278 adults with type 2 diabetes (T2D) on basal insulin therapy who initiated and managed mealtime insulin therapy with a patch pump versus insulin pen. We assessed changes in key glycemic metrics among a subset of patients who wore a continuous glucose monitoring (CGM) device., Methods: Study participants (patch, n = 49; pen, n = 48) wore a CGM device in masked setting during the baseline period and prior to week 24. Glycemic control was assessed using international consensus guidelines for percentage of Time In Range (%TIR: >70% at 70-180 mg/dL), Time Below Range (%TBR: <4% at <70 mg/dL; <1% at <54 mg/dL), and Time Above Range (%TAR: <25% at >180 mg/dL; <5% at >250 mg/dL)., Results: Both the patch and pen groups achieved recommended targets in %TIR (74.1% ± 18.7%, 75.2 ± 16.1%, respectively) and marked reductions in %TAR >180 mg/dL (21.1% ± 19.9%, 19.7% ± 17.5%, respectively) but with increased %TBR <70 mg/dL (4.7% ± 5.2%, 5.1 ± 5.8, respectively), all P < .0001. No significant between-group differences in glycemic improvements or adverse events were observed., Conclusions: CGM confirmed that the patch or pen can be used to safely initiate and optimize basal-bolus therapy using a simple insulin adjustment algorithm with SMBG. Preference data suggest that use of the patch vs pen may enhance treatment adherence.

Objective: To assess the efficacy and safety of the glucagon-like peptide 1 receptor agonist (GLP-1 RA) efpeglenatide versus placebo in patients with type 2 diabetes inadequately controlled with diet and exercise alone., Research Design and Methods: AMPLITUDE-M was a phase 3, double-blind, placebo-controlled, multicenter trial that randomized adults with type 2 diabetes suboptimally controlled with diet and exercise alone to once-weekly efpeglenatide (2, 4, or 6 mg) or placebo for up to 56 weeks. The primary objective was to demonstrate the superiority of efpeglenatide versus placebo for HbA1c reduction at week 30. Secondary objectives included changes in other measures of glycemic control and body weight at weeks 30 and 56., Results: At week 30, HbA1c was reduced from a baseline of 8.1% (65 mmol/mol) to 6.9% (52 mmol/mol), 6.6% (49 mmol/mol), and 6.4% (47 mmol/mol) with efpeglenatide 2, 4, and 6 mg, respectively. Least squares mean HbA1c reductions from baseline were statistically superior for each efpeglenatide dose versus placebo (2 mg, -0.5% [95% CI -0.9, -0.2; P = 0.0054]; 4 mg, -0.8% [-1.2, -0.5; P < 0.0001]; 6 mg, -1.0% [-1.4, -0.7; P < 0.0001]). A greater proportion of efpeglenatide-treated patients (all doses) achieved HbA1c <7% (53 mmol/mol) versus placebo by week 30 (P < 0.0001 for all), and significant reductions in body weight and fasting plasma glucose were also observed for efpeglenatide (4 and 6 mg doses) versus placebo at week 30 (P < 0.05 for all). Consistent with the GLP-1 RA class, gastrointestinal adverse events were most commonly reported; these were generally transient and mild/moderate in severity. Few patients reported hypoglycemia., Conclusions: As monotherapy in patients with type 2 diabetes, once-weekly efpeglenatide significantly improved glycemic control and body weight with a safety and tolerability profile similar to that of other GLP-1 RAs., (© 2022 by the American Diabetes Association.)

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide 3.0 and 4.5 mg compared to dulaglutide 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. This post hoc analysis examined the change from baseline in glycated haemoglobin (HbA1c) and proportions of patients achieving HbA1c <7% at weeks 36 and 52 with dulaglutide 1.5 mg, 3.0 mg or 4.5 mg across clinically relevant baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%). Mean reductions in HbA1c were observed across all baseline HbA1c subgroups at 36 weeks (range of HbA1c change: 1.5 mg: -1.0% to -2.2%; 3.0 mg: -1.2% to -2.5%; and 4.5 mg: -1.2% to -3.2%). More patients randomized to 3.0 mg or 4.5 mg (vs. 1.5 mg) achieved HbA1c <7% at 36 weeks regardless of baseline HbA1c; the difference in proportions was greater at higher baseline HbA1c (P-interaction = 0.096). Similar patterns in glycaemic improvement and proportions achieving HbA1c <7% were observed at 52 weeks. Hypoglycaemia and gastrointestinal adverse events were similar among the HbA1c subgroups. Glycaemic control was improved with dulaglutide dose escalation from 1.5 mg to 3.0 mg or 4.5 mg across baseline HbA1c subgroups (<8%; 8.0% to < 9.0%; 9.0% to < 10%; and ≥ 10%)., (© 2021 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To evaluate the efficacy and safety of dulaglutide 3.0 and 4.5 mg versus 1.5 mg when used as an add-on to metformin in subgroups defined by age (<65 and ≥65 years)., Materials and Methods: Of 1842 patients included in this post hoc analysis, 438 were aged 65 years or older and 1404 were younger than 65 years. The intent-to-treat (ITT) population, while on treatment without rescue medication, was used for all efficacy analyses; the ITT population without rescue medication was used for hypoglycaemia analyses; all other safety analyses used the ITT population., Results: Patients aged 65 years or older and those younger than 65 years had a mean age of 69.5 and 53.2 years, respectively. In each age subgroup, the reduction from baseline in HbA1c and body weight (BW), and the proportion of patients achieving a composite endpoint of HbA1c of less than 7% (<53 mmol/mol) with no weight gain and no documented symptomatic or severe hypoglycaemia, were larger for dulaglutide 3.0 and 4.5 mg compared with dulaglutide 1.5 mg, but the treatment-by-age interactions were not significant. The safety profile for the additional dulaglutide doses was consistent with that of dulaglutide 1.5 mg and was similar between the age subgroups., Conclusion: Dulaglutide doses of 3.0 or 4.5 mg provided clinically relevant, dose-related improvements in HbA1c and BW with no significant treatment-by-age interactions, and with a similar safety profile across age subgroups., (© 2021 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Gastrointestinal (GI) events are the most frequent treatment-emergent adverse events (TEAEs) reported for glucagon-like peptide-1 receptor agonist therapies. This post hoc analysis of the AWARD-11 phase 3 trial assessed the GI tolerability of dulaglutide at once-weekly doses of 1.5, 3.0, and 4.5 mg., Methods: The AWARD-11 trial randomized patients to once-weekly dulaglutide 1.5 mg (n = 612), 3.0 mg (n = 616), or 4.5 mg (n = 614) for 52 weeks. Patients started on dulaglutide 0.75 mg for 4 weeks before escalating stepwise every 4 weeks until the final randomized dose was reached. This study analyzes the onsets, incidences, prevalences, and severities of nausea, vomiting, and diarrhea events reported through 52 weeks., Results: The highest incidences of nausea (≤ 8%), vomiting (≤ 2%), and diarrhea (≤ 4%) were primarily observed soon after the initiation of dulaglutide treatment at 0.75 mg. Incidence then declined throughout the remainder of the study, even with dose escalation to 1.5, 3.0, and 4.5 mg. Most of these GI TEAEs were mild to moderate in severity, with severe nausea, vomiting, or diarrhea events occurring in ≤ 0.6% of patients. Treatment discontinuation due to nausea was low across treatment groups (≤ 1.5%)., Conclusions: The tolerability profiles of dulaglutide 3.0 mg and 4.5 mg were consistent with that of the 1.5-mg dose. Patients experiencing GI events were most likely to do so within 2 weeks of treatment initiation, and few patients experienced a new GI event after escalating to the 3.0-mg or 4.5-mg dose. Severe events were infrequent, and when they did occur, no relationship with dose at time of event was observed. Supplementary file1 (MP4 33880 kb)., (© 2021. The Author(s).)

Aim: To evaluate the impact of dulaglutide 3.0 and 4.5 mg versus 1.5 mg on body weight in patients with type 2 diabetes (T2D) based on exploratory analyses of the AWARD-11 trial., Materials and Methods: Patients were randomized to once-weekly dulaglutide 1.5 (n = 612), 3.0 (n = 616) or 4.5 mg (n = 614) for 52 weeks. The primary objective was superiority of dulaglutide 3.0 and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary and exploratory assessments included weight reduction in the overall trial population and baseline body mass index (BMI) and HbA1c subgroups., Results: At baseline, patients had a mean age of 57.1 years, HbA1c 8.6% (70 mmol/mol), weight 95.7 kg and BMI 34.2 kg/m 2 . At 36 weeks, dulaglutide 3.0 and 4.5 mg were superior to 1.5 mg for weight change from baseline (1.5 mg, -3.1 kg; 3.0 mg, -4.0 kg [P = .001]; 4.5 mg, -4.7 kg [P < .001]). Higher dulaglutide doses were associated with numerically greater weight reduction compared with 1.5 mg in each baseline BMI and HbA1c subgroup. Absolute weight reduction increased with increasing BMI category, but percentage weight loss was similar between subgroups. Weight reductions with dulaglutide were greater in patients with lower versus higher baseline HbA1c., Conclusions: In patients with T2D, inadequately controlled by metformin, incremental weight loss was observed with dulaglutide 1.5, 3.0 and 4.5 mg doses regardless of baseline BMI or HbA1c. Although absolute weight loss was numerically greater in patients with higher baseline BMI, percentage of weight loss was similar between BMI subgroups., (© 2021 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors., Methods: In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA 1c ) of 7·0-10·5%, body-mass index of at least 25 kg/m 2 , stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA 1c , and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA 1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA 1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA 1c and bodyweight, and the proportion of participants achieving HbA 1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA 1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete., Findings: Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA 1c of 8·17% (SD 0·91), the reductions in HbA 1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA 1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment., Interpretation: In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA 1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests AR, RB, KB, and LFL are employees and shareholders of Eli Lilly and Company. BL reports grants from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Madrigal, and Novo Nordisk; consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, MSD, Novo Nordisk, and Sanofi; and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, MSD, Novo Nordisk, and Sanofi. FG reports grant and research support from Eli Lilly and Company, Lifescan, and Roche Diabetes Care; and scientific advisory board participation and consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, MSD, Novo Nordisk, Roche Diabetes Care, and Sanofi. EJ reports grants from Amgen, AstraZeneca, Boehringer, Eli Lilly and Company, Faes Farma, Janssen, MSD, Novo Nordisk, Pfizer, Sanofi, Shire, and UCB; lecture fees from Amgen, Asofarma, Astellas, AstraZeneca, Bayer, BMS, Boehringer, Eli Lilly and Company, Faes Farma, MSD, Mundipharma, Novo Nordisk, Technofarma, UCB, and Viatris; and advisory board participation and consultancy fees from Amgen, AstraZeneca, Eli Lilly and Company, Faes Farma, Helios-Fresenius, Italfármaco, MSD, Mundipharma, Novo Nordisk, UCB, and Viatris. JPF reports grants from AbbVie, Akero, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly and Company, Intercept, Janssen, Madrigal, Merck, Metacrine, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxil, Sanofi, and Theracos; advisory board participation and consultancy fees from Akero, Altimmune, Axcella Health, Boehringer Ingelheim, Coherus Therapeutics, Echosens, 89bio, Eli Lilly and Company, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and speaker bureau participation from Eli Lilly and Company, Merck, and Sanofi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches., Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity., Design, Setting, and Participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30)., Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks., Main Outcomes and Measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight., Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants., Conclusions and Relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT03611582.

Objective: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin., Research Design and Methods: Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA 1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients., Results: Mean baseline HbA 1c and BMI in randomly assigned patients ( N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m 2 , respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA 1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA 1c , using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%)., Conclusions: In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA 1c and body weight with a similar safety profile., (© 2021 by the American Diabetes Association.)

Sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1/SGLT2 inhibitor, is currently approved in Europe as an adjunct to optimal insulin therapy in adults with type 1 diabetes (T1D) and a body mass index (BMI) ≥ 27 kg/m 2 . In this post hoc analysis, efficacy at 24 weeks and safety at 52 weeks from pooled phase 3 clinical trials were evaluated in patients with baseline BMI ≥ 27 kg/m 2 . Sotagliflozin 200 mg and 400 mg added to insulin reduced glycated haemoglobin level and increased time in range assessed by continuous glucose monitoring versus placebo and also reduced body weight and systolic blood pressure. Differences in efficacy endpoints between sotagliflozin and placebo tended to be greater among patients with BMI ≥ 27 kg/m 2 compared to those with baseline BMI < 27 kg/m 2 . Consistent with published results for the entire population, fewer severe hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a higher incidence of diabetic ketoacidosis occurred with sotagliflozin versus placebo in patients with BMI ≥ 27 kg/m 2 . Sotagliflozin as an adjunct to optimized insulin therapy in overweight/obese patients with T1D addressed some unmet needs and may help achieve optimal glycaemic control, mitigating weight gain without increasing hypoglycaemia risk in this high-risk population., (© 2020 John Wiley & Sons Ltd.)

Background & Aims: Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH)., Methods: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution., Results: At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%-1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group., Conclusions: In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in patients with type 2 diabetes on a basal-bolus insulin regimen., Research Design and Methods: This was a phase 3, treat-to-target, double-blind 26-week study. After an 8-week lead-in to optimize basal insulin glargine or degludec in combination with prandial lispro treatment, patients were randomized to blinded URLi ( n = 336) or lispro ( n = 337) injected 0-2 min prior to meals. Patients could continue metformin and/or a sodium-glucose cotransporter 2 inhibitor. The primary end point was change in HbA 1c from baseline to 26 weeks (noninferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions during a standardized meal test., Results: HbA 1c improved for both URLi and lispro, and noninferiority was confirmed: estimated treatment difference (ETD) 0.06% (95% CI -0.05; 0.16). Mean change in HbA 1c was -0.38% for URLi and -0.43% for lispro, with an end-of-treatment HbA 1c of 6.92% and 6.86%, respectively. URLi was superior to lispro in controlling 1- and 2-h PPG excursions: 1-h ETD, -0.66 mmol/L (95% CI -1.01, -0.30); 2-h ETD, -0.96 mmol/L (-1.41, -0.52). Significantly lower PPG excursions were evident from 0.5 to 4.0 h postmeal with URLi treatment. There were no significant treatment differences in rates of severe or documented hypoglycemia (<3.0 mmol/L). Incidence of overall treatment-emergent adverse events was similar between treatments., Conclusions: URLi compared with lispro in a basal-bolus regimen was confirmed to be noninferior for HbA 1c and superior to lispro for PPG control in patients with type 2 diabetes., (© 2020 by the American Diabetes Association.)

Aim: To evaluate the efficacy of iGlarLixi by C-peptide levels and duration of diabetes in an exploratory analysis of the LixiLan-G study., Methods: LixiLan-G was a 26-week, randomized, open-label study in adults with type diabetes (T2D) inadequately controlled while on a glucagon-like peptide-1 receptor agonist (GLP-1 RA), with metformin, with or without pioglitazone and/or a sodium-glucose co-transporter-2 inhibitor. This analysis investigated the efficacy of switching to iGlarLixi by fasting baseline quartile C-peptide levels and baseline quartile of duration of T2D compared with continued GLP-1 RA use., Results: Change in glycated hemoglobin (HbA1c) from baseline to week 26 was significantly greater with iGlarLixi compared with continued GLP-1 RAs across all fasting C-peptide quartiles (-1.00% to -1.06% vs. -0.23% to -0.54% range, respectively) and irrespective of all T2D duration quartiles (-0.94% to -1.07% vs. -0.25% to -0.50% range). A significantly greater proportion of participants in the iGlarLixi arm achieved an HbA1c of <7% across all C-peptide quartiles (51%-73% range) than in the GLP-1 RA arm (19%-32% range). The greatest reductions in HbA1c in participants receiving iGlarLixi were observed in those with the shortest duration of disease, although consistently greater than reductions observed with continued GLP-1 RAs. Reductions in HbA1c were comparable across C-peptide quartiles within the iGlarLixi arm., Conclusions: The results of this study suggest that iGlarLixi is an effective treatment option, irrespective of C-peptide levels or duration of diabetes, in adults with insufficiently controlled T2D receiving GLP-1 RAs., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To evaluate the efficacy and safety of dapagliflozin (DAPA) + saxagliptin (SAXA) compared with glimepiride (GLIM) in patients with type 2 diabetes who were inadequately controlled [glycated haemoglobin (HbA1c) 7.5-10.5% (58-91 mmol/mol)] on metformin monotherapy., Materials and Methods: This 52-week, multicentre, double-blind, active-controlled study (NCT02419612) randomized (1:1) patients on metformin to add-on DAPA 10 mg + SAXA 5 mg (n = 227) or GLIM 1-6 mg (titrated; n = 217). The primary efficacy endpoint was change in HbA1c from baseline to week 52., Results: Baseline mean ± standard deviation of age, duration of diabetes and HbA1c were 56.1 ± 9.7 years, 7.8 ± 6.4 years and 8.5% ± 0.8% (69 ± 9.0 mmol/mol), respectively. Adjusted mean change from baseline in HbA1c was -1.35% (-14.8 mmol/mol) with DAPA + SAXA versus -0.98% (-10.7 mmol/mol) with GLIM (P <0.001). Changes from baseline in body weight and systolic blood pressure were -3.1 kg and -2.6 mmHg with DAPA + SAXA versus +1.0 kg (P <0.001) and +1.0 mmHg (P = 0.007) with GLIM. More patients achieved HbA1c <7.0% (53 mmol/mol) (44.3% vs. 34.3%; P = 0.044), and fewer patients required treatment intensification (1.3% vs. 8.8%; P = 0.002) with DAPA + SAXA than with GLIM., Conclusions: Compared with GLIM, concurrent addition of DAPA + SAXA significantly improved glycaemic control, body weight and other metabolic parameters in patients inadequately controlled on metformin. Trial: NCT02419612, ClinicalTrials.gov., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To assess the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes., Materials and Methods: In this double-blind, placebo-controlled study, patients were randomized (1:1:1:1) to receive either once-weekly subcutaneous tirzepatide or placebo. The tirzepatide dose groups and dose-escalation regimens were: 12 mg (4 mg weeks 0-3; 8 mg weeks 4-7; 12 mg weeks 8-11), 15 mg-1 (2.5 mg weeks 0-1; 5 mg weeks 2-3; 10 mg weeks 4-7; 15 mg weeks 8-11) and 15 mg-2 (2.5 mg weeks 0-3; 7.5 mg weeks 4-7; 15 mg weeks 8-11). The primary objective was to compare tirzepatide with placebo in HbA1c change from baseline at 12 weeks., Results: Overall, 111 patients were randomized: placebo, 26; tirzepatide 12 mg, 29; tirzepatide 15 mg-1, 28; tirzepatide 15 mg-2, 28. The mean age was 57.4 years, HbA1c 8.4% and body mass index 31.9 kg/m 2 . At week 12, absolute HbA1c change from baseline (SE) was greater in the tirzepatide treatment groups compared with placebo (placebo, +0.2% [0.21]; 12 mg, -1.7% [0.19]; 15 mg-1, -2.0% [0.20]; 15 mg-2, -1.8% [0.19]). The incidence of nausea was: placebo, 7.7%; 12 mg group, 24.1%; 15 mg-1 group, 39.3%; 15 mg-2 group, 35.7%. Three patients discontinued the treatment because of adverse events, one from each of the placebo, 12 mg and 15 mg-1 groups., Conclusions: Tirzepatide treatment for 12 weeks resulted in clinically significant reductions in HbA1c. This suggests that lower starting doses and smaller dose increments are associated with a more favourable side effect profile., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes., Methods: Type 2 diabetes patients (18-75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC 0 - 3h ) in a mixed meal tolerance test (MMTT) at day 29. Secondary endpoints included changes in fasting plasma glucose (FPG), insulin, HbA1c, lipids and body weight and adverse events. ANCOVA model was used for efficacy analysis., Results: The placebo-corrected least-squares mean differences (ΔLSM) in MMTT PPG AUC0-3 h (mmol/L) were -5.96 and -5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected ΔLSM in FPG (mmol/L) was -2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (ΔLSM, -0.56 mmol/L, p = 0.07 and -0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%)., Conclusions: MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796., Competing Interests: Declaration of competing interest All other authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly semaglutide in subjects with type 2 diabetes., Materials and Methods: Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose-confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta-cell function., Results: Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (-0.9%, -1.2%,-1.5%, -1.7% and -2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and -1.1%, -1.4%, -1.9%, -2.1% and -2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%-7.3% and 6.1%-6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (-4.4, -3.9, -3.9, -3.3 and -2.9 kg [P = 0.004], and -6.4, -5.9, -5.2, -4.5 and -4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta-cell function subgroups. Adverse events with semaglutide were consistent with the glucagon-like peptide-1 receptor agonist class, with gastrointestinal events the most common., Conclusions: Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Context: Intermediate-term glycemic control metrics fulfill a need for measures beyond hemoglobin A1C., Objective: Compare glycated albumin (GA), a 14-day blood glucose measure, with other glycemic indices., Design: 24-week prospective study of assay performance., Setting: 8 US clinics., Participants: Subjects with type 1 (n = 73) and type 2 diabetes (n = 77) undergoing changes to improve glycemic control (n = 98) or with stable diabetes therapy (n = 52)., Interventions: GA, fructosamine, and A1C measured at prespecified intervals. Mean blood glucose (MBG) calculated using weekly self-monitored blood glucose profiles., Main Outcome Measures: Primary: Pearson correlation between GA and fructosamine. Secondary: magnitude (Spearman correlation) and direction (Kendall correlation) of change of glycemic indices in the first 3 months after a change in diabetes management., Results: GA was more concordant (60.8%) with changes in MBG than fructosamine (55.5%) or A1C (45.5%). Across all subjects and visits, the GA Pearson correlation with fructosamine was 0.920. Pearson correlations with A1C were 0.655 for GA and 0.515 for fructosamine (P < .001) and with MBG were 0.590 and 0.454, respectively (P < .001). At the individual subject level, Pearson correlations with both A1C and MBG were higher for GA than for fructosamine in 56% of subjects; only 4% of subjects had higher fructosamine correlations with A1C and MBG. GA had a higher Pearson correlation with A1C and MBG in 82% and 70% of subjects, respectively., Conclusions: Compared with fructosamine, GA correlates significantly better with both short-term MBG and long-term A1C and may be more useful than fructosamine in clinical situations requiring monitoring of intermediate-term glycemic control (NCT02489773)., (© Endocrine Society 2019.)

Aims/hypothesis: Intra-abdominal or visceral obesity is associated with insulin resistance and an increased risk for cardiovascular disease. This study aimed to compare the effects of semaglutide 1.0 mg and canagliflozin 300 mg on body composition in a subset of participants from the SUSTAIN 8 Phase IIIB, randomised double-blind trial who underwent whole-body dual-energy x-ray absorptiometry (DXA) scanning., Methods: Adults (age ≥18 years) with type 2 diabetes, HbA 1c 53-91 mmol/mol (7.0-10.5%), on a stable daily dose of metformin (≥1500 mg or maximum tolerated dose) and with an eGFR ≥60 ml min -1 [1.73 m] -2 were randomised 1:1 to semaglutide 1.0 mg once weekly and canagliflozin placebo once daily, or canagliflozin 300 mg once daily and semaglutide placebo once weekly. Body composition was assessed using whole-body DXA scans. The study participants and investigator remained blinded throughout the trial, and quality of DXA scans was evaluated in a blinded manner. Change from baseline to week 52 in total fat mass (kg) was the confirmatory efficacy endpoint., Results: A subset of 178 participants (semaglutide, n = 88; canagliflozin, n = 90) underwent DXA scanning at screening and were randomised into the substudy. Of these, 114 (semaglutide, n = 53; canagliflozin, n = 61) participants had observed end-of-treatment data included in the confirmatory efficacy analysis. Of the 178 participants in the substudy, numerical improvements in body composition (including fat mass, lean mass and visceral fat mass) were observed after 52 weeks with both treatments. Total fat mass (baseline 33.2 kg) was reduced by 3.4 kg and 2.6 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.79 [95% CI -2.10, 0.51]). Although total lean mass (baseline 51.3 kg) was also reduced by 2.3 kg and 1.5 kg with semaglutide and canagliflozin, respectively (estimated treatment difference: -0.78 [-1.61, 0.04]), the proportion of lean mass (baseline 59.4%) increased by 1.2%- and 1.1%-point, respectively (estimated treatment difference 0.14 [-0.89, 1.17]). Changes in visceral fat mass and overall changes in body composition (assessed by the fat to lean mass ratio) were comparable between the two treatment groups., Conclusions/interpretation: In individuals with uncontrolled type 2 diabetes on stable-dose metformin therapy, the changes in body composition with semaglutide and canagliflozin were not significantly different. Although numerical improvements in body composition were observed following treatment in both treatment arms, the specific impact of both treatments on body composition in the absence of a placebo arm is speculative at this stage., Trial Registration: ClinicalTrials.gov NCT03136484., Funding: This trial was supported by Novo Nordisk A/S, Denmark.