Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus.

BACKGROUND: The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. METHOD: Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). RESULTS: At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. CONCLUSION: Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Abolishing ß-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists.

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced ß-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease ß-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios. MATERIALS AND METHODS: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays. RESULTS: First, we show that very substantial reductions in ß-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics. CONCLUSIONS: Completely abolishing ß-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.

Greater time spent with HbA1c less than 7.0% with oral semaglutide versus oral comparators: An exploratory analysis of the PIONEER studies.

AIM: To assess how long participants with type 2 diabetes spent with HbA1c less than 7.0% and how likely they were to maintain this target with oral semaglutide 7 mg versus sitagliptin 100 mg or oral semaglutide 14 mg versus empagliflozin 25 mg, sitagliptin 100 mg or subcutaneous liraglutide 1.8 mg. MATERIALS AND METHODS: Analyses used on-treatment data without rescue medication for all randomized participants (semaglutide [approved maintenance doses], n = 1880; comparators [not including placebo], n = 1412). Duration of time with HbA1c less than 7.0% was calculated using an HbA1c time curve. A binary endpoint of achieving HbA1c less than 7.0% at weeks 26 (week 24 for PIONEER 7) and 52 of each trial (and week 78 for PIONEER 3) was analysed. RESULTS: Mean duration of time with HbA1c less than 7.0% was greater with oral semaglutide 7 mg versus sitagliptin in PIONEER 3 (27 vs. 22 weeks) and with oral semaglutide 14 mg versus empagliflozin and sitagliptin (27-34 vs. 19 vs. 22 weeks, respectively), and similar versus subcutaneous liraglutide. A greater proportion of participants achieved and maintained HbA1c less than 7.0% for more than 75% of the trial with oral semaglutide 14 mg versus oral comparators. The odds of achieving HbA1c less than 7.0% at weeks 24/26 and 52/78 were significantly greater with oral semaglutide 14 mg versus oral comparators or subcutaneous liraglutide, and with oral semaglutide 7 mg versus sitagliptin. CONCLUSIONS: Oral semaglutide 7 and 14 mg resulted in greater time spent with HbA1c less than 7.0%, and a greater likelihood of achieving and maintaining HbA1c less than 7.0% versus oral comparators.

Albuminuria-lowering effect of adding semaglutide on top of empagliflozin in individuals with type 2 diabetes: A randomized and placebo-controlled study.

AIM: To investigate whether combined treatment with empagliflozin (a sodium-glucose cotransporter-2 inhibitor) and semaglutide (a glucagon-like peptide-1 receptor agonist) can reduce urinary albumin-creatinine ratio (UACR) compared to treatment with empagliflozin alone in individuals with type 2 diabetes (T2D) and albuminuria. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel study including 60 individuals with T2D and albuminuria. All participants initiated open-label empagliflozin 25 mg once daily, on top of renin-angiotensin system inhibition, in a run-in period of 26 weeks. Subsequently, participants were randomized to semaglutide or placebo 1 mg once weekly for 26 weeks. The primary endpoint was change in UACR. Secondary endpoints were change in: (i) measured glomerular filtration rate (GFR); (ii) 24-hour systolic blood pressure; (iii) glycated haemoglobin (HbA1c) level; (iv) body weight; and (v) plasma renin and aldosterone levels. RESULTS: Addition of semaglutide to empagliflozin provided no additional change in UACR from randomization to end-of-treatment. The mean (95% confidence interval) difference in UACR was -22 (-44; 10)% (P = 0.15) between treatment groups. Neither GFR, 24-hour blood pressure, body weight, nor plasma renin activity was changed with semaglutide. HbA1c (-8 [-13; -3] mmol/mol; P = 0.003) and plasma aldosterone (-30 [-50; -3] pmol/L; P = 0.035) were reduced with semaglutide compared to placebo. CONCLUSIONS: Semaglutide added to empagliflozin did not change UACR, measured GFR, 24-hour systolic blood pressure, body weight or plasma renin levels in individuals with T2D and albuminuria. Semaglutide improved glycaemic control and plasma aldosterone levels compared to placebo.

Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.

AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS: This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Cardiovascular and renal outcomes with varying degrees of kidney disease in high-risk people with type 2 diabetes: An epidemiological analysis of data from the AMPLITUDE-O trial.

AIMS: To estimate the incidence of a major adverse cardiovascular event (MACE) and a composite kidney outcome across estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) levels, and to determine whether efpeglenatide's effect varies with these indices. MATERIALS AND METHODS: AMPLITUDE-O trial data were used to estimate the relationship of eGFR, UACR, and Kidney Disease Improving Global Outcomes (KDIGO) category to the hazard of MACE and the kidney composite. Interactions on these outcomes between eGFR and the UACR, and between each of these variables and efpeglenatide were also assessed. RESULTS: Baseline eGFR and UACR were available for 3983 participants (mean age 64.5 years). During a median follow-up of 1.8 years, the hazards of MACE and the kidney composite for the lowest versus highest eGFR third were 1.6 (95% confidence interval [CI] 1.2, 2.2) and 2.3 (95% CI 1.9, 2.8), respectively. The hazards for the highest versus the lowest UACR third were 2.3 (95% CI 1.8, 3.1) and 18.0 (95% CI 12.7, 25.5), respectively, and for the high- versus low-risk KDIGO categories the hazards were 2.4 (95% CI 1.8, 3.1) and 16.0 (95% CI 11.6, 22.0), respectively. eGFR and UACR were independent determinants of both outcomes, but negatively interacted with each other for the kidney outcome. Efpeglenatide's effect on both outcomes did not vary with any kidney disease measure (all interaction p values ≥0.26). CONCLUSIONS: In high-risk people with diabetes, eGFR, UACR, and KDIGO category have different relationships to incident cardiovascular and kidney outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of kidney-related risk category.

Opportunities to optimize lifestyle interventions in combination with glucagon-like peptide-1-based therapy.

Obesity is a chronic multi-system disease and major driver of type 2 diabetes and cardiometabolic disease. Nutritional interventions form the cornerstone of obesity and type 2 diabetes management. Some interventions such as Mediterranean diet can reduce incident cardiovascular disease, probably independently of weight loss. Weight loss of 5% or greater can improve many adiposity-related comorbidities. Although this can be achieved with lifestyle intervention, it is often difficult to sustain in the longer term due to adaptive endocrine changes. In recent years glucagon-like-peptide-1 receptor agonists (GLP-1RAs) have emerged as effective treatments for both type 2 diabetes and obesity. Newer GLP-1RAs can achieve average weight loss of 15% or greater and improve cardiometabolic health. There is heterogeneity in the weight loss response to GLP-1RAs, with a substantial number of patients unable to achieve 5% or greater weight. Weight loss, on average, is lower in older adults, male patients and people with type 2 diabetes. Mechanistic studies are needed to understand the aetiology of this variable response. Gastrointestinal side effects leading to medication discontinuation are a concern with GLP-1RA treatment, based on real-world data. With weight loss of 20% or higher with newer GLP-1RAs, nutritional deficiency and sarcopenia are also potential concerns. Lifestyle interventions that may potentially mitigate the side effects of GLP-1RA treatment and enhance weight loss are discussed here. The efficacy of such interventions awaits confirmation with well-designed randomized controlled trials.

Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study).

AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.

Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial.

AIM: To investigate the effects of once-daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying. METHODS: A clinical pharmacology, double-blind study was conducted in 61 adults with obesity randomized to once-daily oral semaglutide (dose-escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant-reported appetite ratings and Control of Eating Questionnaire responses were assessed. Gastric emptying was measured using paracetamol absorption following a standardized breakfast. RESULTS: The relative change from baseline in ad libitum energy intake at week 20 (primary endpoint) was -39.2% points (95% confidence interval -59.0%, -19.4%) with semaglutide compared with placebo. Body weight was reduced by 9.8% with semaglutide and by 1.5% with placebo. Semaglutide reduced hunger, increased fullness and satiety, and was associated with fewer food cravings and better control of eating versus placebo. No statistically significant difference in gastric emptying was observed at week 20. CONCLUSIONS: In participants with obesity, once-daily oral semaglutide 50 mg reduced energy intake, body weight and appetite, and improved control of eating. There was no evidence of delayed gastric emptying at week 20, as measured through paracetamol absorption.

Glucagon agonism in the treatment of metabolic diseases including type 2 diabetes mellitus and obesity.

Type 2 diabetes mellitus (T2DM) is associated with obesity and, therefore, it is important to target both overweight and hyperglycaemia. Glucagon plays important roles in glucose, amino acid and fat metabolism and may also regulate appetite and energy expenditure. These physiological properties are currently being exploited therapeutically in several compounds, most often in combination with glucagon-like peptide-1 (GLP-1) agonism in the form of dual agonists. With this combination, increases in hepatic glucose production and hyperglycaemia, which would be counterproductive, are largely avoided. In multiple randomized trials, the co-agonists have been demonstrated to lead to significant weight loss and, in participants with T2DM, even improved glycated haemoglobin (HbA1c) levels. In addition, significant reductions in hepatic fat content have been observed. Here, we review and discuss the studies so far available. Twenty-six randomized trials of seven different GLP-1 receptor (GLP-1R)/glucagon receptor (GCGR) co-agonists were identified and reviewed. GLP-1R/GCGR co-agonists generally provided significant weight loss, reductions in hepatic fat content, improved lipid profiles, insulin secretion and sensitivity, and in some cases, improved HbA1c levels. A higher incidence of adverse effects was present with GLP-1R/GCGR co-agonist treatment than with GLP-1 agonist monotherapy or placebo. Possible additional risks associated with glucagon agonism are also discussed. A delicate balance between GLP-1 and glucagon agonism seems to be of particular importance. Further studies exploring the optimal ratio of GLP-1 and glucagon receptor activation and dosage and titration regimens are needed to ensure a sufficient safety profile while providing clinical benefits.

Analyses of potential causal contributors to increased waist/hip ratio-associated cardiometabolic disease: A combined and sex-stratified Mendelian randomization study.

BACKGROUND: Increased waist/hip ratio (WHR) contributes to type 2 diabetes, fatty liver, dyslipidaemia, hypertension and coronary artery disease, with potential sex-differential effects. Postulated mediators include increased lipid flux, branched-chain amino acids, glycine and glycoprotein acetyl, but their relative contributions and sex-specific impact on WHR-associated cardiometabolic disease (CMD) are not established. METHODS: We therefore undertook combined and sex-stratified Mendelian randomization (MR) to assess the relative causal contributions of these mediators to WHR-associated CMD using summary statistics from the largest genome-wide association studies in European ancestries. RESULTS: In sex-combined MR analyses, increased WHR significantly reduces high-density lipoprotein (beta = -0.416, SE = 0.029, p = 2.87E-47), increases triglyceride (beta = 0.431, SE = 0.029, p = 1.87E-50), type 2 diabetes (odds ratio = 2.747, SE = 0.09, p = 26E-23), coronary artery disease (odds ratio = 1.478, SE = 0.045, p = 6.96E-18), alanine transaminase (beta = 0.062, SE = 0.004, p = 6.88E-67), and systolic (beta = 0.134, SE = 0.022, p = 7.81E-10) and diastolic blood pressure (beta = 0.162, SE = 0.026, p = 5.38E-10). Adjustment for the mediators attenuated WHR's effects, but the associations remained significant with concordant results in females. In males, a similar pattern was seen, except after adjusting for the effect of the ratio of monounsaturated fatty acid to total free fatty acid, the potential causal effect of WHR was no longer significant: high-density lipoprotein (beta = -0.117, SE = 0.069, p = .09) and triglyceride (beta = 0.051, SE = 0.068, p = .459). CONCLUSIONS: MR suggests WHR increases the risk of CMD independent of these mediators, with the exception of dyslipidaemia in males, which is largely driven by the monounsaturated fatty acid to total free fatty acid ratio.

Effect of combination pioglitazone with sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists on outcomes in type 2 diabetes: A systematic review, meta-analysis, and real-world study from an international federated database.

AIMS: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database. METHODS: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. RESULTS: The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001). CONCLUSION: Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.

Liraglutide enhances insulin secretion and prolongs the remission period in adults with newly diagnosed type 1 diabetes (the NewLira study): A randomized, double-blind, placebo-controlled trial.

AIM: To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. RESULTS: Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P = .002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P < .001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. CONCLUSIONS: Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.

Utilization and cost of non-insulin glucose-lowering drugs in Australia from 2013 to 2023.

OBJECTIVES: To investigate the utilization and costs of non-insulin glucose-lowering drugs (GLDs) in Australia from 2013 to 2023. MATERIALS AND METHODS: We conducted a retrospective analysis of the Australian Pharmaceutical Benefits Scheme (PBS) administrative dataset of 118 727 494 GLD prescriptions. The main outcome measures were the annual number of GLD prescriptions dispensed, accounting for type 2 diabetes mellitus (T2DM) prevalence and healthcare system costs, adjusted for inflation. RESULTS: Utilization of GLDs doubled from 6.4 million prescriptions in 2013 to 15.6 million in 2023. The average annual percent increase in utilization was 8.1%, compared to the average annual increase in prevalence of T2DM of 1.8%. The biggest change was in sodium-glucose cotransporter-2 (SGLT2) inhibitors, for which there was an average annual increase in utilization of 59.4% (95% confidence interval [CI] 51.7%, 68.2%; p < 0.05) from 2014 (first full year of PBS listing), followed by glucagon-like peptide-1 receptor agonists (GLP-1RAs), which showed an increase of 31.4% (95% CI 28.5%, 33.8%; p < 0.05) annually (2013 to 2023). Dipeptidyl peptidase-4 inhibitor utilization tripled, with an average annual increase of 10.9% (95% CI 8.1%, 13.8%; p < 0.05), but this plateaued from 2020. Metformin utilization increased by 4.7% (95% CI 2.0%, 6.9%; p < 0.05) annually. In contrast, sulphonylurea, glitazone and acarbose utilization declined. Total GLD costs increased threefold over the same period. Despite only accounting for 11.7% of utilization, GLP-1RAs contributed to 35% of the costs. CONCLUSION: Utilization of GLDs doubled, and associated costs tripled over the past 11 years, with no sign of either utilization or costs plateauing, predominantly due to increased GLP-1RA and SGLT2 inhibitor prescribing.

Oral or injectable semaglutide for the management of type 2 diabetes in routine care: A multicentre observational study comparing matched cohorts.

AIM: To investigate the real-world utilization and comparative clinical outcomes of injectable and oral semaglutide in individuals with type 2 diabetes (T2D) with the aim of enhancing understanding of the practical implications associated with choosing between these formulations. METHODS: New users of oral or injectable semaglutide were selected from a cohort of 14 079 initiators of glucagon-like peptide-1 receptor agonists. Propensity-score matching (PSM) was employed to create balanced groups, ensuring comparability. The analysis encompassed dose exposure, drug persistence, and clinical outcomes, including changes in glycated haemoglobin (HbA1c) and body weight, with up to 18 months' follow-up. RESULTS: We analysed two matched groups of 107 participants each, who comprised on average 63.6% men, aged 64 years, with diabetes duration of approximately 10 years, body mass index of 29 kg/m2 and HbA1c level of 7.7-7.8% (61-62 mmol/mol). The proportion of low, intermediate and high doses were similar with the oral and the injectable formulation. The change in HbA1c was similar between groups (-0.9% / -10 mmol/mol at 18 months) as was the proportion of individuals reaching HbA1c <6.5% (48 mmol/mol). The average change in body weight was similar in the two groups (-3.7 kg with injectable and -3.3 kg with oral at 18 months) but more new users of injectable semaglutide lost ≥5% body weight. Persistence on drug was longer with injectable than with oral semaglutide. CONCLUSION: In a real-world setting, improvements in HbA1c and body weight were similar after initiation of oral or injectable semaglutide. These results may be specific to the features of the matched cohorts under investigation, with limited generalizability to populations with different characteristics.

Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors.

BACKGROUND AND AIMS: In a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. METHODS AND RESULTS: We digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: -0.7 %, 1.1 %) to -1.9 % (-3.1, -0.7), for primary outcome; and from -0.2 % (-0.5, 0.2) to -0.4 % (-0.7 %, -0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from -0.1 % (-0.4, 0.1) to -5.0 % (-7.7, -2.6), for primary outcome; and from -0.1 % (-0.2, 0.1) to -1.9 % (-4.4 %, 0.6 %), for mortality. CONCLUSION: The YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.

Semaglutide treatment of hypothalamic obesity - a real-life data study.

PURPOSE: Patients with tumors involving the hypothalamic region are at high risk of developing morbid obesity due to disturbances in the appetite regulative nuclei in hypothalamus. We evaluated the effect of the Glucagon-like peptide 1 (GLP-1) analogue semaglutide in patients with hypothalamic obesity. METHODS: We recorded weight changes from real-time data before and after treatment with semaglutide in patients with hypothalamic obesity from our outpatient clinic at the Department of Endocrinology at Rigshospitalet, from September 2020 to November 2023. RESULTS: A total of 26 patients were included in this study (15 females, median age at initiation of semaglutide was 52 (range 18-65) years). Body mass index (BMI) at initial diagnosis was median 25 (range 20-38) kg/m2 while BMI at initiation of semaglutide was median 38 (range 28-58) kg/m2. All but one patient lost weight during semaglutide treatment with a mean weight loss of 13.4 kg (95% CI 10.3-16.5 kg, p = < 0.001) after 12 months corresponding to a loss in BMI of 4.4 kg/m2 (95% CI 3.4-5.4 kg/m2, p = < 0.001) with a median dosage of semaglutide of 1.6 (range 0.5-2.5) mg. Fifteen patients (58%) lost more than 10% and two patients (8%) lost more than 20% of initial body weight, respectively. CONCLUSION: Treatment with semaglutide shows promising results in reducing body weight in patients with acquired hypothalamic obesity. Whether the weight reduction remains stable after long time follow-up needs further investigation.