OBJECTIVE: 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.
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.

BACKGROUND: The study was designed to assess outcomes with once-daily oral semaglutide in adults with type 2 diabetes (T2D) naïve to injectable glucose-lowering agents, in Swedish clinical practice.
METHODS: In this non-interventional, multicentre study, participants initiated oral semaglutide and were followed for 34-44 weeks. The primary endpoint was glycated haemoglobin (HbA1c) change from baseline to end of study (EOS). Secondary endpoints included body weight (BW) change from baseline to EOS, proportion of participants achieving HbA1c < 7%, and proportion achieving both a HbA1c reduction ≥ 1% and BW reduction of ≥ 3% or ≥ 5%, at EOS. Participants completed Diabetes Treatment Satisfaction Questionnaires (DTSQ status/change) and a dosing conditions questionnaire.
RESULTS: A total of 187 participants (mean age 62.5 years) initiated oral semaglutide. Baseline mean HbA1c and BW were 7.8% (n = 177) and 96.9 kg (n = 165), respectively. Estimated mean changes in HbA1c and BW were - 0.88%-points (95% confidence interval [CI] - 1.01 to - 0.75; P < 0.0001) and - 4.72% (95% CI - 5.58 to - 3.86; P < 0.0001), respectively. At EOS, 64.6% of participants had HbA1c < 7%, and 22.9% achieved HbA1c reduction of ≥ 1% and BW reduction of ≥ 5%. DTSQ status and change scores improved by 1.44 (P = 0.0260) and 12.3 points (P < 0.0001), respectively. Oral semaglutide was easy or very easy to consume for 86.4% of participants. Most common adverse events (AEs) were gastrointestinal disorders; nine participants (4.8%) had serious AEs; one (0.5%) experienced severe hypoglycaemia.
CONCLUSIONS: In this real-world study population, we observed significant reductions in HbA1c and BW in people living with T2D when prescribed semaglutide tablets as part of routine clinical practice in Sweden, with improved treatment satisfaction among participants and no new safety concerns.
BACKGROUND: NCT04601753.

OBJECTIVE: 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: 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.
BACKGROUND: ClinicalTrials.gov NCT04109547.
BACKGROUND: Novo Nordisk A/S.

OBJECTIVE: 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: 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.
BACKGROUND: ClinicalTrials.gov NCT04017832.
BACKGROUND: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

BACKGROUND: In this phase 4, multicentre, prospective, non-interventional PIONEER REAL Netherlands study, we assessed clinical outcomes associated with once-daily oral semaglutide use in real-world clinical practice in adults living with type 2 diabetes (T2D) naïve to injectable glucose-lowering medication.
METHODS: Participants initiated on oral semaglutide were followed for 34-44 weeks. Change in glycated haemoglobin (HbA1c) from baseline (BL) to end of study (EOS) was the primary endpoint; secondary endpoints included change in body weight (BW) from BL to EOS, the proportion of participants with HbA1c < 7.0% at EOS and the composite endpoints of HbA1c reduction ≥ 1.0%-points with BW reduction ≥ 3% or ≥ 5% at EOS. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ status/change). Safety was evaluated in all participants who initiated oral semaglutide treatment.
RESULTS: Oral semaglutide was initiated in 187 participants; 94.1% completed the study and 78.6% remained on treatment at EOS. At BL, 54.0% of participants were male, mean age was 58.8 years, mean duration of T2D was 8.7 years and mean body mass index was 35.1 kg/m2; mean HbA1c was 8.6% and mean BW was 103.1 kg. Significant improvements from BL to EOS were observed for HbA1c and BW (estimated change [95% confidence interval]: - 1.16%-points [- 1.48 to - 0.85]; p < 0.0001, and - 5.84 kg [- 6.88 to - 4.80]; p < 0.0001, respectively). At EOS, 47.5% of participants had an HbA1c level < 7.0%; 41.8% and 35.5% of participants achieved composite endpoints of HbA1c reduction ≥ 1.0%-points plus BW reduction ≥ 3% or ≥ 5%, respectively. DTSQ status and change scores improved by 2.1 (p = 0.0003) and 10.8 points (p < 0.0001), respectively. Oral semaglutide was easy or very easy to consume for 81.5% of participants. Adverse events were mostly mild/moderate, with gastrointestinal disorders being the most common.
CONCLUSIONS: In this real-world population, we reported clinically significant reductions in HbA1c and BW, improved treatment satisfaction and no new safety concerns. A graphical abstract is available with this article.
BACKGROUND: NCT04601740.

BACKGROUND: Real-world data provide insight into how medications perform in clinical practice. The PIONEER REAL Switzerland study aimed to understand clinical outcomes with oral semaglutide in adults with type 2 diabetes (T2D).
METHODS: PIONEER REAL Switzerland was a 34-44-week, multicentre, prospective, non-interventional, single-arm study of adults with T2D naïve to injectable glucose-lowering medication who were initiated on oral semaglutide in routine clinical practice. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline (BL) to end of study (EOS); secondary endpoints included change in body weight (BW) from BL to EOS and the proportion of participants achieving HbA1c < 7.0% and the composite endpoints HbA1c reduction ≥ 1%-points with BW reduction ≥ 3% or ≥ 5% at EOS. Safety was assessed in participants who received ≥ 1 dose of oral semaglutide.
RESULTS: Of the 185 participants (female/male, n = 67/118) initiating oral semaglutide, 168 (90.8%) completed the study and 143 (77.3%) remained on treatment with oral semaglutide at EOS. At BL, participants had a mean age of 62 years, diabetes duration of 6.4 years, HbA1c of 7.7%, BW of 95.6 kg and body mass index of 33.2 kg/m2; 56.2% of participants were receiving glucose-lowering medications. Significant reductions were observed for HbA1c (estimated change - 0.91%; 95% confidence interval [CI] - 1.10, - 0.71; p < 0.0001) and BW (estimated change - 4.85%; 95% CI - 5.70, - 4.00; p < 0.0001). In total, 139 adverse events (AEs) were reported in 65 (35.1%) participants; most were mild or moderate. The most frequent AEs were gastrointestinal disorders (27.0%); 31 AEs in 20 (10.8%) participants led to discontinuation of oral semaglutide. Six serious AEs were reported; all were considered unlikely to be related to oral semaglutide.
CONCLUSIONS: People living with T2D treated with oral semaglutide in Switzerland achieved clinically significant reductions in HbA1c and BW, with no new safety signals.
BACKGROUND: ClinicalTrials.gov: NCT04537624. A graphical abstract is available for this article.

OBJECTIVE: 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).
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.

To assess the in-market use of Saxenda (liraglutide 3.0 mg) and Victoza (liraglutide 1.2 mg/1.8 mg) according to approved indications and posology.
This retrospective, non-interventional study was conducted at 41 sites from December 2016 to May 2019. Via medical record review, physicians at each site identified patients who had been prescribed Saxenda (Italy) or Victoza (Italy/Germany) within the 24 months following launch in each country. Pseudonymized data were abstracted on patient and site characteristics, indication for the prescription, posology and duration of usage. Adherence to the approved indications and posology, and to the Saxenda stopping rule, were assessed. No formal statistical analysis was performed.
A total of 440 patients were prescreened and 225 (51.1%) were enrolled (Saxenda: N = 75, all in Italy; Victoza: N = 75 in Italy and N = 75 in Germany). In all, 96% (72/75) of Saxenda prescriptions, and 98.7% (148/150) of Victoza, were in accordance with the approved indications. Among the 40 patients treated with Saxenda for 16 weeks or longer, only two (5.0%) were confirmed as non-adherent to the stopping rule. Adherence could not be assessed in 23 (57.5%) patients because of missing body weight measurements.
This retrospective, real-world post-authorization safety study provides reassurance that Saxenda and Victoza are primarily used according to the approved European label, thus their real-world utilization did not raise safety concerns.

To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher.
Intention-to-treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures. Subgroup analyses with factors for baseline HbA1c categories and their interaction with treatment group, as well as analyses within the HbA1c subgroups, were conducted. Additionally, sensitivity analyses were performed for baseline HbA1c subgroups of 6.5% or less and more than 6.5%.
Of the 9876 eligible participants, 3921 and 5955 had a baseline HbA1c of less than 7% and 7% or higher, respectively. Mean baseline HbA1c was 6.3% and 8.0% and the mean duration of diabetes was 9.0 and 11.6 years in the respective subgroups. The less than 7% subgroup was slightly older and less frequently insulin-treated. There was no evidence of a differential dulaglutide treatment effect on body mass index (BMI) reduction, cardiovascular or safety outcomes of interest between the baseline HbA1c subgroups. Treatment-by-baseline HbA1c group interaction was significant for HbA1c change from baseline (P < .001), with a greater reduction in the subgroup with higher baseline HbA1c values. Sensitivity analyses by baseline HbA1c subgroups of 6.5% or less and more than 6.5% showed similar results.
The reduced incidence of cardiovascular events, and the reduction in BMI in participants treated with once-weekly dulaglutide, were independent of the baseline HbA1c level. Conversely, participants with a higher baseline HbA1c level had greater reductions in HbA1c. Dulaglutide has a positive benefit-risk profile and can be considered in patients with comparatively well-controlled HbA1c levels seeking optimal metabolic control and cardiovascular benefits.

To compare the benefits of iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi), with insulin glargine (iGlar) for reducing residual hyperglycaemia (defined as HbA1c ≥ 7% despite fasting plasma glucose [FPG] < 130 mg/dL) in Japanese people with type 2 diabetes (T2D) inadequately controlled on oral antidiabetic drugs.
The open-label LixiLan JP-O2 study compared iGlarLixi with iGlar over 26 weeks in 521 people with T2D. This post hoc analysis assessed the proportions of participants with residual hyperglycaemia in the overall population, and in subgroups defined by age and dipeptidyl peptidase-4 inhibitor (DPP4i) use at screening.
At 26 weeks, significantly fewer participants had residual hyperglycaemia in the iGlarLixi versus the iGlar arm (8.1% vs. 19.6%; P = .0002). There was also less residual hyperglycaemia with iGlarLixi than iGlar in all subgroup analyses: 9.0% versus 16.8% in participants aged younger than 65 years (P = .0369); 6.5% versus 24.2% in participants aged 65 years or older (P = .0008); 10.1% versus 20.5% (P = .0202) in participants with DPP4i use; and 6.2% versus 18.8% in those without DPP4i use (P = .0024). The proportion reaching both HbA1c less than 7% and FPG less than 130 mg/dL was higher with iGlarLixi versus iGlar in the overall population (50.8% vs. 31.5%; P < .0001), and in all studied subgroups.
iGlarLixi reduced the prevalence of residual hyperglycaemia in Japanese people with uncontrolled T2D compared with iGlar, both in the overall population and in subgroups defined by age and DPP4i use at screening.