Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial.

Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < -1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 μg/L [95% CI -5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 μg/L versus placebo 62.3 μg/L [95% CI -10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5-307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine -0.018 g/cm3 [95% CI -0.031 to -0.005]; p = 0.007); ETD total hip -0.020 g/cm2 ([95% CI -0.032 to -0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD -6.8 kg [95% CI -8.8 to -4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.

Hansen MS ，Wölfel EM ，Jeromdesella S ，Møller JK ，Ejersted C ，Jørgensen NR ，Eastell R ，Hansen SG ，Frost M ... -  《EClinicalMedicine》

Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes. In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0-9·5% (53-80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-30. Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA1c at week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with subcutaneous liraglutide, and -0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p<0·0001) and superior to placebo (ETD -1·1%, -1·2 to -0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and placebo (ETD -1·2%, -1·4 to -1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and placebo (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p<0·0001) and placebo (ETD -4·0 kg, -4·8 to -3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]). Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care. Novo Nordisk A/S.

Pratley R ，Amod A ，Hoff ST ，Kadowaki T ，Lingvay I ，Nauck M ，Pedersen KB ，Saugstrup T ，Meier JJ ，PIONEER 4 investigators ... -  《-》

Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial.

Semaglutide 2·4 mg once weekly has been investigated for weight management in global populations. Differences exist between Asian and non-Asian populations in terms of body composition and definitions of obesity. In the Semaglutide Treatment Effect in People with obesity (STEP) 6 trial, we assessed the effect of semaglutide versus placebo for weight management in adults from east Asia with obesity, with or without type 2 diabetes. This randomised, double-blind, double-dummy, placebo-controlled, phase 3a superiority trial was done at 28 outpatient clinics in Japan and South Korea. Eligible participants were adults (aged ≥18 years in South Korea; ≥20 years in Japan) with a BMI of at least 27·0 kg/m2 with two or more weight-related comorbidities or a BMI of 35·0 kg/m2 or more with one or more weight-related comorbidity (one comorbidity had to be either hypertension, dyslipidaemia, or, in Japan only, type 2 diabetes) who had at least one self-reported unsuccessful dietary attempt to lose bodyweight. Participants were randomly assigned (4:1:2:1) to once-weekly subcutaneous semaglutide 2·4 mg or matching placebo, or semaglutide 1·7 mg or matching placebo, plus lifestyle recommendations for 68 weeks. Data for the placebo groups were pooled in statistical analyses. The primary endpoints were percentage change in bodyweight from baseline at week 68 and the proportion of participants who had achieved a reduction of at least 5% of baseline bodyweight at week 68. Change in abdominal visceral fat area was assessed as a supportive secondary endpoint using computed tomography scanning in a subset of participants. Efficacy outcomes were assessed in the full analysis set, which included all randomly assigned participants according to the intention-to-treat principle. Safety was assessed in all participants who received at least one dose of the study drug. This trial was registered with ClinicalTrials.gov, NCT03811574. Between Jan 21, 2019 and June 4, 2019, 437 participants were screened, of whom 401 were randomly assigned to semaglutide 2·4 mg (n=199), semaglutide 1·7 mg (n=101), or placebo (n=101) and included in the intention-to-treat analysis. Estimated mean change in bodyweight from baseline to week 68 was -13·2% (SEM 0·5) in the semaglutide 2·4 mg group and -9·6% (0·8) in the semaglutide 1·7 mg group versus -2·1% (0·8) in the placebo group (estimated treatment difference [ETD] -11·1 percentage points [95% CI -12·9 to -9·2] for semaglutide 2·4 mg vs placebo; -7·5 percentage points [95% CI -9·6 to -5·4] for semaglutide 1·7 mg vs placebo; both p<0·0001). At week 68, a larger proportion of participants had achieved a 5% or higher reduction in baseline bodyweight in the semaglutide 2·4 mg group (160 [83%] of 193 participants) and semaglutide 1·7 mg group (71 [72%] of 98 participants) than in the placebo group (21 [21%] of 100 participants); odds ratio [OR] 21·7 [95% CI 11·3 to 41·9] for semaglutide 2·4 mg vs placebo; OR 11·1 [95% CI 5·5 to 22·2] for semaglutide 1·7 mg vs placebo; both p<0·0001). Abdominal visceral fat area was reduced by 40·0% (SEM 2·6) among participants in the semaglutide 2·4 mg group and 22·2% (3·7) among participants in the semaglutide 1·7 mg group versus 6·9% (3·8) in the placebo group (ETD -33·2% [95% CI -42·1 to -24·2] for semaglutide 2·4 mg vs placebo; -15·3% [95% CI -25·6 to -4·9] for semaglutide 1·7 mg vs placebo). 171 (86%) of 199 participants in the semaglutide 2·4 mg group, 82 (82%) of 100 participants in the semaglutide 1·7 mg group, and 80 (79%) of 101 participants in the placebo group reported adverse events. Gastrointestinal disorders, which were mostly mild to moderate, were reported in 118 (59%) of 199 participants in the semaglutide 2·4 mg group, 64 (64%) of 100 participants in the semaglutide 1·7 mg group, and 30 (30%) of 101 participants in the placebo group. Adverse events leading to trial product discontinuation occurred in five (3%) of 199 participants in the semaglutide 2·4 mg group, three (3%) of 100 participants in the semaglutide 1·7 mg group, and one (1%) of 101 participants in the placebo group. Adults from east Asia with obesity, with or without type 2 diabetes, given semaglutide 2·4 mg once a week had superior and clinically meaningful reductions in bodyweight, and greater reductions in abdominal visceral fat area compared with placebo, representing a promising treatment option for weight management in this population. Novo Nordisk. For the Korean and Japanese translations of the abstract see Supplementary Materials section.

Kadowaki T ，Isendahl J ，Khalid U ，Lee SY ，Nishida T ，Ogawa W ，Tobe K ，Yamauchi T ，Lim S ，STEP 6 investigators ... -  《-》

Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes. This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete. Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m-2 L min-2 kg-1 (SE 0·03) at baseline by 1·9 pmol m-2 L min-2 kg-1 (0·16) to total 2·3 pmol m-2 L min-2 kg-1 (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m-2 L min-2 kg-1 [SE 0·04]; change from baseline 0·0 pmol m-2 L min-2 kg-1 [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59-2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m-2 L min-2 kg-1 [95% CI 0·46-1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min-1 m-2 [51·84-152·33]) and insulin sensitivity (ETD 1·52 mg min-1 kg-1 [0·53-2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths. The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely β-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies. Eli Lilly.

Heise T ，Mari A ，DeVries JH ，Urva S ，Li J ，Pratt EJ ，Coskun T ，Thomas MK ，Mather KJ ，Haupt A ，Milicevic Z ... -  《-》

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.

Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both. We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA1c 7·0-10·5% [53·0-91·0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0·5 mg and 1·0 mg) were pooled for the analyses. The primary endpoint was change in HbA1c from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188. Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0·5 mg, 409 received semaglutide 1·0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA1c was 8·1% (SD 0·93); at week 56, HbA1c was reduced by 1·3% in the semaglutide 0·5 mg group, 1·6% in the semaglutide 1·0 mg group, and 0·5% with sitagliptin (estimated treatment difference vs sitagliptin -0·77% [95% CI -0·92 to -0·62] with semaglutide 0·5 mg and -1·06% [-1·21 to -0·91] with semaglutide 1·0 mg; p<0·0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89·5 kg (SD 20·3); at week 56, bodyweight reduced by 4·3 kg with semaglutide 0·5 mg, 6·1 kg with semaglutide 1·0 mg, and 1·9 kg with sitagliptin (estimated treatment difference vs sitagliptin -2·35 kg [95% CI -3·06 to -1·63] with semaglutide 0·5 mg and -4·20 kg [-4·91 to -3·49] with semaglutide 1·0 mg; p<0·0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0·5 mg, 39 (10%) for semaglutide 1·0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0·5 mg, 72 (18%) who received semaglutide 1·0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0·5 mg, 53 (13%) who received semaglutide 1·0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0·5 mg group, two (<1%) in the semaglutide 1·0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0·5 mg group, one in the semaglutide 1·0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs. Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population. Novo Nordisk A/S.

Ahrén B ，Masmiquel L ，Kumar H ，Sargin M ，Karsbøl JD ，Jacobsen SH ，Chow F ... -  《-》