Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p<0·0001; and trial product estimand: 5·54, 3·54–8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p<0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding: Novo Nordisk A/S

Association between tryptophan hydroxylase gene polymorphism and painful non-osseous temporomandibular disorders

[Abstract not Available

Clear cell chondrosarcoma of the proximal femur with intrapelvic extension

Clear cell chondrosarcoma is a rare tumor that can be easily confused with benign tumors. The aim of this report is to present a case that is rare, initially diagnosed as aneurysmal bone cyst and then chondroblastoma, and has an interesting extension pattern. A 41-year-old male patient was treated for an apparently benign cystic lesion of the right proximal femur by intralesional excision and bone grafting. The pathological diagnosis was aneurysmal bone cyst. Two years later, the patient presented with a pathological fracture at the same site and a total hip arthroplasty was performed. The pathological specimen was diagnosed as chondroblastoma. Three years later, clinical and radiological examination of the patient revealed a large mass located on the intrapelvic side of the acetabulum. There was no evidence of distant metastases. Both tumors were resected with a wide margin on the femoral side and a marginal margin on the intrapelvic side. The extremity was reconstructed with a resection-type total hip prosthesis. Again, the pathological diagnosis was chondroblastoma. The patient developed a deep infection that was treated by antibiotic therapy and surgical debridement. One year later, there was recurrence of the femoral and intrapelvic masses and right hemipelvectomy was performed; the specimen was reported as clear cell chondrosarcoma. Since then, the patient has been leading an active life., and there is no evidence of local recurrence or distant metastasis. Clinically and pathologically, clear cell chondrosarcoma may be confused with benign bone tumors. This caused a delay in the final diagnosis of this patient and he received inadequate surgical treatment, leading to a hemipelvectomy. We also found that the intrapelvic mass seemed to have developed independently on the intrapelvic side of the acetabulum. We were unable to find an exact explanation for this finding and postulated that tumor cells might have been seeded into the inner wall of the acetabulum during acetabular preparation of the total hip prosthesis

Three-Dimensional Stress State Around Corrosive Cavities on Pressure Vessels

Internal surfaces of pressure vessels used in many industrial sectors are subjected to corrosive effects leading to cavities. In this study, corrosive cavities on investigated pressure vessels are classified according to their shapes and dimensions. Distribution of stress was experimentally investigated around regions of different types of cavities using three-dimensional photoelastic models. An empirical expression is proposed to determine where maximum stress occurs in type of ellipsoidal cavity in the case of uniaxial loading. The obtained results show quite high stress levels around the cavity regions in pressure vessels, which increase the risk of crack formation.</jats:p

Urethral adenocarcinoma mimicking urethral caruncle

Urethral caruncles are considered as benign tumors. They need to be treated surgically; specimens should carefully be evaluated for the presence of any malignancy. We are presenting a 57-year-old female patient with a urethral lesion that looks like caruncle, but histopathologic examination of the excised lesion was reported as urethral adenocarcinoma