Insulin degludec/liraglutide (IDegLira) is a novel combination of insulin degludec (IDeg) and liraglutide. This trial investigated the contribution of the liraglutide component of IDegLira versus ...IDeg alone on efficacy and safety in patients with type 2 diabetes.
In a 26-week, double-blind trial, patients with type 2 diabetes (A1C 7.5-10.0% 58-86 mmol/mol) on basal insulin (20-40 units) and metformin with or without sulfonylurea/glinides were randomized (1:1) to once-daily IDegLira + metformin or IDeg + metformin with titration aiming for fasting plasma glucose between 4 and 5 mmol/L. Maximum allowed doses were 50 dose steps (equal to 50 units IDeg plus 1.8 mg liraglutide) and 50 units for IDeg. The primary end point was change in A1C from baseline.
A total of 413 patients were randomized (mean A1C 8.8% 73 mmol/mol; BMI 33.7 kg/m2). IDeg dose, alone or as part of IDegLira, was equivalent (45 units). A1C decreased by 1.9% (21 mmol/mol) with IDegLira and by 0.9% (10 mmol/mol) with IDeg (estimated treatment difference -1.1% 95% CI -1.3, -0.8, -12 mmol/mol 95% CI -14, -9; P < 0.0001). Mean weight reduction with IDegLira was 2.7 kg vs. no weight change with IDeg, P < 0.0001. Hypoglycemia incidence was comparable (24% for IDegLira vs. 25% for IDeg). Overall adverse events were similar, and incidence of nausea was low in both groups (IDegLira 6.5% vs. IDeg 3.5%).
IDegLira achieved glycemic control superior to that of IDeg at equivalent insulin doses without higher risk of hypoglycemia and with the benefit of weight loss. These findings establish the efficacy and safety of IDegLira and the distinct contribution of the liraglutide component.
To compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of ...dulaglutide 1.5 mg versus placebo in HbA1c change at 26 weeks.
This 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 μg, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500-3,000 mg) and pioglitazone (30-45 mg). Mean baseline HbA1c was 8.1% (65 mmol/mol).
Least squares mean ± SE HbA1c change from baseline to the primary end point was -1.51 ± 0.06% (-16.5 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, -1.30 ± 0.06% (-14.2 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, -0.99 ± 0.06% (-10.8 ± 0.7 mmol/mol) for exenatide, and -0.46 ± 0.08% (-5.0 ± 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P < 0.001) and exenatide at 26 and 52 weeks (both adjusted one-sided P < 0.001). Greater percentages of patients reached HbA1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P < 0.001). At 26 and 52 weeks, total hypoglycemia incidence was lower in patients receiving dulaglutide 1.5 mg than in those receiving exenatide; no dulaglutide-treated patients reported severe hypoglycemia. The most common gastrointestinal adverse events for dulaglutide were nausea, vomiting, and diarrhea. Events were mostly mild to moderate and transient.
Both once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile.
Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM), lowers blood glucose by inhibiting renal glucose reabsorption and ...increasing urinary glucose excretion. It has been reported that SGLT2 inhibitors may have potential adverse effects on bone, including increased fracture risk and decreased bone mineral density (BMD). Across clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, vitamin D, or parathyroid hormone. Minimal increases in serum phosphate and magnesium that were within normal limits were seen with canagliflozin versus placebo. Canagliflozin was associated with increases in serum collagen type 1 beta-carboxy telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker. Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus placebo after 2 years (-1.7%, -2.1%, -0.8%; differences of -0.9% and -1.2%), but not at other skeletal sites (normal age-related bone loss, ~0.5-1.0%/year). Changes in beta-CTX and total hip BMD were significantly associated with weight loss, which is known to increase bone resorption markers and decrease BMD. Canagliflozin was associated with a higher fracture incidence in an interim analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) in patients with a history or high risk of cardiovascular disease (incidence per 100 patient-years of 1.6, 1.6, and 1.1 with canagliflozin 100 and 300 mg and placebo), but not in other clinical studies of patients with T2DM. Fractures tended to occur as early as 12 weeks after initiating treatment and were primarily located in the distal parts of the upper and lower extremities. The reason for increased fracture risk with canagliflozin treatment is unknown, but is likely not related to a direct effect of canagliflozin on bone-related biomarkers. Data from ongoing canagliflozin studies, including CANVAS, will provide additional information on fracture risk in patients with T2DM.
Aims
To assess the efficacy, insulin dose, safety and immunogenicity when people with type 1 diabetes mellitus switched between MYL‐1501D and reference insulin glargine (Lantus®; Sanofi‐Aventis US ...LLC, Bridgewater, New Jersey).
Materials and methods
Eligible participants from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n = 63; reference insulin glargine for 36 weeks) or to the treatment‐switching sequence (n = 64; MYL‐1501D weeks 0–12, reference insulin glargine weeks 12–24 and MYL‐1501D weeks 24–36). Change in glycated haemoglobin (HbA1c) from baseline to week 36 was the primary efficacy endpoint used to demonstrate equivalence between the two treatment sequences. Secondary endpoints included: change in fasting plasma glucose (FPG), self‐monitored blood glucose (SMBG) and insulin dose; immunogenicity; and adverse events, including hypoglycaemia.
Results
Mean changes in HbA1c (least squares LS mean SE) from baseline to week 36 were −0.05 (0.032) and −0.06 (0.034) for the treatment‐switching and reference sequences, respectively (LS mean difference 0.01 95% CI −0.085 to 0.101). Treatment sequences were comparable in terms of secondary endpoints, including FPG, SMBG and insulin dose, and the safety and immunogenicity profiles of the two sequences were similar.
Conclusions
Switching participants between MYL‐1501D and reference insulin glargine demonstrated equivalent efficacy and similar safety and immunogenicity, showing that people taking reference insulin glargine can safely switch to MYL‐1501D.
Aim
To test the safety and efficacy of MYL‐1501D, a proposed insulin glargine biosimilar, in patients with type 1 diabetes mellitus (T1DM).
Methods
The safety and efficacy of MYL‐1501D and reference ...insulin glargine were evaluated in INSTRIDE 1, a 52‐week, open‐label, randomized, phase III study in patients with T1DM. The primary objective was to determine whether once‐daily MYL‐1501D was non‐inferior to once‐daily insulin glargine when administered in combination with mealtime insulin lispro based on change in glycated haemoglobin (HbA1c) from baseline to week 24. Secondary endpoints were changes in fasting plasma glucose, insulin dose, self‐monitored blood glucose and immunogenicity from baseline, and occurrences of hypoglycaemic, nocturnal hypoglycaemic and adverse events up to week 52.
Results
Overall, 558 patients were randomized 1:1 to MYL‐1501D or reference insulin glargine in combination with thrice‐daily mealtime insulin lispro for 52 weeks. The mean change in HbA1c from baseline to week 24 was 0.14% (standard error SE 0.054; 95% confidence interval CI 0.033, 0.244) for MYL‐1501D and 0.11% (SE 0.054; 95% CI 0.007, 0.220) for reference insulin glargine. MYL‐1501D had a safety profile similar to that of reference insulin glargine and was well tolerated in patients with T1DM up to week 52.
Conclusions
The upper 95% CI limit for mean change in HbA1c at week 24 indicated that MYL‐1501D was non‐inferior to reference insulin glargine. There were no clinically meaningful differences between groups in incidence of overall and nocturnal hypoglycaemia, local or systemic reactions, safety or immunogenicity.
Aims
To assess the non‐inferiority of MYL‐1501D, a proposed biosimilar or follow‐on biological agent to marketed insulin glargine, to reference insulin glargine (Lantus®; Sanofi‐Aventis US LLC, ...Bridgewater, New Jersey) based on change in glycated hemoglobin (HbA1c).
Materials and methods
INSTRIDE 2 was a multicentre, open‐label, randomized, parallel‐group, phase III non‐inferiority study comparing the efficacy and safety of MYL‐1501D with those of reference insulin glargine in insulin‐naive and insulin‐non‐naive patients with type 2 diabetes mellitus receiving oral antidiabetic drugs (OADs). The primary efficacy endpoint was change in HbA1c from baseline to week 24. Secondary endpoints included metabolic readouts (eg, changes in fasting plasma glucose, insulin dosage, self‐monitored blood glucose), immunogenicity and adverse events, including hypoglycaemia and nocturnal hypoglycaemic events.
Results
In all, 560 patients were randomized to MYL‐1501D or insulin glargine in combination with OADs for 24 weeks. The mean change in HbA1c from baseline to week 24 was −0.60% (95% CI −0.78, −0.41) and − 0.66% (95% CI −0.84, −0.48) for MYL‐1501D and reference insulin glargine, respectively. MYL‐1501D was well tolerated and had a safety profile similar to that of reference insulin glargine.
Conclusions
Demonstration of non‐inferiority between MYL‐1501D and reference insulin glargine for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycaemia and nocturnal hypoglycaemia, local and systemic reactions, other safety variables, and immunogenicity.
Molecular testing for oncogenic gene mutations and chromosomal rearrangements plays a growing role in the optimal management of thyroid nodules, yet lacks standardized testing modalities and ...systematic validation data. Our objective was to assess the performance of molecular cytology on preoperative thyroid nodule fine-needle aspirates (FNAs) across a broad range of variables, including independent collection sites, clinical practices, and anatomic pathology interpretations.
Single-pass FNAs were prospectively collected from 806 nodules 1 cm or larger by ultrasonography at five independent sites across the United States. Specimens were shipped in a nucleic acid stabilization solution and tested at a centralized clinical laboratory. Seventeen genetic alterations (BRAF, KRAS, HRAS, and NRAS mutations, PAX8-PPARG and RET-PTC rearrangements) were evaluated by multiplex polymerase chain reaction and liquid bead array cytometry in 769 FNAs that met inclusion criteria. Cytology, histology, and clinical care followed local procedures and practices. All results were double-blinded.
Thirty-two specimens (4.2%) failed to yield sufficient nucleic acid to generate molecular data. A single genetic alteration was detected in 80% of cytology malignant cases, 21% of indeterminate, 7.8% of nondiagnostic, and 3.5% of benign cases. Among 109 nodules with surgical histology reference standard, oncogenic mutations were present in 50% of malignant nodules missed by cytology. There were 14 cancers not identified by cytology or molecular tests, including 5 carcinomas with histologic sizes less than 1 cm (3 multifocal) and 8 noninvasive follicular variants of papillary carcinoma (4 encapsulated). No mutations were detected in 89% of the nodules benign by histopathology with 6 false-positive molecular results in 5 adenomas (2-5.5 cm) and 1 cystic nodule with an incidental papillary microcarcinoma (0.15 cm). The posttest probability of thyroid cancer was 100% for nodules positive for BRAF or RET-PTC, 70% for RAS or PAX8-PPARG, and 88% for molecular cytology overall.
Centralized and standardized molecular testing for genetic alterations associated with a high risk of malignancy efficiently complements the local cytopathologic diagnosis of thyroid nodule aspirates in the clinical setting. Actionable molecular cytology can improve the personalized surgical and medical management of patients with thyroid cancers, facilitating one-stage total thyroidectomy and reducing the number of unnecessary diagnostic surgeries.
Background
MYL-1601D is a proposed biosimilar of originator insulin aspart, Novolog
®
/NovoRapid
®
(Ref-InsAsp-US/Ref-InsAsp-EU).
Objective
This study assessed the immunogenicity, efficacy, and ...safety of MYL-1601D with Ref-InsAsp-US in patients with type 1 diabetes mellitus (T1D).
Methods
This was a 24-week, open-label, randomized, phase III study. Patients were randomized 1:1 to mealtime MYL-1601D or Ref-InsAsp-US in combination with insulin glargine (Lantus SoloSTAR
®
) once daily. The treatment-emergent antibody response (TEAR) rate (defined as patients who were anti-insulin antibody AIA negative at baseline and became positive at any timepoint post-baseline or patients who were AIA positive at baseline and demonstrated a 4-fold increase in titer values at any timepoint post-baseline) was the primary endpoint. The study also compared the change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), prandial, basal, and total daily insulin, 7-point self-monitored blood glucose (SMBG) profiles, immunogenicity, and adverse events (AEs) including hypoglycemia.
Results
In total, 478 patients were included in the intent-to-treat analysis (MYL-1601D: 238; Ref-InsAsp-US: 240) set. The 90% confidence interval (CI) for the primary endpoint was within the pre-defined equivalence margin of ±11.7% and the treatment differences (SE) in TEAR responders between the treatment groups was − 2.86 (4.16) with 90% CI − 9.71 to 3.99. The mean (SD) changes from baseline for HbA1c, FPG, and insulin dosages were similar in both groups at week 24. The safety profiles including hypoglycemia, immune-related events, AEs, and other reported variables were similar between the treatment groups at week 24.
Conclusions
MYL-1601D demonstrated similar immunogenicity, efficacy, and safety profiles to Ref-InsAsp-US in patients with T1D over 24 weeks.
Clinical Trial Registration ClinicalTrials.gov:
NCT03760068.
Background:
Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma ...RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III–VI). In this study we report the development and clinical performance of this MTC classifier.
Methods:
Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette.
Results:
The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval CI = 83.9–100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1–100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology.
Conclusions:
The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.
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