RESUMEN

OBJECTIVE: In SUSTAIN 7, once-weekly semaglutide demonstrated superior glycated haemoglobin (HbA1c) and body weight (BW) reductions versus once-weekly dulaglutide in subjects with type 2 diabetes (T2D). This post hoc analysis investigated the impact of clinically relevant subject characteristics on treatment effects of semaglutide versus dulaglutide. DESIGN: Analyses by baseline age (<65, ≥65 years), sex (male, female), diabetes duration (≤5, >5-10, >10 years), HbA1c (≤7.5, >7.5-8.5, >8.5% (≤58, >58-69, >69 mmol/mol)) and body mass index (BMI) (<30, 30-<35, ≥35 kg/m2). SETTING: 194 sites; 16 countries. PARTICIPANTS: Subjects with T2D (n=1199) exposed to treatment. INTERVENTIONS: Semaglutide 0.5 mg versus dulaglutide 0.75 mg (low-dose comparison); semaglutide 1.0 mg versus dulaglutide 1.5 mg (high-dose comparison), all subcutaneously once weekly. PRIMARY AND SECONDARY OUTCOME MEASURES: Change in HbA1c (primary endpoint) and BW (confirmatory secondary endpoint) from baseline to week 40; proportion of subjects achieving HbA1c targets (<7%, ≤6.5% (<53, ≤48 mmol/mol)) and weight-loss responses (≥5%, ≥10%) at week 40; and safety. RESULTS: HbA1c and BW reductions (estimated treatment difference ranges: -0.22 to -0.70%-point; -1.76 to -3.84 kg) and proportion of subjects achieving HbA1c targets and weight-loss responses were statistically significantly greater for the majority of comparisons of semaglutide versus dulaglutide within each subgroup category and, excepting glycaemic control within the low-dose comparison in HbA1c subgroups, this was irrespective of subgroup or dose comparison. Gastrointestinal adverse events, the most common with both treatments, were reported by more women than men and, with semaglutide, decreased with increasing BMI. CONCLUSIONS: Consistently greater improvements in HbA1c and BW with semaglutide versus dulaglutide, regardless of age, sex, diabetes duration, glycaemic control and BMI, support the efficacy of semaglutide across the continuum of care in a heterogeneous population with T2D. TRIAL REGISTRATION NUMBER: NCT02648204.

Asunto(s)

Diabetes Mellitus Tipo 2 , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Péptidos Similares al Glucagón/efectos adversos , Péptidos Similares al Glucagón/análogos & derivados , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Fragmentos Fc de Inmunoglobulinas , Masculino , Proteínas Recombinantes de Fusión

RESUMEN

AIM: To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly semaglutide in subjects with type 2 diabetes. MATERIALS AND METHODS: Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose-confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta-cell function. RESULTS: Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (-0.9%, -1.2%,-1.5%, -1.7% and -2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and -1.1%, -1.4%, -1.9%, -2.1% and -2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%-7.3% and 6.1%-6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (-4.4, -3.9, -3.9, -3.3 and -2.9 kg [P = 0.004], and -6.4, -5.9, -5.2, -4.5 and -4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta-cell function subgroups. Adverse events with semaglutide were consistent with the glucagon-like peptide-1 receptor agonist class, with gastrointestinal events the most common. CONCLUSIONS: Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

Asunto(s)

Diabetes Mellitus Tipo 2 , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos

RESUMEN

BACKGROUND: Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes. METHODS: This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA1c 7·0-10·5% (53·0-91·0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA1c; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA1c non-inferiority (margin 0·4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204. FINDINGS: Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to semaglutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving semaglutide 0·5 mg, 13 receiving dulaglutide 0·75 mg, 21 receiving semaglutide 1·0 mg, and 16 receiving dulaglutide 1·5 mg). From overall baseline mean, mean percentage HbA1c was reduced by 1·5 (SE 0·06) percentage points with semaglutide 0·5 mg versus 1·1 (0·05) percentage points with dulaglutide 0·75 mg (estimated treatment difference [ETD] -0·40 percentage points [95% CI -0·55 to -0·25]; p<0·0001) and by 1·8 (0·06) percentage points with semaglutide 1·0 mg versus 1·4 (0·06) percentage points with dulaglutide 1·5 mg (ETD -0·41 percentage points [-0·57 to -0·25]; p<0·0001). From overall baseline mean, mean bodyweight was reduced by 4·6 kg (SE 0·28) with semaglutide 0·5 mg compared with 2·3 kg (0·27) with dulaglutide 0·75 mg (ETD -2·26 kg [-3·02 to -1·51]; p<0·0001) and by 6·5 kg (0·28) with semaglutide 1·0 mg compared with 3·0 kg (0·27) with dulaglutide 1·5 mg (ETD -3·55 kg [-4·32 to -2·78]; p<0·0001). Gastrointestinal disorders were the most frequently reported adverse event, occurring in 129 (43%) of 301 patients receiving semaglutide 0·5 mg, 133 (44%) of 300 patients receiving semaglutide 1·0 mg, 100 (33%) of 299 patients receiving dulaglutide 0·75 mg, and in 143 (48%) of 299 patients receiving dulaglutide 1·5 mg. Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide. There were six fatalities: one in each semaglutide group and two in each dulaglutide group. INTERPRETATION: At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile. FUNDING: Novo Nordisk.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/análogos & derivados , Hipoglucemiantes/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Glucemia/análisis , Peso Corporal , Femenino , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico

RESUMEN

OBJECTIVE: The present study aimed to assess the patient preference and tolerability of oral dipeptidyl peptidase-4 inhibitor (vildagliptin) versus injectable glucagon-like peptide-1 analog (liraglutide) in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy. METHODS: This 24-week, randomized, multicenter, crossover study, patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy with hemoglobin A1c (HbA1c) ⩾6.5% and ⩽9.0% were randomized in a crossover manner to receive either vildagliptin/metformin single-pill combination (SPC) 50/1000 mg twice daily (n = 32) or 1.2 mg liraglutide as an add-on to metformin (0.6 mg [weeks 0-1] followed by 1.2 mg [weeks 2-12] once daily/1000 mg twice daily) (n = 30) for the first 12 weeks. RESULTS: Patient preference at week 24 was similar, with 51.7% (n = 31) patients preferring vildagliptin/metformin SPC compared with 48.3% (n = 29) preferring liraglutide as an add-on to metformin therapy (p = 0.449). Post hoc analyses showed that more elderly patients (⩾65 years) preferred vildagliptin (65%; n = 13) over liraglutide (35%; n = 7) therapy. Liraglutide was associated with better improvement in fasting plasma glucose (-21.5 mg/dl versus -3.4 mg/dl) and HbA1c (-0.5% versus -0.3%) levels. Fewer adverse events were reported with vildagliptin/metformin SPC (n = 16) compared with liraglutide as add-on to metformin treatment (n = 46). CONCLUSIONS: In this pilot study, although both vildagliptin and liraglutide therapies were preferred similarly by the patients and showed effective control of glycemia over 12 weeks, vildagliptin was associated with fewer adverse events and was preferred more by elderly patients.