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Dulaglutide 1.5 mg as an add-on option for patients uncontrolled on insulin: Subgroup analysis by age, duration of diabetes and baseline glycated haemoglobin concentration.

ABSTRACT: To assess efficacy and safety of dulaglutide 1.5 mg combined with insulin, categorized by subgroups of baseline glycated haemoglobin (HbA1c; ?9% and >9% [?74.9 and >74.9 mmol/mol]), age (<65 and ?65?years), and duration of diabetes (<10 and ?10 years) at 6 months in patients with type 2 diabetes (T2D).This pooled analysis was conducted in a population of patients with T2D with similar baseline characteristics who were included in the AWARD-4 and AWARD-9 clinical trials and randomized to dulaglutide 1.5 mg (pooled mean baseline age 59?years, duration of diabetes 13?years, HbA1c 8.4% [68.3 mmol/mol]). Weight and hypoglycaemia were analysed by individual trial. In AWARD-4, dulaglutide plus lispro three times daily was assessed against glargine plus lispro three times daily. In AWARD-9, dulaglutide added to glargine was assessed against placebo added to glargine. Insulins were titrated to target in both trials.A total of 445 patients were included in this analysis (73% with HbA1c ?9%, 27% [?74.9 mmol/mol] with HbA1c >9% [>74.9 mmol/mol]; 70% aged <65?years, 30% aged ?65?years; 36% with duration of diabetes <10 years, 64% with duration of diabetes ?10 years). At 6 months, dulaglutide 1.5 mg significantly reduced HbA1c in all subgroups (P?9% (>74.9 mmol/mol) (range?-?1.3% to -2.5% [-14.2 to -27.3 mmol/mol]). The incidence rates of documented symptomatic and severe hypoglycaemia were similar in all subgroups in both trials. The most common adverse events observed in each trial were gastrointestinal in nature.Dulaglutide 1.5 mg combined with basal or prandial insulin is efficacious for patients with T2D irrespective of age, duration of diabetes or baseline HbA1c.

SUBMITTER: Pantalone KM

PROVIDER: S-EPMC5969314 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Dulaglutide 1.5 mg as an add-on option for patients uncontrolled on insulin: Subgroup analysis by age, duration of diabetes and baseline glycated haemoglobin concentration.

Pantalone Kevin M KM Patel Hiren H Yu Maria M Fernández Landó Laura L

Diabetes, obesity & metabolism 20180323 6

<h4>Aims</h4>To assess efficacy and safety of dulaglutide 1.5 mg combined with insulin, categorized by subgroups of baseline glycated haemoglobin (HbA1c; ≤9% and >9% [≤74.9 and >74.9 mmol/mol]), age (<65 and ≥65 years), and duration of diabetes (<10 and ≥10 years) at 6 months in patients with type 2 diabetes (T2D).<h4>Materials and methods</h4>This pooled analysis was conducted in a population of patients with T2D with similar baseline characteristics who were included in the AWARD-4 and AWARD-9 ...[more]

PMID: 29430801

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Project description:AimsTo evaluate the efficacy and safety of dulaglutide 1.5 and 0.75?mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD-1 to -6 and -8 clinical trials).MethodsChange in HbA1c was analysed by gender, duration of diabetes (<5, ?5?years and <10, ?10?years), and baseline HbA1c (<8.5%, ?8.5%) in pooled and individual studies. Changes from baseline in weight, hypoglycaemia and gastrointestinal adverse events were evaluated for individual trials.ResultsIn the pooled analysis of patients treated with dulaglutide 1.5?mg at 6?months, the reductions in HbA1c from baseline were similar across gender (men: least squares [LS] mean -1.26% [95% confidence interval {CI} -1.36, -1.16]; women: LS mean -1.33% [95% CI -1.43, -1.24]) and among duration of diabetes subgroups (<5?years: LS mean -1.32% [95% CI -1.43, -1.22]; ?5 and <10?years: LS mean -1.33% [95% CI -1.43, -1.22]; ?10?years: -1.24% [95% CI -1.35, -1.14]). Patients with baseline HbA1c ?8.5% had greater HbA1c reductions than patients with baseline HbA1c <8.5%, (?8.5%: LS mean -1.86% [95% CI -1.97, -1.75]; <8.5%: LS mean -1.02% [95% CI -1.12, -0.93]). Reductions in fasting blood glucose (FBG) were consistent with HbA1c changes. Similar results were observed with dulaglutide 0.75?mg. In general, body weight changes were similar among duration of diabetes and in baseline HbA1c subgroups, respectively; women had a numerically greater weight loss or less weight gain than men with both dulaglutide doses. There was no clinically meaningful difference in hypoglycaemia trends by gender or duration of diabetes. Hypoglycaemia incidence and rate were generally lower in patients with baseline HbA1c ?8.5% than in those with <8.5%, except for the AWARD-4 study (combination with mealtime insulin).ConclusionsAcross the AWARD studies, dulaglutide demonstrated significant improvements in glycaemic control irrespective of gender, duration of diabetes, or baseline HbA1c, with greater HbA1c and FBG reductions in patients with a higher baseline HbA1c. Dulaglutide was well tolerated, with a safety profile similar to other glucagon-like peptide-1 receptor agonists.

Project description:ObjectiveTo compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin.Research design and methodsPatients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients.ResultsMean baseline HbA1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA1c, using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%).ConclusionsIn patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile.

Project description:ObjectivesTo investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A(1C)) achieved during therapy.DesignPost hoc epidemiological analysis of a double 2x2 factorial, randomised, controlled trial.SettingDiabetes clinics, research clinics, and primary care clinics.Participants10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A(1C) concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control.Main outcome measuresSevere hypoglycaemia was defined as episodes of "low blood glucose" requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.ResultsThe annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A(1C) concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A(1C) concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21).ConclusionsA greater drop in haemoglobin A(1C) concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk.Trial registrationClinicalTrials.gov number NCT00000620.

Dataset Information

Dulaglutide 1.5 mg as an add-on option for patients uncontrolled on insulin: Subgroup analysis by age, duration of diabetes and baseline glycated haemoglobin concentration.

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Dulaglutide 1.5 mg as an add-on option for patients uncontrolled on insulin: Subgroup analysis by age, duration of diabetes and baseline glycated haemoglobin concentration.

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