Addition of Liraglutide to Overweight Patients With Type 2 Diabetes Treated With Multiple Daily Insulin Injections (MDI) With Inadequate Glycaemic Control
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 124
- 试验地点
- 14
- 主要终点
- Change in HbA1c from baseline to week 24.
研究概览
简要总结
Liraglutide, a GLP-1-analogue has been shown to be an effective treatment option in patients on oral anti-diabetes therapy with beneficial effects on both glycaemic control and weight. However, to date there are no clinical trials of liraglutide added to insulin therapy, a population of patients generally having worse glycaemic control and weight gain. In clinical guidelines, use of multiple daily insulin injections (MDI) is usually the final therapeutic option for type 2 diabetic patients.
The primary study aim is to evaluate whether the addition of liraglutide, compared to placebo, reduces the HbA1c level for overweight and obese type 2 diabetes patients with inadequate glycaemic control treated with multiple daily insulin injections (MDI). MDI is defined as treatment with any basal insulin combined with separate meal time insulin injections before the main meals, i.e. an insulin regimen with premixed insulin is not considered as MDI.
The planned study duration is 24 weeks and includes 120 patients at 15 centers in Sweden.
详细描述
Background
Patients with type 2 diabetes are generally treated with metformin and diet as first-line therapy (1). In Sweden sulphonylureas are generally recommended as the next treatment option due to their low cost and evidence for reducing diabetes complications (2). The next line of therapy includes adding basal or premixed insulin. As a final step multiple daily insulin injections with basal and prandial insulin have become the standard if glycaemic control does not meet targets. Obesity is another co-morbid condition in this population (3). The United Kingdom Prospective Diabetes Study (UKPDS) published 1998, the seminal trial demonstrating the importance of glycaemic control in type 2 diabetes, illustrated that insulin therapy (mostly basal insulin alone) is accompanied by significant weight gain in patients with type 2 diabetes (4). MDI generally results in even greater weight gain. Today there are few treatment options in patients with type 2 diabetes on MDI with poor glycaemic control.
In patients with basal, intermediate or premixed insulin, addition of sitagliptin has shown further reduction in HbA1c of 0.6 percentage units (6 mmol/mol) with no change in weight (5). However, the effect in patients with the most severe disease, namely those requiring MDI, was not evaluated. In combination with metformin or sulphonylurea, adding the GLP-1-analogue liraglutide, compared with adding sitagliptin, has shown greater reductions in HbA1c and significant weight reductions (6). In an uncontrolled study in clinical practice, the addition of exanatide (n=22) or liraglutide (n=43) to patients on insulin therapy, the majority using MDI, was associated with a mean reduction in HbA1c by 1.0 percentage units (10 mmol/mol), reduction in weight of 7.1 kg and, simultaneously, a mean reduction in insulin dose by 37 units (7). At baseline patients were generally obese (mean BMI 36kg/m2), had poor glycaemic control, mean HbA1c of 8.9% (74 mmol/mol) and insulin doses of 92 units. The number of hypoglycaemic events was low, treatment satisfaction was high and patients rated hypoglycaemic episodes to be fewer than with insulin therapy alone. From these results it seems that there may be a beneficial effect associated with liraglutide when added to type 2 diabetic patients on MDI; however, this requires confirmation in a randomised clinical trial. This question is of particular concern since currently there are no treatment options for reducing weight and insulin doses while simultaneously improving glycaemic control for this patient group having most advanced disease. Further, many clinicians today use a therapeutic strategy consisting of MDI as a final treatment option, but many patients do still not reach target HbA1c and some even continue to have very poor glycaemic control (7). Therefore, the aim of this study is to study the effect on HbA1c when adding liraglutide to MDI in overweight and obese patients with impaired glycaemic control.
The proposed study is a randomised double-blind trial for 24 weeks including patients with type 2 diabetes and poor glycaemic control despite being treated with MDI for at least 6 months.
The aim is to study the effect on HbA1c when adding liraglutide to MDI in overweight or obese patients with impaired glycaemic control.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent obtained before trial-related activities (i.e., any activity that would not have been performed during routine patient management)
- •Type 2 diabetes
- •Adult patients over 18 years of age and less than or equal to 80 years of age
- •HbA1c greater than or equal to 7.5% (NGSP standard=DCCT standard)=58 mmol/mol (IFCC standard) and less than or equal to 11.5%=102 mmol/mol
- •Treated with MDI for at least the last 6 months
- •Treated with/without metformin as only diabetes therapy apart from insulin
- •Fasting C-peptide of 0.10 nmol/l or greater (ref. 0.25-1.0 nmol/l)
- •BMI greater than 27,5 kg/m2 and less than 45 kg/m2
排除标准
- •Type 1 diabetes
- •Fasting glucose less than 6.0 mmol/l or greater than 15.0 mmol/l
- •Unstable cardiovascular disease, NYHA Class II or greater heart failure , new symptoms of cardiovascular disease)
- •Proliferative diabetic retinopathy or clinically significant macula oedema. Retinal photograph should not be older than 3 years.
- •Systemic glucocorticoid treatment during the last 3 months, however, patients using systemic corticoid treatment only for substitution of cortisol deficiency (physiologic doses) such as Addisons Disease, do not need to be excluded
- •Acute coronary syndrome, stroke, coronary artery intervention or myocardial infarction during the previous 6 months
- •Creatinine greater than 150 micromol/l
- •Liver transaminases greater than double of the normal reference interval
- •Treatment with other oral antidiabetic agents than metformin during the previous 3 months
- •Treatment with GLP-1 receptor agonists within 90 days of screening
- •Severe psychiatric disorder (untreated severe depression, schizophrenia, dementia or severe alcohol or drug abuse)
- •Frequent non-severe hypoglycaemia (greater than 2 times per week) or any severe hypoglycaemia during the previous month.
- •Hypoglycaemic unawareness
- •Current cancer or diagnosis of cancer in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer).
- •Personal history of non-familial thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2)
- •Screening calcitonin values greater than 14.6 pmol/l.
- •Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice; accepted methods: oral contraceptive pills, depo provera contraceptive injections, implanted contraceptive, transdermal patch, intrauterine device, vasectomized partner, or abstinence.)
- •Blood pressure greater than 160/100 mmHg
- •Need for continuous use of paracetamol. During the 3 periods of 7 days with CGM, paracetamol cannot be used. Alternative pain killers can be substituted if plausible because paracetamol is the only medication influencing CGM results.
- •History of chronic or acute pancreatitis
- •Inflammatory Bowel Disease
- •Participation in another study
研究组 & 干预措施
Liraglutide
Liraglutide injected once per day for 24 weeks. Dose is 1,8 mg or highest tolerable dose.
干预措施: Liraglutide (Drug)
Placebo
Placebo injected once per day for 24 weeks. Dose is 1,8 or highest tolerable dose.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in HbA1c from baseline to week 24.
时间窗: Baseline, week 24
次要结局
- Change in weight from baseline to week 24(Baseline, week 24)
- Change in fasting glucose from baseline to week 24(Baseline, week 24)
- Change in the standard deviation of CGM from the run-in period to week 23-24(Run-in period, week 23-24)
- Change in mean glucose levels on CGM from the run-in period to week 23-24(Run-in period, week 23-24)
- Change in 1.5 hour postprandial glucose levels on capillary glucose measurements from the run-in period to week 23-24(Run-in period, week 23-24)
- Change in the score of the DTSQs from baseline to week 24(Baseline, week 24)
- Score of the DTSQc at week 24(Week 24)
- Proportion of patients with HbA1c less than 8.0% (64 mmol/mol) at week 24(Week 24)
- Frequency of non-severe documented symptomatic hypoglycaemia (PG less than 3.0 mmol/l) from baseline to week 24(Baseline, week 24)
- Frequency of asymptomatic non-severe hypoglycaemia (PG less than 3.0 mmol/l) from baseline to week 24(Baseline, week 24)
- Frequency of severe hypoglycaemia from baseline to week 24(Baseline, week 24)
- Change in blood lipid levels from baseline to week 24(Baseline, week 24)
- Proportion of patients with HbA1c less than 7.0% (53 mmol/mol) at week 24(Week 24)
- Change in blood pressure from baseline to week 24(Baseline, week 24)
- Frequency of non-severe documented symptomatic hypoglycaemia (plasma glucose [PG] less than 4.0 mmol/l) from baseline to week 24(Baseline, week 24)
- Proportion of patients with HbA1c less than 7.5% (58 mmol/mol) at week 24(Week 24)
- Change in total insulin dose from baseline to week 24(Baseline, week 24)
- Frequency of asymptomatic non-severe hypoglycaemia (PG less than 4.0 mmol/l) from baseline to week 24(Baseline, week 24)