Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The combination of insulin and glucagon-like peptide-1 (GLP-1) receptor agonist therapy improves glycaemic control, induces weight loss, and reduces insulin dose needed in type 2 diabetes. We assessed the efficacy and safety of the GLP-1 receptor agonist liraglutide as an add-on therapy to insulin for overweight adult patients with type 1 diabetes. METHODS: We did a randomised, double-blind, placebo-controlled trial at Steno Diabetes Center (Gentofte, Denmark). Patients aged 18 years or older with type 1 diabetes, insufficient glycaemic control (HbA1c >8% [64 mmol/mol]), and overweight (BMI >25 kg/m(2)) were randomly assigned (1:1) to receive insulin treatment plus either liraglutide or placebo (saline solution) by subcutaneous injection once per day. Randomisation was done in blocks of four. Treatment assignment was masked to investigators and patients. Treatment lasted 24 weeks and liraglutide was started at a dose of 0·6 mg per day, escalated to 1·2 mg per day after 1 week, and then again to 1·8 mg per day after another week. Intervals between dose increments could be extended at the discretion of the investigator. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints were changes in hypoglycaemic events, glycaemic variability, glycaemic excursions, insulin dose, bodyweight, postprandial plasma concentrations of glucagon and GLP-1, gastric emptying, blood pressure, heart rate, patient-reported outcome measures, time spent in hypoglycaemia, near-normoglycaemia, and hyperglycaemia, plasma fasting glucose, mean glucose, and cholesterol. Efficacy analyses were calculated by use of a mixed model, whereby a patient's data are used as long as the patient is in the study. The safety analyses were done in the intention-to-treat population, which consisted of all patients who received at least one dose of their randomly assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01612468. FINDINGS: Between July 10, 2012, and May 30, 2014, we enrolled 100 patients with type 1 diabetes, with 50 patients allocated liraglutide and 50 to placebo. Four patients from the liraglutide group and six patients from the placebo group discontinued treatment before 24 weeks. At the end of treatment, change in HbA1c from baseline did not differ between groups (-0·5%, 95% CI -0·8 to -0·4 [-6·0 mmol/mol, 95% CI -8·7 to -4·4] with liraglutide vs -0·3%, -0·6 to -0·2 [-4·0 mmol/mol, -6·6 to -2·3] with placebo; between-group difference -0·2% [-0·5 to 0·1; 2·2 mmol/mol, -5·5 to 1·1], p=0·1833). The number of hypoglycaemic events was reduced with liraglutide, with an incident rate ratio of 0·82 (95% CI 0·74 to 0·90). However, we detected no changes in glycaemic variability (continuous overall net glycaemic action per 60 min from 10·3 [95% CI 9·8 to 10·8] to 9·9 [9·2 to 10·6] in the liraglutide treated patients vs 10·2 [9·7 to 10·7] to 9·7 [9·1 to 10·3] in the placebo treated patients). Both bolus insulin (difference -5·8 IU, 95% CI -10·7 to -0·8, p=0·0227) and bodyweight (difference -6·8 kg, 95% CI -12·2 to -1·4, p=0·0145) decreased with liraglutide treatment compared with placebo. Heart rate increased with liraglutide, with a difference between groups of 7·5 bpm (95% CI 2·8-12·2, p=0·0019). Postprandial plasma glucagon and GLP-1 concentrations did not differ between groups (difference between groups at end of treatment: -408 mmol/L per 240 min [95% CI -941 to 125, p=0·1309] for glucagon and -266 mmol/L per 240 min [-1034 to 501, p=0·4899] for GLP-1). Gastric emptying was delayed after 3 weeks of treatment with liraglutide (19·9 min, 95% CI 0·8 to 39·0, p=0·0412), but we detected no difference after 24 weeks of treatment (-1·5 min, -20·5 to 17·6, p=0·8793). Patient-reported outcome measures differed between groups only with respect to perceived frequency of hypoglycaemia, which was higher with placebo, with a difference between groups of -0·6 (95% CI -1·1 to -0·07, p=0·0257). Liraglutide was associated with more frequent nausea (29 [58%] patients with liraglutide vs five [10%] with placebo), dyspepsia (11 [22%] patients with liraglutide vs one [2%] with placebo), diarrhoea (ten [20%] patients with liraglutide vs one [2%] with placebo), decreased appetite (seven patients [14%] with liraglutide vs none with placebo), and vomiting (seven [14%] patients with liraglutide vs one [2%] with placebo). INTERPRETATION: In patients with type 1 diabetes, overweight, and insufficient glycaemic control, the reduction in HbA1c did not differ between insulin plus placebo and insulin plus liraglutide treatment. Liraglutide was associated with reductions in hypoglycaemic events, bolus and total insulin dose, and bodyweight, and increased heart rate. FUNDING: Novo Nordisk.

Efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide added to insulin therapy in poorly regulated patients with type 1 diabetes--a protocol for a randomised, double-blind, placebo-controlled study: the Lira-1 study.

INTRODUCTION: Intensive insulin therapy is recommended for the treatment of type 1 diabetes (T1D). Hypoglycaemia and weight gain are the common side effects of insulin treatment and may reduce compliance. In patients with insulin-treated type 2 diabetes, the addition of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy has proven effective in reducing weight gain and insulin dose. The present publication describes a protocol for a study evaluating the efficacy and safety of adding a GLP-1RA to insulin treatment in overweight patients with T1D in a randomised, double-blinded, controlled design. METHODS AND ANALYSIS: In total, 100 patients with type 1 diabetes, poor glycaemic control (glycated haemoglobin (HbA1c) >8%) and overweight (body mass index >25 kg/m(2)) will be randomised to either liraglutide 1.8 mg once daily or placebo as an add-on to intensive insulin therapy in this investigator initiated, double-blinded, placebo-controlled parallel study. The primary end point is glycaemic control as measured by changes in HbA1c. Secondary end points include changes in the insulin dose, hypoglyacemic events, body weight, lean body mass, fat mass, food preferences and adverse events. Glycaemic excursions, postprandial glucagon levels and gastric emptying rate during a standardised liquid meal test will also be studied. ETHICS AND DISSEMINATION: The study is approved by the Danish Medicines Authority, the Regional Scientific-Ethical Committee of the Capital Region of Denmark and the Data Protection Agency. The study will be carried out under the surveillance and guidance of the good clinical practice (GCP) unit at Copenhagen University Hospital Bispebjerg in accordance with the ICH-GCP guidelines and the Helsinki Declaration. TRIAL REGISTRATION NUMBER: NCT01612468.

Environmental factors in inflammatory bowel disease: a case-control study based on a Danish inception cohort.

BACKGROUND: The role of environmental factors in development of inflammatory bowel disease (IBD) remains uncertain. The aim of the present study was to assess a number of formerly suggested environmental factors in a case-control study of an unselected and recently diagnosed group of patients with IBD and a control group of orthopaedic patients. METHODS: A total of 123 patients diagnosed with Crohn's disease (CD) and 144 with ulcerative colitis (UC) in Copenhagen (2003-2004) were matched 1:1 on age and gender to 267 orthopaedic controls. Participants received a questionnaire with 87 questions concerning environmental factors prior to IBD/orthopaedic admission. Odds ratios (OR) were calculated by logistic regression. RESULTS: Being breastfed >6 months (OR, 0.50; 95% CI, 0.23-1.11) and undergoing tonsillectomy (OR, 0.49; 95% CI, 0.31-0.78) decreased the odds for IBD, whereas appendectomy decreased the odds for UC only (OR, 0.29; 95% CI, 0.12-0.71). Vaccination against pertussis (OR, 2.08; 95% CI, 1.07-4.03) and polio (OR, 2.38; 95% CI, 1.04-5.43) increased the odds for IBD, whereas measles infection increased the odds for UC (OR, 3.50; 95% CI, 1.15-10.6). Low consumption of fibres and high consumption of sugar were significantly associated with development of CD and UC. Smoking increased the risk for CD and protected against UC. CONCLUSION: Among Danish patients with CD and UC belonging to an unselected cohort, disease occurrence was found to be associated both with well-known factors such as smoking and appendectomy, and with more debated factors including breastfeeding, tonsillectomy, childhood vaccinations, childhood infections, and dietary intake of fibres and sugar.

Genetic and environmental factors as predictors of disease severity and extent at time of diagnosis in an inception cohort of inflammatory bowel disease, Copenhagen County and City 2003-2005.

BACKGROUND AND AIMS: The etiology of the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) remains unknown. We aimed to investigate the influence of genetic, serological, and environmental factors on phenotypic presentation of IBD at diagnosis in a population-based Danish inception cohort from 2003-2005. METHODS: Three-hundred-forty-seven (62%) of 562 cohort patients were genotyped. ASCA and p/c-ANCA were determined and patients answered a questionnaire concerning environmental factors with possible influence on IBD. RESULTS: Fourteen percent of CD patients vs. 11% of controls were positive for common CARD15 mutation (ns), whereas more CD patients than healthy controls were homozygous for the OCTN-TC haplotype (p=0.03). ASCA was more common in CD (22%) than UC (14%) (p=0.045) and was related to age and localization of CD. p-ANCA was more frequent in UC (p=0.00001) but was related to pure colonic CD (p=0.0001). Sugar consumption was significantly higher in CD patients than in UC patients (p=0.0001) and more CD patients than UC patients had undergone appendectomy prior to IBD diagnosis (p=0.03). A possible relation between tonsillectomy and disease severity in CD, and a relation between use of oral contraception and disease localization of UC to rectum/left-sided colon were found. CONCLUSIONS: In this cohort of unselected IBD patients we found a very low frequency of mutations in IBD susceptibility genes and observed a greater impact of ASCA and ANCA than of genetic factors on disease phenotypes. In addition, several environmental factors seemed to influence disease occurrence and disease presentation in both UC and especially CD.