To examine the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on visceral fat adiposity, appetite, food preference, and biomarkers of cardiovascular system in Japanese patients with type 2 diabetes.
The study subjects were 20 inpatients with type 2 diabetes treated with liraglutide [age; 61.2 ± 14.0 years, duration of diabetes; 16.9 ± 6.6 years, glycated hemoglobin (HbA1c); 9.1 ± 1.2%, body mass index (BMI); 28.3 ± 5.2 kg/m2, mean ± SD]. After improvement in glycemic control by insulin or oral glucose-lowering agents, patients were switched to liraglutide. We assessed the estimated visceral fat area (eVFA) by abdominal bioelectrical impedance analysis, glycemic control by the 75-g oral glucose tolerance test (OGTT) and eating behavior by the Japan Society for the Study of Obesity questionnaire.
Treatment with liraglutide (dose range: 0.3 to 0.9 mg/day) for 20.0 ± 6.4 days significantly reduced waist circumference, waist/hip ratio, eVFA. It also significantly improved the scores of eating behavior, food preference and the urge for fat intake and tended to reduce scores for sense of hunger. Liraglutide increased serum C-peptide immunoreactivity and disposition index.
Short-term treatment with liraglutide improved visceral fat adiposity, appetite, food preference and the urge for fat intake in obese Japanese patients with type 2 diabetes.
liraglutide; glucagon-like peptide-1; obesity; eating behavior
The authors discuss the strategy of use of incretin hormones in type 2 diabetes treatment in the context of cardiovascular complications. The results of the phase III study on human GLP-1 (Glucagon-like peptide-1) analogue-liraglutide have been presented under common acronym LEAD (Liraglutide-Effect and Action In Diabetes). The liraglutide therapy improved glycemic control with low hypoglycemia risk and decreased glycated hemoglobin by an average 1,13%. Decreases in systolic pressure and significant body weight loss were observed. Not only did the index describing beta cells function HOMA-B improve but also did the ratio of insulin to proinsulin. Summing up, incretin hormones beneficially influence blood glucose level, moreover, their use decreases blood pressure and body weight which might indicate their positive influence on cardiovascular system in diabetic patients.
Liraglutide is a glucagon-like peptide-1 analog with pharmacokinetic properties suitable for once-daily administration approved by the Food and Drug Administration for the treatment of patients with type 2 diabetes. Clinical trial data from large, controlled studies demonstrate the safety and efficacy of liraglutide in terms of hemoglobin A1c (HbA1c) reduction, reductions in body weight, and the drug’s low risk for hypoglycemic events when used as monotherapy. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase III trials. Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in HbA1c and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with incretin analog therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia when used with non-secretagogue medications. Data to date on patient-reported outcomes with liraglutide treatment are encouraging. The most common adverse events associated with liraglutide therapy are dose-dependent nausea, vomiting, and diarrhea. Diligent postmarketing surveillance to elucidate the risk of pancreatitis and medullary thyroid carcinoma in a heterogeneous population are likely warranted.
incretin analog; incretin effect; liraglutide; diabetes
GLP-1 receptor agonists (GLP-1 RA) are unique antidiabetic agents that have the ability to lower blood glucose without causing hypoglycemia, while at the same time promoting weight loss. Information on the efficacy and safety of GLP-1 RA in the Indian diabetic population is limited.
(1) To evaluate the effect of GLP-1 RA, Liraglutide on glycemic control, and weight in obese Indian patients with type 2 diabetes. (2) To study the adverse event profile of Liraglutide in these patients in real-world clinical setting.
Settings and Design:
Observational study conducted in a tertiary care hospital.
Materials and Methods:
Liraglutide was prescribed to 196 obese patients with type 2 diabetes who had poor glycemic control on oral medications ± insulin. The initial dose of Liraglutide was 0.6 mg, which was up-titrated to 1.2 mg after 1 week; further up-titration to 1.8 mg was done based on tolerance. Dipeptidyl peptidase-IV (DPP-IV) inhibitors were discontinued and dose of other medications adjusted according to clinical judgment during the study period.
Mean age of patients was 49.9 ± 9.6 years. Three month data were available for 175 patients out of a total of 196. At 3 months, glycosylated hemoglobin (HbA1c) was 7.6 ± 0.9% vs. 9.2 ± 1.9% at baseline (P = 0.007) and mean body weight was 96.0 ± 16.5 kg vs. 100.1 ± 17.5 kg at baseline (P < 0.001). Most common adverse events were nausea, burping, and eructation (10%).
Liraglutide significantly improves glycemic control with low risk of hypoglycemia and is associated with significant weight loss in obese Indian patients with type 2 diabetes mellitus.
GLP-1 receptor agonists; India; obesity; type 2 diabetes
In phase 3 trials, the once-daily human glucagon-like peptide-1 analog liraglutide provided effective glycemic control with low rates of hypoglycemia, weight loss, and reduced systolic blood pressure (SBP) in patients with type 2 diabetes. Through a retrospective clinical audit, the authors aimed to assess the clinical effectiveness of liraglutide, from initiation to first hospital visit, when prescribed at a center in Northern Ireland.
Patients attending Ulster Hospital who were prescribed liraglutide (June 2009–September 2010) and assessed both at baseline and first post-initiation visit were included in the analysis. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline. Weight, blood pressure, and frequency of hypoglycemic events were also assessed.
Data from 193 patients are reported (baseline HbA1c 9.0%, mean age 55.8 years, diabetes duration 8.8 years, 66.8% male). Average time to first visit after initiation was 13.5 weeks, at which point 174 patients (90.2%) were prescribed 1.2 mg liraglutide. Mean change in HbA1c from initiation to first visit was −0.9%, while mean body weight change was −2.4 kg and change in SBP was −2.0 mmHg. Transient gastrointestinal side effects were experienced by 11.9% of patients. The number of patients experiencing minor hypoglycemic events was low (5.7%) and no major events were reported.
Data from clinical studies translate into clinical practice: liraglutide provided improved glycemic control after 13.5 weeks of treatment, accompanied by weight loss and low incidence of hypoglycemia.
Audit; Glucagon-like peptide-1; Glycemic control; Liraglutide; Type 2 diabetes
Liraglutide, a human glucagon-like peptide-1 receptor agonist, decreases glycosylated hemoglobin and causes weight loss. However, the cost of therapy and gastrointestinal side- effects such as nausea and diarrhea are important impediments to adherence and long-term compliance. We assessed the efficacy, safety and tolerability of low dose (0.6 mg) liraglutide in obese uncontrolled longstanding type 2 diabetes in Indian patients. Low dose liraglutide improved glycemic control and decreased weight. However, there was a significant drop out because of gastrointestinal intolerance and financial constraints.
India; liraglutide; type 2 diabetes
The efficacy of liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, to prevent or delay diabetes in UCD-T2DM rats, a model of polygenic obese type 2 diabetes, was investigated.
RESEARCH DESIGN AND METHODS
At 2 months of age, male rats were divided into three groups: control, food-restricted, and liraglutide. Animals received liraglutide (0.2 mg/kg s.c.) or vehicle injections twice daily. Restricted rats were food restricted to equalize body weights to liraglutide-treated rats. Half of the animals were followed until diabetes onset, whereas the other half of the animals were killed at 6.5 months of age for tissue collection.
Before diabetes onset energy intake, body weight, adiposity, and liver triglyceride content were higher in control animals compared with restricted and liraglutide-treated rats. Energy-restricted animals had lower food intake than liraglutide-treated animals to maintain the same body weights, suggesting that liraglutide increases energy expenditure. Liraglutide treatment delayed diabetes onset by 4.1 ± 0.8 months compared with control (P < 0.0001) and by 1.3 ± 0.8 months compared with restricted animals (P < 0.05). Up to 6 months of age, energy restriction and liraglutide treatment lowered fasting plasma glucose and A1C concentrations compared with control animals. In contrast, liraglutide-treated animals exhibited lower fasting plasma insulin, glucagon, and triglycerides compared with both control and restricted animals. Furthermore, energy-restricted and liraglutide-treated animals exhibited more normal islet morphology.
Liraglutide treatment delays the development of diabetes in UCD-T2DM rats by reducing energy intake and body weight, and by improving insulin sensitivity, improving lipid profiles, and maintaining islet morphology.
Background. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. Aims. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. Methods. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. Results. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, P < 0.01). On the other hands, the body weight significantly increased in pioglitazone group and did not change in sitagliptin group. Multivariate regression analysis indicated that administration of liraglutide as an independent factor of body weight reduction for more than 5% (OR 9.04; 95% CI 1.12–73.1, P = 0.04). Conclusions. Administration of liraglutide improved T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight.
Type 2 diabetes is characterized by a progressive decline in beta cell function, with consequent worsening of glycemic control. The ideal antihyperglycemic treatment should achieve good and sustained glycemic control, with a low risk of hypoglycemia and no weight gain. This paper reviews the efficacy and tolerability of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes. Once-daily injection of liraglutide (at doses of 1.2 mg and 1.8 mg), as monotherapy or in combination with one or two oral antihyperglycemic agents, was associated with greater improvements in glycemic control compared with active comparators or placebo in several controlled, randomized Phase III trials, including the six trials of the LEAD (Liraglutide Effect and Action in Diabetes) program. Liraglutide also improved beta cell function, body weight, systolic blood pressure, and lipid profile, thereby achieving many of the goals of ideal antihyperglycemic therapy. Liraglutide was generally well tolerated in the Phase III trials. The most common adverse events were nausea, vomiting, and diarrhea, usually of mild to moderate intensity. The observed rate of pancreatitis was low and comparable with that of the general diabetic population. In conclusion, although most trials were relatively short and focused on surrogate endpoints, liraglutide emerges as an effective and well tolerated treatment for type 2 diabetes, carrying a low risk of hypoglycemia, weight loss, and possible reduction of cardiovascular risk.
body weight; hypoglycemia; cardiovascular; incretin
This study assessed the endocrine pancreatic responses to liraglutide (0.9 mg once a day) during normal living conditions in Japanese patients with type 2 diabetes. The study included 14 hospitalized patients with type 2 diabetes. Meal tests were performed after improvement of glycemic control achieved by two weeks of multiple insulin injection therapy and after approximately two weeks of liraglutide treatment. Continuous glucose monitoring was performed to compare daily variation in glycemic control between multiple insulin injection therapy and liraglutide treatment. Liraglutide reduced plasma glucose levels after the test meals (60–180 min; p<0.05), as a result of significant increases in insulin secretion (0–180 min; p<0.05) and decreases in the incremental ratio of plasma glucagon (15–60 min; p<0.05). Continuous glucose monitoring showed that liraglutide treatment was also associated with a decrease in glucose variability. We also demonstrated that optimal glycemic control seen as a reduction in 24-h mean glucose levels and variability was obtained only with liraglutide monotherapy. In conclusion, liraglutide treatment increases insulin secretion and suppresses glucagon secretion in Japanese patients with type 2 diabetes under normal living conditions. The main therapeutic advantages of liraglutide are its use as monotherapy and its ability to decrease glucose variability.
liraglutide; insulin; glucagon; test meal; continuous glucose monitoring
To evaluate the efficacy of switching from insulin to the GLP-1 receptor agonist liraglutide in type 2 diabetes mellitus patients.
The subjects were 231 outpatients with type 2 diabetes mellitus being treated with liraglutide for the first time. For 161 patients, liraglutide was continued for 24 weeks (continuation group), and for 70 patients, liraglutide was discontinued before 24 weeks (discontinuation group). Fasting and postprandial blood glucose levels, HbA1c, body weight, and insulin dose were evaluated before the switch to liraglutide (baseline) and at 12 and 24 weeks of administration. Trends in HbA1c and weight were compared at 12 and 24 weeks of administration. Multiple regression analyses were conducted to identify clinical factors predicting a successful switch to liraglutide.
Multiple regression analysis with ΔHbA1c as the dependent variable in the continuation group indicated that HbA1c at 12 weeks of administration decreased with higher baseline HbA1c and increased with higher baseline daily insulin doses. Multiple regression analysis with Δweight as the dependent variable indicated that Δweight at 24 weeks of liraglutide administration was higher with higher baseline daily insulin doses and longer duration of diabetes. Based on the area under the receiver operating characteristic curve, cut-off values of 19 units for daily insulin dose and nine years for duration of diabetes were identified.
Switching from insulin to liraglutide therapy is possible for carefully selected patients. Daily insulin dosage and duration of insulin therapy appear to be clinically useful indicators for the efficacy of liraglutide therapy.
Type 2 diabetes mellitus; HbA1c; GLP-1 receptor agonist; Liraglutide; Hypoglycemia
To assess the efficacy and safety of adding liraglutide to established insulin therapy in poorly controlled Chinese subjects with type 2 diabetes and abdominal obesity compared with increasing insulin dose.
A 12-week, randomized, parallel-group study was carried out. A total of 84 patients completed the trial who had been randomly assigned to either the liraglutide-added group or the insulin-increasing group while continuing current insulin based treatment. Insulin dose was reduced by 0-30% upon the initiation of liraglutide. Insulin doses were subsequently adjusted to optimized glycemic control. Glycosylated hemoglobin (HbA1c) values, blood glucose, total daily insulin dose, body weight, waist circumference, and the number of hypoglycemic events and adverse events were evaluated.
At the end of study, the mean reduction in HbA1c between the liraglutide-added group and the insulin-increasing group was not significantly different (1.9% vs. 1.77%, p>0.05). However, the percentage of subjects reaching the composite endpoint of HbA1c ≤ 7.0% with no weight gain and no hypoglycemia, was significantly higher in the liraglutide-added group than in the insulin-increasing group (67% vs. 19%, p<0.001). Add-on liraglutide treatment significantly reduced mean body weight (5.62 kg, p<0.01), waist circumference (5.70 cm, p<0.01), body mass index (BMI) (1.93 kg/m2, p<0.01) and daily total insulin dose (dropped by 66%) during 12-week treatment period, while all of these significantly increased with insulin increasing treatment. Add-on liraglutide treated patients had lower rate of hypoglycemic events and greater insulin and oral antidiabetic drugs discontinuation. Gastrointestinal disorders were the most common adverse events in the liraglutide added treatment, but were transient.
Addition of liraglutide to abdominally obese, insulin-treated patients led to improvement in glycemic control similar to that achieved by increasing insulin dosage, but with a lower daily dose of insulin and fewer hypoglycemic events. Adding liraglutide to insulin also induced a significant reduction in body weight and waist circumference. Liraglutide combined with insulin may be the best treatment option for poorly controlled type 2 diabetes and abdominal obesity.
Liraglutide; Abdominal obesity; Insulin therapy; Weight reduction
Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH.
Methods and analysis
Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis.
Ethics and dissemination
The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations.
Clinical Pharmacology; Histopathology
Treatment with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, which target the incretin axis, has the potential to improve glycemic control in type 2 diabetes patients without the weight gain associated with traditional therapies. To evaluate the relative cost-effectiveness of incretin therapies, the present study aimed to compare the long-term clinical and cost implications associated with liraglutide and sitagliptin in type 2 diabetes patients in Spain.
Data were taken from a randomized, controlled trial (NCT00700817) in which adults with type 2 diabetes failing metformin monotherapy were randomly allocated to receive either liraglutide 1.2 mg or sitagliptin 100 mg daily in addition to metformin. Long-term projections of clinical outcomes and direct costs (2012 EUR) based on observed treatment effects were made using a published and validated type 2 diabetes model. Costs were taken from published sources. Future costs and clinical benefits were discounted at 3% annually. Sensitivity analyses were performed.
Liraglutide was associated with improved discounted life expectancy (14.05 versus 13.91 years) and quality-adjusted life expectancy [9.04 versus 8.87 quality-adjusted life years (QALYs)] compared to sitagliptin. Improved clinical outcomes were driven by improved glycemic control, leading to reduced incidence of diabetes-related complications, including renal disease, cardiovascular disease, ophthalmic and diabetic foot complications. Liraglutide was associated with increased direct costs of EUR 2,297, yielding an incremental cost-effectiveness ratio of EUR 13,266 per QALY gained versus sitagliptin.
Liraglutide was projected to improve life expectancy, quality-adjusted life expectancy and reduce incidence of diabetes-related complication. Liraglutide is likely to be cost-effective versus sitagliptin from a healthcare payer perspective in Spain.
Cost; Cost-effectiveness; DPP-4; GLP-1; Incretin; Liraglutide; Sitagliptin; Spain; Type 2 diabetes
Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist. Liraglutide is presently used in the treatment of selected patients with type 2 diabetes mellitus (T2DM).
To assess efficacy and safety of liraglutide in, overweight and obese Indian patients with T2DM.
A single center, prospective, open-labeled, single-arm, observational study for 24 weeks in a real-world setting. Fourteen overweight and obese patients with T2DM who were clinically suitable for liraglutide therapy received liraglutide injections. The starting dose of liraglutide (Victoza) injection was 0.6 mg/day for 3 days followed by 1.2 mg for next 10 days and finally 1.8 mg/day for 22 weeks. Patients were evaluated at baseline and after 12 and 24 weeks of therapy. Adverse events (AE) noted during course of therapy were recorded. A repeated measure analysis of variance was performed to assess statistical significance.
Fourteen patients were studied for 24 weeks. After 24 weeks of liraglutide therapy, mean fasting and postprandial plasma glucose decreased by 48.5 mg/dL and 66.71 mg/dL, respectively (P = 0.002 and P = 0004 over 24 weeks, respectively). A mean reduction of 2.26% of glycosylated hemoglobin was noted (P < 0.001 over 24 weeks). Mean decrease in body weight of 8.65 kg and mean decrease in body mass index of 3.26 kg/m2 was noted (P < 0.001 over 24 weeks for each parameter). Systolic blood pressure was reduced by 15.15 mm of Hg (P = 0.004). Significant improvement in total cholesterol, low-density lipoprotein, triglycerides, and serum creatinine was noted. Nine patients reported AEs. The AEs noticed were nausea (n = 6), feeling of satiety (n = 3), and vomiting (n = 1). No serious AE or hypoglycemic episodes were observed.
Liraglutide once a day improved overall glycemic control and was well tolerated. Clinically significant reduction in body weight, systolic blood pressure and improvement in lipid profile were noticed with liraglutide therapy in addition to glycemic control.
liraglutide; weight loss; type 2 diabetes; obesity; GLP-1 analog; lipid profile; blood pressure; India
Incretin-based therapies have been gaining much attention recently as a new class of therapeutics for type 2 diabetes worldwide. Among them, glucagon-like peptide-1 receptor agonist liraglutide has been rapidly increasing its global usage. Once daily injection of liraglutide significantly ameliorates glycemic control in patients with type 2 diabetes by enhancing insulin secretion and suppressing glucagon secretion glucose-dependently. Liraglutide delays gastric emptying and suppresses food intakes, both of which contribute to glucose lowering and weight reduction. Efficacy and safety of liraglutide in management of type 2 diabetes have been well documented in several key clinical trials such as series of phase 3 Liraglutide Effect and Action in Diabetes (LEAD) trials, and the liraglutide-versus-sitagliptin trial. Recent two trials dealing with monotherapy and sulfonylurea combination therapy on Japanese patients with type 2 diabetes furthermore indicate liraglutide’s effectiveness in non-obese diabetes. In this review, we summarize results from such clinical trials, and discuss efficacy and safety of liraglutide in management of type 2 diabetes in various countries, along with a pitfall of liraglutide usage in real clinical setting.
liraglutide; type 2 diabetes; incretin
Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown.
A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound.
After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholesterol increased by 18% (p < 0.01 for all lipid changes). Carotid IMT decreased from 1.19 ± 0.47 to 0.94 ± 0.21 mm (p < 0.01). Yet, changes in carotid IMT did not correlate with changes in any other variable studied.
Liraglutide decreases carotid IMT after 8 months treatment independently of its effect on plasma glucose and lipids concentrations.
Liraglutide; Carotid intima-media thickness; Cardiovascular risk; Type2 diabetes
Liraglutide is a long-acting analog of GLP-1, being developed by Novo Nordisk and currently undergoing regulatory review for the treatment of type 2 diabetes. Upon injection, liraglutide binds non-covalently to albumin, giving it a pharmacokinetic profile suitable for once-daily administration. In clinical trials of up to 1 year duration, liraglutide has been demonstrated to have beneficial effects on islet cell function, leading to improvements in glycemic control. Both fasting and postprandial glucose concentrations are lowered, and are associated with lasting reductions in HbA1c levels. Liraglutide is effective as monotherapy and in combination therapy with oral antidiabetic drugs, and reduces HbA1c by up to ∼1.5% from baseline (8.2%–8.4%). Because of the glucose-dependency of its action, there is a low incidence of hypoglycemia. Liraglutide is associated with body weight loss, and reductions in systolic blood pressure have been observed throughout the clinical trials. The most common adverse events reported with liraglutide are gastrointestinal (nausea, vomiting and diarrhea). These tend to be most pronounced during the initial period of therapy and decline with time. Further clinical experience with liraglutide will reveal its long-term durability, safety and efficacy.
liraglutide; GLP-1; incretin mimetic; type 2 diabetes
To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes.
RESEARCH DESIGN AND METHODS
In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged.
Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA1c) by −0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, −0.2%, P = 0.006; 1.8 mg/day, −0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, −0.8 mmol/L, P = 0.0004; 1.8 mg/day, −1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, −1.6 kg; 1.8 mg/day, −2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA1c <7% (from ∼30% to ∼50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3–4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA1c (baseline 8.3 and 8.4%, respectively) by −0.9 and −1.3%, respectively; FPG by −1.3 and −1.7 mmol/L, respectively; and weight by −2.6 and −3.1 kg, respectively, with 9–10% of participants reporting minor hypoglycemia.
Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.
Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. It is based on human GLP-1 with the addition of a 16-carbon fatty acid, which facilitates binding to plasma proteins, thus prolonging the elimination half-life and allowing once-daily administration. It has not been possible to quantify liraglutide protein binding by ultrafiltration (the usual method of choice), as the lipophilic molecule becomes trapped in the filter membrane. Therefore, the aim of this study was to develop a methodology that could determine the extent of liraglutide binding to plasma proteins in vitro. We report here the details of a novel reiterated stepwise equilibrium dialysis assay that has successfully been used to quantify liraglutide plasma protein binding. The assay allowed quantification of liraglutide binding to proteins in purified plasma protein solutions and human plasma samples and was effective at plasma dilutions as low as 5%. At a clinically relevant liraglutide concentration (104 pM), greater than 98.9% of liraglutide was bound to protein. Specific binding to human serum albumin and α1-acid glycoprotein was 99.4% and 99.3%, respectively. The novel methodology described herein could have an application in the quantification of plasma protein binding of other highly lipophilic drug molecules.
liraglutide; type 2 diabetes mellitus; protein binding; plasma proteins; human serum albumin; in vitro method; equilibrium dialysis; insulin detemir; acylated peptides
The aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes.
In an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day (n= 225), liraglutide 1.8 mg/day (n= 221) or sitagliptin 100 mg/day (n= 219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension.
Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA1c from baseline (8.4–8.5%) to 52 weeks: −1.29% and −1.51% vs. −0.88% respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: −0.40% (95% confidence interval −0.59 to −0.22) for 1.2 mg and −0.63% (−0.81 to −0.44) for 1.8 mg (both p < 0.0001). Weight loss was greater with liraglutide 1.2 mg (−2.78 kg) and 1.8 mg (−3.68 kg) than sitagliptin (−1.16 kg) (both p < 0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p = 0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks.
Liraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports.
Background and aims
Liraglutide treatment can improve glycemic control with a concomitant weight loss, but the underlying mechanism on weight loss is not completely understood. Cardiac natriuretic peptides (NPs) can resist body fat accumulation through increasing adipocytes lypolysis. In this study, we tested the hypothesis that liraglutide-induced weight loss was associated with increased plasma NPs concentrations.
Thirty-one outpatients with type 2 diabetes (T2D) treated with metformin and other oral antidiabetic drugs except for thiazolidinediones (TZDs) were subcutaneously administered with liraglutide for 12 weeks. Body composition, abdominal visceral adipose tissue areas (VAT) and subcutaneous adipose tissue areas (SAT) were assessed at pre- and post-treatment by dual-energy X-ray absorptiometry (DXA) scanning and abdominal computerized tomography (CT). Plasma atrial natriuretic peptides (ANP) and B-type ventricular natriuretic peptides (BNP) concentrations were tested by commercial ELISA Kit quantitatively.
Following 12-week liraglutide treatment, body weight, waist circumference, total fat and lean mass, fat percentage, SAT and VAT areas were significantly reduced from baseline. Concurrently, plasma ANP and BNP levels were significantly increased following 12-week liraglutide treatment. There were significant correlations between the reductions in body compositions and the increases in both plasma ANP and BNP levels.
There were significant correlations between increases in both plasma ANP and BNP levels and changes in liraglutide-induced body composition. Our data implied that increases in plasma NPs may add a novel dimension to explain how liraglutide induces weight loss.
Liraglutide; Body composition; Weight loss; Cardiac natriuretic peptides
In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin.
basal insulin; GLP-1; glycaemic control; type 2 diabetes; weight loss therapy
To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n ≥ 228) or placebo (n = 114) with glimepiride (2–4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes.
In total, 1041 adults (mean ± sd), age 56 ± 10 years, weight 82 ± 17 kg and glycated haemoglobin (HbA1c) 8.4 ± 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study.
Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA1c from baseline, (−1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (−0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (−0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [−2.5 to −2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (−0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (−1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (−0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (−0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%).
Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.
dipeptidyl peptidase-4; glucagon-like peptide-1 receptor agonist; incretin; insulinotropic; thiazolidinedione
Liraglutide is a glucagon-like peptide 1 (GLP-1) analog indicated for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise in adults. Liraglutide lowers blood glucose levels by stimulating insulin secretion and decreasing glucagon release in glucose-dependent manners, increases satiety, and delays gastric emptying. Liraglutide, unlike metformin and insulin, is not approved for use in the pediatric population. We report the successful off-label use of liraglutide in an obese, 16 year old Caucasian female with type 2 diabetes mellitus.