Once-daily Human GLP-1 Analogue Research Articles

Erratum: Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

Correction to: International Journal of Obesity 36: 843–854; doi:10.1038/ijo.2011.158 Since publication of this article the authors have noticed the following errors. The original article has not been amended with these corrections. In the analysis of covariance analyses used in the paper, two different approaches were used in the model estimation of least square (LS) means.

Erratum: Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analogue, liraglutide

Erratum: Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analogue, liraglutide

The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species.

Glucagon-like peptide (GLP)-1 analogs have been implicated as a risk factor for pancreatitis in humans. We investigated whether liraglutide, the once-daily human GLP-1 analog, induces pancreatitis in rats, mice, and monkeys. Pancreata from mice, rats, and nonhuman primates were examined macro- and microscopically. Evaluation of preneoplastic proliferative lesions in the pancreata from nonhuman primates was performed. After 2 years of treatment, 3 of 79 male mice in the control group and 2, 1, 1, and 1 mice in the different liraglutide groups (of 67–79 mice per group) had pancreatitis based on microscopic criteria. For females, the numbers were 0 of 79 mice in the control group and 3 mice in all the liraglutide groups (of 66–76 mice per group). Pancreatitis was not the cause of death in any animals. There were no cases of pancreatitis, macroscopically or microscopically, in 400 rats. Neither pancreatitis nor preneoplastic proliferative lesions was found in monkeys dosed for 87 weeks, with plasma liraglutide exposure 60-fold higher than that observed in humans at the maximal clinical dose. In conclusion, liraglutide did not induce pancreatitis in mice, rats, or monkeys when dosed for up to 2 years and at exposure levels up to 60 times higher than in humans.

Effect of the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes

AimsLiraglutide reduces bodyweight in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanisms underlying this effect. MethodsThe comparative effects of liraglutide, glimepiride and placebo on energy intake, appetite, nausea, gastric emptying, antral distension, bodyweight, gastrointestinal hormones, fasting plasma glucose and resting energy expenditure (REE), were assessed in subjects with T2DM randomised to treatment A (liraglutide–placebo), B (placebo–glimepiride) or C (glimepiride–liraglutide). Assessments were performed at the end of each 4-week treatment period. ResultsEnergy intake was less (NS) with liraglutide vs placebo and glimepiride, and 24-h REE was higher (NS) with liraglutide vs placebo and glimepiride. Fasting hunger was less (p=0.01) with liraglutide vs placebo and glimepiride, and meal duration was shorter with liraglutide (p=0.002) vs placebo. Paracetamol AUC0–60min and Cmax were less (p<0.01) and fasting peptide YY was lower (p≤0.001) after liraglutide vs placebo and glimepiride. Bodyweight reductions of 1.3 and 2.0kg were observed with liraglutide vs placebo and glimepiride (p<0.001). There were no differences on antral distension, nausea, or other gastro-intestinal hormones. ConclusionLiraglutide caused decreased gastric emptying and increased reduction in bodyweight. The mechanisms of the liraglutide-induced weight-loss may involve a combined effect on energy intake and energy expenditure.

The Pharmacokinetics, Pharmacodynamics, and Tolerability of Liraglutide, a Once-Daily Human GLP-1 Analogue, After Multiple Subcutaneous Administration in Healthy Chinese Male Subjects

In this single-center, randomized, double-blind, within dose group, placebo-controlled, dose escalation trial, the pharmacokinetics, pharmacodynamics, tolerability, and safety of liraglutide were evaluated in 37 healthy Chinese subjects. Subjects were randomized to 1 of 3 dose groups (0.6, 1.2, or 1.8 mg), and within each group, randomized to liraglutide or placebo (3:1). All subjects started at 0.6 mg liraglutide (or placebo) once daily for 1 week, and the dose was increased for dose groups 1.2 mg and 1.8 mg in weekly steps of 0.6 mg to the predefined dose targets. Liraglutide or placebo was administered once daily by subcutaneous injection for 21 consecutive days. The dose relationships of AUC(0-24h), C(max), and C(trough) at steady state do not deviate in a relevant way from dose proportionality. t(max) and t(1/2) were 8 hours (median) and 11.2 to 12.2 hours (geometric mean), respectively. The plasma glucose levels in all liraglutide groups were decreased, while reduced serum insulin level was observed in the 1.2- and 1.8-mg groups after liraglutide treatment. The most common adverse events were of gastrointestinal origin. Other adverse events were comparable between the liraglutide and placebo groups. Liraglutide was well tolerated in healthy Chinese subjects. No major safety concerns were identified.

Treatment With Liraglutide-a Once-Daily GLP-1 Analog-Does Not Reduce the Bioavailability of Ethinyl Estradiol/Levonorgestrel Taken as an Oral Combination Contraceptive Drug

Liraglutide is a once-daily human GLP-1 analog for treatment of type 2 diabetes. Like other GLP-1 analogs, liraglutide delays gastric emptying, which could potentially affect absorption of concomitantly administered oral drugs. This study investigated the effect of liraglutide on the pharmacokinetics of the components of an oral contraceptive (ethinyl estradiol/levonorgestrel). Postmeno-pausal healthy women (n = 21) were included. A single dose of this contraceptive was administered. Blood samples for ethinyl estradiol/levonorgestrel measurements were drawn until 74 hours post dosing of the contraceptive during liraglutide and placebo treatments. The 90% confidence interval (CI) of the ratio of the area under the curve (AUC) (1.06; 90% CI, 0.99-1.13) for ethinyl estradiol (during liraglutide and placebo) was within defined limits, demonstrating equivalence. The 90% CI for the ratio of AUC for levonorgestrel was not fully contained within the limits (1.18; 90% CI, 1.04-1.34) (levonorgestrel AUC was 18% greater with liraglutide vs placebo). However, equivalence was demonstrated for levonorgestrel AUC(0-t) (1.15; 90% CI, 1.06-1.24). Equivalence was not demonstrated for maximum concentration (C(max)); values for ethinyl estradiol and levonorgestrel C(max) were 12% and 13% lower with liraglutide versus placebo, respectively. Both reached C(max) ~1.5 hours later with liraglutide. No clinically relevant reduction in bioavailability of ethinyl estradiol/levonorgestrel occurred.

Comparison of the Efficacy and Tolerability Profile of Liraglutide, a Once-Daily Human GLP-1 Analog, in Patients With Type 2 Diabetes ≥65 and

Background Managing elderly patients with type 2 diabetes poses particular challenges, so it is important to evaluate the efficacy and tolerability profile of antidiabetic therapies specifically in this patient population. Objective The aim of our study was to compare the efficacy and tolerability profile of liraglutide, a GLP-1 analog, in elderly (≥65 years) and younger (<65 years) patients with type 2 diabetes. Methods A pooled analysis of 6 randomized, placebo-controlled, multinational trials included data from 3967 patients aged18 to 80 years with type 2 diabetes and glycosylated hemoglobin (HbA 1c) of 7% to 11%. Of these, 552 patients ≥65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo; 2231 patients <65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo for 26 weeks. End points were: change in HbA 1c, fasting plasma glucose, body weight, and blood pressure: as marked to identify elements tracked for change from baseline; hypoglycemic episodes; and adverse events. Results Reduction in HbA 1c from baseline was significantly greater with liraglutide 1.8 mg versus placebo (least squares mean difference: ≥65 years, 0.91% [95% CI, 0.69–1.12]; <65 years, 1.17% [95% CI, 1.06–1.28]; both, P < 0.0001) and with liraglutide 1.2 mg versus placebo (≥65 years, 0.87% [95% CI, 0.64–1.11]; <65 years, 1.10% [95% CI, 0.98–1.22]; both, P < 0.0001). For fasting plasma glucose, comparable results were observed between liraglutide 1.8 mg or 1.2 mg and placebo for both age groups ( P < 0.0001). No statistically significant difference in body weight change was seen with liraglutide between the age groups. The proportion of patients reporting minor hypoglycemia was low and appeared comparable between the ≥65-year-old (4.3%–15.2%) and <65-year-old (8%–13.2%) groups. Likewise, adverse events appeared comparable in nature and frequency. Conclusion Liraglutide provides effective glycemic control and is well tolerated in patients ≥65 and <65 years of age with type 2 diabetes. These data suggest that liraglutide may be a suitable treatment option for older patients who may have additional age-related complications.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

Objective:Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.Design:A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.Subjects:A total of 564 adults (n=90–98 per group; body mass index 30–40 kg m−2) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90–95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007–April 2009 and is registered with Clinicaltrials.gov, number NCT00480909.Results:From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7–8.0) more weight than those on placebo and 3.8 kg (1.6–6.0) more than those on orlistat (P⩽0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3–4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids.Conclusion:Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Liraglutide - overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes

Type 2 diabetes is characterized by a progressive decline in glycaemic control. Many standard diabetes treatments, however, fail to achieve or maintain glycaemic control, and are often associated with an increased risk of hypoglycaemia and weight gain. Recently developed incretin-based therapies are a promising addition to the current armamentarium of diabetes treatments. Two types of incretin-based therapies are currently available: glucagon-like peptide (GLP)-1 receptor agonists (liraglutide and exenatide) and dipeptidyl peptidase-4 inhibitors (sitaglipin, vildagliptin and saxagliptin). This review aims to summarize the key efficacy and safety data of liraglutide, a once-daily human GLP-1 analogue. Extensive phase III clinical trials have shown liraglutide to improve glycaemic control with additional benefits on body weight, blood pressure and β-cell function. Liraglutide is also generally well tolerated with a low risk of hypoglycaemia. Liraglutide has recently been approved for marketing in Europe, Japan and the USA.

Liraglutide, a once-daily human GLP-1 analogue, reduces systolic blood pressure within 2 weeks in patients with type 2 diabetes

Liraglutide, a once-daily human GLP-1 analogue, reduces systolic blood pressure within 2 weeks in patients with type 2 diabetes

Pharmacology of GLP-1-based therapies

Glucagon-like peptide-1 GLP-1 is a naturally occurring 30-amino acid peptide synthesised in intestinal endocrine L cells. GLP-1 mediates glucose homeostasis through stimulation of glucose-dependent insulin secretion, biosynthesis of insulin and inhibition of glucagon secretion. These effects have potential clinical value in type 2 diabetes. However, because native GLP-1 is rapidly degraded to its inactive form by dipeptidyl peptidase-4 (DPP-4), it has a short half-life in vivo . Strategies to overcome this therapeutic limitation include developing GLP-1 mimetics and analogues with longer half-lives and to inhibit DPP-4. Exenatide (exendin-4) is a 39-amino acid peptide originally derived from the venom of the Gila monster lizard, and shares a 53% sequence identity with human GLP-1. Exenatide has a longer circulating half-life, reflecting relative resistance to DPP-4 degradation, and is administered twice daily. Liraglutide is a once-daily human GLP-1 analogue with high (97%) sequence identity. The specific structural modifications that characterise liraglutide result in increased self-association (allowing slow absorption from the subcutaneous depot), promote albumin binding and reduce susceptibility to DPP-4, giving liraglutide a half-life of 13 hours after once-daily administration. Preliminary studies of exenatide and liraglutide show clinically relevant reductions in glycosylated haemoglobin A1c (HbA1c) compared with placebo, without hypoglycaemia and with weight loss of up to 3 kg. DPP-4 inhibitors, such as vildagliptin (not available in the USA) and sitagliptin can help stabilise postprandial GLP-1 levels and thus produce desirable effects on insulin and glucagon production. The potential for weight reduction with DPP-4 inhibitors appears limited, perhaps reflecting the limited increase in GLP-1 levels achieved with these agents.Br J Diabetes Vasc Dis, 2008;8 (Suppl 2) : S10—S18

Patient‐reported rating of gastrointestinal adverse effects during treatment of type 2 diabetes with the once‐daily human GLP‐1 analogue, liraglutide

Diabetes, Obesity and MetabolismVolume 10, Issue 7 p. 593-596 Patient-reported rating of gastrointestinal adverse effects during treatment of type 2 diabetes with the once-daily human GLP-1 analogue, liraglutide M. Horowitz, Corresponding Author M. Horowitz Department of Medicine, North Terrace, Royal Adelaide Hospital, Adelaide, AustraliaMichael Horowitz, Department of Medicine, Level 6, Eleanor Harrald Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.E-mail:michael.horowitz@adelaide.edu.auSearch for more papers by this authorT. Vilsbøll, T. Vilsbøll Department of Internal Medicine F, Gentofte Hospital, Copenhagen, DenmarkSearch for more papers by this authorM. Zdravkovic, M. Zdravkovic Novo Nordisk A/S, Bagsværd, DenmarkSearch for more papers by this authorM. Hammer, M. Hammer Novo Nordisk A/S, Bagsværd, DenmarkSearch for more papers by this authorS. Madsbad, S. Madsbad Department of Endocrinology, Hvidovre University Hospital, University of Copenhagen, Hvidovre, DenmarkSearch for more papers by this author M. Horowitz, Corresponding Author M. Horowitz Department of Medicine, North Terrace, Royal Adelaide Hospital, Adelaide, AustraliaMichael Horowitz, Department of Medicine, Level 6, Eleanor Harrald Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.E-mail:michael.horowitz@adelaide.edu.auSearch for more papers by this authorT. Vilsbøll, T. Vilsbøll Department of Internal Medicine F, Gentofte Hospital, Copenhagen, DenmarkSearch for more papers by this authorM. Zdravkovic, M. Zdravkovic Novo Nordisk A/S, Bagsværd, DenmarkSearch for more papers by this authorM. Hammer, M. Hammer Novo Nordisk A/S, Bagsværd, DenmarkSearch for more papers by this authorS. Madsbad, S. Madsbad Department of Endocrinology, Hvidovre University Hospital, University of Copenhagen, Hvidovre, DenmarkSearch for more papers by this author First published: 28 June 2008 https://doi.org/10.1111/j.1463-1326.2008.00861.xCitations: 19Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume10, Issue7July 2008Pages 593-596 RelatedInformation

The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats.Female Sprague–Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3±7.0 versus 593.2±13.2g, p<0.01), body weight (306.6±4.2 versus 276.4±3.6 g, p<0.001), subcutaneous inguinal fat (3.4±0.3 versus 1.9±0.1 g, p<0.001), mesenteric fat (3.1±0.2 versus 1.7±0.2g, p<0.001), retroperitoneal fat (6.2±0.6 versus 2.8±0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906±66 versus 1770±28 mM×min, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8±20.4 g, p<0.01; body weight: 280.2±5.6 g, p<0.001; subcutaneous inguinal fat: 2.4±0.2 g, p<0.001; mesenteric fat: 1.8±0.1 g, p<0.001; retroperitoneal fat: 3.5±0.4 g, p<0.001; AUC: 1764±32 mM×min, p<0.05).In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study

Liraglutide is a once-daily human GLP-1 analog being developed as a Type 2 diabetes therapy. A dose-finding study in Japanese patients with Type 2 diabetes showed liraglutide to produce dose-dependent decreases in HbA(1C). Studies have also shown that, with stepped dose titration, liraglutide is well tolerated. This double-blind trial in 24 healthy Japanese men assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily subcutaneous (s.c.) liraglutide using doses exceeding those previously studied, and using the stepped titration approach. Subjects were randomized to three groups in each of which 6 received liraglutide, and 2 placebo for 35 consecutive days. The daily dose of liraglutide was stepped from 5 microg/kg (s.c. abdomen, morning) to 10 and then 15 microg/kg at 7-day intervals. One group remained at this dose, the others titrating further to 20 and 25 microg/kg, respectively. Subjects remained at the study site from Day 21 until the end of the trial, with standard meals served during inhouse periods. No safety issues, hypoglycemia, gastrointestinal or any other adverse events were observed. Liraglutide showed dose-dependent increases in the pharmacokinetic parameters of AUC0-24 h, C(max) and C(trough), while t(max), t(1/2) and V(d/F) were constant. Mean plasma glucose concentrations were similar across all treatment groups at baseline, but dose-dependent decreases in mean and postprandial plasma glucose were seen with liraglutide, although all values remained within normal ranges. There was a tendency for weight to decrease with liraglutide in comparison to placebo. Liraglutide appears to be well tolerated at doses of up to 25 microg/kg in Japanese subjects. Despite clear pharmacodynamic effects in this euglycemic cohort, a low risk for hypoglycemia was suggested together with good gastrointestinal tolerability.

Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: A double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes

Aims To evaluate dose–response efficacy and safety of once-daily human GLP-1 analog liraglutide in Japanese subjects with type 2 diabetes. Methods Patients (226, treated with diet with/without OADs, mean HbA 1c 8.30%, mean BMI 23.9 kg/m 2) were randomized after OAD discontinuation and washout to receive liraglutide 0.1, 0.3, 0.6 or 0.9 mg once daily, or placebo in double-blind, parallel-group design for 14 weeks. Results Liraglutide dose levels reduced HbA 1c versus placebo (by 0.79%, 1.22%, 1.64% and 1.85%, respectively; p < 0.0001 for linear contrast). Liraglutide 0.9 mg/day resulted in 75% of patients achieving HbA 1c <7.0% and 57% achieving HbA 1c <6.5%. There were no major or minor hypoglycemic events. Liraglutide also reduced, with significant dose–response (each p < 0.0001 for linear contrast) versus placebo: fasting plasma glucose (up to 2.5 mmol/L), postprandial (0–3 h) glucose excursion (up to 12.8 mmol/(L h)); and increased postprandial insulin secretion (up to 23.0 μU/(mL h)) and beta-cell function as evaluated by HOMA-β (up to around 20.0 (μU/mL)/(mg/dL)). Body weight was unchanged; no development of liraglutide antibodies was detected. Conclusions Liraglutide was highly effective and well tolerated at doses up to 0.9 mg/day in Japanese patients with type 2 diabetes, allowing glycemic control without weight gain or hypoglycemia.

Significantly Better Glycemic Control and Weight Reduction with Liraglutide, a Once-daily Human GLP-1 Analog, Compared with Insulin Glargine: All as Add-on to Metformin and a Sulfonylurea in Type 2 Diabetes.

A 26-week, randomized trial compared the efficacy and safety of liraglutide (lira; 1.8 mg, QD), lira placebo (plb) and open label insulin glargine (glar), all as add-on to metformin (met; 1 mg, BID) and glimepiride (glim; 2–4 mg QD). 581 subjects were randomized (mean age 57.5±9.9; mean BMI 30.5±5.3 kg/m2 mean HbA1c 8.2±0.9 %). Lira+met+glim reduced HbA1c more than glarg and plb in combination with met and glim (ANCOVA, p=0.0015; p<0.0001) and more of the subjects in the lira group reached HbA1c ≤6.5% (p<0.0001). Estimated weight difference between lira and glar groups was −3.4 kg (p<0.0001) and −1.4 kg between lira and plb groups (p=0.0001). Glar was individually titrated according to a patient-driven algorithm, and the average dose of glar was 24 IU/day at end of trial. Most common AEs in the lira group were GI disorders (mainly nausea). Nausea occurred in ~15% of subjects in the lira group, but was transient. Frequency of minor hypoglycemic episodes (<56 mg/dL) were similar for the lira and glar groups and more frequent than in the plb group. Five subjects reported major hypoglycemic events in the lira group (only one required medical assistance; none resulted in coma or seizure). Presence of lira antibodies was 9.8%. Lira+met and a sulfonylurea (SU) was generally well tolerated and statistically significantly improved glycemic control, and reduced body weight in comparison to met and an SU alone and to glar added to met and an SU. Tabled 1 lira1.8+met+glim plb+met+glim glar+met+glim Final HbA1c, % (SE)Change HbA1c, % (SE) 7.0 (1.0)-1.33 (0.09)*^ 8.1 (1.3)-0.24 (0.11) 7.2 (0.9)-1.09 (0.09) % HbA1c S6.5% 37.1*^ 10.9 23.6 Weight change, kg (SE) −1.81 (0.33)*^ −0.42 (0.39) 1.62 (0.33) Final FPG, mg/dL (SE)Change FPG, mg/dL 137.7 (39.3)-27.92* 180.2 (51.4)9.56 133.2 (38.1)-32.16 % reporting minor hypo events 27.4 16.7 28.9 % reporting nausea 13.9 3.5 1.3 Week 26 FPG titration targets reached: 100 mg/dL (% subjects)120 mg/dL (% subjects) 47 (20.26)93 (40.09) *Statistically significant compared to: *met+glim; ^glar+met+glim Open table in a new tab *Statistically significant compared to: *met+glim; ^glar+met+glim

Liraglutide, a Once-daily Human GLP-1 Analog, In Type 2 Diabetes Provides Similar Glycem1c Control with Reduced Body Weight Compared with Glimepiride when Added to Metformin.

This placebo-controlled (plb), double-blind, randomized 26-week trial investigated the effect on glycem1c control (HbA1c) of three liraglutide doses (lira; 0.6, 1.2 or 1.8 mg sc, qD) added to metformin (met; 1 g BD) compared with met monotherapy (plb+met) or glimepiride (glim, 4 mg QD) added to met (glim+met). The trial included 1091 subjects with T2DM previously treated with oral antidiabet1c drug (OAD) mono-therapy (35%) or combination therapy (65%), with mean±SD baseline HbA1c 8.4±1.0% and body weight (BW) 88.6±17.3 kg. HbA1c was signif1cantly reduced in all lira groups vs plb+met. Reduction in HbA1c was greater in subjects previously treated with OAD mono vs combination therapy. The fraction of subjects achieving HbA1C<7.0% or ≤6.5% was signif1cantly higher in lira+met vs plb+met, with no difference between lira+met vs glim+met. Change in fasting plasma glucose followed the same pattern as for HbA1c. BW decreased signif1cantly in all lira groups vs glim+met. Reduction in BW was signif1cantly greater in lira1.2+met and lira1.8+met vs plb+met. Presence of lira antibodies was 0-4% (only patients not entering the extension phase of the study were included: lira0.6, n=28; lira1.2, n=25; lira1.8, n=32). Minor hypoglycemia (<3.1 mmol/L) occurred in <4% of subjects in lira+met and plb+met, and in 16.9% in glim+met. There was no major hypoglycemia. The most common adverse events in lira+met were GI disorders (mainly nausea). Nausea initially occurred in 6-12% of subjects in lira+met, declining to plb+met levels (2%) after 8–16 weeks' treatment. Liraglutide was well tolerated, produced a clin1cally signif1cant reduction in HbA1c, and in contrast to met+glim resulted in few hypoglycemec episodes and weight loss in T2DM subjects. Tabled 1 Lira 0.6 mg+met Lira 1.2 mg+met Lira 1.8 mg+met Plc+met Glim+met Final HbA1c, % (8D) a No statistical analysis. Change HbA1c, % (SE) 7.8 (1.1)-0.7 (0.1) * p<0.05 compared to plb+met 7.5 (1.1)-1.0 (0.1) * p<0.05 compared to plb+met 7.5 (1.2)-1.0 (0.1) * p<0.05 compared to plb+met 8.6 (1.4)+ 0.1 (0.1) 7.5 (1.1)-1.0 (0.1) Mono/combi changeHbA1c, % (SD) a No statistical analysis. −0.8 (0.8)/ -0.5 (1.1) -1.3 (1.2)/ -0.6 (0.9) -1.3 (1.1)/ -0.7 (1.1) −0.5 (1.3)/ + 0.5 (1.0) -1.1 (0.8)/ -0.8 (1.0) % HbA1c <7.0% HbA1c ≤6.5 28.0 * p<0.05 compared to plb+met † p<0.05 compared to glim+met 11.3 * p<0.05 compared to plb+met † p<0.05 compared to glim+met 35.3 * p<0.05 compared to plb+met 19.8 * p<0.05 compared to plb+met 42.4 * p<0.05 compared to plb+met 24.6 * p<0.05 compared to plb+met 10.84.2 36.322.2 Final FPG, mmol/L (SD) a No statistical analysis. Change FPG, mmol/L (SE) 9.1 (2.6)-1.1 (0.2) * p<0.05 compared to plb+met 8.4 (2.6)-1.6 (0.2) * p<0.05 compared to plb+met 8.5 (2.3)-1.7 (0.2) * p<0.05 compared to plb+met 10.7 (57)+ 0.4 (0.2) 8.8 (2.4)-1.3 (0.2) Weight change, kg (SE) -1.8 (0.2) † p<0.05 compared to glim+met −2.6 (0.2) * p<0.05 compared to plb+met † p<0.05 compared to glim+met −2.8 (0.2) * p<0.05 compared to plb+met † p<0.05 compared to glim+met -1.5 (0.3) +1.0 (0.2) % minor hypos reported a No statistical analysis. 3.3 0.8 2.5 2.5 16.9 * p<0.05 compared to plb+met † p<0.05 compared to glim+met a No statistical analysis. Open table in a new tab

Liraglutide, a Once-daily Human GLP-1 Analog, In Type 2 Diabetes Provides Similar Glycemic Control with Reduced Body Weight Compared with Glimepiride when Added to Metformin.

This placebo-controlled (plb), double-blind, randomized 26-week trial investigated the effect on glycemic control (HbA1c) of three liraglutide doses (lira; 0.6, 1.2 or 1.8 mg sc, QD) added to metformin (met; 1 g BD) compared with met monotherapy (plb+met) or glimepiride (glim, 4 mg QD) added to met (glim+met). The trial included 1091 subjects with T2DM previously treated with oral antidiabetic drug (OAD) mono-therapy (35%) or combination therapy (65%), with mean±SD baseline HbA1c 8.4±1.0% and body weight (BW) 88.6±17.3 kg. HbA1c was significantly reduced in all lira groups vs plb+met. Reduction in HbA1c was greater in subjects previously treated with OAD mono vs combination therapy. The fraction of subjects achieving HbA1c<7.0% or <6.5% was significantly higher in lira+met vs plb+met, with no difference between lira+met vs glim+met. Change in fasting plasma glucose followed the same pattern as for HbA1c. BW decreased significantly in all lira groups vs glim+met. Reduction in BW was significantly greater in lira1.2+met and lira1.8+met vs plb+met. Presence of lira antibodies was 0-4% (only patients not entering the extension phase of the study were included: lira0.6, n=28; lira1.2, n=25; lira1.8, n=32). Minor hypoglycemia (<3.1 mmol/L) occurred in <4% of subjects in lira+met and plb+met, and in 16.9% in glim+met. There was no major hypoglycemia. The most common adverse events in lira+met were GI disorders (mainly nausea). Nausea initially occurred in 6-12% of subjects in lira+met, declining to plb+ met levels (2%) after 8–16 weeks' treatment. Liraglutide was well tolerated, produced a clinically significant reduction in HbA1c, and in contrast to met+glim resulted in few hypoglycemic episodes and weight loss in T2DM subjects. Tabled 1 Lira 0.6 mg + met Lira 1.2 mg + met Lira 1.8 mg + met Plc + met Glim + met Final HbA1c, % (SD) a No statistical analysis Change HbA1c, % (SE) 7.8 (1.1)−0.7 (0.1) * p<0.05 compared to plb+met 7.5 (1.1)−1.0 (0.1) * p<0.05 compared to plb+met 7.5 (1.2)−1.0 (0.1) * p<0.05 compared to plb+met 8.6 (1.4)+ 0.1 (0.1) 7.5 (1.1)−1.0 (0.1) Mono/combi changeHbA1c, % (SD) a No statistical analysis −0.8 (0.8)/−0.5 (1.1) −1.3 (1.2)/−0.6 (0.9) −1.3 (1.1)/−0.7 (1.1) −0.5 (1.3)/+ 0.5 (1.0) −1.1 (0.1)/−0.8 (1.0) % HbA1c <7.0% HbA1c <6.5 28.0 * p<0.05 compared to plb+met † p<0.05 compared to glim+met 11.3 * p<0.05 compared to plb+met † p<0.05 compared to glim+met , 35.3 * p<0.05 compared to plb+met 19.8 * p<0.05 compared to plb+met 42.4 * p<0.05 compared to plb+met 24.6 * p<0.05 compared to plb+met 10.84.2 36.322.2 Final FPG, mmol/L (SD) a No statistical analysis Change FPG, mmol/L (SE) 9.1 (2.6)−1.1 (0.2) * p<0.05 compared to plb+met 8.4 (2.6)−1.6 (0.2) * p<0.05 compared to plb+met 8.5 (2.3)−1.7 (0.2) * p<0.05 compared to plb+met 10.7 (57)+ 0.4 (0.2) 8.8 (2.4)−1.3 (0.2) Weight change, kg (SE) −1.8 (0.2) † p<0.05 compared to glim+met −2.6 (0.2) * p<0.05 compared to plb+met † p<0.05 compared to glim+met −2.8 (0.2) * p<0.05 compared to plb+met † p<0.05 compared to glim+met −1.5 (0.3) +1.0 (0.2) % minor hypos reported a No statistical analysis 3.3 0.8 2.5 2.5 16.9 * p<0.05 compared to plb+met † p<0.05 compared to glim+met a No statistical analysis Open table in a new tab