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1.  Long-term impact of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on body weight and glycemic control in Japanese type 2 diabetes: an observational study 
Background
Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been shown to possess pleiotropic effects including body weight reduction. However, long-term effect of liraglutide on body weight and glycemic control has not been elucidated in Japanese type 2 diabetes (T2D) subjects. Present study investigates whether liraglutide treatment maintains the body weight-decreasing and glucose-lowering effects for 2 years in Japanese T2D subjects.
Methods
The enrolled subjects were 86 T2D patients [age; 59.8 ± 12.8 years, duration of diabetes; 15.8 ± 9.5 years, glycated hemoglobin (HbA1c); 8.5 ± 1.5%, body mass index (BMI); 27.3 ± 5.4 kg/m2 (15.8 - 46.5 kg/m2), mean ± SD]. Among 86 subjects, liraglutide was introduced in 25 inpatients and 61 outpatients, and 46 subjects were followed for 2 years. Clinical parameters were measured at baseline and 3, 6, 9, 12, and 24 months after liraglutide introduction. The increase in liraglutide dosage and the additional usage of glucose-lowering agents depended on each attending physician.
Results
At 1 year after liraglutide introduction, 69 patients (80.2%) decreased body weight and 58 patients (67.4%) improved glycemic control. Body mass index (BMI) was changed 27.3 ± 5.4 kg/m2 to 25.9 ± 4.8 kg/m2 and percent reduction of body weight was significant and maintained over 4% at 2 years after liraglutide introduction. HbA1c was significantly decreased from 8.5 ± 1.5% to 7.7 ± 1.2% for 2 years. Liraglutide treatment tended to ameliorate lipid profile and hepatic enzymes. Stepwise regression analysis demonstrated that baseline BMI and previous insulin dose were positively associated with body weight reduction and baseline HbA1c was positively associated with reduction of HbA1c at 2 years after liraglutide introduction.
Conclusions
Long-term liraglutide treatment effectively maintained the reduction of body weight and the fair glycemic control, and also improved lipid profile and liver enzymes in Japanese T2D subjects.
doi:10.1186/1758-5996-6-95
PMCID: PMC4167135  PMID: 25237400
Liraglutide; Glucagon-like peptide-1; Obesity; Diabetes; Metabolic syndrome; Eating behavior
2.  Short-term effects of liraglutide on visceral fat adiposity, appetite, and food preference: a pilot study of obese Japanese patients with type 2 diabetes 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1475-2840-10-109
PMCID: PMC3260096  PMID: 22132774
liraglutide; glucagon-like peptide-1; obesity; eating behavior
3.  Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults 
Introduction:
Mechanisms for liraglutide-induced weight loss are poorly understood.
Objective:
We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals.
Design:
Participants (N=49, 18–75 years, body mass index: 30–40 kg m−2) were randomized to two of three treatments: liraglutide 1.8 mg, 3.0 mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-h energy expenditure (EE) and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters and appetite were assessed during a 5-h meal test. Ad libitum energy intake during a subsequent lunch was also assessed.
Results:
Five-hour gastric emptying (AUC0–300 min) was found to be equivalent for liraglutide 1.8 versus 3.0 mg (primary end point), and for both liraglutide doses versus placebo, as 90% confidence intervals for the estimated treatment ratios were contained within the prespecified interval (0.80–1.25). However, 1-h gastric emptying was 23% lower than placebo with liraglutide 3.0 mg (P=0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8 mg (P=0.14). Both liraglutide doses similarly reduced fasting glucose (0.5–0.6 mmol l−1 versus placebo, P<0.0001), glucose Cmax and 1-h AUC versus placebo; only liraglutide 3.0 mg reduced iAUC0–300 min (by ∼26% versus placebo, P=0.02). Glucagon iAUC0–300 min decreased by ∼30%, and iAUC0–60 min for insulin and C-peptide was ∼20% lower with both liraglutide doses versus placebo. Liraglutide doses similarly increased mean postprandial satiety and fullness ratings, reduced hunger and prospective food consumption and decreased ad libitum energy intake by ∼16%. Liraglutide-associated reductions in EE were partly explained by a decrease in body weight. A relative shift toward increased fat and reduced carbohydrate oxidation was observed with liraglutide. Clinicaltrials.gov ID:NCT00978393. Funding: Novo Nordisk.
Conclusion:
Gastric emptying AUC0–300 min was equivalent for liraglutide 1.8 and 3.0 mg, and for liraglutide versus placebo, whereas reductions in 1-h gastric emptying of 23% with liraglutide 3.0 mg and 13% with 1.8 mg versus placebo were observed. Liraglutide 3.0 mg improved postprandial glycemia to a greater extent than liraglutide 1.8 mg. Liraglutide-induced weight loss appears to be mediated by reduced appetite and energy intake rather than increased EE.
doi:10.1038/ijo.2013.162
PMCID: PMC4052428  PMID: 23999198
postprandial glucose; energy intake; energy expenditure; substrate oxidation; weight management
4.  Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1475-2840-11-142
PMCID: PMC3533748  PMID: 23153177
Liraglutide; Abdominal obesity; Insulin therapy; Weight reduction
5.  Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin‐secreting capacity 
Abstract
Aims/Introduction:  Recently, glucagon‐like peptide‐1 (GLP‐1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide‐effective patients from liraglutide‐ineffective patients.
Materials and Methods:  We reviewed 23 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with diet plus insulin (or plus oral antidiabetic drugs) to improve fasting plasma glucose (FPG) and postprandial glucose below 150 and 200 mg/dL, respectively. After insulin secretion and insulin resistance were evaluated, insulin was replaced by liraglutide. The efficacy of liraglutide was determined according to whether glycemic control was maintained at the target levels.
Results:  Liraglutide was effective in 13 of 23 patients. There were significant differences in the parameters of insulin secretion, including fasting C‐peptide (F‐CPR), C‐peptide index (CPI), insulinogenic index (I.I.) and urine C‐peptide (U‐CPR), between liraglutide‐effective and ‐ineffective patients. The duration of diabetes was significantly shorter in liraglutide‐effective patients than in liraglutide‐ineffective patients. In receiver operating characteristic analyses, the cut‐off value for predicting the efficacy of liraglutide was 0.14 for I.I., 1.1 for CPI, 1.5 ng/mL for F‐CPR, 33.3 μg/day for U‐CPR and 19.5 years for duration of type 2 diabetes.
Conclusions:  Insulin secretion evaluated by F‐CPR, CPI, I.I., U‐CPR and the duration of type 2 diabetes were useful parameters for predicting the efficacy of liraglutide in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00168.x, 2011)
doi:10.1111/j.2040-1124.2011.00168.x
PMCID: PMC4014952  PMID: 24843579
Glucagon‐like peptide‐1; Incretin; Type 2 diabetes
6.  Clinical experience with Liraglutide in 196 patients with type 2 diabetes from a tertiary care center in India 
Context:
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.
Aims:
(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.
Results:
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%).
Conclusion:
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.
doi:10.4103/2230-8210.126572
PMCID: PMC3968738  PMID: 24701434
GLP-1 receptor agonists; India; obesity; type 2 diabetes
7.  Chronic Administration of the Glucagon-Like Peptide-1 Analog, Liraglutide, Delays the Onset of Diabetes and Lowers Triglycerides in UCD-T2DM Rats 
Diabetes  2010;59(10):2653-2661.
OBJECTIVE
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/db09-1564
PMCID: PMC3279561  PMID: 20622169
8.  Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD) 
Diabetes Care  2009;32(7):1224-1230.
OBJECTIVE
To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes.
RESEARCH DESIGN AND METHODS
This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m2.
RESULTS
Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient.
CONCLUSIONS
Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.
doi:10.2337/dc08-2124
PMCID: PMC2699702  PMID: 19289857
9.  The once‐daily human glucagon‐like peptide‐1 analog, liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes 
Abstract
Aims/Introduction:  β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide.
Materials and Methods:  Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m2) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B).
Results:  Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) insulin 0–3 h was improved (P < 0.001 for all) and the AUCinsulin 0–3 h:AUCglucose 0–3 h ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups.
Conclusions:  In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)
doi:10.1111/j.2040-1124.2012.00193.x
PMCID: PMC4019260  PMID: 24843595
Insulin‐secreting cells; Liraglutide; Type 2 diabetes
10.  Liraglutide therapy beyond glycemic control: an observational study in Indian patients with type 2 diabetes in real world setting 
Video abstract
Video
Background
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).
Objective
To assess efficacy and safety of liraglutide in, overweight and obese Indian patients with T2DM.
Methods
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.
Results
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.
Conclusion
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.
doi:10.2147/IJGM.S27886
PMCID: PMC3333831  PMID: 22536087
liraglutide; weight loss; type 2 diabetes; obesity; GLP-1 analog; lipid profile; blood pressure; India
11.  Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes 
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.
doi:10.3164/jcbn.13-14
PMCID: PMC3705157  PMID: 23874074
liraglutide; insulin; glucagon; test meal; continuous glucose monitoring
12.  Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults 
Background:
Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect.
Objective:
To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight.
Design:
A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058).
Subjects:
After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18–65 years, body mass index (BMI) 30–40 kg m−2) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively).
Results:
The intention-to-treat population comprised 561 participants (n=90–98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m−2 (mean±s.d.)). In year 1, more participants reported ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2–3.0 mg (17–38%) than with placebo or orlistat (both 4%, P⩽0.001). Most episodes occurred during dose escalation (weeks 1–6), with ‘mild' or ‘moderate' symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5–5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg.
Conclusion:
Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.
doi:10.1038/ijo.2013.149
PMCID: PMC4010971  PMID: 23942319
GLP-1 analog; liraglutide; nausea; quality of life; vomiting; weight loss
13.  Clinical Effectiveness of Liraglutide Across Body Mass Index in Patients with Type 2 Diabetes in the United States: A Retrospective Cohort Study 
Advances in Therapy  2014;31(9):986-999.
Introduction
Clinical trials have shown that liraglutide effectively lowers glycated hemoglobin A1c (A1C) levels in adult patients with type 2 diabetes (T2D). However, no studies have evaluated the effectiveness of liraglutide by body mass index (BMI) in the United States (US) in clinical practice. This study examined liraglutide’s clinical effectiveness to lower A1C and body weight after 6 months in T2D patients stratified by baseline BMI.
Methods
This was a retrospective cohort study using the General Electric Centricity electronic medical records database. Adult patients with T2D (≥18 years and BMI≥ 25 kg/m2) and A1C >7% at baseline who started liraglutide between January 1, 2010 and January 31, 2013 and who did not use insulin or a glucagon-like peptide-1 analog 12 months before initiating liraglutide (N = 3,005) were selected. Changes from baseline, stratified by BMI, in A1C, body weight, A1C <7% goal attainment, and incidence of severe hypoglycemia at 6-month follow-up were examined.
Results
After 6 months, A1C levels decreased on average by 0.95%, 1.02%, 0.99%, and 0.84% for BMI categories 25.0–29.9 (n = 333), 30.0–34.9 (n = 793), 35.0–39.9 (n = 821), and ≥40.0 kg/m2 (n = 1,058), respectively (P = 0.30). The proportions of patients achieving A1C <7% at 6 months were 38.2%, 37.0%, 40.9%, and 41.0% (P = 0.54). The absolute body weight decreased by 1.5 to 4.0 kg across BMI and the rate of severe hypoglycemia (0.2%) was low.
Conclusion
Patients with T2D experienced statistically significant decreases in A1C and body weight after initiating liraglutide regardless of their BMI. Liraglutide reduced A1C equally well across baseline BMI in clinical practice in the US.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0153-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-014-0153-5
PMCID: PMC4176953  PMID: 25245811
Body mass index; Clinical effectiveness; Glycated hemoglobin; Liraglutide; Type 2 diabetes
14.  Efficacy and Safety of Switching From the DPP-4 Inhibitor Sitagliptin to the Human GLP-1 Analog Liraglutide After 52 Weeks in Metformin-Treated Patients With Type 2 Diabetes 
Diabetes Care  2012;35(10):1986-1993.
OBJECTIVE
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.
RESULTS
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.
CONCLUSIONS
Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.
doi:10.2337/dc11-2113
PMCID: PMC3447855  PMID: 22851600
15.  Liraglutide administration in type 2 diabetic patients who either received no previous treatment or were treated with an oral hypoglycemic agent showed greater efficacy than that in patients switching from insulin 
Abstract
Aims/Introduction
Liraglutide, a glucagon‐like peptide‐1 receptor agonist, is expected to provide a new treatment option for diabetes. However, the suitable timing of liraglutide administration in type 2 diabetic patients has not yet been clarified.
Materials and Methods
We reviewed type 2 diabetic patients (n = 155) who visited the Osaka Red Cross Hospital for glycemic control, with administration of liraglutide at a dose of 0.6 mg (average glycated hemoglobin [HbA1c] level, 8.7 ± 0.1%). The effect of liraglutide based on the pretreatment status was compared. We also analyzed the background factors of both a successful and failed group of patients who switched to liraglutide from insulin.
Results
An improvement in blood glucose levels was confirmed in 122 of 155 patients. During the 4‐month observation period, the improvement in HbA1c levels was significantly greater in the group of drug‐naïve/previous oral hypoglycemic agent (9.1 ± 0.2 to 7.2 ± 0.2%) than that in the group switching from insulin (8.6 ± 0.2 to 7.8 ± 0.2%). In addition, C‐peptide immunoreactivity levels (fasting > 2.2 ng/mL; delta >1.6 ng/mL; urine > 70 μg/day), younger age and a smaller number of insulin units used per day were considered important when deciding on switching to liraglutide from insulin.
Conclusions
Liraglutide was more effective in patients who had not been treated previously or received oral hypoglycemic agents than in patients switching from insulin. With respect to switching to liraglutide from insulin, the most important factors to be considered were C‐peptide immunoreactivity levels, age, and the number of insulin units used per day.
doi:10.1111/j.2040-1124.2012.00242.x
PMCID: PMC4019290  PMID: 24843633
Glucagon‐like peptide‐1; Incretin; Type 2 diabetes
16.  Liraglutide in Adults with Type 2 Diabetes: Global Perspective on Safety, Efficacy and Patient Preference 
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.
doi:10.4137/CMED.S5976
PMCID: PMC3411533  PMID: 22879794
liraglutide; type 2 diabetes; incretin
17.  Retrospective analysis of safety and efficacy of insulin‐to‐liraglutide switch in Japanese type 2 diabetes: A caution against inappropriate use in patients with reduced β‐cell function 
Abstract
Aims/Introduction
The safety and efficacy of insulin‐to‐liraglutide switch in type 2 diabetes has not been studied adequately. Here, we retrospectively characterize clinical parameters that might predict insulin‐to‐liraglutide treatment switch without termination due to hyperglycemia, and examine the effects of switching the therapies on glycated hemoglobin (HbA1c) and bodyweight in Japanese type 2 diabetes.
Materials and Methods
Japanese type 2 diabetes patients who underwent the switch of therapy were evaluated for their clinical data including β‐cell function‐related indices, such as increment of serum C‐peptide during glucagon stimulation test (GST‐ΔCPR). HbA1c and bodyweight were analyzed in patients continuing with liraglutide after switching from insulin for 12 weeks.
Results
Of 147 patients, 28 failed in the switch due to hyperglycemia, nine failed because of other reasons and 110 continued with liraglutide for the 12‐week period. Patients failing in the switch due to hyperglycemia showed longer duration and higher daily insulin dose, as well as lower GST‐ΔCPR. Receiver–operating characteristic analysis showed that GST‐ΔCPR of 1.34 ng/mL is a cut‐off point for insulin‐to‐liraglutide switch without termination due to hyperglycemia. In patients continuing liraglutide for 12 weeks, the switch significantly reduced HbA1c and bodyweight with no severe hypoglycemia, irrespective of sulfonylurea co‐administration, body mass index, duration and total daily insulin dose. The switch also significantly reduced the percentage of body fat and visceral fat areas.
Conclusions
Insulin‐to‐liraglutide switch can improve glycemic control and reduce bodyweight in Japanese type 2 diabetes patients. However, caution must be taken with the switch in patients with reduced insulin secretory capacity as predicted by GST‐ΔCPR.
doi:10.1111/jdi.12111
PMCID: PMC4020254  PMID: 24843713
Glucagon stimulation test; Glucagon‐like peptide‐1 receptor agonist; β‐Cell function
18.  The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide 
Diabetes, Obesity & Metabolism  2012;14(4):304-314.
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.
doi:10.1111/j.1463-1326.2011.01523.x
PMCID: PMC3488291  PMID: 22051096
basal insulin; GLP-1; glycaemic control; type 2 diabetes; weight loss therapy
19.  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.
doi:10.1038/ijo.2011.158
PMCID: PMC3374073  PMID: 21844879
liraglutide; GLP-1 analog; weight loss
20.  Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial 
Diabetologia  2009;52(10):2046-2055.
Aims/hypothesis
The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride.
Methods
This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA1c 7.5–10%) and combination therapy (7.0–10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA1c. Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times.
Results
The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA1c significantly vs glargine (1.33% vs 1.09%; −0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (−1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference –1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference −3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (−4.0 mmHg) vs glargine (+0.5 mmHg; −4.5 mmHg difference, 95% CI 6.8, −2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies.
Conclusions/interpretation
Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA1c was within the predefined non-inferiority margin.
Trial registration: ClinicalTrials.gov NCT00331851
Funding: The study was funded by Novo Nordisk A/S.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-009-1472-y) contains a list of members of the LEAD-5 Study Group, which is available to authorised users.
doi:10.1007/s00125-009-1472-y
PMCID: PMC2744824  PMID: 19688338
DPP-4; Exenatide; Incretin; Insulin glargine; LEAD-5
21.  Four Weeks of Treatment With Liraglutide Reduces Insulin Dose Without Loss of Glycemic Control in Type 1 Diabetic Patients With and Without Residual β-Cell Function 
Diabetes Care  2011;34(7):1463-1468.
OBJECTIVE
To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual β-cell function.
RESEARCH DESIGN AND METHODS
Ten type 1 diabetic patients with residual β-cell function (C-peptide positive) and 19 without (C-peptide negative) were studied. All C-peptide–positive patients were treated with liraglutide plus insulin, whereas C-peptide–negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy. Continuous glucose monitoring with identical food intake and physical activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA1c; time spent with blood glucose <3.9, >10, and 3.9–9.9 mmol/L; and body weight were evaluated.
RESULTS
Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P < 0.001) in C-peptide–positive patients and from 0.72 ± 0.08 to 0.59 ± 0.06 units/kg per day (P < 0.01) in C-peptide–negative patients treated with liraglutide but did not change with insulin monotherapy. HbA1c decreased in both liraglutide-treated groups. The percent reduction in daily insulin dose was positively correlated with β-cell function at baseline, and two patients discontinued insulin treatment. In C-peptide–positive patients, time spent with blood glucose <3.9 mmol/L decreased from 3.0 to 1.0 h (P = 0.03). A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] −2.3 ± 0.3 kg [−0.5 to −5.1]; P < 0.001). Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide.
CONCLUSIONS
Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control.
doi:10.2337/dc11-0096
PMCID: PMC3120168  PMID: 21593296
22.  A Retrospective Audit of Type 2 Diabetes Patients Prescribed Liraglutide in Real-Life Clinical Practice 
Diabetes Therapy  2013;4(1):147-151.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s13300-013-0025-z
PMCID: PMC3687089  PMID: 23715814
Audit; Glucagon-like peptide-1; Glycemic control; Liraglutide; Type 2 diabetes
23.  One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial 
Aim
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1742-1241.2011.02656.x
PMCID: PMC3085127  PMID: 21355967
24.  Carbohydrate restricted diet in conjunction with metformin and liraglutide is an effective treatment in patients with deteriorated type 2 diabetes mellitus: Proof-of-concept study 
Background
Type 2 diabetes mellitus is a chronic progressive disease. During the course of the disease intensive treatment is often necessary resulting in multiple interventions including administration of insulin. Although dietary intervention is highly recommended, the clinical results of the widely prescribed diets with low fat content and high carbohydrates are disappointing. In this proof-of-concept study, we tested the effect of dietary carbohydrate-restriction in conjunction with metformin and liraglutide on metabolic control in patients with type 2 diabetes.
Methods
Forty patients with type 2 diabetes already being treated with two oral anti-diabetic drugs or insulin treatment and who showed deterioration of their glucose metabolism (i.e. HbA1c >7.5), were treated. A carbohydrate-restricted diet and a combination of metformin and liraglutide were instituted, after stopping either insulin or oral anti-diabetic drugs (excluding metformin). After enrollment, the study patients were scheduled for follow-up visits at one, two, three and six months. Primary outcome was glycemic control, measured by HbA1c at six months. Secondary outcomes were body weight, lipid-profile and treatment satisfaction.
Results
Thirty-five (88%) participants completed the study. Nearly all participating patients experienced a drop in HbA1c and body weight during the first three months, an effect which was maintained until the end of the study at six months. Seventy-one percent of the patients reached HbA1c values below 7.0%. The range of body weight at enrollment was extreme, reaching 165 kg as the highest initial value. The average weight loss after 6 months was 10%. Most patients were satisfied with this treatment. During the intervention no significant change of lipids was observed. Most patients who were on insulin could maintain the treatment without insulin with far better metabolic control.
Conclusions
Carbohydrate restriction in conjunction with metformin and liraglutide is an effective treatment option for patients with advanced diabetes who are candidates for instituting insulin or who are in need of intensified insulin treatment. This proof-of-principle study showed a significant treatment effect on metabolic control.
doi:10.1186/1743-7075-8-92
PMCID: PMC3278381  PMID: 22196251
25.  Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes 
Diabetes Care  2009;32(1):84-90.
OBJECTIVE—The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy.
RESEARCH DESIGN AND METHODS—In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25–79 years) had type 2 diabetes, A1C of 7–11% (previous OAD monotherapy for ≥3 months) or 7–10% (previous OAD combination therapy for ≥3 months), and BMI ≤40 kg/m2.
RESULTS—A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8–2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide (∼3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11–19% of the liraglutide-treated subjects versus 3–4% in the placebo and glimepiride groups. The incidence of nausea declined over time.
CONCLUSIONS—In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.
doi:10.2337/dc08-1355
PMCID: PMC2606836  PMID: 18931095

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