A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus

Clinical Therapeutics/Volume 31, Number 11, 2009

A Review of Efficacy and Safety Data Regarding the Use of Liraglutide, a Once-Daily Human Glucagon-Like Peptide 1 Analogue, in the Treatment of Type 2 Diabetes Mellitus Eduard Montanya, MD1–3; and Giorgio Sesti, MD4 1Endocrine

Unit, University Hospital of Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain; 2Department of Clinical Sciences, University of Barcelona, Barcelona, Spain; 3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; and 4Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy ABSTRACT Background: Liraglutide, a human glucagon-like peptide 1 (GLP-1) analogue that has received marketing approval from the European Commission, is a treatment for type 2 diabetes mellitus (DM) that is administered as a once-daily subcutaneous injection. Objective: The aim of this review was to summarize the efficacy and safety data published about liraglutide, focusing on data from Phase III clinical trials. Methods: Relevant English-language publications were identified through a search of MEDLINE and EMBASE (from 1948 to October 2009). The search terms included the following: GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and vildagliptin. Original research papers about liraglutide that were published in peer-reviewed journals were considered. Results: The literature search identified 39 relevant publications. The efficacy and tolerability of oncedaily liraglutide at doses of 0.6, 1.2, and 1.8 mg for type 2 DM, in combination with, and compared with, other type 2 DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program. In the LEAD studies, consistent reductions in glycosylated hemoglobin (HbA1c) of up to 1.6% were seen with liraglutide, and up to 66% of patients achieved the HbA1c goal of <7%. Fasting and postprandial plasma glucose levels were also consistently reduced across the LEAD trials by up to 43 mg/dL (2.4 mmol/L) and 49 mg/dL (2.7 mmol/L), respectively. Hypoglycemia was reported at a rate of 0.03 to 1.9 events per patient annually. Liraglutide significantly improved β-cell function, as measured by homeostasis model assessment for β-cell function 2472

analysis (20%–44%) and by ratios of pro-insulin to insulin (–0.11 to 0.01). Consistent reductions in systolic blood pressure up to 6.7 mm Hg were also observed for liraglutide treatment. Liraglutide treatment, as monotherapy and in combination with oral antidiabetic drugs (OADs), was associated with weight loss of up to 3.24 kg. Overall, liraglutide was well tolerated. Nausea was the most common adverse event observed with liraglutide treatment, reported by 5% to 29% of patients; however, nausea was generally mild and transient. Conclusion: Once-daily liraglutide was effective and well tolerated when used as monotherapy or in combination with OADs in patients with type 2 DM, and is therefore a promising new treatment option for the management of type 2 DM. (Clin Ther. 2009;31: 2472–2488) © 2009 Excerpta Medica Inc. Key words: diabetes mellitus, type 2, liraglutide, glucagon-like peptide 1.

INTRODUCTION Type 2 diabetes mellitus (DM) is a progressive disease and its management is associated with several key This work was presented in part at the 68th Scientific Session of the American Diabetes Association, June 6–10, 2008, San Francisco, California; the 44th Annual Meeting of the European Association for the Study of Diabetes, September 7–11, 2008, Rome, Italy; the 12th Annual Professional Conference and Annual Meeting of the Canadian Diabetes Association, October 15–18, 2008, Montreal, Canada; and the 24th International Conference on Pharmacoepidemiology and Therapeutic Risk Management, August 17–20, 2008; Copenhagen, Denmark. Accepted for publication November 5, 2009. doi:10.1016/j.clinthera.2009.11.034 0149-2918/$ - see front matter © 2009 Excerpta Medica Inc. All rights reserved.

Volume 31 Number 11

E. Montanya and G. Sesti challenges that should be taken into consideration when developing new DM treatments.1 Defective β-cell function may be the primary defect in type 2 DM, resulting in deterioration in glycemic control.2 The UK Prospective Diabetes Study (UKPDS) found that, at diagnosis, β-cell function may be compromised by up to 50%,3 although some data suggest that a mere 20% of β-cell function remains by the time of diagnosis.4 It has been reported, however, that impaired β-cell function can be improved if treated in the early stages of the disease.5,6 Treatments that reverse or prevent β-cell decline are, therefore, important for the management of type 2 DM.7 It is well recognized that, over time, deterioration in glycemic control is seen in patients with type 2 DM if interventions are not intensified to keep pace with the declining β-cell function.8,9 However, it is important to achieve and maintain tight glycemic control at all times, because this significantly reduces the risk of DM-related complications.10 Although the cardiovascular (CV) disease benefits of very aggressive glucoselowering interventions have been questioned,11 the UKPDS found that reducing glycosylated hemoglobin (HbA1c) by 1% early in the treatment of patients with type 2 DM was associated with a 37% reduction in the risk of microvascular complications (P < 0.001), a 21% reduction in the risk of DM-related death (P < 0.001), and a 14% reduction in the risk of myocardial infarction (P < 0.001).10 Not all patients with type 2 DM achieve glycemic targets (HbA1c <7%) with standard treatment, however. A survey examining trends in glycemic control between 1999 and 2004 among 1334 US participants with type 2 DM found that, although the percentage of patients achieving glycemic targets (HbA1c <7%) significantly increased from 37% in 1999–2000 to 57% in 2003–2004 (P < 0.000), 43% of patients still did not reach HbA1c targets.12 Another challenge in the treatment of DM is the occurrence of hypoglycemia. Some DM treatments, particularly sulfonylureas (SU) and insulin, are associated with an increased risk of hypoglycemia.9,13 Patients and physicians may be concerned about this increased risk because severe hypoglycemia can lead to unconsciousness, brain damage, or death if untreated.14 Furthermore, patients with type 2 DM are often overweight or obese.15 A number of the currently available treatments, such as insulin, thiazolidinediones, and SU, are associated with weight gain over time,8,9 presentNovember 2009

ing another obstacle to patients trying to comply with standard DM therapies. Indeed, insulin and some SUs have been associated with weight gain of ~2 to ~4 kg.1 On the other hand, metformin, which is often used as first-line treatment, is weight neutral. Treatments that minimize the risk of hypoglycemia and weight gain may have a positive effect on patients’ adherence to therapy.16,17 CV risk management is an important part of type 2 DM treatment. CV risk factors, such as hypertension, are an additional complication associated with DM and obesity. Systolic blood pressure (SBP) increases with the duration of DM.18 Hypertension is a risk factor for DM-related coronary artery disease and mortality from heart disease19,20; a decrease in SBP of only 5.6 mm Hg has been associated with a significant reduction of 18% in the relative risk of death from CV disease.21 Therefore, treatments that improve CV risk factors in patients with type 2 DM are actively sought.

The Incretin Effect Glucagon-like peptide 1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) are naturally occurring hormones that are responsible for the incretin effect, a phenomenon whereby more insulin is secreted in response to glucose ingested after a meal than in response to glucose administered intravenously.22 Research suggests that, among patients with type 2 DM, the incretin effect may be impaired, possibly by reduced levels of active GLP-1, even though GIP concentrations appear to be near normal.23,24 A study evaluating GLP-1 secretion during a 4-hour standard mixed-meal test in 54 patients with type 2 DM, with a mean disease duration of 4.9 years, and 33 matched control subjects with normal glucose tolerance found a significant decrease in GLP-1 response in patients with type 2 DM compared with healthy subjects (mean [SD], 2482 [145] vs 3101 [198] pmol/L in 240 min; P = 0.024).25 In vitro and animal studies have reported that GLP-1 is associated with multiple positive effects on pancreatic β-cells. It has also been reported that GLP-1 regulates the expression of β-cell specific genes,26,27 regulates β-cell mass by inhibiting β-cell apoptosis and preventing β-cell glucolipotoxicity,28,29 and improves β-cell function.30 In clinical studies, it has been reported that exogenous GLP-1 has a beneficial effect on β-cell function 2473

Clinical Therapeutics in patients with type 2 DM.31 Furthermore, GLP-1 stimulates pro-insulin biosynthesis and insulin secretion, increasing both early- and late-phase insulin secretion in patients with type 2 DM.32 The insulin secretory action of GLP-1 is glucose dependent. Furthermore, it has been reported that GLP-1 suppresses glucagon release and hepatic glucose output, leading to maintenance of normal glucose levels in patients with type 2 DM.33,34 GLP-1 also decreases the rate of gastric emptying and acid secretion, and reduces appetite in patients with type 2 DM.31 GLP-1 is, however, rapidly inactivated and degraded intravascularly through N-terminal cleavage by dipeptidyl-peptidase 4 (DPP-4), resulting in a very short t1/2 of 1 to 2 minutes in both patients with type 2 DM and healthy volunteers.35,36 Continuous infusion of GLP-1 would therefore be required to achieve a clinical effect in patients with type 2 DM.37 These biological characteristics of GLP-1 suggest that it may be a promising candidate for the treatment of type 2 DM. However, its short t1/2 limits its treatment utility, and several incretin-based therapies have been developed that overcome this limitation. Exenatide and liraglutide are GLP-1 receptor agonists, and both provide pharmacologic levels of GLP-1 between 100 and 130 pmol/L.32,38 In comparison, physiological levels of GLP-1 in healthy individuals are in the range of 5 to 10 pmol/L in the fasting state and 20 to 40 pmol/L postprandially.39,40 Exenatide is an analogue of exendin-4, a protein with 53% sequence identity to human GLP-1 that is injected twice daily for the treatment of type 2 DM.41,42 Liraglutide is a human GLP-1 analogue with 97% sequence identity to native GLP-1, and is injected once daily for the treatment of type 2 DM.43–45 DPP-4 inhibitors such as sitagliptin and vildagliptin, which inhibit the degradation of GLP-1 and thus preserve physiologic levels, are also marketed for the treatment of type 2 DM.46,47 The European Commission granted marketing authorization for liraglutide throughout the European Union in June 2009.48 This review aims to provide a clear and concise summary of the efficacy and safety data published about liraglutide to date, focusing on data from Phase III clinical trials.

METHODS A literature search was performed using EMBASE and MEDLINE with the search terms GLP-1, incretin effect, liraglutide, NN2211, exenatide, sitagliptin, and 2474

vildagliptin to identify relevant English-language publications (from the year 1948 to October 2009). Original research papers related to liraglutide that were published in peer-reviewed journals were considered. Studies were assessed regarding primary and secondary efficacy parameters and safety assessments.

RESULTS An initial search yielded 4052 potential literature citations. Of those, 3643 citations were excluded by limiting our search to full-text, English-language publications reporting on clinical trials or randomized controlled trials. Thirty-nine publications were considered to be relevant for this review. Liraglutide is an acylated analogue of GLP-1 that has 97% amino acid sequence identity to the endogenous GLP-1 hormone. The t1/2 of liraglutide has been estimated to be 13 hours in both healthy subjects and patients with type 2 DM, making it suitable for once-daily administration.49 Following subcutaneous injection, the fatty acid chain allows liraglutide to selfassociate and form heptamers at the injection site depot.50 It is thought that the size of the heptamer and the drug’s self-association are the most likely mechanisms by which delayed absorption of liraglutide from the subcutis is facilitated. Once in the bloodstream, the fatty acid chain allows reversible binding to serum albumin providing partial stability and resistance to metabolism by DPP-4 and reduces renal clearance. This stability, coupled with albumin binding, gives liraglutide a protracted duration of action, allowing once-daily injection.49–52

Preclinical Studies Liraglutide has been reported to increase β-cell mass in animal models,53,54 and increased β-cell replication and reduced apoptosis may account for treatment effect on β-cell mass. When mice with DM (db/db mice) were exposed to liraglutide, significantly increased β-cell mass (P < 0.05) and β-cell proliferation rate (P < 0.001) were observed in comparison with vehicle, as measured by bromodeoxyuridine incorporation.53 The effect of liraglutide or vehicle treatment on β-cell mass was also evaluated in Zucker diabetic fatty (ZDF) rats. After 6 weeks of treatment, a higher total β-cell mass was observed in ZDF rats treated with liraglutide than in those treated with vehicle (20.9 vs 12.4 mg; P < 0.03).54 Liraglutide has, furthermore, been reported to inhibit β-cell apoptosis in Volume 31 Number 11

E. Montanya and G. Sesti vitro.43 In a recent in vitro study using human pancreatic islet cells, liraglutide promoted β-cell proliferation up to 3-fold after 1 day incubation and inhibited interleukin-1β–induced apoptosis after 4 days of incubation.44 Liraglutide has been reported to be associated with a reduction in food intake in normal and obese rats, resulting in weight loss.45 In normal rats, single doses of liraglutide (50 and 200 μg/kg) were associated with overnight inhibition of food intake compared with administration of vehicle (16.3 and 8.7 g, respectively, vs 22.4 g of food intake; P < 0.05), and obese rats (10.0 and 5.8 g, respectively, vs 12.5 g of food intake; P < 0.05). This decrease in food intake was accompanied by ~15% reduction in body weight. Thus, data from preclinical studies suggest that liraglutide may improve β-cell function, may increase β-cell mass, and may lead to reductions in appetite and body weight. In particular, the effects of liraglutide on β-cell mass, replication, and apoptosis are difficult to measure directly in humans; therefore, results from in vitro and animal models of β-cell function provide important information about the potential of liraglutide in these areas.

Phase II Studies Liraglutide monotherapy, as a single subcutaneous injection of 7.5 μg/kg, improved β-cell responsiveness to increased glucose levels, as measured by the insulin secretion rate (ISR) AUC in a randomized, doubleblind, placebo-controlled, crossover study of 10 patients with type 2 DM (mean [SD] HbA1c: 6.5% [0.8%]; duration of DM: 5.4 [5.7] years).55 An increase of ~70% in the ISR AUC was observed with liraglutide treatment (1130 vs 668 pmol/kg; P < 0.001), and the ISR AUC was similar to that seen in healthy volunteers (1206 pmol/kg). This suggested that liraglutide may have restored β-cell sensitivity to the level that would be anticipated in healthy volunteers. Hypoglycemic events were not reported; however, 1 patient treated with liraglutide experienced mild diarrhea on the day of treatment. Furthermore, in a double-blind, placebo-controlled study of 39 patients with type 2 DM randomized to receive 0.65, 1.25, or 1.9 mg/d liraglutide or placebo for 14 weeks (subcutaneous injection), once-daily liraglutide was associated with improved β-cell insulin secretory capacity.56 An improvement in first- and second-phase insulin secretion was seen. First-phase insulin secretion significantly November 2009

increased by 118% and 103%, respectively, with the 2 highest doses of liraglutide (P < 0.05), and secondphase insulin secretion significantly increased in the 1.25-mg/d liraglutide group compared with placebo (79%; P = 0.005). This may imply that liraglutide improves the biphasic insulin secretion in response to hyperglycemia: an initial rapid increase of insulin to a peak within a few minutes (first phase), followed by a small decrease, and then a gradual increase to a plateau after 2 to 3 hours (second phase).57 As reported in a double-blind, placebo-controlled, randomized, crossover study of 13 patients with type 2 DM,52 the 24-hour AUC of glucagon significantly decreased with liraglutide treatment compared with placebo (2179 vs 2371 pg/mL/h; P = 0.04); this was primarily thought by the investigators to be the result of a significant reduction in postprandial glucagon levels (397.3 vs 470.1 pg/mL/h; P < 0.01). No hypoglycemic events were reported for liraglutide; however, 3 patients experienced a transient gastrointestinal adverse event (AE) during the treatment period.58 In a double-blind, placebo-controlled, crossover study of 11 patients with type 2 DM (mean [SD] HbA1c: 6.5% [0.6%]; duration of DM: 2.7 [3.2] years), gastric emptying was significantly delayed with liraglutide treatment (single injection of 10 μg/kg) compared with placebo, as assessed by AUC1130–1530 of 3-ortho-methylglucose (400 vs 440 mg/L/h; P = 0.02). No hypoglycemic events occurred during this study; however, 2 patients treated with liraglutide experienced mild to moderate nausea on the day of treatment. Thus, these study results suggest that liraglutide may decrease gastrointestinal tract motility and gastric emptying, which may contribute to weight loss and improve postprandial glycemic control.58 Indeed, a mean decrease in body weight of up to 1.2 kg (P < 0.019 vs placebo) was observed for liraglutide 0.45 mg (subcutaneous injection) in a 12-week, double-blind, randomized, parallel-group, placebo-controlled trial of 193 patients with type 2 DM with a mean HbA1c of 7.6% and mean duration of DM of 4.4 years at baseline.59 The investigators also observed a sustained improvement in glycemic control among those receiving liraglutide, with HbA1c reductions of up to 0.75% (P < 0.001 vs placebo). AEs were mild and transient. The most common AE was nausea, with 7.4% and 3.4% of patients treated with liraglutide and placebo, respectively, experiencing nausea. 2475

Clinical Therapeutics

Phase III Studies The Liraglutide Effect and Action in Diabetes (LEAD) program was a Phase III trial program designed to compare the efficacy and tolerability of once-daily liraglutide at doses of 0.6, 1.2, and 1.8 mg with those of standard treatments, alone or in combination with other commonly used oral agents, for type 2 DM. The LEAD program comprised 6 randomized controlled trials (Figure 1) that included 4456 patients recruited in 40 countries (Table I).60–66 Recruitment for these trials has ended, but several extensions are still ongoing. Patient demographics in the 6 studies are summarized in Table II. LEAD-1 (liraglutide + SU vs thiazolidinediones [TZD] + SU)61 and LEAD-2 (liraglutide + metformin vs SU + metformin)62 compared liraglutide in combination with 1 oral antidiabetic drug (OAD) versus standard treatment with 2 OADs;

liraglutide monotherapy was compared with standard OAD therapy in LEAD-3 (liraglutide vs SU)63; combination therapy of liraglutide with 2 OADs was studied in LEAD-4 (liraglutide + metformin + TZD vs metformin + TZD)64; and combination therapy of liraglutide with 2 OADs was compared with insulin glargine plus 2 OADs in LEAD-5 (liraglutide + metformin + SU vs glargine + metformin + SU).65 Finally, LEAD-6 (liraglutide ± metformin ± SU vs exenatide ± metformin ± SU)66 compared liraglutide with exenatide. All studies were of 26 weeks’ duration, except the LEAD-3 trial,63 which continued for 52 weeks.

Liraglutide and HbA1c Values

In all of the LEAD trials except LEAD-2,61,63–66 reductions of up to 1.6% in HbA1c were observed with liraglutide as monotherapy or in combination

Liraglutide monotherapy versus SU LEAD-363 Liraglutide + MET versus SU + MET LEAD-262

Add a third oral agent or start insulin

Liraglutide + SU versus TZD + SU LEAD-161


Add another oral agent


Start an oral agent




Liraglutide + MET + TZD versus MET + TZD LEAD-464 Liraglutide + MET + SU versus glargine + MET + SU LEAD-565 Liraglutide ± MET ± SU versus exenatide ± MET ± SU LEAD-666

Diet/exercise

Figure 1. Design of the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program to compare liraglutide monotherapy or combination therapy versus other treatments for type 2 diabetes mellitus. SU = sulfonylurea; MET = metformin; TZD = thiazolidinedione.

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November 2009

Table I. Design and overview of key efficacy and safety data of Phase III clinical trials of liraglutide for the treatment of type 2 diabetes mellitus. Liraglutide and insulin glargine were injected subcutaneously; metformin, glimepiride, and rosiglitazone were administered orally.

Study

Description, Patients Randomized, and Combination Therapy

LEAD-161 Liraglutide 0.6 mg (n = 233) Liraglutide 1.2 mg (n = 228) Liraglutide 1.8 mg (n = 234) Rosiglitazone 4 mg (n = 232) Placebo (n = 114)

26-Week, double-blind, doubledummy, randomized, activecontrolled, 5-arm parallel-group study of 1041 patients who previously received ≥1 OAD; all study treatments were in combination with glimepiride 2–4 mg/d

LEAD-262

26-Week, double-blind, doubledummy, randomized, placebo- and active-controlled, parallel-group study of 1091 patients who previously received ≥1 OAD; all study treatments were in combination with metformin 1 g BID

Liraglutide 0.6 mg (n = 242) Liraglutide 1.2 mg (n = 241) Liraglutide 1.8 mg (n = 242) Glimepiride 4 mg (n = 244) Placebo (n = 122) LEAD-363

52-Week, double-blind, doubledummy, randomized, activecontrolled, parallel-group study of 746 patients previously on diet/ exercise program or receiving OAD

Change in Body Weight, Mean (SD), kg

Change in SBP, Mean (SD), mm Hg

Nausea, No. (%) of Patients*

All Adverse Events, No. (%) of Patients*

–0.60 (1.1)†‡

0.7 (3.0)§=

–0.9 (12.8)

12 (5.2)

162 (69.5)

–1.08 (1.1)‡§

0.3 (3.0)§

–2.6 (12.7)

24 (10.5)

158 (69.3)

–1.13 (1.1)‡§

–0.2 (3.0)§

–2.8 (13.1)

16 (6.8)

164 (70.1)

–0.44 (1.1)

2.1 (3.0)

–0.9 (12.7)

6 (2.6)

143 (61.6)

0.23 (0.7)

–0.1 (2.9)

–2.3 (12.4)

2 (1.8)

73 (64.0)

–0.69 (1.1)‡

–1.8 (3.6)§

–0.6 (13.1)

26 (10.7)

168 (69.4)

–0.97 (1.1)‡

–2.6 (3.7)§=

–2.8 (13.2)†

39 (16.3)

169 (70.4)

–1.00 (1.1)‡

–2.8 (3.6)§¶

–2.3 (12.9)†

45 (18.6)

178 (73.6)

–0.98 (1.1)

1.0 (3.5)

0.4 (13.1)

8 (3.3)

160 (66.1)

0.09 (1.0)

–1.5 (3.4)

–1.8 (12.5)

5 (4.1)

74 (61.2)

–0.84 (1.2)#

–2.05 (4.4)§

–2.12 (14.2)

69 (27.5)

207 (82.5)

–1.14 (1.2)§

–2.45 (4.4)§

–3.64 (14.1)†

72 (29.3)

195 (79.3)

1.12 (4.2)

–0.69 (13.8)

21 (8.5)

177 (71.4)

–0.51 (1.2)

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(continued)

E. Montanya and G. Sesti

Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 247) Glimepiride 8 mg (n = 248)

HbA1c, Mean (SD), %

Study

Description, Patients Randomized, and Combination Therapy

LEAD-464 Liraglutide 1.2 mg (n = 178) Liraglutide 1.8 mg (n = 178) Placebo (n = 177)

26-Week, double-blind, randomized, placebo-controlled, parallel-group study of 533 patients who previously received ≥1 OAD; all study treatments were in combination with metformin 1 g BID and rosiglitazone 4 mg BID

LEAD-565

26-Week, randomized, placebocontrolled, parallel-group study of 581 patients who previously received ≥1 OAD; all study treatments were in combination with metformin 1 g BID and glimepiride 4 mg/d

Liraglutide 1.8 mg (n = 232) Insulin glargine (n = 234) Placebo (n = 115) LEAD-666 Liraglutide 1.8 mg (n = 233) Exenatide 10 μg BID (n = 231)

26-Week, open-label, randomized, active-controlled, parallel-group study of 464 patients who previously received metformin and/or SU; all study treatments were in combination with metformin and/or SU (pretrial OAD treatment regimen was maintained)

HbA1c, Mean (SD), %

Change in Body Weight, Mean (SD), kg

Change in SBP, Mean (SD), mm Hg

Nausea, No. (%) of Patients*

All Adverse Events, No. (%) of Patients*

–1.5 (1.0)‡

–1.0 (4.4)‡

–6.7 (15.1)‡

52 (29.2)

149 (83.7)

–1.5 (1.0)‡

–2.0 (4.3)‡

–5.6 (14.7)‡

71 (40.0)

148 (83.1)

–0.5 (1.0)

0.6 (4.4)

–1.1 (15.2)

15 (8.5)

123 (69.5)

–1.33 (1.4)‡#

–1.81 (5.0)‡§

–3.97 (19.73)§

32 (13.9)

151 (65.7)

–1.09 (1.4)

1.62 (5.0)

0.54 (20.1)

3 (1.3)

127 (54.7)

–0.24 (1.2)

–0.42 (4.2)

–1.44 (16.8)

4 (3.5)

64 (56.1)

–1.12 (1.2)‡

–3.24 (5.0)

–2.51 (17.5)

60 (25.5)

176 (74.9)

–0.79 (1.2)

–2.87 (5.0)

–2.0 (17.9)

65 (28.0)

183 (78.9)

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HbA1c = glycosylated hemoglobin; SBP = systolic blood pressure; LEAD = Liraglutide Effect and Action in Diabetes; OAD = oral antidiabetic drug; SU = sulfonylurea. =



P < 0.05 versus placebo. *Based on safety-analysis population. † P < 0.05 versus active comparator. ¶ P < 0.01 versus placebo. ‡ P < 0.001 versus placebo. # P < 0.01 versus active comparator. § P < 0.001 versus active comparator.

Clinical Therapeutics

2478 Table I (continued).

November 2009 Table II. Patient demographics and baseline characteristics in Phase III clinical trials of liraglutide for the treatment of type 2 diabetes mellitus (DM). All values are shown as mean (SD).

Liraglutide Monotherapy

LEAD-464: Liraglutide Metformin + TZD

LEAD-565: Liraglutide + Metformin + SU

LEAD-666: Liraglutide + Metformin and/or SU

53.0 (10.9)

55.1 (10.2)

57.5 (9.9)

56.7 (10.3)

7.4 (5.2)

5.4 (5.3)

9.0 (5.6)

9.4 (6.2)

8.2 (6.0)

9.8 (2.5)

10.0 (2.4)

9.5 (2.6)

10.1 (2.5)

9.2 (2.0)

9.6 (2.5)

8.4 (1.0)

8.4 (1.0)

8.2 (1.1)

8.5 (1.2)

8.2 (0.9)

8.2 (1.0)

29.9 (5.1)

31.0 (4.7)

33.1 (5.8)

33.5 (5.2)

30.5 (5.3)

32.9 (5.6)

LEAD-161:

LEAD-262:

LEAD-363:

Liraglutide + SU

Liraglutide + Metformin

56.1 (9.8)

56.8 (9.5)

Time since DM diagnosis, y

7.9 (5.4)

Fasting plasma glucose, mM HbA1c, %

Variable Age, y

Body mass index,

kg/m2

LEAD = Liraglutide Effect and Action in Diabetes; SU = sulfonylurea; TZD = thiazolidinedione; HbA1c = glycosylated hemoglobin.

E. Montanya and G. Sesti

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Clinical Therapeutics with OAD(s) that exceeded those observed with other treatments (Figure 2). In LEAD-2,62 reductions of HbA1c of 1.3% were observed with once-daily subcutaneous injections of liraglutide 1.2 and 1.8 mg (P < 0.001 vs placebo) and 1.2% with glimepiride, both of which were administered in combination with metformin. In the LEAD-6 study,66 liraglutide combined with either metformin or an SU, or with both, was associated with a reduction in HbA1c of 1.1% compared with a 0.8% reduction with exenatide in combination with metformin or SU, or both (P < 0.001). Thus, liraglutide, as monotherapy and in combination with OADs, was consistently associated with reduced HbA1c values across the Phase III trials (Table I).61–66

Liraglutide alone or in combination with OADs allowed most patients to achieve HbA1c targets <7.0%.61–67 Liraglutide monotherapy was associated with sustained reductions in HbA1c, reaching targets of <7.0%, over 52 weeks in a study of 746 patients with type 2 DM.63 Changes in HbA1c from baseline with a single daily dose of 1.2 or 1.8 mg of liraglutide were –0.84% and –1.14%, respectively, compared with a 0.51% reduction observed with glimepiride. Reductions of HbA1c in both liraglutide subgroups were significantly greater than those seen with glimepiride, as measured by the 0.63% difference between liraglutide 1.8 mg and glimepiride (P < 0.001) and the 0.33% difference between liraglutide 1.2 mg

Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Rosiglitazone Placebo Glargine Exenatide

Baseline HbA1c (%) 0

SU Combination LEAD-161 8.5 8.6 8.3 8.5

MET Combination LEAD-262 8.4 8.2 8.2 8.4

Monotherapy LEAD-363 8.4 8.6 8.6

MET + TZD Combination LEAD-464 8.5 8.6 8.4

MET + SU Combination LEAD-565 8.3 8.2 8.3

Change in HbA1c (%)

–0.2

−0.2 −0.3

–0.4

−0.4 −0.5

–0.6 –0.8

−0.8

−0.8 −0.9

–1.0 –1.2 –1.4 –1.6 –1.8

MET ± SU Combination LEAD-666 8.4 8.2

−1.2 −1.3 −1.3 −1.4 −1.4 ‡

−1.1 −1.2 *

−1.1 ‡

−1.3 †

−1.5 −1.5

‡

−1.6

‡

‡

‡

Figure 2. Reductions from baseline values in glycosylated hemoglobin (HbA1c) in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program to compare liraglutide monotherapy or combination therapy versus other treatments for type 2 diabetes mellitus. LEAD-1 and LEAD-2 show results for patients who previously received oral antidiabetic drug monotherapy; LEAD-3 shows results for patients who previously received diet and exercise therapy alone; and LEAD-4 through LEAD-6 show results for the whole population. SU = sulfonylurea; MET = metformin; TZD = thiazolidinedione. *P = 0.05 versus active comparator; †P < 0.01 versus active comparator; ‡P < 0.001 versus active comparator.

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E. Montanya and G. Sesti and glimepiride (P < 0.01). Furthermore, reductions of HbA1c with liraglutide 1.8 mg were significantly greater than with liraglutide 1.2 mg (P < 0.01).63 Additionally, a subgroup of patients in the monotherapy trial who had been previously treated with diet and exercise (n = 272 [36.5%]) experienced greater reductions in HbA1c with liraglutide than with glimepiride.63 Liraglutide 1.2 and 1.8 mg were associated with reductions from baseline HbA1c of 1.2% (P = 0.02) and 1.6% (P < 0.001), respectively, compared with the 0.9% reduction observed with glimepiride. HbA1c was sustained at <7.0% with liraglutide 1.8 mg for the duration of the study. Treatment with liraglutide was associated with greater reductions in HbA1c in very poorly controlled (baseline HbA1c >9.5%) patients than was treatment with any of the comparators in the Phase III studies61–66; higher baseline HbA1c was associated with greater reduction in HbA1c at the end of the study.68 Indeed, patients who had previously received OAD monotherapy and had baseline HbA1c >9.5% (n = 16) experienced reductions up to 2.7% after 26 weeks of liraglutide 1.2 mg plus metformin.67 Also, a higher proportion of patients reached HbA1c <7.0% with liraglutide in combination with 1 OAD (up to 66%) than with standard treatments (up to 56%).

Liraglutide and Fasting and Postprandial Plasma Glucose Levels Liraglutide treatment was associated with consistent and rapid reductions (full impact before 2 weeks) in fasting plasma glucose (FPG) in the Phase III trials.61–66 FPG reductions from baseline were up to 43 mg/dL (2.4 mmol/L) with liraglutide. Both liraglutide groups in the monotherapy study were associated with significantly greater changes in FPG than was the glimepiride group.63 Liraglutide 1.2 and 1.8 mg were associated with FPG reductions of 15 mg/dL (0.84 mmol/L) (P = 0.02) and 26 mg/dL (1.42 mmol/L) (P < 0.001), respectively, compared with the 5.29 mg/dL (0.29 mmol/L) reduction observed with glimepiride. Moreover, in the head-to-head comparison with exenatide, liraglutide was associated with significantly greater reductions in FPG (29 mg/dL [–1.61 mmol/L] vs 11 mg/dL [–0.60 mmol/L]; P < 0.001).66 Liraglutide treatment was associated with significant reductions in postprandial glucose (PPG) values in patients with type 2 DM in the first 5 Phase III trials studies, but not in LEAD-6. Reductions in PPG November 2009

concentrations were noted after 3 meals with liraglutide at 1.2 or 1.8 mg.61–66 In the monotherapy study, greater reductions in PPG levels were noted with liraglutide 1.2 or 1.8 mg (–31 mg/dL [–1.71 mmol/L] and –37 mg/dL [–2.08 mmol/L], respectively) than with glimepiride (–24 mg/dL [–1.36 mmol/L]).63 The reduction in PPG seen with liraglutide 1.8 mg was significantly greater than the reduction observed with glimepiride (P < 0.01). No notable treatment difference was observed for liraglutide 1.2 mg compared with glimepiride (P = NS). In the metformin + TZD study of 533 patients with type 2 DM, treatment with liraglutide 1.2 or 1.8 mg was associated with reductions in PPG concentrations of 50 mg/dL (2.6 mmol/L) and 49 mg/dL (2.7 mmol/L) (P < 0.05 vs placebo), respectively, compared with a 14-mg/dL (0.8-mmol/L) reduction seen in the placebo group.64

Liraglutide and β-Cell Function Preclinical trials and Phase II studies have found that liraglutide may have a positive influence on β-cell function,69–71 which corresponds to findings in preclinical studies showing that GLP-1 can reduce apoptosis, promote β-cell differentiation, and promote proliferation.28,30,72 Clinical data from the Phase III trial program also support the hypothesis that liraglutide has a beneficial effect on β-cell function. Improvements in β-cell function were observed with liraglutide in all of the Phase III studies (improvements of 20% and 44% from baseline), as measured by homeostasis model assessment for β-cell function analysis (HOMA-B).66,73 Also, glimepiride treatment in combination with metformin led to an improvement of 25% in HOMA-B.62 Reductions in the ratio of pro-insulin to insulin, which is a marker for β-cell function, were also seen (changes of –0.11 to 0.01 from baseline).66,73 Combination therapy of liraglutide (1.2 and 1.8 mg) with an SU was associated with significant improvements in β-cell function, as measured by HOMA-B analysis (44% and 36% for liraglutide 1.2 and 1.8 mg, respectively), compared with rosiglitazone (6%; P < 0.03).73 Furthermore, reductions in the ratio of pro-insulin to insulin were significantly greater for both liraglutide 1.2 and 1.8 mg (–0.11 and –0.10, respectively) than for rosiglitazone (–0.05; P < 0.03). Comparison of liraglutide and exenatide indicated a significantly greater improvement in HOMA-B scores with liraglutide (32% vs 3%; P < 0.001).66 2481

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Liraglutide and Body Weight Liraglutide as monotherapy or in combination with OAD(s) has been associated with substantial and sustained weight reductions in patients with type 2 DM in the Phase III clinical trials (Table I; Figure 3).61–66 Weight reductions did not appear to be caused by gastrointestinal AEs; body weight was reduced both in patients with and without gastrointestinal AEs. Liraglutide 1.2 and 1.8 mg monotherapy was associated with significant weight reductions of 2.1 and 2.5 kg, respectively, compared with a 1.1-kg weight gain seen with glimepiride therapy (P < 0.001).63 The observed weight loss with liraglutide occurred primarily during the first 16 weeks, and thereafter weight loss was maintained throughout the remainder of the 52-week trial. Liraglutide 1.8 mg monotherapy was associated with a mean reduction of 3.0 cm in waist circumference, compared with a decrease of 0.4 cm with glimepiride (P < 0.001). Liraglutide plus metformin + SU was

associated with a mean weight loss of 1.8 kg, compared with a mean weight gain of 1.6 kg with glargine combined with metformin + SU (P < 0.001).65 Additionally, numerically greater weight loss was seen among patients with a higher baseline body mass index (BMI) across the first 5 Phase III trials: up to 4.4, 3.0, and 2.7 kg among patients with baseline BMI ≥35 kg/m2, BMI ≥30 kg/m2 but <35 kg/m2, and BMI ≥25 kg/m2 but <30 kg/m2, respectively; however, this was not assessed for statistical significance.74 Total lean body tissue, total fat, and percentage of body fat were also measured by dual-energy X-ray absorptiometry; visceral and abdominal subcutaneous adipose tissue were assessed using computerized tomography in a LEAD-2 substudy of 160 patients with type 2 DM.75 It was estimated that two thirds of weight loss associated with liraglutide therapy 1.8 mg + metformin was related to a reduction in fat tissue, which consisted mostly of visceral body fat.

Change in Body Weight (kg)

Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Rosiglitazone Placebo Glargine Exenatide

3

SU Combination LEAD-161

–4

MET + SU Combination LEAD-565

MET ± SU Combination LEAD-666

1.1 0.6

−0.2 *

−0.1

−0.42 −1.0 *

−1.5

–2 –3

MET + TZD Combination LEAD-464

1.6 1.0

* 0.3

0 –1

Monotherapy LEAD-363

2.1

2 1

MET Combination LEAD-262

−2.1 −2.6 −2.8 * *

−2.5

−2.0 *

−1.8 * −3.2

−2.9

Figure 3. Change from baseline in body weight in the Liraglutide Effect and Action in Diabetes (LEAD) Phase III clinical trial program to compare liraglutide monotherapy or combination therapy versus other treatments for type 2 diabetes mellitus. LEAD-1 and LEAD-2 show results for patients who previously received oral antidiabetic drug monotherapy; LEAD-3 through LEAD-6 show results for overall population. SU = sulfonylurea; MET = metformin; TZD = thiazolidinedione. *P < 0.001 versus active comparator.

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Liraglutide and SBP Liraglutide was associated with lower SBP in all 6 Phase III studies (Table I), with reductions up to 6.7 mm Hg seen for liraglutide with metformin + TZD, whereas metformin + TZD was associated with a reduction in SBP from baseline of 1.1 mm Hg.76 Significant reductions in SBP were observed as early as 2 weeks after initiation of liraglutide treatment and could be observed before any significant weight loss occurred.

Tolerability The Phase III clinical trial program found that liraglutide was associated with 0.03 to 1.9 hypoglycemic events per patient with type 2 DM annually.61–66 The incidence of minor hypoglycemic events (plasma glucose concentration <56 mg/dL [3.1 mmol/L]) was at the level observed with placebo in LEAD-2.62 Combination therapy with liraglutide 1.2 or 1.8 mg and metformin (0.03 and 0.09 episodes per patient annually, respectively) or liraglutide 1.2 or 1.8 mg and a TZD (0.02 and 0.04 episodes per patient annually, respectively) was not associated with an increased risk of minor hypoglycemia, compared with metformin (0.13 episodes per patient annually) or TZDs (0.03 episodes per patient annually) only.61,64 There was, however, an increase of 1 minor hypoglycemic event per subject every other year when liraglutide was used in combination with SU.61 No major hypoglycemic events (requiring third-party assistance with food only, glucagon, or intravenous glucose) were reported in the LEAD-2, -3, -4, or -6 studies.62–64,66 Although no major hypoglycemic events were reported in the LEAD-2, -3, -4, or -6 studies, LEAD-1 reported 1 major hypoglycemic event for liraglutide 1.8 mg plus glimepiride, and LEAD-5 reported 5 major hypoglycemic events for liraglutide in combination with metformin and glimepiride; of the 6 major events, only 1 required medical assistance, and none resulted in coma or seizure.61,65 Most AEs reported in the Phase III trials were of short duration and mild or moderate in severity.61–66 Liraglutide treatment was associated with gastrointestinal AEs, such as nausea, which was observed in 5.2% to 40.0% of patients (Table I). The majority of gastrointestinal AEs were mild and transient, and tended to decrease after 3 to 4 weeks of treatment.61–65 Indeed, <10% of patients treated with liraglutide monotherapy (1.8 mg) suffered from nausea after 4 weeks of treatment.63 No clear dose–response relaNovember 2009

tionship was observed between nausea and vomiting for liraglutide 1.2 or 1.8 mg combined with metformin.62 Overall, only 0.3% to 6.0% of patients withdrew from the Phase III trial program because of nausea61,62,64–66; however, a greater proportion of these patients withdrew from treatment because of nausea and vomiting in the liraglutide groups compared with the glimepiride group in the monotherapy trial (4% [1.2 mg] and 2% [1.8 mg] vs 0% [glimepiride]).63 A number of cases of acute pancreatitis have been observed in controlled clinical trials with exenatide, a twice-daily human GLP-1 analogue.77 A large retrospective US health care claims database search was conducted to analyze incidence rates of pancreatitis between January 1999 and December 2005 in patients with type 2 DM and patients without DM.78 According to that large database search, patients with type 2 DM have a 3-fold increased risk of acute pancreatitis. However, the Phase III trial program for liraglutide found a relatively low number of cases of pancreatitis, with an incidence rate comparable to that expected in the type 2 DM population overall.61–66,78 The Phase III trial program reported a relatively low rate of antiliraglutide antibodies, with ≤8.6% of patients experiencing an increase in these antibodies.63,65,79 The presence of antiliraglutide antibodies did not appear to influence the efficacy of liraglutide therapy in terms of glycemic control in any of the Phase III trials. For example, in the SU trial (LEAD-1), antiliraglutide antibodies were observed in 67 patients (6.4%), and the majority (73.1%) of patients with antiliraglutide antibodies experienced HbA1c reductions ≥0.4%.63

Comparison of Liraglutide With Other Incretin-Based Therapies The LEAD-6 trial made a direct comparison between the efficacy of liraglutide and exenatide, in combination with metformin and/or SU.66 It was observed that liraglutide was associated with significantly greater improvements in glycemic control than exenatide (HbA1c change: –1.12% vs –0.79%, respectively; P < 0.001) and with less hypoglycemia (minor hypoglycemic events: 1.9 vs 2.6 events per annually, respectively; P < 0.014). The difference in HbA1c reductions observed for liraglutide versus exenatide was modest but sufficient enough to yield a significantly higher proportion of patients reaching HbA1c target 2483

Clinical Therapeutics (<7.0%) with liraglutide than with exenatide (54% vs 43%; P < 0.002).10 Greater reductions from baseline in FPG were also observed with liraglutide than with exenatide (–28.98 mg/dL [–1.61 mmol/L] vs –10.80 mg/dL [–0.60 mmol/L]; P < 0.001). However, greater reductions in PPG (self-measured with 7-point plasma glucose profiles) were observed with exenatide than with liraglutide after breakfast (estimated treatment difference [ETD]: 23.94 mg/dL [1.33 mmol/L]; P < 0.001) and after dinner (ETD: 18.18 mg/dL [1.01 mmol/L]; P < 0.001); no significant treatment differences were observed after lunch. Furthermore, significantly greater improvements in β-cell function, as measured by HOMA-B, were noted with liraglutide than with exenatide (32.1% vs 2.7%; P < 0.001). Similar weight reductions were observed with liraglutide and exenatide (–3.24 and –2.87 kg, respectively; P = NS). A study assessing the efficacy of liraglutide plus metformin compared with the DPP-4 inhibitor sitagliptin plus metformin is now ongoing (ClinicalTrial.gov identifier NCT00700817).

DISCUSSION In Phase III clinical trials, liraglutide as monotherapy and in combination with OAD(s) was associated with substantial and sustained reductions in all glucose parameters studied: HbA1c, FPG, and PPG. Standard type 2 DM treatments, especially insulin and SU, are often associated with an increased risk for hypoglycemia.9,13 Liraglutide enhances insulin secretion and suppresses elevated glucagon, both in a glucosedependent manner, which then limits the risk of experiencing hypoglycemia. Indeed, the significant improvement in glycemic control reported for liraglutide across the Phase III clinical trials was associated with a low risk of hypoglycemia (0.03 to 1.9 events per patient annually), comparable with that seen with placebo, unless combined with SU. Liraglutide has also been reported to improve β-cell function, as measured by HOMA-B analysis and the ratio of pro-insulin to insulin. Moreover, liraglutide was associated with significant reductions in body weight, in contrast with most other type 2 DM treatments, including insulin and OADs, which can cause weight gain.8,9 Hypertension is a serious risk factor for the development of CV disease in patients with type 2 DM.10,20 Significant reductions in SBP were observed as early as 2 weeks after initiation of liraglutide treatment. It has been reported that reductions in 2484

SBP may decrease the risk of the development of longterm CV disease.80 In these trials, liraglutide use was, in some patients, associated with gastrointestinal AEs, such as nausea; however, this was generally mild and transient and led to few withdrawals. Indeed, only 2.8% of patients treated with liraglutide in the Phase III trials withdrew because of nausea.61–66 Furthermore, liraglutide was associated with low antibody formation, most likely because of the greater amino acid sequence identity to human GLP-1 (97%).81 In contrast, exenatide has a rather low sequence identity (53%) to endogenous GLP-1. This may explain the incidence of antiexenatide antibody formation in up to 43% of exenatide-treated patients. High levels of exenatide antibodies can be seen in 6% of exenatide-treated patients; in 3% of these patients, the glycemic response to exenatide was attenuated.41 Further long-term trials with liraglutide are needed to evaluate the durability of improvements in glycemic control, weight loss, and reductions in SBP, as well as liraglutide’s long-term effect on DM-related complications. Finally, in terms of treatment choice, GLP-1 receptor agonists such as liraglutide and exenatide were recently added to the American Diabetes Association/ European Association for the Study of Diabetes consensus algorithm for the management of type 2 DM.1 These guidelines reflect the increasing clinical use of incretin-based therapies in clinical practice, and may signal a paradigm shift in the management of patients with type 2 DM. The current review has several limitations that should be recognized. First, only studies that were published in English were included in this review. Second, a systematic review would have yielded full coverage of the existing data. However, the scope of this review did not warrant such a method.

CONCLUSIONS Liraglutide, a once-daily human GLP-1 analogue, was an effective and well-tolerated treatment for type 2 DM in Phase III trials data. When used as monotherapy or in combination with OAD(s), liraglutide was associated with substantial improvements in glycemic control, weight loss, and reductions in SBP, and a low risk of hypoglycemia. Therefore, liraglutide is a promising new treatment for type 2 DM. Volume 31 Number 11

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ACKNOWLEDGMENTS Dr. Montanya has served on advisory boards for or received consulting fees from Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk A/S, and sanofi-aventis. Dr. Sesti has served on advisory boards for MSD and Novo Nordisk A/S. The authors acknowledge the assistance of Dr. Elien Moës, Watermeadow Medical PLC (Witney, United Kingdom) with preparing this article for publication. The preparation of this article was supported financially by Novo Nordisk A/S. The authors have indicated that there are no other conflicts of interest regarding the content of this article.

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Address correspondence to: Eduard Montanya, MD, Hospital Universitari Bellvitge, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain. E-mail: [email protected] Volume 31 Number 11