The British Journal of Diabetes & Vascular Disease http://dvd.sagepub.

com/

Liraglutide, a once-daily human GLP-1 analogue

Michael A Nauck British Journal of Diabetes & Vascular Disease 2008 8: S26 DOI: 10.1177/1474651408100524 The online version of this article can be found at: http://dvd.sagepub.com/content/8/2_suppl/S26

Published by:
http://www.sagepublications.com

Additional services and information for The British Journal of Diabetes & Vascular Disease can be found at: Email Alerts: http://dvd.sagepub.com/cgi/alerts Subscriptions: http://dvd.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://dvd.sagepub.com/content/8/2_suppl/S26.refs.html

>> Version of Record - Feb 13, 2009 What is This?

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

Liraglutide, a once-daily human GLP-1 analogue

MICHAEL A NAUCK
Abstract

lucagon-like peptide-1 (GLP-1) is an incretin hormone physiologically playing a role in glucose homeostasis, together with the partner incretin, glucose dependent insulinotropic peptide (GIP). Active concentrations of this hormone are not maintained for long because of its very rapid degradation and elimination. The effects of the hormone are of potential therapeutic value in type 2 diabetes; therefore, analogues of GLP-1 have been developed that are characterised by a prolonged circulating half-life relative to the naturally occurring hormone. One such long-acting analogue is liraglutide. The effects of liraglutide are maintained over 24 h, allowing once-daily dosing. Liraglutide provides all of the beneficial actions of endogenous GLP-1: glucosedependent stimulation of insulin secretion, glucagon suppression, deceleration of gastric emptying, appetite suppression/weight loss and, in animal models, inhibition of -cell apoptosis and promotion of -cell regeneration. Because liraglutide stimulates insulin secretion and suppresses glucagon secretion only when blood glucose levels are elevated, the risk of treatment-associated hypoglycaemia is low. In clinical studies, liraglutide substantially lowered fasting and postprandial glucose concentrations, with an overall reduction in haemoglobin A1c of up to 1-2%. In some studies, liraglutide has decreased several biomarkers of cardiovascular risk and lowered triglyceride levels significantly. Side effects most commonly are gastrointestinal symptoms; they are usually mild to moderate and resolve over time. Long-term clinical trials are needed to assess whether the effects of liraglutide on the cell translate into a durable improvement in -cell function and mass in patients with type 2 diabetes and, if so, whether this will slow or halt disease progression and help prevent complications. Br J Diabetes Vasc Dis, 2008; 8 (Suppl 2): S26S33 Key words: glucagon-like peptide-1, haemoglobin A1c, liraglutide, type 2 diabetes, weight loss
Diabeteszentrum, Bad Lauterberg, Germany Correspondence to: Dr Michael A Nauck Diabeteszentrum Bad Lauterberg, Kirchberg 21, 37431 Bad Lauterberg, Germany Tel: +49 (0)5524 81218; Fax: +49 (0)5524 81398 E-mail: [email protected]

Michael A Nauck

Introduction
Type 2 diabetes is a progressive disease characterised by insulin resistance and pancreatic -cell dysfunction, leading to insulin deficiency and hyperglycaemia.1 Loss of metabolic control is also attributed to increased hepatic glucose release in the fasting and postprandial states, with increased gluconeogenesis.2 Increased glucagon levels3 and a reduced response of GLP-1 to meals4 have been described. Potential sequelae include an increased risk of vascular complications, which account for about two-thirds of deaths in persons with diabetes.5 The importance of glucose-lowering therapy to prevent complications in type 2 diabetes was established in the landmark UK Prospective Diabetes Study.6 In that 10-year trial of 3,867 patients with newly diagnosed type 2 diabetes, intensive pharmacotherapy aimed at reducing FPG to below 6 mmol/L (108 mg/dL) provided a 25% reduction in the risk of microvascular complications compared with conventional therapy.6 Despite improvements in diabetes treatment, however, glycaemic control, particularly adequate long-term control, is elusive for many patients.7 An analysis of data from the National Health and Nutrition Examination Survey 19992000 reported that only 37% of adults with diabetes in the USA had reached the American Diabetes Association goal of HbA1c under 7%, despite a marked increase in the percentage of those receiving pharmacological treatment. Thus, there is an

SAGE Publications 2008 Los Angeles, London, New Delhi and Singapore

10.1177/1474651408100524

26 S2

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

Abbreviations and acronyms AUC DPP-4 FPG GIP GLP-1 HbA1c area under the curve dipeptidyl peptidase-4 fasting plasma glucose glucose dependent insulinotropic peptide glucagon-like peptide-1 glycosylated haemoglobin A1c

urgent need for effective new approaches to improve glycaemic control and thereby help prevent microvascular and macrovascular complications. Among the new avenues of treatment being investigated are analogues of GLP-1, an incretin hormone secreted from intestinal mucosa in response to food ingestion. As discussed in greater detail in the accompanying article by Jens Holst (pp. S10S18), GLP-1 helps regulate glucose homeostasis by stimulating insulin secretion and inhibiting glucagon secretion. Both of these actions are glucose-dependent. However, in its endogenous form, GLP-1 has a very short half-life because of rapid degradation by DPP-4 and renal elimination. Longer-acting analogues have been developed that circumvent this problem and are making it possible to take advantage of the beneficial actions of GLP-1 in patients with type 2 diabetes. In contrast other insulinotropic agents such as the sulphonylureas, the insulinotropic effect of GLP-1 depends even more closely on the actual glucose concentration, thereby facilitating normalisation of glucose parameters without the risk of hypoglycaemia. Liraglutide is an acylated GLP-1 analogue. It has a fatty acid molecule, which is covalently attached to the GLP-1 sequence (figure 1). This binds to albumin, prolonging the half-life of the circulating complex without otherwise changing its biological

activity.8 Also, apparently, the fatty acid molecule may sterically inhibit DPP-4 from degrading liraglutide. Liraglutide is now in phase III clinical trials (the Liraglutide Effect and Action in Diabetes trial, comprising 3,800 patients), with initial results being reported in 2008. This article will review the current understanding of liraglutide, with regard to its pharmacokinetics, GLP-1-like effects, efficacy in type 2 diabetes at various doses, adverse event profile and positive effects on the cardiovascular profile. Avenues of future study will also be described.

Pharmacokinetics
Single and multiple-dose studies have confirmed that liraglutide has a half-life between 11 and 15 h, which means that once-daily dosing in humans is appropriate.9,10 Elbrnd and colleagues conducted a double-blind, randomised study with eight different single doses of liraglutide (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5 and 20.0 g/kg), injected subcutaneously in healthy men (n=72). They found a clear doseresponse relationship in the AUC measurements for plasma liraglutide. After doses of 2.520 g/kg, plasma liraglutide increased steadily, reaching a peak concentration after 9.312 h.10 Elimination half-life was 1115 h. At a dose of 5 g/kg, the time to maximum concentration was 9.3 h and the half-life, 15 h. A double-blind, randomised, dose-escalation, placebocontrolled study in 30 healthy subjects likewise concluded that the pharmacokinetic profile of liraglutide supports once-daily dosing. Subjects were randomly assigned to receive liraglutide, in doses of 1.2512.5 g/kg subcutaneously, or placebo. Liraglutide was administered on day 1 and days 511, while the 84-h pharmacokinetic and 24-h glucose and insulin profiles were assessed on days 1 and 11.9 Steady state was reached after three doses; half-life

Figure 1.

Comparative structures of GLP-1 and liraglutide. There is one arginine instead of lysine in the sequence of GLP-1 and there is another amino acid plus a free fatty acid attached to GLP-1. These differences prolong the half-life of liraglutide but do not change its biologic activity

GLP-1
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg

Amide (736) Amide

10

15

20

25

30

35 36

Proteolytic inactivation (DPP-4)

Liraglutide
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly

Glu

Albumin

C-16 free fatty acid (non-covalent binding to albumin)

Key: DPP-4 = dipeptidyl peptidase-4; GLP = glucagon-like peptide-1 Reprinted with kind permission from Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, vol no 368, pp. 1696705. Copyright 2006 Elsevier.

THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

S27

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

Figure 2.

Effect of once-daily administration of liraglutide on 24-h steady-state levels of liraglutide. Steady state was reached after three 5 g/kg doses and the level remained relatively constant thereafter. The curve is based on the data obtained on days 1 and 11. Data from Novo Nordisk21 and Agers et al.9

Figure 3.

Plasma liraglutide (pmol/L)

Relation between insulin secretion rate and plasma glucose levels during graded glucose infusion in patients with type 2 diabetes who received liraglutide or placebo and in healthy control subjects who did not receive the drug. The insulin secretion rate, derived by deconvolution of peripheral C-peptide concentrations, was similar in patients with type 2 diabetes who received liraglutide and in healthy control subjects who did not receive drug.11

8000 6000

Model curve fitted to data points

14 12
4000

Healthy controls (n=10)

Liraglutide 7.5 g/kg
Placebo

Insulin secretion rate (pmol min1 kg1)

2000 0 0

10 8 6 4 2 0 4 6 8 10 12
mmol/L

Day 1

7 8 6 Time (days) Day 5

10

11

12

was approximately 12 h at end of study in all dose groups. Before steady state, a slight but statistically significant accumulation was observed at doses of 7.5 g/kg or more, as indicated by an accumulation index of 1.41.5. Figure 2 presents data from a patient receiving daily doses of 5 g/kg.

80

100

120

140 160 Glucose

180

200

220 mg/dL

Liraglutide: GLP-1-like effects

Although in the development of liraglutide the GLP-1 molecule was altered to extend its half-life, the beneficial effects of GLP1 in diabetic patients have been preserved.

Reprinted with kind permission from Chang et al.11 Copyright American Diabetes Association.

2003

Glucagon suppression Beta-cell sensitivity

Studies show that a single dose of liraglutide is sufficient to reinstate the insulin response to glucose to a level similar to that in healthy non-diabetic persons. Chang and colleagues assessed the effect of liraglutide on -cell sensitivity in a doubleblind, crossover study of 10 patients with type 2 diabetes. Ten healthy subjects were included as controls. Nine hours before the study, patients with type 2 diabetes received a single subcutaneous dose of liraglutide (7.5 g/kg) or a single dose of placebo; the control group did not receive any medication. In addition, all groups received a small intravenous bolus of insulin (0.0070.014 U/kg). This bolus reduced blood glucose to approximately 5 mmol/L (90 mg/dL) in healthy control subjects and 6 mmol/L (108 mg/dL) in the type 2 diabetic group. The following day, subjects received a graded glucose infusion to create gradually rising plasma glucose levels ranging from 5 to 12 mmol/L (90216 mg/dL) over 3 h. As shown in figure 3, insulin secretion increased concomitantly with increases in glucose concentration in all groups. However, in patients receiving liraglutide, the effect was more pronounced than in those receiving placebo (insulin AUC 1,130150 vs. 668106 pmol/kg; p<0.001). The secretion rate in the patients with type 2 diabetes who received liraglutide was similar to that in the non-diabetic controls. These findings indicate that liraglutide restored -cell sensitivity to physiological hyperglycaemia in patients with type 2 diabetes.11
S28

In type 2 diabetes, excessive glucagon secretion in relation to plasma glucose stimulates hepatic glucose production and therefore contributes to fasting hyperglycaemia. It is important that treatments for type 2 diabetes carry a low risk of hypoglycaemia because this condition can restrict efforts to achieve glycaemic targets. Because GLP-1 analogues suppress glucagon secretion, there has been concern that they could disturb hypoglycaemia counterregulation. Several clinical studies of liraglutide affirm that this is not the case (table 1), with a reported risk of minor events ranging between 0 and 2.8 % in patients not receiving sulphonylurea drugs. 1214 The low risk of hypoglycaemia is probably due to the glucose-dependent insulinotropic action of liraglutide. Evidence for the low risk of liraglutide-associated hypoglycaemia was provided by a study of 11 patients with type 2 diabetes.15 All received a single subcutaneous dose of liraglutide, 7.5 g/kg at midnight. In the morning, regular insulin infusions of 2 mUkg-1min-1 were administered to provide fasting euglycaemia. With use of a hypoglycaemic clamp, capillary glucose concentrations were sequentially maintained at 4.3, 3.7, 3.0 and 2.3 mmol/L (77, 67, 54 and 41 mg/dL) for 60 min each. Glucagon secretion increased to a similar extent with liraglutide and placebo as the glycaemic plateau was reduced. Furthermore, the glucose infusion required to maintain the specified glycaemic plateau did not differ during treatment with placebo and liraglutide (figure 4). As the glucose plateau was lowered, there was a similar increase in cortisol and catecholamines with
VOLUME 8 SUPPL 2 . NOVEMBER/DECEMBER 2008

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

Figure 4.

Liraglutide did not impair glucagon secretion in response to induced hypoglycaemia. Glucose infusion rate was similar with liraglutide and placebo. Overall hypoglycaemic counterregulatory response remained intact. Data from Novo Nordisk21 and Nauck et al.15

Figure 5.

Effect of liraglutide vs. glimepiride on weight and HbA1c in patients with type 2 diabetes. Data from Novo Nordisk21 and Madsbad et al.12
Glimepiride 1 4 mg open label (n=27)

Liraglutide 0.75 mg OD (n=29)

Capillary glucose concentrations mmol/l (mg/dl)

160

Weight (kg) vs. placebo after 12 weeks

2 1 0 1 2 1.0 0.5 0.0

HbA1c (%) vs. placebo after 12 weeks

4.3 (77)

3.7 (67)

3.0 (54)

2.3 (41)

Glucagon (pg/ml)

120

80

p=0.0096

p=0.9605

Key: OD = once daily Mean SEM

40
0 60 120 Time (min) 180 240

Liraglutide (7.5 g/kg of body weight) (n=11) Placebo (n=11) Mean SEM

both treatments. Growth hormone also increased in both groups, although this increase was slightly but significantly lower during liraglutide treatment (p=0.034).

glimepiride (mean daily dose 2.7 mg) treatment (approximately 0.75 percentage points).12 This improvement in glycaemic control was associated with a decrease in weight of 0.39 kg in the liraglutide group, compared with an increase of 0.94 kg in the glimepiride group (figure 5). Thus, liraglutide and glimepiride offered similar glycaemic control but liraglutide was associated with a weight reduction that was not observed during glimepiride treatment.

GLP-1 analogues: extended half-life

A benefit of GLP-1 analogues over endogenous GLP-1 is their longer half-life, making them practical for clinical use. Exenatide, the only GLP-1 receptor agonist currently available for clinical use, has a half-life of 2.4 h and is approved for twice-daily dosing as a subcutaneous injection.18 Since liraglutide has a longer half-life, it is anticipated that once-daily dosing will be recommended. The sustained blood glucose-lowering action of liraglutide was demonstrated in a study of 13 patients with type 2 diabetes. Patients received 1 week of once-daily subcutaneous liraglutide injections (6 g/kg) and 1 week of once-daily placebo injections in a double-blind, crossover trial.19 Oral antidiabetic agents were discontinued 2 weeks before the study treatment period. After 1 week of liraglutide treatment, plasma glucose was consistently lower during a 24-h test period than after placebo treatment, including after an overnight fast. This finding was confirmed statistically in an assessment of AUC (mmolL-1h) for this 24-h test period (187.5 for liraglutide vs. 232.3 for placebo; p=0.01).19

Gastric emptying and appetite suppression

The potent dose-dependent inhibition of gastric emptying observed after GLP-1 infusion in human subjects with type 2 diabetes will produce significant lowering of meal-related glycaemic concentrations, even without any increase in levels of circulating insulin.16 This may in part explain the ability of GLP-1 to suppress appetite and promote weight loss. Most current type 2 diabetes treatments are associated with weight gain, which is detrimental to the course of the disease. This issue is discussed in more detail in this supplement by Philip Larsen (pp. S34S41) and will be reviewed only briefly herein. Madsbad et al. evaluated the effect of liraglutide therapy on weight in a multiple-dose, 12-week, multicentre, parallel-group, double-blind trial. The 193 patients with type 2 diabetes were randomised to a once-daily, morning subcutaneous injection of liraglutide (0.045, 0.225, 0.45, 0.6 or 0.75 mg) or placebo, or to open-label tablet treatment with glimepiride (dose adjusted according to control during first 4 weeks, aiming at FPG. < 7 mmol/L; < 126 mg/dL).12 Oral anti-diabetic treatment was discontinued during a 4-week pretreatment washout period. Liraglutide doses were selected based on studies that showed a dose of 10 g/kg (equivalent to approximately 0.80 mg dose) to have a significant effect on glycaemia.9,10,17 Lower doses were used to reduce the risk of adverse effects such as nausea. The reduction in HbA1c relative to placebo was similar after liraglutide (0.75 mg once-daily subcutaneous injection) and
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

Effectiveness of various doses of liraglutide

Liraglutide has a dose-dependent effect on glycaemic control. In early studies, relatively small doses of this agent were used, and results were not impressive. At larger doses, however, 0.60.75 mg given as a single daily subcutaneous injection, the impact on HbA1c was similar to that of a sulphonylurea, but without the increase in weight characteristic of sulphonylureas.
S29

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

Figure 6.

Glycemic control with liraglutide. Mean reduction in HbA1c with monotherapy. *vs. placebo. Data from Vilsbll et al.20

Figure 7.

FPG levels after an overnight fast at various doses of liraglutide. Data from Vilsbll et al.20

0.4

Placebo

0.65 mg/day
Mean baseline HbA1c = 8.1%

1.25 mg/day
Mean baseline HbA1c = 8.3%

1.90 mg/day
Mean baseline HbA1c = 8.5%

0.65 mg/day 0.0 0.5 1.0

FPG (mmol/L) vs. placebo

1.25 mg/day

1.90 mg/day
0

Mean change in HbA1c (%) vs. baseline

0.0 0.4 0.8 1.2 1.6

2.0 2.5 3.0 3.5 4.0

40 50 60 70 80
p<0.0001 p<0.0001 p<0.0001

p<0.0001*

p<0.0001*

p<0.0001*

4.5

90

Key: FPG = fasting plasma glucose Mean SEM

In the study by Madsbad et al., HbA1c progressively decreased during the course of the trial and was still falling at week 12 when the trial ended.12 Thus, even greater therapeutic benefit may be achievable with longer-term treatment. Because of the doseresponse relationship seen with liraglutide, achieving the effective dose as rapidly as possible is desirable. However, patients may initially experience gastrointestinal events. Nauck and colleagues showed that, by increasing the dosage by 0.5 mg per week, the patient can be safely titrated to a substantially higher and well-tolerated dose. In 144 patients with type 2 diabetes who had received metformin treatment (1,000 mg twice daily), the patients were randomised to 5 weeks of treatment (double-blind) with metformin plus liraglutide, liraglutide or metformin, or metformin plus glimepiride (open label). The dose of liraglutide was increased weekly from 0.5 to 2 mg once daily. Liraglutide added to metformin monotherapy was associated with a significant reduction in fasting serum glucose (3.9 mmol/L; 70 mg/dL) and HbA1c levels (0.8%) after 5 weeks.14 Furthermore, liraglutide in combination with metformin vs. metformin plus glimepiride significantly reduced fasting serum glucose (1.2 mmol/L; 22 mg/dL). Body weight was significantly lower with metformin plus liraglutide than with metformin plus glimepiride, even after only 5 weeks (2.9 kg). There were no confirmed episodes of hypoglycaemia with liraglutide treatment. Nausea was the most common adverse event with liraglutide therapy, but it was transient and led to withdrawal of only 4% of the patients treated.14 While the study by Nauck et al.14 showed reductions in HbA1c with liraglutide alone or in combination, the study was only 5 weeks long. In a 14-week study of 377 patients, doses of 1.25 and 1.9 mg/day of liraglutide given as monotherapy yielded decreases of about 1.7% in HbA1c (p<0.0001 vs. placebo) (figure 6).20 Body weight decreased by 3.0 kg in patients receiving 1.9 mg of liraglutide, and the weight loss was dose-dependent.20 This weight loss occurred regardless of the gastrointestinal side effects, which were, in any event, transient.20 As would be expected, in view of its pharmacokinetic profile, liraglutide continued to reduce FPG after an overnight fast.
S30

While the effect is dose dependent, even at the lowest dose used in this study the effect was significantly (p<0.05) different from placebo (figure 7).20

Adverse event profile of liraglutide

Liraglutide is well tolerated, with nausea and diarrhoea as the most common treatment-emergent adverse events.20,21 As discussed earlier and as shown in table 1, the risk of hypoglycaemia during treatment with liraglutide is low.12,13 The incidence of hypoglycaemia is similar to that reported with metformin and lower than that reported with glimepiride, despite similar glycaemic control. In a 5-week study involving larger doses of liraglutide (0.52 mg), there were no reported hypoglycaemic events of any type in patients receiving liraglutide or metformin monotherapy. One patient reported a symptoms-only event during treatment with liraglutide plus metformin, and three reported hypoglycaemia (one minor, two symptoms only) during treatment with glimepiride plus metformin (n=36) (table 1).14

Effect of liraglutide on cardiovascular risk profile

One of the goals of treatment of type 2 diabetes is to reduce the risk of cardiovascular events, which is elevated in diabetic patients.22 Liraglutide may decrease this risk, as evidenced by its effect on several cardiovascular parameters. The weight loss that is characteristic of liraglutide may ultimately be found to help reduce cardiovascular risk. In addition, treatment with liraglutide has also been shown to improve several biomarkers of cardiovascular risk. In a study of 377 patients with type 2 diabetes, Vilsbll and colleagues found that 14 weeks of treatment with liraglutide 1.90 mg/day reduced triglyceride levels by 22% (p=0.01 vs. placebo).20 C-reactive protein, a marker of inflammation, decreased by 20% (not significant); B-type natriuretic peptide, a serologic marker of myocardial vulnerability, decreased by 38% (p=0.01); and plasminogen activator inhibitor-1, a marker of impaired fibrinolysis, decreased by 25% (p=0.05) (figure 8).23
VOLUME 8 SUPPL 2 . NOVEMBER/DECEMBER 2008

Downloaded from dvd.sagepub.com by guest on April 1, 2012

FPG (mg/dL) vs. placebo

Mean baseline HbA1c = 8.2%

10 20 30

1.5

REVIEW

Table 1.

Percentage of patients reporting hypoglycemia in three liraglutide trials. No major hypoglycemic events were reported. Liraglutide is associated with a low risk for hypoglycemia, indicating that counterregulatory mechanisms are not adversely affected1214

Liraglutide (0.0452 mg OD) Madsbad et al. (2004)12 (n=193) Minor events (<2.8 mmol/L; 50 mg/dL) Symptoms only Feinglos et al. (2005)13 (n=210) Minor events (<2.8 mmol/L; 50 mg/dL) Symptoms only Nauck et al. (2006)14 (n=144) Minor events (<2.8 mmol/L; 50 mg/dL) Symptoms only n=137 1% 5% n=105 3% n/a n=36 0% 0%

Glimepiride ( 4 mg) n=27 15% 19%

Metformin (1 g BID)

Liraglutide (0.52 mg OD) + metformin (up to 1 g BID)

n=105 6% n/a n=36 0% 0% n=36 0% 3%

Key: BID = twice daily; n/a = not available; OD = once daily

Figure 8.

Effect of 14 weeks of liraglutide treatment on biomarkers of cardiovascular risk. Data from Vilsbll et al. 23

Figure 9.

Decreases in blood pressure after 14 weeks of treatment with three doses of liraglutide vs. placebo. Data from Vilsbll et al.20

0
% Change vs. placebo

Change in systolic blood pressure vs. baseline (mm Hg)

PAI-1

BNP

CRP

Triglycerides

6 4 2 0 2 4 6 8

Placebo

0.65 mg/day

1.25 mg/day

1.90 mg/day

10 20 20% 30 40 p<0.05 25% 22%

38% p<0.01

NS

p=0.01

10
12

Key: BNP = B-type natriuretic peptide; CRP = C-reactive protein; NS = not significant; PAI-1 = plasminogen activator inhibitor-1

p<0.01 p<0.05 p<0.01

In the same trial, systolic blood pressure decreased significantly at all three dosages, and diastolic blood pressure non-significantly (figure 9);20 the mechanism of this decrease is unclear. These improvements were in addition to the decrease in HbA1c of up to 1.7%, with half of the patients reaching their goal HbA1c. Further, body weight decreased with liraglutide treatment. The effect on blood pressure preceded the effect on body weight, suggesting that the effect cannot be ascribed to the decreased body weight.

Key: Mean SEM

Liraglutide: future directions

GLP-1 analogues are a relatively recent innovation in type 2 diabetes treatment only one (exenatide) is available in the USA, and liraglutide has completed the LEAD phase III trials and the durability of their beneficial effects has not been investigated in clinical studies. Nevertheless, there is reason to believe that therapy with liraglutide may result in long-term

improved glucose control. Continued, progressive -cell failure is a pathogenic feature of type 2 diabetes.6 Liraglutide is associated with improvement in -cell function, as evidenced by enhanced -cell neogenesis/ proliferation,24,25 and inhibition of apoptosis.26 The effects of GLP-1 inhibitors on -cell function are discussed in detail by Gallwitz elsewhere in this supplement (pp. S19S25). Briefly, GLP-1 analogues improve -cell function not only through indirect metabolic action, but also through direct recruitment of signal transduction pathways in the cells that promote glucose-dependent insulin secretion.27 Two animal studies showed that liraglutide increases -cell mass in animals and the effect occurs within weeks of the

THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

S31

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

References
1.

Key messages
2. G G G G G

GLP-1 is a gut hormone playing a physicological role in glucose homeostasis GLP-1 has antidiabetic properties, but cannot be used in clinical practice due to its rapid degradation and elimination GLP-1 can be modified to retain the antidiabetic properties, but to acquire a more prolonged pharmacokinetic profile The first intentionally modified GLP-1 receptor agonist is liraglutide Liraglutide is a once-daily GLP-1 analogue that has a proven a promising clinical profile including substantial improvement in glycaemic control without a risk for hypoglycaemia, and weight loss as an added benefit

3.

4.

5.

6.

7.

8.

start of liraglutide administration. In one study, Zucker diabetic fatty rats (which show insulin resistance and -cell defects) received subcutaneous injections of 150 g/kg liraglutide or vehicle twice daily for 6 weeks. At the end of the treatment period, -cell mass was significantly greater in the liraglutide group.24 In the second study, db/db (diabetic) mice received subcutaneous injections of vehicle or liraglutide (200 g/kg) twice daily for 2 weeks. Blood glucose tests on days 1, 8 and 15 demonstrated that mice treated with liraglutide had lower blood glucose (as measured using 24-h AUC) relative to those receiving vehicle. Furthermore, at the end of the trial, -cell mass and proliferation rate were greater with liraglutide treatment.25

9.

10.

11.

12.

Discussion
Liraglutide is a human GLP-1 analogue that has maintained a great degree of similarity to endogenous GLP-1; only one amino acid has been exchanged, and another one has been added to attach a free fatty acid. Once-daily injections cover a full 24 h, including fasting periods (e.g., sleep). Liraglutide provides substantial reductions in glucose and HbA1c, as expected in an efficacious anti-diabetic drug. At the same time, liraglutide has little or no effect on hypoglycaemia counterregulatory mechanisms via glucagon and thus has a low risk of hypoglycaemia. Unlike the sulphonylureas, which often induce some weight gain, liraglutide actually causes a decrease in weight, possibly as a result of its effect on gastric emptying and satiety. The most commonly reported adverse events have been nausea, vomiting and diarrhoea, which were usually mild to moderate and rarely lead to discontinuation of therapy. In light of the improvement in cell function and -cell mass observed in preliminary studies, the long-term effects of liraglutide on progression of type 2 diabetes will be of particular interest.
13.

14.

15.

16.

17.

Ferrannini E. Insulin resistance versus insulin deficiency in non-insulindependent diabetes mellitus: problems and prospects. Endocrine Rev 1998;19:47790. Magnusson I, Rothman DL, Katz LD et al. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest 1992;90:13237. Shah P, Vella A, Basu A et al. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2000;85:40539. Vilsbll T, Krarup T, Deacon CF et al. Reduced postprandial concentrations of intact, biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001;50:60913. American Diabetes Association. Complications of Diabetes in the United States. http://www.diabetes.org/type-2-diabetes/well-being/heart-diseaseand-stroke.jsp. (Accessed 10 April 2007) UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patient with type 2 diabetes (UKPDS 33). Lancet 1998;352:83753. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:33542. Knudsen LB, Nielsen PF, Huusfeldt PO et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 2000;41:16649. Agers H, Jensen LB, Elbrnd B et al. The pharmacokinetics, pharmacodynamics, safety, and tolerability of NN2211, a new longactive GLP-1 derivative, in healthy men. Diabetologia 2002; 465:195202. Elbrnd B, Jakobsen G, Larsen S et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a longacting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care 2002;25:1398404. Chang AM, Jakobsen G, Sturis J et al. The GLP-1 derivative NN2211 restores -cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2005;52:178691. Madsbad S, Schmitz O, Ranstam J et al. On behalf of the NN22111310 International Study Group: Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211). A 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004;27:133542. Feinglos MN, Saad MF, Pi-Sunyer FX et al. Liraglutide Dose-Response Study Group. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with type 2 diabetes. Diabet Med 2005;22:101623. Nauck MA, Hompesch M, Filipczak R et al. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes 2006;114:41723. Nauck MA, El-Ouaghlidi A, Hompesch M et al. No impairment of hypoglycemia counterregulation via glucagon with NN221, a GLP-1 derivative, in subjects with type 2 diabetes. Diabetes 2003;52(suppl 1):A128. Meier JJ, Gallwitz B, Salmen S et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003;88:271925. Juhl CB, Hollingdal M, Sturis J et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002; 51:4249.

S32

VOLUME 8 SUPPL 2 . NOVEMBER/DECEMBER 2008

Downloaded from dvd.sagepub.com by guest on April 1, 2012

REVIEW

18. Byetta (exenatide injection) [product information]. San Diego: Amylin Pharmaceuticals and Indianapolis: Eli Lilly and Company, 2007. 19. Degn KB, Juhl CB, Sturis J et al. One weeks treatment with the longacting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and - a n d -cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004;53:118794. 20. Vilsbll T, Zdravkovic M, Le-Thi T et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care 2007;30:160810. 21. Novo Nordisk (data on file). 22. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:22934.

23. Vilsbll T, Zdravkovic M, Le-Thi T et al. Liraglutide treatment, blood pressure and biomarkers of cardiovascular risk in patients with type 2 diabetes: 14 weeks monotherapy study. Diabetes 2006;55(suppl 1):A465. 24. Sturis J, Gotfredsen CF, Rmer J et al. GLP-1 derivative liraglutide in rats with -cell deficiencies: influence of metabolic state on cell mass dynamics. Br J Pharmacol 2003;140:12332. 25. Rolin B, Larsen MO, Gotfredsen CF et al. The long-active GLP-1 derivative NN2211 ameliorates glycemia and increases -cell mass in diabetic mice. Am J Physiol Endocrinol Metab 2002;283:E74552. 26. Bregenholt S, Moldrup A, Blume N et al. The long-acting glucagonlike peptide-1 analogue, liraglutide, inhibits -cell apoptosis in vitro. J Biochem Biophys Res Comm 2005;330:57784. 27. Friedrichsen BN, Neubauer N, Lee YC et al. Stimulation of pancreatic beta-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways. J Endocrinol 2006;88:48192.

THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

S33

Downloaded from dvd.sagepub.com by guest on April 1, 2012