liraglutide 7

Early clinical studies with liraglutide

W. E. Schmidt

The need for novel approaches todiabetes treatment

Type 2 diabetes is characterised by progressive

impairment in beta-cell function and regeneration,

elevated glucagon levels and reduced insulin sensitiv-

ity, leading to deteriorating glycaemic control over

time. This cluster of defects in glucose regulation is

reflected in escalating HbA1c levels, rising fasting

plasma glucose (FPG) and postprandial glucose

(PPG), and increased microvascular and macrovascu-

lar disorders. As such, the goals of treatment are to

improve and maintain glycaemic control in a manner

that is acceptable to patients.

The traditional classes of oral antidiabetic agents

(OADs), as well as conventional human insulin for-

mulations, are limited in their ability to help patients

achieve glycaemic control targets and are associated

with adverse effects for reasons that relate to their

mode of action, pharmacokinetic and pharmacody-

namic properties. For example, the thiazolidinedi-

ones, indicated in combination with metformin in

patients with metabolic syndrome (1), are frequently

associated with weight gain and sometimes with

peripheral oedema (1). The insulin secretagogues

(sulphonylureas or glinides), appropriate as first-line

therapy in some patients and as second-line in others

(1), remain effective as long as the patient retains

pancreatic beta-cell function, but can induce hypo-

glycaemia; sulphonylureas are also associated with

mild-to-moderate weight gain (1). Although different

human insulin formulations have different draw-

backs, the main limitations of this type of insulin

include slow onset and prolonged duration of action

(a disadvantage in the case of short-acting insulins),

leading to impaired efficacy and considerable risk of

between-meal hypoglycaemia. For this reason, regular

human and NPH insulin are no longer recom-

mended for management of type 2 diabetes in the

United States (1), although they remain included in

guidelines in the UK (2). The hypoglycaemia and

weight gain that result when using these treatments

also cause distress among patients and may limit

treatment adherence (3–5); concerns about lifestyle

SUMMARY

Aims: To describe Phase 1 and 2 clinical trials of liraglutide with a focus on clini-

cal pharmacology. Key findings: In early clinical trials of liraglutide, 0.05–1.9 mg

daily improved multiple aspects of glycaemic control and beta-cell function. Early

trials demonstrated typical reductions in glycated haemoglobin (HbA1c) and fasting

plasma glucose (FPG) of up to 1.5% and 3.3–3.9 mmol ⁄ l, respectively, at daily

doses of 1.25–1.9 mg, with 45–50% of patients reaching HbA1c < 7%. The

effects of liraglutide in restoring beta-cell response to fasting and postprandial hy-

perglycaemia and in reinstating near-normal insulin secretion under hyperglycaemic

conditions suggest a beta-cell-protective effect. By delaying gastric emptying and

promoting satiety, liraglutide is weight sparing at low doses and causes clinically

meaningful weight loss at higher doses and in combination with other anti-diabe-

tes therapies with weight-modifying benefits, such as metformin. Significant

improvements in other cardiovascular risk factors, including blood pressure, lipids

and cardiovascular risk biomarkers, were also evident. Adverse effects of liraglutide

were primarily gastrointestinal; dose-dependent nausea was the most commonly

reported effect, but was typically mild-to-moderate in severity and transient in nat-

ure. Conclusions: Early clinical trials of liraglutide indicate the ability to improve

glycaemic control in a glucose-dependent manner, with low risk of hypoglycaemia.

Promotion of weight loss, along with improvements in multiple cardiovascular risk

factors, suggests that liraglutide may offer a novel and clinically valuable approach

to disease management for patients with type 2 diabetes.

Dept of Medicine I, St. Josef

Hospital, Ruhr-University of

Bochum Medical School,

Bochum, Germany

Correspondence to:

Wolfgang E. Schmidt, Direktor

der Medizinischen Klinik 1, St

Josef-Hospital, Klinikum der

Ruhr-Universitat Bochum,

Gudrunstraße 56, Bochum

44791, Germany

Tel.: +49 234 509 2311

Fax: +49 234 509 2309

Email:

Wolfgang.e.schmidt@ruhr-uni-

bochum.de

Disclosures

This article forms part of a

supplement funded by Novo

Nordisk.

WES has received consulting

fees (advisory boards) and

grant support from: Roche,

Novartis, Eli Lilly, Novo

Nordisk, Schering-Plough,

Takeda, AstraZeneca, Eisai,

Merck Sharpe & Dohme, Falk

Foundation, Bristol-Meyers

Squibb and Berlin Chemie.

REV IEW PAPER

ª 2010 Blackwell Publishing Ltd Int J Clin Pract, October 2010, 64 (Suppl. 167), 12–2012 doi: 10.1111/j.1742-1241.2010.02500.x

constraints attributable to the stigma and inconve-

nience of injections delivered using cumbersome

devices also act as barriers to the acceptance of

treatment (5). There is a need for effective, new

agents that can facilitate attainment of glycaemic

control targets and weight reduction while addressing

other comorbidities commonly associated with type

2 diabetes, and with an improved side-effect profile.

The ability to slow the decline in beta-cell mass

and ⁄ or sustain improvement in beta-cell function

over the long-term would be a milestone in diabetes

care, with the potential to alter the natural history

of the disease in a highly clinically significant

manner.

The recently developed incretin-based therapies,

designed to enhance the physiological effects of

native glucagon-like peptide-1 (GLP-1), have the

potential to address many of the core metabolic

defects in type 2 diabetes and to improve substan-

tially the range of treatment options. By virtue of

their glucose-dependent mode of action, these agents

have an adverse event profile notable for its very low

risk of hypoglycaemia unless combined with insulin

secretagogues (1). Their most frequent adverse effect

is usually transient, dose-dependent nausea ⁄ vomiting

and development of anti-drug antibodies (GLP-1 ag-

onists) or a slightly increased risk of infections and

headache [inhibitors of dipeptidyl peptidase-4 (DPP-

4), the enzyme responsible for rapid in vivo degrada-

tion of GLP-1] (1,6). Incretin-based treatments that

are currently commercially available in both Europe

and the U.S. include the exendin-4-based GLP-1

receptor agonist exenatide; the human GLP-1 ana-

logue liraglutide; and three DPP-4 inhibitors, namely

sitagliptin, vildagliptin (Europe only) and saxagliptin.

Agents in development include the long-acting

release (LAR) formulation of exenatide, the long-

acting GLP-1 analogue taspoglutide, and new DPP-4

inhibitors including alogliptin and linagliptin, among

others.

The preclinical development programme for lira-

glutide, which demonstrated that liraglutide exerts its

metabolic effects through actions on multiple physio-

logical systems, yielded promising efficacy data (see

Knudsen in this supplement*). This review considers

the early clinical trials of liraglutide, including

aspects of clinical pharmacology. Clinical pharmacol-

ogy may be considered the essential interface

between preclinical and large-scale clinical studies;

the stage at which safety, dosing and efficacy data are

gathered to determine the viability of progressing to

Phase 3 clinical studies in patients. In covering

aspects of clinical pharmacology within the early

clinical trials of liraglutide, this article describes the

metabolism and pharmacokinetics ⁄ pharmacodynam-

ics of liraglutide, reports data from early dose-finding

clinical studies and highlights the efficacy and safety

of liraglutide in human volunteers, as well as in stud-

ies in small numbers of patients with type 2 diabetes.

The data examined suggest that liraglutide may

address many of the limitations of current diabetes

treatments, offering patients a novel approach to dia-

betes management.

Liraglutide: the first human GLP-1analogue

Endogenous GLP-1 is secreted primarily in response

to food by L-cells throughout the distal small intes-

tine and colon (7), and subsequently induces a range

of metabolic actions. These include

• Effects on glucose control (8–11):

o glucose-dependent insulin release

o increased insulin synthesis and secretion

o increased beta-cell glucose sensitivity

o glucose-dependent inhibition of glucagon secre-

tion

• Effects on weight and food intake (12–14):

o reduction in body weight due to increased

satiety

o reduced food intake

o delayed gastric emptying

Although GLP-1 secretion may be impaired in

some patients with type 2 diabetes, its action on the

beta-cell seems to be reduced as a more general phe-

nomenon in the disease (15–18) (Figure 1). Adminis-

tration of supraphysiological levels of GLP-1 lowers

serum glucose levels by immediately restoring the

important first phase insulin response, and by reduc-

ing exaggerated glucagon secretion (8). However,

GLP-1 itself is not a therapeutically viable agent

because of its rapid degradation by DPP-4, which

results in an in vivo half-life of approximately 2 min

(19,20).

The human GLP-1 analogue liraglutide was devel-

oped to address this therapeutic limitation. The early

clinical study programme investigated doses of

0.6 mg, 1.25 mg and 1.9 mg, whereas the Liraglutide

Effect and Action in Diabetes (LEAD) series of clini-

cal trials has focused on doses of 0.6 mg, 1.2 mg and

1.8 mg daily. The liraglutide molecule binds revers-

ibly to albumin, has self-association properties that

lead to metabolic stability and has a partial resistance

to DPP-4 (21), leading it to be metabolised by DPP-

4 and neutral endopeptidases in a manner similar to

that for GLP-1, but at a much slower rate (22). This*Knudsen LB. Liraglutide: the therapeutic promise from animal models. Int J Clin

Pract 2010; 64 (Suppl. 167): 4–11.

Early clinical studies with liraglutide 13

ª 2010 Blackwell Publishing Ltd Int J Clin Pract, October 2010, 64 (Suppl. 167), 12–20

results in a protracted half-life of 13 h after subcuta-

neous injection (23).

As a result of its kinetic properties, liraglutide can

be given once daily without regard to mealtimes

(11,23–25) and, although data in patients with renal

and hepatic impairment are limited, a fact recognised

in restrictions to the product licence for these condi-

tions, they indicate a limited tendency for drug accu-

mulation in such patients, suggesting that dose

adjustment is unlikely to be necessary (22,26). Indi-

vidual trial data suggest that liraglutide is an effective

blood-glucose-lowering agent in men and women of

different ages and ethnicities (27). The use of liraglu-

tide was not associated with any clinically relevant

drug–drug interactions in studies evaluating concom-

itant administration of other agents with varying sol-

ubility and permeability, including atorvastatin

(40 mg), griseofulvin (500 mg), paracetamol (acet-

aminophen) (1 g), lisinopril (20 mg) and digoxin

(1 mg) (28,29). As interaction with warfarin has not

yet been investigated, INR should be checked more

frequently in warfarin users who subsequently start

taking liraglutide.

Liraglutide improves many aspects ofglycaemic control

Results of early dose-finding trials that investigated a

range of liraglutide doses on glycaemic control

are presented in Table 1. These indicate typical

reductions in HbA1c and FPG of up to 1.5% and

3.3–3.9 mmol ⁄ l, respectively, at daily doses of 1.25–

1.9 mg, with 45–50% of patients reaching HbA1c

< 7% (25). Details on the study design and out-

comes of the comprehensive LEAD programme,

which form the main body of clinical data on lira-

glutide, can be found in Raskin and Mora and McG-

ill in this supplement*.

A

B

Figure 1 Type 2 diabetes (T2D) may be associated with impaired glucagon-like peptide 1 (GLP-1) secretion in some

patients. i.v., intravenous. *p < 0.05 T2D vs. healthy. Part (A) ª 2001, The Endocrine Society. From Toft-Nielsen M et al.,

Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 86:

3717–23. Part (B) With kind permission from Springer Science + Business Media: Diabetologia, Reduced incretin effect in

type 2 (non-insulin-dependent) diabetes, 29, 1986, 46–52, M Nauck et al.

*Raskin P, Mora PF. Glycaemic control with liraglutide: the phase 3 trial

programme. Int J Clin Pract 2010; 64 (Suppl. 167): 21–7. McGill JB. Liraglutide:

effects beyond glycaemic control in diabetes treatment. Int J Clin Pract 2010; 64

(Suppl. 167): 28–34.

14 Early clinical studies with liraglutide


Effects on circulating glucose levelsBy increasing insulin secretion in a glucose-depen-

dent manner, liraglutide lowers blood glucose

concentrations with a low risk of inducing

hypoglycaemia. During a series of hypoglycaemic

clamp studies in 11 subjects with type 2 diabetes,

Nauck et al. observed increased insulin secretion fol-

lowing administration of liraglutide at higher glucose

levels (4.3 and 3.7 mmol ⁄ l), but not at lower glucose

levels (3.0 or 2.3 mmol ⁄ l) (9) (Figure 2). What is

more, in a short-term investigation conducted by

Degn et al., once-daily liraglutide (6 lg ⁄ kg) signifi-

cantly decreased 24-h exposure to glucose (p = 0.01)

and significantly slowed fasting glucose release

(p = 0.04) because of reduced glycogenolysis (11).

Importantly, despite the marked improvement in gly-

caemic control, no episodes of hypoglycaemia were

reported. Similarly, in a study by Juhl et al. a single

injection of liraglutide (10 lg ⁄ kg) resulted in a small,

but significant, elevation in fasting insulin secretion

rate (p = 0.03) and significantly lower glucose levels

throughout the day vs. placebo, including during

fasting (6.9 vs. 8.1 mmol ⁄ l; 124.2 vs. 145.8 mg ⁄ dl;

p < 0.01) (30). There was no change in fasting gluca-

gon levels. Reduction in FPG concentration was also

demonstrated in a longer study in 33 overweight

patients (body mass index = 36.6 kg ⁄ m2) who

received a single low dose of liraglutide (0.6 mg) for

8 weeks; in this case, FPG levels decreased by

1.9 mmol ⁄ l from baseline (p = 0.002 vs. placebo)

(31).

In addition to lowering fasting glycaemia, liraglu-

tide has demonstrated the ability to reduce PPG

excursions. This is a key finding with important clin-

ical implications as PPG may be an independent risk

factor for cardiovascular disease (32), as well as an

important contributor to raised HbA1c. In the study

by Degn et al., once-daily liraglutide (6 lg ⁄ kg) led to

a 20% reduction in PPG values after all three main

meals (p = 0.01; p = 0.02; p = 0.01, respectively),

indicating that the drug enhances the capacity of

beta-cells to respond to prandial stimuli (11). The

study by Juhl et al. also demonstrated benefits to

postprandial glycaemia: glucose exposure following a

mixed meal decreased by 23% vs. placebo in liraglu-

tide-treated patients (p < 0.001), and peak glucose

concentration was reduced. These effects presumably

resulted from the delayed gastric emptying and

Table 1 Summary of key glycaemic control and weight data from selected early clinical trials. FPG, fasting plasma

glucose

N

Liraglutide

dose(s),

mg ⁄ day

Study

duration

(weeks)

Change in glycaemic control vs.

placeboWeight loss

from baseline,

kgHbA1c, % FPG, mmol ⁄ l (mg ⁄ dl)

Madsbad et al. (36) Proof of concept study 193 0.045–0.75 12 £ )0.75* £ 2.14* (£ 38.5*) £ 1.2

Harder et al. (31) 33 0.6 8 )0.33– )1.9� ()34.2�) 0.7

Vilsbøll et al. (25) 165 0.65 14 )0.98� )2.7� ()48.6�) –

1.25 )1.40� )3.4� ()61.2�) –

1.90 )1.45� )3.4� ()61.2�) 2.99§

Vilsbøll et al. (40) Substudy of above 39 0.65 14 )1.0 )3.6 ()64.8) 1.3

1.25 )1.3 )3.4 ()61.2) 2.4

1.90 )1.5 )3.9 ()70.2) 2.8

*p < 0.0001 vs. placebo; �p < 0.001 vs. placebo; �p = 0.002 vs. placebo; §p = 0.04 vs. placebo; –p = 0.03 vs. placebo.

Figure 2 In a series of stepwise hypoglycaemic clamp

studies, Nauck et al. demonstrated that liraglutide

stimulates insulin secretion in a glucose-dependent manner.

From Nauck M et al. No impairment of hypoglycaemia

counter-regulation via glucagon with NN2211, a GLP-1

derivative, in subjects with type 2 diabetes. Diabetes 2003;

52(Suppl. 1): A128. Reprinted with permission from the

American Diabetes Association



suppression of glucagon secretion that were demon-

strated during the study (30). Similarly, in a 3-week

randomised, double-blind crossover trial that

employed a standard meal test to determine the

effects of once-daily liraglutide (0.6, 1.2 and 1.8 mg

daily) on glycaemic control, significant, dose-depen-

dent reductions in PPG were evident after 1 week for

all three doses tested, and mean incremental PPG

was also significantly reduced (33) (Figure 3). These

improvements were likely mediated through the

dose-dependent increase in insulin response and

delay in gastric emptying also demonstrated in the

study.

Liraglutide has been shown to lower glucose levels

during the night, even when administered in the

morning. This was demonstrated in a randomised,

double-blind crossover study in which 13 patients

with type 2 diabetes who discontinued OADs before

the study received liraglutide (6 lg ⁄ kg once daily, at

07:45) for 9 days, and ate three standard meals on

the test day (day 8) (34). Liraglutide decreased noc-

turnal glucose levels from 8.3 to 6.8 mmol ⁄ l (149.4

to 122.4 mg ⁄ dl; p < 0.01 vs. placebo).

Effects on beta-cell functionThe data from studies exploring the effects of liraglu-

tide on beta-cells suggest the ability to improve and

maintain beta-cell function. In a double-blind, sin-

gle-dose, crossover study in 11 patients with type 2

diabetes conducted by Juhl et al., a single injection

of liraglutide (10 lg ⁄ kg) resulted in a small, but sig-

nificant elevation in fasting insulin secretion rate

(p = 0.03) vs. placebo (30). Similarly, in another

double-blind, single-dose, placebo-controlled cross-

over study in which 10 subjects with well controlled

type 2 diabetes received a graded glucose infusion, a

single dose of liraglutide (7.5 lg ⁄ kg) restored

beta-cell response to elevated glucose levels (35)

(Figure 4). This was reflected in increased insulin

and C-peptide levels vs. placebo (p < 0.001 for both

parameters), which approximated those of healthy

subjects who did not receive the drug. Subjects also

experienced an increased overall insulin secretory

response, which occurred in a glucose-dependent

manner and not during euglycaemia. Beta-cell sensi-

tivity to glucose, measured using the insulin secre-

tion rate area under the curve, increased by 70%

(p < 0.001), again reaching values similar to those in

non-diabetic controls.

Improved islet cell function following admini-

stration of liraglutide, leading to an enhanced

insulin response to hyperglycaemia, has also been

demonstrated in several placebo-controlled short-

term studies. An early proof-of-concept study, in

Figure 3 Mean absolute (A) and incremental (B) postprandial plasma glucose levels in subjects with type 2 diabetes (T2D)

following administration of liraglutide 1.8 mg or placebo during a standard meal test. From Flint et al. The once-daily

human GLP-1 analogue liraglutide improves both absolute and baseline corrected postprandial glucose levels. Diabetes

2008; 57(Suppl. 1): P556. Reprinted with permission from the American Diabetes Association

Figure 4 A single dose of liraglutide restores beta-cell

sensitivity. Data are means ± SE; n = 10 for each group.

From Chang AM et al. The GLP-1 derivative NN2211

restores beta-cell sensitivity to glucose in type 2 diabetic

patients after a single dose. Diabetes 2003; 52: 1786–91.

Reprinted with permission from the American Diabetes

Association



which 193 patients with type 2 diabetes received

liraglutide 0.045–0.75 mg daily for 12 weeks, demon-

strated significantly improved beta-cell function

[measured using the Homeostasis Model Assessment

(HOMA)] following liraglutide treatment vs. placebo

(p = 0.0002 at the highest liraglutide dose). Further

to this, there was a significant decrease in proinsu-

lin:insulin ratio vs. placebo (p = 0.02 at the highest

liraglutide dose) (36), an important finding given

that a raised proinsulin:insulin ratio is a central

feature of prediabetes and type 2 diabetes (37,38).

Fasting C-peptide remained unchanged.

Improved beta-cell function was also demonstrated

by Degn et al. in a 1-week double-blind, placebo-

controlled, crossover study in 13 patients in whom

the main study was followed by a 1-day hyperglycae-

mic clamp (11). Following liraglutide administration,

the first-phase insulin response, almost uniformly

absent in type 2 diabetes (39), increased by 60% after

the intravenous glucose bolus (p < 0.01). Circulating

glucagon levels over 24 h were significantly reduced

(p = 0.04), and maximal beta-cell secretory capacity,

measured using arginine-stimulated insulin secretory

response, improved significantly (p < 0.01). Other

measures indicating improved islet cell function were

a 30% increase in HOMA-B concentration (60% of

normal vs. 46%; p = 0.01) following liraglutide

administration, and a 40–50% reduction in proinsu-

lin:insulin ratio during the hyperglycaemic clamp

(0.09 vs. 0.18; p = 0.001).

In a longer, 14-week, placebo-controlled trial in 39

patients with type 2 diabetes (40), patients received

liraglutide at doses of 0.65, 1.25 or 1.9 mg ⁄ day. The

first-phase insulin response was partially restored at

both 1.25 mg ⁄ day (118% increase) and 1.9 mg ⁄ day

(103% increase) doses of liraglutide, and the second-

phase insulin response improved in the 1.25 mg ⁄ day

group; arginine-stimulated insulin secretion increased

at the two highest dose levels, by 114% and 94%,

respectively, vs. placebo (p < 0.05).

The actions of liraglutide on glucagon specifically

include reduced postprandial glucagon release

(11,30) without effect on the overall counter-regula-

tory glucagon response to hypoglycaemia (9). This is

particularly beneficial in light of the impaired post-

prandial inhibition of glucagon release that contrib-

utes to postprandial hyperglycaemia (41) and is

known to accompany type 2 diabetes (42).

Increasingly, data are emerging to suggest that the

actions of liraglutide on the beta-cell extend beyond

its role as an insulin secretagogue. Evidence indicates

additional effects of liraglutide on the beta-cell life

cycle in vitro, including the slowing of programmed

beta-cell death (apoptosis) and possibly induction of

beta-cell proliferation in human islets (43). Further

research is warranted to determine the range of clini-

cally meaningful effects we can expect.

Effects on satietyLiraglutide treatment has been shown to result in a

variety of ancillary metabolic actions that limit food

intake, thereby limiting weight gain and addressing

one of the key limitations of most existing type 2

diabetes therapies: that of pronounced weight gain.

These effects include significantly delayed gastric

emptying (30,31,44), promotion of satiety (44) and a

slight reduction in energy intake associated with ear-

lier satiety (33,44).

Adverse effects of liraglutideSimilar to data reported from trials of other GLP-1

receptor analogues, data from the early clinical stud-

ies on liraglutide indicate that the most common

adverse events were dose-related gastrointestinal

symptoms, which caused study withdrawal only

rarely. The predominant symptom was nausea that

was typically mild-to-moderate in severity and tran-

sient, decreasing in the majority of patients within a

week or less (35,44). The mild, transient nature of

nausea associated with liraglutide was confirmed in

the LEAD clinical trial programme (see trial data in

Raskin and Mora and Peterson and Pollom in this

supplement*). No episodes of major hypoglycaemia

occurred during the early clinical, non-LEAD studies

detailed in this article, and minor hypoglycaemia

occurred with similar or lower frequency than in

comparator groups receiving metformin or placebo.

Antibodies against liraglutide were detected (in

9–13% of liraglutide-treated patients) during only

one (46) of three trials in which they were evaluated

(46–48).

Liraglutide reduces weight andimproves cardiovascular riskbiomarkers

In contrast to the weight gain seen with most tradi-

tional treatments and the weight neutrality of DPP-4

inhibitors (49), these improvements in glycaemic

control were associated with weight loss of approxi-

mately 3 kg (25). When compared directly with

metformin, widely used in type 2 diabetes for its

weight-sparing effects, liraglutide has demonstrated

the potential to induce comparable weight loss

(reductions of up to 1.9% vs. 0.6% of body weight;

p = ns) after 12 weeks of low-dose treatment

*Raskin P, Mora PF. Glycaemic control with liraglutide: the phase 3 trial

programme. Int J Clin Pract 2010; 64 (Suppl. 167): 21–7. Peterson GE, Pollom RD.

Liraglutide in clinical practice: closing, safety and efficacy. Int J Clin Pract 2010; 64

(Suppl. 167): 35–43.



(£ 0.75 mg daily), although HbA1c increased by

0.86% in patients taking the liraglutide dose associ-

ated with the greatest weight reduction (0.225 mg

daily) (50). At the higher mean daily dose of approx-

imately 1.9 mg, used for 5 weeks (n = 144), liraglu-

tide monotherapy reduced body weight by 2.1 kg

from baseline (45). When liraglutide was combined

with metformin 1000 mg twice daily, body weight

decreased by 2.2 kg in contrast to the weight gain of

0.8 kg observed in patients who combined glimepi-

ride with metformin (p < 0.0001 for liraglutide +

metformin vs. glimepiride + metformin) (45). In

contrast with glimepiride monotherapy 4 mg ⁄ day,

4 weeks of treatment with liraglutide 1.8 mg daily

led to weight loss of 1–2 kg in patients with type 2

diabetes (n = 46; estimated treatment difference =

2.0 kg) (44).

The beneficial weight loss seen with liraglutide is

accompanied by improvements in other cardiovascu-

lar risk factors, including PPG (as described above),

blood pressure, triglycerides and cardiovascular risk

biomarkers. In a 14-week trial of liraglutide mono-

therapy (1.9 mg ⁄ day) in 163 patients with poorly

controlled type 2 diabetes, reductions in HbA1c

(1.74% vs. placebo; p < 0.0001), FPG (3.4 mmol ⁄ lvs. placebo; p < 0.0001) and PPG (approximately

50% of patients achieved PPG < 10 mmol ⁄ l after

each main meal) (25) occurred in conjunction with

significant reductions in several cardiovascular risk

biomarkers (51). Systolic blood pressure decreased

by 7.9 mmHg vs. placebo (p = 0.002) and triglycer-

ide levels demonstrated a 22% reduction vs. placebo

(p = 0.01). Significant reductions were also observed

in the concentrations of plasminogen-activator inhib-

itor-1, a risk factor for atherosclerosis (reduction of

25–30%; p = 0.05 at the highest liraglutide dose) and

B-type natriuretic peptide, a marker of left ventricu-

lar function (30–40% decrease; p = 0.009 at the

highest liraglutide dose). No hypoglycaemic event

was reported.

Conclusions

Liraglutide, the first human GLP-1 analogue, exerts

its metabolic effects through actions on multiple

physiological systems and demonstrates beneficial

effects on several aspects of glycaemic control. These

include glucose-dependent insulin secretion, reduced

glucose excursions, glucose-dependent inhibition of

glucagon release in the postprandial period and pres-

ervation of the counter-regulatory glucagon response

to hypoglycaemia, with additional beneficial effects

on beta-cell function and, potentially, preservation.

Further beneficial metabolic actions include limita-

tion of food intake with the potential to facilitate

weight loss through diverse mechanisms relating to

gastrointestinal motility, induction of satiety and

reduced energy intake. The protracted half-life of

liraglutide permits once-daily, meal-independent dos-

ing. The promising results achieved during preclini-

cal development of liraglutide have been reinforced

during Phase 1 and 2 clinical testing. This encourag-

ing body of early studies, which determined the

pharmacokinetic ⁄ pharmacodynamic profile of lira-

glutide and defined optimal dosing, supported lira-

glutide as an effective and well-tolerated candidate

for a comprehensive Phase 3 clinical development

programme.

Acknowledgements

The author is grateful to Esther Nathanson, MD, of

Watermeadow Medical (supported by Novo Nordisk

Inc.) for writing assistance.

Author contributions

The outline and drafts were developed in close

conjunction with the author, who also approved the

final version before submission.

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Paper received July 2010, accepted July 2010



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