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Summary

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References

Aims:  To describe Phase 1 and 2 clinical trials of liraglutide with a focus on clinical 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 hyperglycaemia 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-diabetes 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 nature.

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.


The need for novel approaches to diabetes treatment

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References

Type 2 diabetes is characterised by progressive impairment in beta-cell function and regeneration, elevated glucagon levels and reduced insulin sensitivity, 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 macrovascular 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 formulations, 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 pharmacodynamic properties. For example, the thiazolidinediones, 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 hypoglycaemia; sulphonylureas are also associated with mild-to-moderate weight gain (1). Although different human insulin formulations have different drawbacks, 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 recommended 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 constraints attributable to the stigma and inconvenience 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 substantially 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 agonists) or a slightly increased risk of infections and headache [inhibitors of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid in vivo degradation 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 analogue 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 liraglutide, which demonstrated that liraglutide exerts its metabolic effects through actions on multiple physiological 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 pharmacology 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/pharmacodynamics 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 studies 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 diabetes management.

Liraglutide: the first human GLP-1 analogue

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References

Endogenous GLP-1 is secreted primarily in response to food by L-cells throughout the distal small intestine 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 secretion
  • • 
    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 phenomenon in the disease (15–18) (Figure 1). Administration of supraphysiological levels of GLP-1 lowers serum glucose levels by immediately restoring the important first phase insulin response, and by reducing 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).

image

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) © 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 Metab86: 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.

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The human GLP-1 analogue liraglutide was developed 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 clinical trials has focused on doses of 0.6 mg, 1.2 mg and 1.8 mg daily. The liraglutide molecule binds reversibly 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 results in a protracted half-life of 13 h after subcutaneous 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 conditions, they indicate a limited tendency for drug accumulation in such patients, suggesting that dose adjustment is unlikely to be necessary (22,26). Individual 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 liraglutide was not associated with any clinically relevant drug–drug interactions in studies evaluating concomitant administration of other agents with varying solubility and permeability, including atorvastatin (40 mg), griseofulvin (500 mg), paracetamol (acetaminophen) (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 of glycaemic control

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References

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 outcomes of the comprehensive LEAD programme, which form the main body of clinical data on liraglutide, can be found in Raskin and Mora and McGill in this supplement*.

Table 1.   Summary of key glycaemic control and weight data from selected early clinical trials. FPG, fasting plasma glucose
 NLiraglutide dose(s), mg/dayStudy duration (weeks)Change in glycaemic control vs. placeboWeight loss from baseline, kg
HbA1c, %FPG, mmol/l (mg/dl)
  1. *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.

Madsbad et al. (36) Proof of concept study1930.045–0.7512≤ −0.75*≤ 2.14* (≤ 38.5*)≤ 1.2
Harder et al. (31)330.68−0.33¶−1.9‡ (−34.2‡)0.7
Vilsbøll et al. (25)1650.6514−0.98†−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 above390.6514−1.0−3.6 (−64.8)1.3
1.25−1.3−3.4 (−61.2)2.4
1.90−1.5−3.9 (−70.2)2.8

Effects on circulating glucose levels

By increasing insulin secretion in a glucose-dependent 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 following 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 μg/kg) significantly 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 glycaemic control, no episodes of hypoglycaemia were reported. Similarly, in a study by Juhl et al. a single injection of liraglutide (10 μg/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 glucagon 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).

image

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

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In addition to lowering fasting glycaemia, liraglutide has demonstrated the ability to reduce PPG excursions. This is a key finding with important clinical 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 μg/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 liraglutide-treated patients (p < 0.001), and peak glucose concentration was reduced. These effects presumably resulted from the delayed gastric emptying and suppression of glucagon secretion that were demonstrated 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-dependent 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.

image

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

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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 μg/kg once daily, at 07:45) for 9 days, and ate three standard meals on the test day (day 8) (34). Liraglutide decreased nocturnal 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 function

The data from studies exploring the effects of liraglutide on beta-cells suggest the ability to improve and maintain beta-cell function. In a double-blind, single-dose, crossover study in 11 patients with type 2 diabetes conducted by Juhl et al., a single injection of liraglutide (10 μg/kg) resulted in a small, but significant elevation in fasting insulin secretion rate (p = 0.03) vs. placebo (30). Similarly, in another double-blind, single-dose, placebo-controlled crossover study in which 10 subjects with well controlled type 2 diabetes received a graded glucose infusion, a single dose of liraglutide (7.5 μg/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 sensitivity to glucose, measured using the insulin secretion rate area under the curve, increased by 70% (p < 0.001), again reaching values similar to those in non-diabetic controls.

image

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

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Improved islet cell function following administration 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 which 193 patients with type 2 diabetes received liraglutide 0.045–0.75 mg daily for 12 weeks, demonstrated 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 proinsulin: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 hyperglycaemic 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 proinsulin: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-regulatory glucagon response to hypoglycaemia (9). This is particularly beneficial in light of the impaired postprandial inhibition of glucagon release that contributes 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 clinically meaningful effects we can expect.

Effects on satiety

Liraglutide 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 earlier satiety (33,44).

Adverse effects of liraglutide

Similar to data reported from trials of other GLP-1 receptor analogues, data from the early clinical studies 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 transient, 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 and improves cardiovascular risk biomarkers

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References

In contrast to the weight gain seen with most traditional treatments and the weight neutrality of DPP-4 inhibitors (49), these improvements in glycaemic control were associated with weight loss of approximately 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 (≤ 0.75 mg daily), although HbA1c increased by 0.86% in patients taking the liraglutide dose associated with the greatest weight reduction (0.225 mg daily) (50). At the higher mean daily dose of approximately 1.9 mg, used for 5 weeks (n = 144), liraglutide 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 glimepiride 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 cardiovascular risk factors, including PPG (as described above), blood pressure, triglycerides and cardiovascular risk biomarkers. In a 14-week trial of liraglutide monotherapy (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/l vs. 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 triglyceride levels demonstrated a 22% reduction vs. placebo (p = 0.01). Significant reductions were also observed in the concentrations of plasminogen-activator inhibitor-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 ventricular function (30–40% decrease; p = 0.009 at the highest liraglutide dose). No hypoglycaemic event was reported.

Conclusions

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References

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 preservation of the counter-regulatory glucagon response to hypoglycaemia, with additional beneficial effects on beta-cell function and, potentially, preservation. Further beneficial metabolic actions include limitation 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 dosing. The promising results achieved during preclinical development of liraglutide have been reinforced during Phase 1 and 2 clinical testing. This encouraging body of early studies, which determined the pharmacokinetic/pharmacodynamic profile of liraglutide and defined optimal dosing, supported liraglutide as an effective and well-tolerated candidate for a comprehensive Phase 3 clinical development programme.

Footnotes
  • *

    Knudsen LB. Liraglutide: the therapeutic promise from animal models. Int J Clin Pract 2010; 64 (Suppl. 167): 4–11.

  • *

    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.

  • *

    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.

References

  1. Top of page
  2. Summary
  3. The need for novel approaches to diabetes treatment
  4. Liraglutide: the first human GLP-1 analogue
  5. Liraglutide improves many aspects of glycaemic control
  6. Liraglutide reduces weight and improves cardiovascular risk biomarkers
  7. Conclusions
  8. Acknowledgements
  9. Author contributions
  10. References
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