1. بنام خداوند جان و خرد
Long-Acting Glucagon-Like Peptide 1 Receptor Agonists A review of their efficacy and tolerability
M. Siavash
Professor of endocrinology
Isfahan University of medical sciences
2017

2. Program Goals

3. Diabetes was one of the first diseases described, with an Egyptian manuscript from c BCE mentioning "too great emptying of the urine".
The Ebers papyrus includes a recommendation for a drink to be taken in such cases.
The first described cases are believed to be of type 1 diabetes.
Indian physicians around the same time identified the disease and classified it as madhumeha or "honey urine", noting the urine would attract ants.

4. The story, from the history
Before the discovery of insulin
discovery of insulin
discovery of NPH insulin
Production of recombinant insulin
Long term survival and chronic complications
Global trends to intensive glycemic control
glucometers
Insulin pumps
CGMs
New medications

5. Introduction

6. [note to speaker – use either this slide or the previous slide depending on the audience and format of your talk]
Here is an overview of the ADA’s treatment algorithm for type 2 diabetes, moving from monotherapy, to duel therapy, to triple therapy, and then to combination injectable therapy. Lifestyle management is emphasized throughout the progression of care, and individualization based on efficacy, hypoglycemia risk, weight, side effects, and costs is recommended.
It is important to note that the ADA’s full Standards of Care provides tables on the properties of these agents, as well as the costs associated with them. Please visit professional-dot-diabetes-org-slash-S-O-C for more information.
The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione.
[SLIDE] 6

7. [note to speaker – use either this slide or the previous slide depending on the audience and format of your talk]
Here is an overview of the ADA’s treatment algorithm for type 2 diabetes, moving from monotherapy, to duel therapy, to triple therapy, and then to combination injectable therapy. Lifestyle management is emphasized throughout the progression of care, and individualization based on efficacy, hypoglycemia risk, weight, side effects, and costs is recommended.
It is important to note that the ADA’s full Standards of Care provides tables on the properties of these agents, as well as the costs associated with them. Please visit professional-dot-diabetes-org-slash-S-O-C for more information.
The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione.
[SLIDE] 7

9. The Family of Incretin-based Therapies
Human GLP-1
analogues, e.g. liraglutide
Exendin-based
therapies, e.g. exenatide
GLP-1 receptor agonists
DPP-4 inhibitors, e.g. sitagliptin, vildagliptin
Incretin-based
therapies
The family of incretin-based therapies
Incretin-based therapies can be broadly divided into:
DPP-4 inhibitors (i.e. sitagliptin, vildagliptin)
GLP-1 receptor agonists (Exenatide, lirgalutide)
Within this second category however, the GLP-1R agonists can be classed as either:
Exendin-based therapies (exenatide, exenatide LAR) which have ~50% sequence identity to human GLP-1
Human GLP-1 analogues (liraglutide) which have share a much higher percentage of amino acids with human GLP-1 (97%)

10. GLP-1 RAs Currently Available

13. Liraglutide: what is it?
Liraglutide: a once-daily GLP-1 analogue under investigation for the treatment of type 2 diabetes

14. R&D effort that led to the approval of liraglutide14

15. Liraglutide is a once-daily, human GLP-1 analogue
3D Structure of the liraglutide molecule
Liraglutide is a once-daily human GLP-1 analogue
In creating liraglutide, two modifications to the amino acid sequence of GLP-1 are made: a fatty acid is acylated to lysine at position 26 and the lysine at position 34 is replaced with arginine.
These modifications result in increased self-association (which slows absorption from the subcutaneous depot), albumin binding and reduced susceptibility to DPP-IV, which combine to prolong its plasma half-life, protracting its action. Thus, the problem of the short half-life, which is the major clinical drawback of native GLP-1, is overcome.
For comparison, the plasma half-life of exenatide is 4 to 6 hours (reviewed in Nauck and Drucker, 2006)
Reference
Knudsen et al. J Med Chem 2000;43:1664–69
Knudsen et al. J Med Chem 2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94

16. Liraglutide has a delayed absorption from the subcutis
Steensgaard et al. Diabetes 2008;57(Suppl. 1):A164 (abstract 552-P)

17. Once-daily liraglutide covers 24 h in type 2 diabetes
Once-daily injection covers 24 hours in type 2 diabetes
The sustained blood glucose lowering action of liraglutide was demonstrated in this study of 13 patients with type 2 diabetes. Patients received 1 week of once-daily subcutaneous liraglutide injections (6 μg/kg) and 1 week of once-daily placebo injections in a double-blind, crossover design. Previous OAD agents were discontinued 2 weeks prior to the study treatment period. Following liraglutide treatment, plasma glucose was consistently lower during a 24-hour test period than following placebo treatment. This observation was borne out statistically in an assessment of area under the curve (AUC; mmol/l/h) for this 24-hour test period (187.5 vs , for liraglutide and placebo, respectively, p = 0.01).
References
Study Degn et al. Diabetes 2004;53:
Degn et al. Diabetes 2004;53:1187–94

18. Concentration of active liraglutide is higher than GLP-1 concentration with a DPP-4 inhibitor
Levels of GLP-1 with liraglutide are pharmacological; with a DPP-4 inhibitor they are physiological
These studies show that the level of the GLP-1 receptor agonist, liraglutide, are higher than that achieved with a DPP-4 inhibitor such as vildagliptin. The pharmacological levels of GLP-1R agonist achieved with liraglutide result in additional clinical benefits for example weight loss, as compared with DPP-4 inhibitors, which are weight neutral.
References
Degn et al. Diabetes 2004;53:1187–94.
Mari et al. J Clin Endocrinol Metab 2005;90:4888–94
*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide
Adapted from Degn et al. Diabetes 2004;53:1187–94; Mari et al. J Clin Endocrinol Metab 2005;90:4888–94

19. Liraglutide has multiple direct effects on human physiology
1. Pancreas and liver
GLP-1 has a direct functional effect on pancreatic cells, influencing secretions from alpha-, beta- and delta-cells. One of its most important effects is to increase insulin secretion. Importantly, however, its insulinotropic action is glucose dependent. Consequently, GLP-1 has the capacity to lower blood glucose while protecting against hypoglycaemia. GLP-1 also regulates glucagon secretion, partly via an increase in somatostatin secretion, and partly via a direct effect on the alpha-cell. This reduction in glucagon secretion serves to decrease hepatic glucose output.
2. GLP-1 stimulates beta-cell regeneration and mass in animal models
Studies have demonstrated that GLP-1 plays an important role in maintaining beta-cells. In animal studies, GLP-1 increases beta-cell mass through the stimulation of beta-cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing beta-cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al., 2002). Additionally, a study using freshly isolated human islets reported a reduction in the number of apoptotic beta-cells following 5 days of in vitro treatment with GLP-1 (Farilla et al., 2003). These observations of increased beta-cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive beta-cell dysfunction is one of the main pathophysiologies of the disease.
3. GLP-1: effects on the gastrointestinal (GI), cardiac and central nervous systems
The net effect of GLP-1’s action on the GI system is to delay absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al., 1993). Combined, these GI effects serve to flatten the meal-related increase in glucose. This may be important in the management of type 2 diabetes because elevated postprandial glucose excursions are a key feature of type 2 diabetes. Reducing this excursion should therefore be an aim of diabetes treatment. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce food intake by increasing the feeling of satiety. Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing feelings of satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing food intake. Recently, GLP-1 has also been shown to improve spatial and associative learning following its intracerebroventricular infusion in the rat (During et al., 2003). Furthermore, studies have shown that GLP-1 can protect CNS cells against apoptosis (in vitro, Perry et al., 2002), and reduce amyloid levels (in vivo, Perry et al., 2003). GLP-1 has also been associated with cardiovascular function in animal and human studies. Specifically, studies have shown that use of GLP-1 or recombinant GLP-1 can protect myocardium in ischaemic conditions (Bose et al., 2005, Kavianipour et al., 2003), improve myocardial function (Thrainsdottir et al., 2004, Nikolaidis et al., 2004), improve endothelial function (Nystrom et al., 2004), and relax arteries (Nystrom et al. 2005).
References
Wettergren et al. Dig Dis Sci 1993;38:665–73. Kieffer, et al. Endocr Rev 1999;20:876–913. During et al. Nat Med 2003;9:1173–9. Flint et al. J Clin Invest 1998;101:515–20. Perry et al. J Pharmacol Exp Ther 2002;302:881–8. Perry et al. J Neurosci Res 2003;72:603–12. Bose et al. Diabetes 2005;54:146–51. Kavianipour et al. Peptides 2003;24:569–78. Thrainsdottir et al. Diab Vasc Dis Res 2004;1:40–3. Nikolaidis et al. Circulation 2004;109:962–5. Nystrom et al. Am J Physiol Endocrinol Metab 2004;287:E1209–15. Nystrom et al. Regul Pept 2005;125:173–7. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–8. Ørskov et al. Endocrinology 1988;123:2009–13. Bulotta et al. J Mol Endocrinol 2002;29:347–60. Farilla et al. Endocrinology 2003;144:5149–58.
*In animal studies

20. LEAD covers the continuum of type 2 diabetes care
LEAD, Liraglutide Effect and Action in Diabetes. Marre et al. Diabet icMed 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)

21. Effect on HbA1c across the LEAD trials
**p<0.01, ***p≤ vs. active comparator
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; 32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: 2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6)

22. LEAD programme: reductions in HbA1c with liraglutide according to baseline HbA1c
The LEAD programme: reduction in HbA1c when adding liraglutide
Estimated means are obtained from an ANCOVA with treatment, country and previous treatment as fixed effects and baseline value as a covariate; Estimated mean ± 1.96 x SE; Table
References
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1)
Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2)
Garber et al. Lancet 2009;373:473–81 (LEAD-3)
Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4)
Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5)
Significant *vs. comparator; #change in HbA1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1)
Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6) 22

23. Percentage of patients reaching ADA targets when adding liraglutide
The LEAD programme: percentage of patients reaching ADA targets when adding liraglutide
Estimated means are obtained from an ANCOVA with treatment, country and previous treatment as fixed effects and baseline value as a covariate; Estimated mean ± 1.96 x SE; Table
References
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1)
Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2)
Garber et al. Lancet 2009;373:473–81 (LEAD-3)
Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4)
Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5)
***p< **p<0.001; *p<0.05 vs. comparator; patients reaching HbA1c ADA targets for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to monotherapy (LEAD-2,-1)
Marre et al. Diabetic Med 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6) 23 23

24. Effect on body weight across the LEAD trials
All subjects. *Significant vs. comparator
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; 32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5)

25. Effect of liraglutide on systolic blood pressure when used to treat type 2 diabetes
Liraglutide consistently reduces blood pressure
Liraglutide reduced SBP across the LEAD studies.
Tight blood pressure control reduces CV events and all-cause mortality (UKPDS 38, 1998; Hansson et al., 1998). A reduction of 5.6 mmHg has been shown to reduce death from CV disease by 18% (Patel et al., 2007).
References
Studies NN , -1572, -1573, and-1697 presented as
Marre et al. Diabetes 2008; 57 (Suppl. 1): A4.
Nauck et al. Diabetes 2008; 57 (Suppl. 1): A150.
Garber et al. Diabetes 2008; 57 (Suppl. 1): LB3.
Russell-Jones et al. Diabetes 2008; 57 (Suppl. 1): A159.
Study NN presented as poster 898 by Zinman at EASD 2008.
UKPDS 38. BMJ 1998:317;703–13.
Hansson et al. Lancet 1998;351:1755–62.
Patel et al. Lancet 2007;370:829–40.
All subjects. ***p≤0.0001, **p<0.001, *p<0.05 vs. comparator
Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: 2046–55 (LEAD-5); Buse et al. Lancet 2009; 374:39–47 (LEAD-6) 25

26. Direct comparison of liraglutide and sitagliptin: change in HbA1c (0–26 weeks)
LS mean (SE)
Liraglutide 1.8 mg: −1.50 (0.06)
Liraglutide 1.2 mg: −1.24 (0.07)
Sitagliptin: −0.90 (0.07)
Liraglutide 1.8 mg non-inferior to sitagliptin LS mean: −0.60; 95% CI [−0.77; −0.43]
Liraglutide 1.8 mg also superior to sitagliptin (p<0.0001)
Liraglutide 1.2 mg non-inferior to sitagliptin LS mean: −0.34; 95% CI [−0.51; −0.16]
Liraglutide 1.2 mg also superior to sitagliptin (p<0.0001)
The estimates are from an ANCOVA model with treatment and country fixed effects and baseline value as a covariate. The p-values correspond to one-sided hypotheses of either superiority or non-inferiority. An asterisk indicates statistical significance on a 2.5% level.
Mean±2SE; data are from the full analysis set (FAS), last observation carried forward (LOCF). Estimated treatment differences are from an analysis of covariance (ANCOVA) model, with treatment and country as fixed effects and baseline value as a covariate
Pratley et al. Lancet 2010:375;1447–56

27. Liraglutide provides multiple clinical benefits
Liraglutide is the first once-daily, human GLP-1 analogue to provide glycaemic control throughout the continuum of care in type 2 diabetes
Liraglutide provides:
substantial and sustained reduction in blood glucose levels
clinically significant weight loss
reduction in SBP
improvement in beta-cell function
Liraglutide SPC

28. Liraglutide is effective across the continuum of care in type 2 diabetes
after one oral antidiabetic drug (OAD)
after two OADs
prior to basal insulin therapy
Marre et al. Diabetic Medicine 2009;26:268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32:84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009;374:39–47 (LEAD-6)

29. Liraglutide is effective across the continuum of care in type 2 diabetes

30. Based on the LEAD studies, liraglutide offers simple dose initiation and titration
One ml of solution contains 6 mg of liraglutide.
One pre-filled pen contains 18 mg liraglutide in 3 ml human GLP-1 analogue (Saccharomyces cerevisiae).

33. Long-term Safety and Efficacy of GLP-1 RAs

34. Pleiotropic Effects of GLP-1 RAs

35. Adverse Events Nausea/Vomiting

36. GLP-1 RAs Safety Issues

37. Summary
Liraglutide is effective across the continuum of care in type 2 diabetes
Liraglutide administration
24-h glucose control
once-daily dosing
can be given at any time of the day
dosing independent of meals
no need for additional self-monitored plasma glucose
Liraglutide offers a simple initiation, titration and maintenance regimen

38. Patient Education

39. Thank you and hope for a good rain