10.2 From the Classical Approach to the New Drugs in the Treatment of Type 2 Diabetes
10.2.6 GLP-1 Receptor Antagonist
10.2.6.1 Mechanism of Action
The two main incretin hormones, GIP and GLP-1, are released predominantly from L and K cells (in the proximal and distal intestine) following nutrient ingestion promoting insulin secretion, glucagon release inhibition, delaying gastric emptying, and enhancing satiety (resulting in weight control) with GLP-1 being much more effective than GIP (Van Genugten et al.2013).
Incretin mimetics or enhancers are one of the latest groups of drugs available for the treatment of T2DM—incretin therapy. Given the novel role of incretin therapy in terms of reducing postprandial hyperglycemia, and the favorable effect on weight with the reduced incidence of hypoglycemia, the used of them as alternative options in T2DM was explored [28].
Some evidence alludes to incretins potentially increasing beta cell mass and altering disease progression, so it might be helpful to introduce these agents earlier in the treatment algorithm.
Incretin acts primarily by increasing the physiological effects mediated via the hormone GLP-1, which is secreted along with GIP by intestinal cells when food is ingested, probably via the neural and endocrine signals associated with feeding.
GLP-1 and GIP have multiple actions that enhance beta-cell response in a glucose-dependent fashion. In T2DM, the incretin response is diminished (Nauck et al.1986).
Two strategies can restore the GLP-1 signal: (1) inhibiting the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4), which rapidly degrades GLP-1 in vivo resulting in increased concentrations of endogenous GLP-1 called incretin enhancers or (2) using parenteral administration of GLP-1 mimetics or GLP-1 RAs (GLP-1 Receptor Agonists) that are DPP4 resistant (Druker2006).
10.2.6.2 GLP-1 Mimetics
Currently four GLP-1 RAs are available.
The insulinotropic and extra-pancreatic effects of GLP-1 RAs have been described. In relation to glucose metabolism, GLP-1 increases insulin secretion and suppresses glucagon secretion; both mechanisms manifest only in the setting of hyperglycemia. In addition, GLP-1 induces satiety and has an effect on weight (Table10.8) (Owens et al.2013).
10.2.6.3 Pharmacological Profile of GLP-1
Pharmacology of GLP-1 can be appreciated in Table10.9.
1. Prandial GLP-1 (Exenatide and Lixisenatide)
Exenatide is a synthetic form of exendin-4, a 39 amino-acid peptide isolate from the salivary secretions of the Gila monster with a 50 % homology with GLP-1 and is a potent agonist of the human GLP-1 receptor. Exenatide has a half-life of 2 h, so two injections daily are necessary. Different studies demonstrated that exenatide in Table 10.8 Effects of
incretin therapy in the treatment of T2DM
(a) Glucose-dependent stimulation of insulin secretion (b) Glucose-dependent suppression of glucagon secretion (c) Reduced gastrointestinal motility
(d) Increased satiety
(e) Increased beta-cell mass with inhibition of beta-cell apoptosis
(f) Improvement of beta-cell function
combination with metformin, a DPP4 inhibitor, or rosiglitazone decreased post-prandial glycemia, and the most significant decrease was with rosiglitazone. When it was compared with glimepiride or glibenclamide, the decrease was almost the same. Another study compared exenatide with insulin glargine or biphasic insulin aspart, HbA1c was lower by both insulins, fasting plasma glycemia was lower with insulin glargine, and post-prandial glycemia improved with exenatide plus metfor-min and TZD (DeFronzo et al.2008,2010; Derosa et al.2010,2011) (Table10.10).
Lixisenatide is a 44 amino-acid exendin-4 analog with an extended c-terminus.
The half time of lixisenatide is 2.8 h, but the binding affinity for the GLP-1 receptor is fourfold greater than native GLP-1 that allows once daily injection. The Phase III GETGOAL program comprised 11 randomized studies that evaluated the efficacy and tolerability of lixisenatide 20 μg daily prandial in individuals with T2DM.
Lixisenatide produces significant improvements in HbA1c, FPG, and PPG com-pared with insulin glargine or oral agents (Ahren et al.2013; Riddle et al.2013;
Bolli et al.2014; Fonseca et al.2012; Pinget et al.2013; Ratner et al.2011; Lorenz et al.2013; Kapitza et al.2013).
2. Non-prandial GLP-1: Extended Release Exenatide, Liraglutide, Albiglutide, and Semaglutide
These are molecules that rely on different mechanisms to delay their absorption from the subcutaneous tissue and extend their duration of action (Table10.10).
2a. Extended release exenatide is a formulation that encapsulates microspheres made of biodegradable polymer that allows once weekly administration. The Phase III clinical development programme of exenatide once weekly involved a series of trials known as the DURATION trials. Safety and efficacy of Exenatide once weekly were compared with exenatide twice daily, pioglitazone or sitagliptin, metformin, liraglutide, and insulin glargine (DURATION 1–6), Table 10.9 Classification of
GLP-1 RA according to pharmacological profile
Prandial GLP-1 RA Exenatide
Lixisenatide
Non-prandial GLP-1 RA Extended release exenatide Liraglutide
Albiglutide Semaglutide
Table 10.10 Comparison of pharmacological profile of GLP-1
Prandial Non-prandial
GLP-1 RA EXENATIDE
LIXISENATIDE
LIRAGLUTIDE EXENATIDE—LAR
Half-life 2–5 h 12 h-many days
Effect on fasting glucose Modest reduction High reduction Effect on post-prandial glucose High reduction Modest reduction
Gastric emptying High impact No effect
respectively (Bergenstal et al.2010; Russell-Jones et al.2012; Buse et al.2012;
Diamant et al.2010; Raskin et al.2005; Blevins et al.2011). Extended release exenatide was superior in lowering PPG, had a low incidence of hypoglycemia but a greater incidence of gastrointestinal adverse events. The sustained ele-vated plasma concentrations of exenatide once weekly formulation induced tachyphylaxis with a progressive inhibition of gastric emptying, a key factor related with the reduction of PPG (Nauck et al.2011).
2b. Liraglutide is an analog of human GLP-1with 97 % sequence homology, which contains a C16palmitoyl fatty acid side chain that allows forming of heptamers when injected subcutaneously, and binding with albumin delays its absorption.
It reaches the maximum concentration at 9–12 h after dosing and plasma levels remains stable for up to 13 h after injection. The LEAD studies were six randomized trials that assessed the safety and efficacy of liraglutide (0.6–
1.8 mg) once daily alone or in combination with oral agents. In all of them liraglutide demonstrated a reduction of HbA1c, FPG, PPG, and weight loss (Buse et al. 2009); Nauck et al. 2009; Russell-Jones et al. 2009; Zinman et al.2009; Garber et al.2009; Marre et al.2009).
2c. Albiglutide is a dimer of GLP-1 that is fused with human albumin that shares 97 % homology with native GLP-1. It has a half-life of 6–7 days giving the possibility of once weekly administration. The Phase III HARMONY program is investigating the safety and efficacy of albiglutide, once weekly. Results are available for HbA1c; it was significantly reduced, but PPG data is not available (Pratley et al.2014).
2d. Semaglutide is a monoacylated human GLP-1 analog. The mode of action is identical to liraglutide but with a longer half-life of 6–7 days; it also allows once weekly administration. The phase III study SUSTAIN is still ongoing (Nauck et al.2012).
10.2.6.4 Additional Benefits Beyond Glucose Lowering GLP-1 and Cardiovascular Disease
Hypertension is a common and serious complication in type 2 diabetic patients and in combination with poorly controlled diabetes doubles the risk of death from CVD and total mortality. The effect of GLP-1 RA on blood pressure has been described.
The majority of clinical trials with GLP-1 RA have demonstrated a significant reduction of systolic and diastolic blood pressure, some of them independent of weight loss. The mechanism is still not clear, but four theories have been described:
all of them have in common the relaxation of the arteries by GLP-1 RA through the receptor of GLP-1 or without the activation of the receptor (Golpon et al.2001;
Nystrom et al.2005; Nathanson et al.2009; Yu et al.2003).
On vascular endothelium GLP-1 RAs have shown to inhibit monocyte/macro-phage accumulation in the arterial wall, inhibit the expression of inflammatory markers as TNFα, reduce adhesion molecules such as VCAM-1, and promote
vascular relaxants such as nitric oxide. The net result seems to be amelioration of endothelial function and plaque stabilization, which should eventually translate into direct protective effects of GLP-1 on the progression of atherosclerosis (Gupta 2012).
Dyslipidemia plays a critical role in the development of macrovascular disease.
The effects of GPL-1 RA on dyslipidemia promote reduction of apolipoprotein B-48 (ApoB-48) production and triglycerides absorption, and this effect could be independent of the delay of gastric emptying. GLP-1 infusions inhibited the post-prandial elevation of triglycerides, Apo B-48, and free fatty acids (Seino and Yabe 2013).
Clinical Relevance of GLP-1 Analogs in Obesity
The effects of the GLP-1 RAs, liraglutide and exenatide, twice daily and once weekly on body weight have been demonstrated. Overall, the weight reductions were significant for GLP-1 RAs (the maximum weight loss from baseline induced by exenatide in a 24-week RCT was 3.1 kg and 3.6 kg in a 52-week RCT). In head-to-head comparison studies, GLP-1 RAs were shown to be superior to DPP-4 inhibitors with respect to weight loss. In general, the GLP-1 RAs, exenatide, exenatide, and liraglutide, once daily seem comparable concerning body weight reduction, confirmed by two head-to-head comparison trials in which liraglutide induced weight loss similar to exenatide (liraglutide 3.24 kg vs. exenatide
2.87 kg, non-significant (NS) and exenatide (liraglutide 3.58 kg vs. exenatide
2.68 kg, NS) (Astrup et al.2009; Buse et al.2010).
Reduced food intake may be a consequence of gastric distension due to delayed gastric emptying, thus inducing satiety, but may also be mediated by neuronal and CNS actions of GLP-1, as stated previously. To date, there are only few studies addressing the central effects of endogenous and exogenous GLP-1 in humans. A relationship between postprandial GLP-1 levels and the activation of brain regions involved in CNS appetite regulating centers was shown.
Many trials have shown that weight reduction by GPL-1 RA was associated with a favorable cardiovascular risk profile (Kim et al.2009; Klonoff et al.2008).
Clinical Relevance of GLP-1 Plus Insulin
There is evidence to sustain that FPG and PPG are independent predictors of cardiovascular disease; hence, the rationale to combine insulin and GLP-1 RA is related with the effect of insulin on hyperglycemia with the risk to induce hypo-glycemia and weight gain. By contrast, GLP-1 is reliant on residual beta-cell function to normalize the blood glucose to complement their other actions on gastric emptying and insulin sensitivity via weight loss. So, the rationale of adding incretins to basal insulin is to counder balance the associated weight gain and
reduction or neutrality of hypoglycemia provoked by insulin (Yoon et al.2009;
Buse et al.2011; Fonseca et al.2007; Arnolds et al.2010) (Table10.11).
The different pharmacological profiles of GLP-1 RA contribute to different impacts on FPG or PPG levels suggesting that the selection of a GLP-1 RA should be guided by the predominant dysglycemic state of the patients. Patients for whom FPG is the primary treatment goal, long-acting non-prandial GLP-1 RAs may be the best option, whereas short-acting prandial GLP-1 RAs have a stronger reducing effect on post-prandial glucose levels because of the delay in gastric emptying (Monnier et al.2003).
Where patient weight control is an issue, long-acting non-prandial GLP-1 RAs have a marginally greater effect on weight loss than short-acting prandial GLP-1 RAs.
10.2.6.5 Doses, Associations, and Efficacy
Storage: GLP-1 should be refrigerated between 2 and 8C (36–46 F) and protected from light. After the first use, it may be stored at room temperature and should not be frozen or used if frozen. The pen should be discarded 30 days after its first use.
Application: Subcutaneously, each dose should be injected in the thigh, abdo-men, or the upper arm.
Doses Exenatide
Multiple dose prefilled pen: 1.2 ml—5 mcg per dose (60 doses) or 2.4 ml—10 mcg per dose (60 doses). The initial dose of exenatide is 5 mcg twice daily, 60 min before breakfast or dinner. Exenatide should not be administered after a meal. The dose can be increased to 10 mcg twice daily after 1 month of therapy.
Exenatide should not be indicated with glomerular filtration rate<30 ml/m/
1.73 m2. Liraglutide
The initial dose is 0.6 mcg once a day for a week. The dose can be increased gradually in a week to 1.2 mcg and to 1.8 mcg per day.
Liraglutide should not be indicated with glomerular filtration rate<60 ml/m/
1.73 m2. Lixisenatide
The usual starting dose of lixisenatide is 10 mcg (green pen) once a day for 14 days. After this the dose will be increased to 20 mcg (purple pen) once a day (Table10.12).
Table 10.11 Advantages of introducing incretin therapy before insulin
Potentially delay the need of insulin Low risk of hypoglycemia Weight loss
Lixisenatide should not be indicated with glomerular filtration rate<30 ml/m/
1.73 m2and used with caution with GFR between 30 and 59 ml/m/1.73 m2. Association: GLP-1 could be associated with metformin, sulfonylureas, meglitinides, thiazolidinedionas, and basal insulin.
Efficacy: GLP-1 reduced HbA1c between 8.0 and 1.8 %.
10.2.6.6 Effects and Contraindications
Side effects: The most common side effects are nausea and occasionally vomiting, both diminish over time. Pancreatitis cases have been reported, but it is important to remark that pancreatitis in diabetic patients has a threefold increased risk compared with individuals without diabetes.
Thyroid cancer of C cell has shown an increased risk in rodents but not in humans or monkeys. However, based on that data, FDA recommended one of the contraindications for use in the family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 (MEN2).
Contraindication: Do not use in patients with a personal or family history of medullary thyroid carcinoma or in patients with MEN 2.