GLP-1 based therapies: differential effects on fasting and postprandial glucose

Diabetes, Obesity and Metabolism 14: 675 688, 2012. 2012 Blackwell Publishing Ltd GLP-1 based therapies: differential effects on fasting and postprandial glucose review article M. S. Fineman 1,B.B.Cirincione 2, D. Maggs 2 &M.Diamant 3 1 Elcelyx Therapeutics, Inc., San Diego, CA, USA 2 Amylin Pharmaceuticals, Inc., San Diego, CA, USA 3 Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1 2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4- resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes. Keywords: antidiabetic drug, DPP-IV inhibitor, exenatide, GLP-1, GLP-1 analogue, incretin therapy Date submitted 27 June 2011; date of first decision 19 August 2011; date of final acceptance 3 January 2012 Introduction The goal of diabetes therapy is to reduce 24-h blood glucose to near normal values. While haemoglobin A1c (HbA1c) is the universally accepted marker of average blood glucose used to determine if additional therapy is necessary, measurements of fasting and postprandial glucose provide guidance for which added therapies are likely to have the most benefit for that patient. Monnier et al. demonstrated that fasting hyperglycaemia is the major contributor to HbA1c in poorly controlled subjects, while postprandial hyperglycaemia is the major contributor to HbA1c in subjects nearing target goals [1]. Thus, it is important to understand both the fasting and postprandial potential of diabetes therapies. While glucagonlike peptide-1 (GLP-1)-mediated therapy was originally considered to be mainly a postprandial treatment, newer generations of these therapies have different attributes. This review focuses on the differences in fasting and postprandial glucose-lowering effectiveness of the various classes and subclasses of GLP-1-mediated therapies. Correspondence to: M.S. Fineman, Elcelyx Therapeutics, Inc., San Diego, CA, USA. E-mail: marksfineman@gmail.com The Biology of GLP-1 GLP-1 is an incretin hormone secreted from gastrointestinal L cells predominantly found in the ileum, colon and rectum in response to nutrients [2 4]. Following food ingestion, GLP-1 appears in the plasma within minutes and due to its rapid degradation by dipeptidyl peptidase-4 (DPP-4), is undetectable by 3 h [5 7]. Given that enteroendocrine L cells are predominantly located in the distal gut, it is proposed that rapid appearance of GLP-1 in the plasma following a meal is likely a result of indirect hormonal and/or neural signalling as opposed to direct nutrient contact with GLP-1 secreting cells in the proximal gut lumen [8]. The human GLP-1 receptor (GLP-1R) is a 463 amino acid G-protein coupled receptor expressed on pancreatic islet α and β cells and many other tissues including the gastrointestinal tract, heart, kidney, lung and the peripheral and central nervous systems [9, 10]. Receptor activation is linked to the cyclic AMP second messenger pathway [11]. Although receptor desensitization has been demonstrated in vitro, 1 week of twice daily administration of the GLP-1R agonist exenatide to wildtype mice, did not result in downregulation of the glucose lowering effect following an oral glucose load [12].

GLP-1 is thought to play an important physiological role to regulate plasma glucose in the postprandial period through several mechanisms of action: enhancement of glucosestimulated insulin secretion, suppression of glucagon secretion and slowing of gastric emptying [13 19]. GLP-1 enhances insulin secretion in a glucose-dependent manner [20], augmenting both the first and second phase of secretion [21]. While GLP-1 clearly has direct effects on pancreatic β cells, a portion of the insulin response may be mediated through an indirect afferent nervous system pathway [22]. The effect of GLP-1 on glucagon secretion is also glucose dependent, occurring during euglycaemia but does not affect the glucagon response to hypoglycaemia ( 3.7 mmol/l) [20]. The mechanisms by which GLP-1 suppresses glucagon secretion could include a direct effect on the pancreatic α-cell but it is conceivable that additional indirect effects include local stimulation of insulin, amylin and somatostatin secretion [8]. GLP-1 is a potent inhibitor of gastric acid secretion and gastric emptying. Although the exact mechanisms by which GLP-1 regulates gastric function are unknown, it is clear that vagal afferents are important [23, 24]. Effects on gastric acid secretion may also be mediated through direct interaction with parietal cells [25]. On balance, the gastric emptying effect may be more important than insulin in controlling postprandial plasma glucose (PPG) as it limits the rate and extent of mealderived glucose presented to the β-cell [26]. In fact, infusion of GLP-1 to subjects with type 2 diabetes results in significant and dose-dependent reductions in PPG and gastric emptying without an increase in plasma insulin [27]. There are also data from experiments in the conscious dog suggesting that GLP-1 may augment non-hepatic glucose clearance through a non insulin-mediated mechanism involving neural signalling in the portal vein [28, 29]. In addition, both animal and human studies suggest that GLP-1 may play a role in reducing insulin resistance. The effect has been observed in a variety of insulinresistant diabetic animal models [30] and in human subjects with type 2 diabetes [31]. In humans, the magnitude of the effect appears to be less than that seen with the thiazolidinedione (TZD) class and it is unclear if the effect is independent of the concomitant weight loss often observed. Pair-feeding experiments in non-diabetic, insulin-resistant obese fa/fa Zucker rats treated with exenatide for 6 weeks suggest that a portion of the insulin-sensitizing effect (25%) could not be explained by weight loss [32]. Lastly, GLP-1 appears to play a role in mealtime satiety signalling, which could impact plasma glucose through a reduction in caloric load ingestion, leading to reductions in bodyweight [13, 19, 33, 34]. In the case of food intake, GLP-1 likely acts centrally by crossing the blood brain barrier and acts indirectly through vagal-mediated pathways [10, 35]. Collectively, these mechanisms work in concert to regulate energy intake and glucose flux during the prandial period, allowing for appropriate consumption and delivery of nutrients from the gut to the circulation in order to optimized fuel storage without large glucose fluctuations in plasma. In addition, GLP-1R knockout mice have fasting hyperglycaemia, suggesting that GLP-1 could play a tonic role in regulating fasting plasma glucose (FPG) [36]. The mechanisms DIABETES, OBESITY AND METABOLISM for such an effect are less clearly discerned. However, the pharmacological potential of this molecule was fully manifested with acute GLP-1 infusion studies in subjects with type 2 diabetes that demonstrated a near-normalization of both FPG and PPG [31]. The wider biologic role of GLP-1 to positively regulate body weight adds to the pharmacological potential of the hormone. GLP-1-Mediated Therapies for Type 2 Diabetes The GLP-1R system has become an attractive target for type 2 diabetes therapies due to the multiple glucose and bodyweight regulating properties attributed to endogenous GLP-1. Native GLP-1, however, has significant limitations as a therapeutic due to its rapid degradation by DPP-4 (plasma half-life of 1 2 min). DPP-4 is a ubiquitous plasma membrane glycopeptidase present on epithelial cells in a host of tissues including the gastrointestinal tract, kidneys, brain, pancreas, lymph nodes, thymus and vascular bed [37]. A soluble form of DPP-4 can also be found in the plasma and in other body fluids. DPP-4 selectively removes N-terminal dipeptides when alanine or proline is in the second position. Thus, both endogenous and exogenous GLP-1 are rapidly metabolized from GLP-1-(7-36) to GLP-1-(9-36) by DPP-4, rendering it without glucose-lowering properties [38]. To circumvent the half-life constraint of GLP-1, two novel classes of glucose-lowering therapeutics have emerged: DPP-4 inhibitors (also referred to as gliptins) and GLP-1R agonists. DPP-4 inhibitors enhance the effects of endogenous GLP-1 by inhibiting the enzyme that inactivates it. GLP-1R agonists mimic the actions of GLP-1 but have DPP-4- resistant properties by virtue of their amino acid sequence and/or through chemical modification. Both classes have demonstrated effective utility for the treatment of type 2 diabetes [8, 35, 39 43]. Differences in their pharmacology, however, result in differential mechanisms of action and ultimately in differences in fasting and postprandial glucoselowering potential as described below. DPP-4 Inhibitors (Gliptins) DPP-4 inhibitors sitagliptin, saxagliptin, and recently, linagliptin have been approved in the United States for the treatment of type 2 diabetes. In Europe, sitagliptin, saxagliptin and vildagliptin are approved for use. DPP-4 inhibition leads to elevated plasma concentrations of GLP-1, which in turn enhances glucose-dependent insulin secretion and suppresses inappropriately elevated glucagon secretion [44]. Notably, DPP-4 inhibitors do not appear to have an effect on gastric emptying [2, 45]. In a meta-analysis of randomized controlled studies of at least 12 weeks, DPP-4 inhibitors resulted in a weighted mean reduction in HbA1c of 0.74% (8.1 mmol/mol) compared to placebo [46]. Similar results were observed in a second metaanalysis by Fakhoury et al. [43]. While DPP-4 inhibitors have a small effect on PPG, the majority of the HbA1c lowering effect results from reductions in FPG [45, 47, 48]. Recently, Hjøllund 676 Fineman et al. Volume 14 No. 8 August 2012

DIABETES, OBESITY AND METABOLISM et al. reported that DPP-4 inhibitors have a greater impact on portal vein GLP-1 concentrations ( fourfold) than on concentrations in the peripheral circulation ( twofold) [49]. One could speculate that DPP-4 inhibitors may therefore exert more of an effect on FPG through augmentation of the portal signal. Glucagon suppression is noted in the prandial state, but stimulation of insulin secretion is modest compared to other GLP-1 based therapies and there is little to no effect on gastric emptying [44, 45, 47, 50]. While both chronic infusions and bolus injections of GLP-1 are associated with weight loss [31, 33], administration of DPP-4 inhibitors typically results in weight neutrality [8, 51 53]. Modest weight loss, however, has been observed with the DPP-4 inhibitor, vildagliptin, in well-controlled patients, and it may reduce intestinal fat absorption [53]. It is not clear if the effects on fat absorption are specific to vildagliptin or if they can be generalized to other DDP-4 inhibitors or GLP-1R agonists. The reasons for the reduced effect of DPP-4 inhibitors on gastric emptying and bodyweight are not clear. DPP-4 inhibition results in an approximate doubling of active GLP-1 in the peripheral circulation and perhaps these concentrations are insufficient to induce these mechanisms of action. Given that both the gastric emptying and satiety effects of GLP-1 are centrally mediated, higher concentrations of circulating GLP-1 may be required compared to the concentrations necessary to affect insulin and glucagon secretion [54]. Additionally, DPP-4 activates peptide tyrosine-tyrosine (PYY) [55], a gut peptide known to slow gastric emptying and reduce food intake [56]. Thus, if DPP-4 inhibitors reduce active PYY (PYY 3-36) concentrations, the effects of GLP-1 to slow gastric emptying and reduce food intake may be masked by the loss of a PYY effect. GLP-1R Agonists with Intermittent Exposure Exenatide Twice Daily The first GLP-1R agonist to be approved for clinical use was exenatide. Exenatide is a synthetic form of exendin-4, a 39 amino acid peptide isolated from the salivary secretions of the gila monster (Heloderma suspectum). It shares 53% sequence identity with GLP-1 and is equipotent at the GLP-1R [57]. Exenatide is DPP-4 resistant, resulting in an extended halflife relative to GLP-1 (2.4 h) [58]. Plasma concentrations of exenatide are detectable for approximately 6 7 h following a subcutaneous injection in the abdomen, arm or thigh [59]. Like GLP-1, exenatide slows gastric emptying [60], suppresses glucagon [61, 62] and enhances first- and second-phase glucose-stimulated insulin secretion, as well as insulin secretion in response to a combined glucose and arginine stimulus [63 65]. Importantly, the actions of exenatide on insulin and glucagon secretion occur during euglycaemia, but not during hypoglycaemia [64], providing a safeguard against inducing or prolonging hypoglycaemia with long-term clinical use. Acute exenatide administration leads to robust dose-dependent reductions in PPG when bolus subcutaneous injections are administered prior to a meal [61, 62] and to reductions in FPG when administered during an extended fast [61]. When exenatide was subcutaneously infused for 24 h review article in patients with type 2 diabetes, dose-dependent reductions in both FPG and PPG were observed [66]. The reductions in PPG observed with acute administration of exenatide were sustained following 28 days of two times a day (BID) or three times a day (TID) treatment [67]. Treatment for 1 year with exenatide BID improved β-cell function compared to insulin glargine with similar overall reductions in HbA1c [68]. At 52 weeks, C-peptide secretion was increased 2.46-fold with exenatide compared to 1.34-fold with insulin glargine (p < 0.0001). The effects of exenatide and sitagliptin on postprandial glucose metabolism were compared in a randomized 2-week crossover study in patients with type 2 diabetes [47]. Both treatments resulted in reductions in PPG (figure 1) and glucagon compared to baseline, although the magnitude of effect was significantly greater (glucose; p < 0.0001, glucagon; p = 0.0011) for exenatide compared to sitagliptin. It is noteworthy that with exenatide treatment, the PPG rise is almost completely blunted following the meal with concentrations falling below the preprandial concentration within 1 h. This suggests that the effects on gastric emptying, glucagon secretion and insulin secretion are all contributing to the overall glucose profile. Exenatide 10 μg significantly slowed gastric emptying while sitagliptin 100 mg did not change the gastric emptying rate from baseline. Finally, mean caloric intake during an ad libitum meal was reduced by 134 kcal from baseline with exenatide compared to an increase of 130 kcal from baseline with sitagliptin (p = 0.0227). Treatment with exenatide 10 μg BID (breakfast and dinner) for 30 weeks resulted in mean reductions in HbA1c of 0.9 1.0% (9.8 10.9 mmol/mol) compared to placebo when added to metformin [69], a sulfonylurea (SFU) [70] or a combination of metformin and a SFU [71]. Consistent with the fact that exenatide is cleared from circulation in 6 7 h, only modest reductions in FPG (1.0 to 1.4 mmol/l) were observed compared to placebo. Placebo corrected weight loss ranged from 0.3 to 2.5 kg with the greatest loss observed in metformin-treated subjects. A subset of the subjects in these studies underwent a Postprandial Glucose (mmol/l) 16 Baseline 15 Exenatide N=61 14 Sitagliptin N=61 13 12 11 10 9 8 7 6 5-30 0 30 60 90 120 150 180 210 240 Figure 1. Mean (s.e.) postprandial plasma glucose concentration during a standard meal at baseline and after treatment with exenatide or sitagliptin. Exenatide was administered at T = 15 min. Sitagliptin was administered at T= 30 min. Standardized meal was given at T = 0 min. Adapted from Ref. [47]. Volume 14 No. 8 August 2012 doi:10.1111/j.1463-1326.2012.01560.x 677

standardized breakfast meal challenge at baseline and after 4 and 30 weeks of treatment. As shown in figure 2, at 4 weeks, the postprandial rise in plasma glucose was almost completely blunted with exenatide treatment. The postprandial profiles at 30 weeks were slightly higher in all three treatment groups (5 μg, 10 μg and placebo) compared to the 4-week profiles, but the differences between exenatide and placebo remain Postprandial Glucose (mmol/l) Postprandial Glucose (mmol/l) Postprandial Glucose (mmol/l) Baseline 5 mcgs BID N=44 10 mcgs BID N=52 16 Baseline 15 14 13 12 11 10 9 8 7 6-30 0 30 60 90 120 150 180 16 Week 4 15 14 13 12 11 10 9 8 7 6-30 0 30 60 90 120 150 180 Week 30 16 15 14 13 12 11 10 9 8 7 6-30 0 30 60 90 120 150 180 Figure 2. Mean (s.e.) postprandial plasma glucose concentration during a standardized meal at baseline (day 1) and after 4 and 30 weeks of twice daily exenatide treatment. Study medication was administered at T = 15 min. A standardized meal was given at T = 0 min. Results are a combined cohort of subjects from three published studies, Refs [69 71]. DIABETES, OBESITY AND METABOLISM constant through 30 weeks. This suggests that there is little to no tachyphylaxis of the effect of exenatide on PPG with intermittent administration. GLP-1R Agonists with Continuous Exposure Although the plasma half-life of exenatide is a significant improvement over native GLP-1, the duration of exposure is still limited to 6 7 h following an injection. Thus, exenatide given twice daily at breakfast and dinner provides intermittent exposure and exerts its main effects during the prandial period of those main meals. Multiple strategies have been employed to extend the apparent half-life of GLP-1R agonists by slowing the rate of absorption and/or by reducing plasma clearance. Such strategies improve patient convenience by reducing the frequency of administration and enhance the effects on FPG by providing continuous exposure. One such product, liraglutide, is currently available in the United States and Europe. In addition, an extended-release version of exenatide has been developed which is available in the United States and Europe. Exenatide Once Weekly The extended-release formulation of exenatide was developed to provide continuous exenatide exposure with once weekly administration (exenatide once weekly). The formulation utilizes biodegradable polymeric microspheres, composed of exenatide in a poly lactide-co-glycolide (PLG) polymeric matrix. This extended-release formulation is injected subcutaneously and slowly releases native exenatide into the subcutaneous space through a complex process of polymer hydration and degradation [72]. Thus, this absorption ratelimited formulation allows for continuous systemic exposure of exenatide without modification of the native peptide. Once absorbed, the general pharmacokinetic properties of exenatide are unchanged compared to exenatide BID. In 26- and 30-week controlled trials, the extended-release formulation of exenatide once weekly resulted in HbA1c reductions from baseline ranging from 1.5 to 1.9% (16.4 to 20.8 mmol/mol) [73 76] with more substantial improvements in FPG than had been observed in the exenatide BID studies. The short and long-acting exenatide formulations were directly compared in two studies of 26-week [74] and 30-week [76] duration. In the 26-week study, exenatide once weekly resulted in significant improvements in HbA1c compared to exenatide BID [ 1.6 vs. 0.9% (17.5 vs. 9.8 mmol/mol); p < 0.0001] with improved FPG relative to exenatide BID ( 1.94 vs. 0.66 mmol/l; p = 0.0008). Reductions in mean body weight from baseline to week 24 were not statistically different between groups ( 2.3 and 1.4 kg). Similar results were observed in the 30-week study [HbA1c: 1.9 vs. 1.5% (20.8 vs. 16.4 mmol/mol), p = 0.0023; FPG: 2.3 vs. 1.4 mmol/l, p < 0.0001]. The 30-week study also included a standardized meal challenge at baseline and 14 weeks (after exenatide once weekly achieved steady-state plasma exenatide concentrations). 678 Fineman et al. Volume 14 No. 8 August 2012

DIABETES, OBESITY AND METABOLISM Notably, the effects on postprandial glucose excursion and gastric emptying were greater with exenatide BID than with exenatide once weekly (figure 3A, B and Table 1). The mean reduction from baseline in 2-h postprandial plasma glucose was 6.9 mmol/l with exenatide BID versus 5.3 mmol/l with exenatide once weekly (p = 0.0124). Gastric emptying was assessed by comparing the absorption of acetaminophen following a 1000-mg oral dose administered before the standardized meal tests. Exenatide BID treatment resulted in a 21% reduction in acetaminophen C max and a 20% reduction in area under the curve (AUC) compared to baseline. In contrast, exenatide once weekly treatment resulted in only a 5% reduction in C max and a 4% reduction in AUC. The reduced PPG and gastric emptying effects of exenatide once weekly cannot be explained by lower exenatide plasma exposure, as the geometric mean plasma concentrations were higher with exenatide once weekly (280 310 pg/ml) than with exenatide BID (60 140 pg/ml) over the 5-h meal test period (figure 3C, D). The differences also cannot be explained by differences in chemical structure between the two therapies because both release unmodified exenatide into circulation. These data therefore suggest that continuous GLP-1 agonist exposure downregulates the effects on gastric emptying which in turn reduces the effect on postprandial glucose excursions. review article Table 1. Acetaminophen pharmacokinetic parameters following a 1000- mg oral dose (N = 75). Geometric mean (SE) Baseline Week 14 Ratio of week 14/baseline Geometric LS mean 90% CI of the mean C max 0 5h (μg/ml) Exenatide QW 11.22 (0.99) 10.61 (0.75) 0.95 0.81, 1.11 Exenatide BID 11.67 (0.80) 9.17 (0.94) 0.79 0.66, 0.93 AUC 0 5h (μg min/ml) Exenatide QW 1729 (113) 1651 (141) 0.96 0.84, 1.09 Exenatide BID 1831 (96) 1462 (158) 0.80 0.70, 0.92 AUC 0 5h, area under the 5 h concentration curve; BID, two times a day; C max, maximum concentration; SE, standard error of the mean; LS, least squares mean; CI, confidence interval; Exenatide QW, exenatide once weekly. This hypothesis is consistent with a recent report by Nauck et al. that demonstrated a reduced gastric emptying and PPG effect at the lunch meal compared to the breakfast meal during a continuous intravenous infusion of native GLP-1 [77]. Postprandial Glucose (mmol/l) Geometric mean (SD) Exenatide pg/ml 16 15 14 13 12 A Exenatide BID 11 10 9 8 7 6 5-30 0 30 60 90 120 150 180 210 240 270 300 400 350 300 250 200 150 100 50 C Baseline Week 14 Week 14 0-30 0 30 60 90 120 150 180 210 240 270 300 Postprandial Glucose (mmol/l) Geometric mean (SD) Exenatide pg/ml 16 15 14 13 B Exenatide Once Weekly 12 11 10 9 8 7 6 5-30 0 30 60 90 120 150 180 210 240 270 300 400 350 300 250 200 150 100 50 D Baseline Week 14 Week 14 0-30 0 30 60 90 120 150 180 210 240 270 300 Figure 3. Mean (s.e.) time profiles of postprandial plasma glucose concentrations at baseline and week 14 during the meal challenge comparing exenatide two times a day (BID) (A) versus exenatide once weekly (B). Geometric mean (s.d.) time profiles of plasma exenatide concentration at week 14 during the meal challenge for exenatide BID (C) versus exenatide once weekly (D). Meal challenge subgroup, N = 51. Adapted from Ref. [76]. Volume 14 No. 8 August 2012 doi:10.1111/j.1463-1326.2012.01560.x 679

DIABETES, OBESITY AND METABOLISM Given the short time course (4 h between meals), the authors proposed that this finding indicated a tachyphylaxis of the gastric emptying effect at the level of the vagal nerve rather than GLP-1R downregulation or desensitization. Interestingly, there appears to be tachyphylaxis of nausea (the most common side effect) with chronic exenatide BID treatment without a loss of effect on gastric emptying or PPG [69 71, 78] and less nausea is observed with exenatide once weekly than with exenatide BID despite higher plasma concentrations [76]. Several groups have described the observation that glucose tolerance is improved at the second meal of the day relative to the first, a phenomenon referred to as the Staub-Traugott effect [79, 80]. Interestingly, Bonuccelli et al. have shown that plasma concentrations of GLP-1 are elevated at the second meal of the day relative to the first, and that the Staub-Traugott effect is mediated through an enhanced insulin response to glucose, and a suppression of hepatic glucose production without changes in the gastric emptying rate [79]. This suggests that augmentation of GLP-1 concentrations by means other than DPP-4 inhibition also does not affect gastric emptying but may improve glucose tolerance through other mechanisms. Liraglutide Liraglutide is a DPP-4-resistant GLP-1 analogue that achieves slowed absorption and increased half-life through the substitution of arginine for lysine at position 34 and the addition of a C16 fatty acid chain at position 26 allowing for reversible binding to albumin [81, 82]. The half-life of liraglutide is 11 15 h resulting in continuous exposure with once-daily (QD) administration [82]. Although the potency of liraglutide is reduced 100-fold relative to GLP-1 (albumin binding is 98 99%), it retains the basic actions of GLP-1 [2]. Longterm treatment with liraglutide 1.8 mg results in reductions in HbA1c of 1.0 1.3% (10.9 14.2 mmol/mol) and reductions in FPG of up to 2.4 mmol/l [83 87]. Clinical trial results with liraglutide support the hypothesis that continuous GLP-1R agonism may downregulate the gastric emptying effect. While there are no head-to-head studies available that directly compare the gastric emptying effects of exenatide BID and liraglutide, it appears that liraglutide has a reduced effect on gastric emptying compared to exenatide BID based on individual observations. In a single dose study of liraglutide on subjects with diabetes, gastric emptying was significantly reduced by 9% compared to placebo as assessed by the 4-h plasma AUC of 3-o-methyl-glucose (3-OMG) following oral administration [88]. No effect on gastric emptying at breakfast or dinner was observed in subjects with type 2 diabetes treated with liraglutide for 1 week as assessed using the acetaminophen technique [89]. In addition, when gastric emptying was assessed at weekly intervals during a dose titration of liraglutide 0.6 mg (week 1), 1.2 mg (week 2) and 1.8 mg (week 3), the effects were more pronounced at week 2 than week 3 despite a higher dose at week 3 [90]. This is suggestive of tachyphylaxis although definitive conclusions cannot be made. Consistent with a reduced effect on gastric emptying, liraglutide lowers PPG mostly through a reduction in preprandial glucose (figure 4) [88 90] although some reduction in the postprandial increment above fasting is evident [90]. The latter Figure 4. Mean postprandial plasma glucose profiles during a meal test performed at steady-state liraglutide doses of 0.6, 1.2 and 1.8 mg or placebo (N = 18). Reprinted with kind permission from Springer Science and Business Media, Ref. [90], figure 3. can be explained by modest reductions in the rate of gastric emptying and more pronounced effects on glucagon and insulin secretion as is the case with exenatide once weekly [76]. This is in contrast to the PPG profiles observed with exenatide BID in which little to no rise above fasting concentrations can be observed following a meal (figures 1, 2 and 3). The differences between exenatide BID and liraglutide are well illustrated in a 26-week head-to-head study in subjects with type 2 diabetes [91]. In that study, the reduction in HbA1c was greater with liraglutide compared to exenatide BID [1.16 vs. 0.87% (12.7 vs. 9.5 mmol/mol)] as a result of larger reductions in FPG (treatment difference = 1.0 mmol/l). In contrast, exenatide BID had greater reductions in PPG compared to liraglutide at breakfast (difference = 1.3 mmol/l) and at dinner (difference = 1.0 mmol/l). The improvements in FPG observed with liraglutide are likely a result of the higher fasting plasma insulin and lower fasting plasma glucagon concentrations observed with liraglutide versus exenatide BID, although the glucagon difference did not achieve statistical significance (p = 0.144). This difference can be explained by differences in pharmacokinetics as exenatide BID should be cleared from circulation by the time the fasting samples were drawn. There is currently no data to directly compare the effects of liraglutide and exenatide on fasting insulin and glucagon when both compounds are at their individual plasma therapeutic concentrations. Additionally, there is currently no data to directly compare the effects of liraglutide and exenatide on postprandial plasma insulin and glucagon. Interestingly, it appears that short- and long-acting GLP-1R agonists have similar effects on bodyweight as described in head-to-head 680 Fineman et al. Volume 14 No. 8 August 2012

DIABETES, OBESITY AND METABOLISM studies [74, 76, 91]. This is somewhat surprising given that exenatide BID administration only results in therapeutic plasma concentrations during the breakfast and dinner meals, and exenatide once weekly and liraglutide administration result in therapeutic concentrations throughout the day (breakfast, lunch, dinner and snack times). This may suggest that the effect of exenatide BID on satiety may last longer than the pharmacokinetics would predict. Alternatively, it may suggest that there is a partial downregulation of the satiety signal with continuous GLP-1R agonism that is compensated for by providing coverage across all meals. GLP-1R agonists in Development There are several GLP-1R agonists in late-stage development including the relatively short-acting lixisenatide, once weekly dulaglutide (LY2189265) and once weekly or once monthly albiglutide. Although public data on the pharmacokinetics and effects on PPG are somewhat limited for these compounds, it appears that the shortest acting compound may have the most robust postprandial effect, while the longacting molecules appear to work predominantly through improvements in FPG. Lixisenatide Lixisenatide is based on the structure of exenatide but it has been C-terminally modified with six lysine residues. Its terminal halflife is reported to be approximately 3 h which may be slightly longer than that of native exenatide [92, 93]. In a phase 3 trial of lixisenatide in patients with type 2 diabetes inadequately treated with metformin, QD and BID administration of lixisenatide for 13 weeks resulted in statistically significant reductions in HbA1c compared to placebo [94]. The highest dose of 20 μg achieved an HbA1c reduction from baseline of 0.76% (8.3 mmol/mol) and 0.87% (9.5 mmol/mol) for the QD and BID regimens, respectively, compared to a reduction of 0.18% (2.0 mmol/mol) for placebo. The authors conclude that the 20-μg dose administered QD provided the best efficacy-totolerability ratio. The 20-μg QD dose was associated with robust reductions in the 2 h PPG value following a breakfast meal (3.57 ± 0.62 mmol/l) but had modest reductions in FPG (0.80 ± 0.25 mmol/l). In a 28-day trial of lixisenatide comparing 20 μgqdto20μg BID, the effects on PPG appeared to wane by the evening meal in the QD arm [95]. These data are consistent with lixisenatide providing intermittent exposure which may be an advantage for targeting PPG either alone or on the background of basal insulin [96]. Dulaglutide Dulaglutide is an analogue of GLP-1 covalently linked to the F c fragment of an IgG 4 [97]. The molecule is DPP-4 resistant and has reduced renal clearance due to the size of the fusion protein. The mean plasma half-life is approximately 4 days and steady-state concentrations are achieved after the second weekly dose [98]. In a 16-week study, 262 overweight/obese patients titrated to 1.0 or 2.0 mg once weekly achieved HbA1c reductions of 1.28% (14.0 mmol/mol) to 1.52% (16.6 mmol/mol) review article compared to a reduction of 0.27% (3.0 mmol/mol) on placebo. These reductions were accompanied by robust effects on FPG ( 2.09 to 2.64 mmol/l for dulaglutide vs. 0.49 mmol/l for placebo) and weight loss ( 1.58 to 2.51 kg dulaglutide vs. 0.07 kg placebo) [99]. Glucose excursions following a test meal were statistically significant on dulaglutide compared to placebo, but the overall effect was small relative to FPG reductions. Albiglutide Albiglutide consists of two copies of a DPP-4-resistant GLP-1 analogue linked to human albumin. The resultant molecule has a plasma half-life of approximately 5 8 days making it very suitable for once-weekly dosing and could possibly be effective as a monthly therapy [100]. Steady-state concentrations of albiglutide are achieved by 5 weeks with weekly dosing. Weekly and monthly treatment regimens were compared in a phase 2 study of 356 patients with type 2 diabetes. After 16 weeks, the HbA1c reduction was 0.87% (9.5 mmol/mol), 0.79% (8.6 mmol/mol) and 0.87% (9.5 mmol/mol) for albiglutide 30 mg weekly, 50 mg biweekly and 100 mg monthly, respectively, compared with a reduction of 0.17% (1.9 mmol/mol) for placebo [101]. As with other long-acting GLP-1 agonists, the predominant effect is a lowering of FPG and preprandial glucose with very little effect on the postprandial rise above the fasting value [102]. Potential Risks of GLP-1-Mediated Therapies Despite the large number of substrates for DPP-4, the adverse event profile in clinical studies of DPP-4 inhibitors appears to be relatively benign. Only upper respiratory tract infection, nasopharyngitis and headache have been identified as adverse events more commonly observed with DPP-4 inhibitors than with placebo [2, 103, 104]. For GLP-1R agonists, gastrointestinal adverse events are common, dose-dependent, transient, and can be reduced through dose-titration strategies in most cases [96]. Gastrointestinal tolerability appears to be better with long-acting GLP-1R agonists than with short-acting GLP-1R agonists at least with regimens that have limited peak-to-trough fluctuations [76, 101]. Pancreatitis Acute pancreatitis has been rarely reported as part of postmarketing surveillance activities for both DPP-4 inhibitors and GLP-1R agonists. Given that type 2 diabetes is associated with an increased risk of acute pancreatitis, large case controlled studies are required to determine if there is a drug-specific association. Three separate controlled healthcare claims database studies have been completed that evaluate the association of exenatide and acute pancreatitis [105 107]. Two of those studies also evaluated the risk of acute pancreatitis with sitagliptin [106, 107]. The studies concluded that rates of acute pancreatitis in patients receiving exenatide or sitagliptin are not different from rates observed in patients using other antidiabetic therapies. Longer term studies are needed, however, to completely rule out any association. Volume 14 No. 8 August 2012 doi:10.1111/j.1463-1326.2012.01560.x 681

Cancer Epidemiological studies indicate that diabetes is associated with an increased risk of several cancers including liver, pancreas, endometrium, colon/rectum, breast and bladder and it may be associated with an increased risk of cancerrelated mortality [108, 109]. Confounding factors such as diabetes duration, hyperglycaemia, obesity, oxidative stress, family history and smoking make it difficult to quantify the true risk of cancer in diabetes or to determine if certain diabetes therapies may increase or decrease that risk. While there is currently no evidence that GLP-1-based therapies alter the incidence of human cancers [108], medullary thyroid cancer and pancreatic cancer both warrant further discussion. Rodent thyroid C-cells express the GLP-1R and continuous high-dose GLP-1R agonist exposure results in increased calcitonin secretion, C-cell hyperplasia and C-cell carcinoma in rats and female mice [110]. In contrast, GLP-1R expression in human C-cells is very low, and high doses of liraglutide did not result in C-cell proliferation in non-human primates [110]. In addition, plasma concentrations of calcitonin were not altered in over 5000 subjects in liraglutide clinical trials [111]. On the basis of the species-specific differences in GLP-1R biology in the thyroid, the FDA considered the risk of developing medullary thyroid cancer as a result of GLP-1R agonist therapy to be low in humans [112]. Liraglutide treatment is, however, contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with Multiple Endocrine Neoplasia syndrome type 2 [112]. The association of GLP-1 based therapies and pancreatitis has led some investigators to speculate that these drugs may promote pancreatic cancer and Elashoff et al. described increased reports of pancreatic cancer with exenatide and sitagliptin usage in the FDA AERS (Adverse Event Reporting System) database compared to other diabetes therapies [113]. The authors indicate, however, that the AERS database is not an ideal source to compare adverse event rates between drugs due to disproportionate reporting across therapies and incomplete data on confounding factors. Drucker et al. described further limitations to using the AERS database in this way, pointing out that the Elashoff AERS analysis showed a sixfold increase in pancreatitis reports with GLP-1-based therapies while the large DIABETES, OBESITY AND METABOLISM controlled healthcare claims studies did not show an increased risk of pancreatitis [103]. As GLP-1-based therapies are still relatively new, there are not sufficient numbers of patients exposed to drug for long enough periods of time to fully assess their possible effects on cancer risk. Currently, the available evidence does not suggest GLP-1-based therapies confer an increased risk of cancer, in pancreas, thyroid or otherwise, but further assessments are required either from epidemiological databases or in a large controlled study setting ideally with long duration to draw conclusions. Cardiovascular Disease Studies of GLP-1R agonists and DPP-4 inhibitors suggest that GLP-1-mediated therapies have beneficial effects on cardiovascular risk factors including bodyweight, blood pressure, postprandial lipids and markers of oxidative stress. In addition, systematic reviews of clinical trial cardiovascular adverse event data from the various GLP-1R agonist and DDP-4 inhibitor drug development programs do not suggest an increase in cardiovascular risk [114-119]. Table 2 summarizes the main details of each analysis and presents the calculated ratio detailed in each report (incidence ratio, relative risk or hazard ratio). While these results are promising, longterm cardiovascular outcomes studies are needed to better understand the cardiovascular risks of these therapies. Large outcomes trials have been initiated for both classes of compounds, but results are still several years away in most cases. Other Treatments for Postprandial Control Several non-glp-1-mediated therapies exist for the treatment of PPG. The α-glucosidase inhibitors (acarbose and miglitol) delay digestion of carbohydrate and thus reduce PPG by 1.5 4.0 mmol/l [120]. Because carbohydrate absorption is delayed but not reduced, neither malabsorption or weight loss occur [121]. α-glucosidase inhibitors have had limited uptake and adherence due to significant gastrointestinal side effects. The amylin analogue pramlintide is indicated as adjunct therapy to improve glucose control in type 1 and type 2 diabetes patients using mealtime insulin. Pramlintide shares Table 2. Cardiovascular safety of incretin-based therapies. Therapy Active/comparator (N/N) Events included RR, IR or HR 95% CI of the ratio Exenatide [114] 2279/1629 CVD-extended events 0.69 RR 0.46, 1.04 Liraglutide [115] 4257/2381 MACE 0.73 IR 0.38, 1.41 Sitagliptin [116] 5429/4817 MACE 0.68 RR 0.41, 1.12 Vildagliptin [117] 6116/6061 CVD event 0.84 RR 0.62, 1.14 Saxagiptin [118] 3356/1251 CVD event 0.43 RR 0.22, 0.86 Linagliptin [119] 3319/1920 CVD composite 0.34 HR 0.16, 0.70 CVD-extended events = myocardial infarction/ischaemia, stroke, cardiac death, arrhythmia, revascularization procedures, heart failure. CVD event = myocardial infarction, ischaemic stroke or coronary revascularization procedure. CVD composite = CV death, nonfatal stroke/myocardial infarction and hospitalization for unstable angina pectoris. CVD, cardiovascular disease; MACE, major adverse cardiovascular events; RR, relative risk; IR, incidence ratio; HR, hazard ratio. 682 Fineman et al. Volume 14 No. 8 August 2012

DIABETES, OBESITY AND METABOLISM some of the mechanisms of action of GLP-1-mediated therapies (glucagon suppression, slowing of gastric emptying, reduction in food intake), but it is currently only indicated in patients using mealtime insulin. PPG reductions of approximately 2 mmol/l are observed above that observed with mealtime insulin alone [120, 121]. Glinides increase insulin secretion by a mechanism similar to SFUs but they have a much more rapid onset of action and a much shorter duration of action. As such, they can be very effective PPG lowering agents (reductions of 2.6 mmol/l) with less hypoglycaemia than that observed with SFUs [120, 121]. Weight gain with glinide treatment is similar to that observed with SFUs. Summary and Clinical Relevance The first in class GLP-1R agonist, exenatide BID, was approved by FDA in 2005 and the first DPP-4 inhibitor, sitagliptin, was approved the following year. These novel therapies should be considered significant treatment advancements as each addresses multiple pathophysiologies of type 2 diabetes. A second generation of GLP-1R agonists have been developed more recently to provide continuous exposure and reduced administration frequency. The first of these to be approved for use is liraglutide, which was approved by the European regulatory authorities in 2009 and by FDA in 2010. Exenatide once weekly was approved in Europe in 2011 and was approved in the United States early in 2012. Although all three classes of GLP- 1-mediated therapies (DDP-4 inhibitors, short-acting GLP-1R agonists and continuous GLP-1R agonists) share the same basic mechanisms, differences in pharmacokinetics and the magnitude of effect for each mechanism results in differences in FPG, PPG and bodyweight. Table 3 summarizes the relative effect of each drug on the main mechanisms of action and on their glucose lowering ability in both the fasting and postprandial states. In their 2009 consensus algorithm, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommended the use of GLP-1R agonists as Tier 2 interventions especially when hypoglycaemia and/or weight gain should be avoided [121]. DPP-4 inhibitors were not included in the current algorithm because of limited data availability at the time the algorithm was created. In contrast, the American Association of Clinical Endocrinologists (AACE) and The American College of Endocrinology (ACE) included both DPP-4 inhibitors and GLP-1R agonists in their 2009 consensus algorithm [122]. Because of their low risk of hypoglycaemia, DPP-4 inhibitors were recommended as monotherapy if pretreatment HbA1c is between 6.5% (48 mmol/mol) and 7.5% (58 mmol/mol), particularly if metformin is contraindicated. For dual therapy, GLP-1R agonists, DPP-4 inhibitors and insulin secretagogues (glinide or sulphonylurea) were recommended (in the order listed) to potentiate insulin secretion in combination with an insulin sensitizer (metformin or a TZD). GLP-1R agonists were the preferred choice in this portion of the treatment algorithm due to their PPG and weight lowering potential despite the greater likelihood of gastrointestinal side effects and the need for twice daily injections. The National Institute for review article Table 3. Relative effects of GLP-1-mediated therapies. GLP-1R agonists DPP-4 inhibitors Short-acting Continuous Mechanism of action in the fasting state Enhance insulin secretion + +/Neutral ++ Suppress glucagon + +/Neutral ++ secretion Mechanism of action in the postprandial state Enhance insulin secretion + +++ ++ Suppress glucagon + +++ ++ secretion Slow gastric emptying Neutral +++ + Reduce food intake Neutral ++ ++ Clinical effects Reduce FPG ++ + +++ Reduce PPG increment + +++ ++ Reduce bodyweight Neutral + + DPP-4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1; FPG, fasting plasma glucose; PPG, postprandial plasma glucose. When considering the lower glycaemic load due to gastric emptying effects. Postprandial plasma glucose rise above fasting levels. Fasting plasma glucose. Health and Clinical Excellence (NICE) also included both GLP-1-mediated therapies in their updated 2009 clinical guideline [123]. Defronzo proposed that treatment algorithms should target the known pathophysiological disturbances in type 2 diabetes by using combinations of drugs and drugs that have multiple mechanisms of action early in the disease [124]. In this regard, GLP-1R agonists have a unique advantage as they can treat disturbances in β-cell function, glucagon secretion, gastric motility and satiety signals. At the time these algorithms were developed, exenatide BID was the only GLP-1R agonist clinically available. Thus, no distinction between short-acting GLP-1R agonists and continuous GLP-1R agonists were made. As described in this review, however, DPP-4 inhibitors and the two generations of GLP-1R agonists have district properties and each can be used to treat different patient phenotypes and different patient preferences. DPP-4 inhibitors have the advantage of simple oral administration, and they produce clinically relevant reductions in HbA1c. However, the effects on PPG are minimal. Shortacting GLP-1R agonists have more complex administration (twice daily injections), but robust effects on PPG. Effects on FPG are less pronounced. The continuous GLP-1R agonists have the advantage of once daily (liraglutide) and once weekly (exenatide) administration and substantial effects on FPG. Effects on the postprandial glucose increment are less robust. In addition, long-acting GLP-1 agonists may have less nausea than observed with short-acting GLP-1 agonists [76, 91]. All three classes of GLP-1-based therapies have a low risk of hypoglycaemia when not combined with a hypoglycaemic agent such as insulin or an SFU. On the basis of the differential pharmacology of GLP-1- mediated therapies, selection of the agent to use should depend, Volume 14 No. 8 August 2012 doi:10.1111/j.1463-1326.2012.01560.x 683

at least in part, on the glycaemic disturbance that is in most need of correction. Because postprandial hyperglycaemia is the major contributor to HbA1c in subjects nearing target goals [1], short-acting GLP-1R agonists should be considered early in the disease and as part of combination therapy for patients nearing glycaemic goals, especially if weight loss would be beneficial. Long-acting GLP-1R agonists should be considered when larger reductions in HbA1c are needed, when fasting glucose elevations are the main problem, and when weight loss would be beneficial. DPP-4 inhibitors could be used in patients with mild to moderate fasting hyperglycaemia and in subjects that need to maintain their bodyweight, especially if subcutaneous injections or gastrointestinal side effects limit the use of other GLP-1-mediated therapies. Exenatide BID was recently approved in the United States as add-on therapy to insulin glargine. Although data are limited, existing results suggest that this combination could be a promising therapy to treat both fasting and postprandial hyperglycaemia with accompanied weight loss and no increase in hypoglycaemia [125]. An indication for use with basal insulin is also being pursued for the other short-acting GLP-1R agonist, lixisenatide, [96]. The availability of three unique GLP-1-mediated therapies is analogous to the current use of modern insulins as short, intermediate, and long-acting versions are all used to optimize fasting and postprandial glucose as needed. Unlike the insulins, however, short and long-acting GLP 1R agonists are not currently approved for use in combination with each other, nor are DPP-4 inhibitors approved for use with GLP-1R agonists. Such combinations could potentially be useful, but further exploration is needed to determine their combined safety and efficacy. Conclusion GLP-1-based therapies operate through multiple novel mechanisms of action that address many of the pathophysiological disturbances in type 2 diabetes. DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists each have unique attributes. Short-acting GLP-1R agonists should be used to target postprandial hyperglycaemia as monotherapy or as part of a combination regimen with orals or basal insulin if fasting hyperglycaemia is also present. DPP-4 inhibitors or long-acting GLP-1R agonists should be used if fasting hyperglycaemia is the main target of therapy. Long-acting GLP-1R agonists appear to be the most potent HbA1c lowering agent of the GLP-1 based therapies and thus may be the best choice for patients that are far from their glycaemic goals. Safety and tolerability, patient preference for administration frequency, concomitant therapies and the need for weight loss or avoidance of weight gain should also be considered when selecting a therapy. Acknowledgement We thank Dr James Ruggles and Lily Kinninger for their manuscript reviews and revisions. Conflict of Interest DIABETES, OBESITY AND METABOLISM M. F. is a consultant and stock holder of Amylin Pharmaceuticals, Inc. B. B. C. and D. M. are employees and stock holders of Amylin Pharmaceuticals, Inc. M. D. is a member of advisory boards for Abbott, Eli Lilly & Co, Merck Sharp & Dohme, Novo Nordisk, Poxel Pharma, consultant for Astra Zeneca/BMS, Eli Lilly & Co, Merck Sharp & Dohme, Novo Nordisk, Sanofi Aventis and speaker for Eli Lilly & Co, Merck Sharp & Dohme, Novo Nordisk. All payments connected to these activities are received by the Diabetes Workshop Foundation, connected to the VU University Medical Center, Amsterdam, the Netherlands. Prof. Diamant does not receive payments personally. Through Prof. Diamant, the VU University Medical Center, Amsterdam, the Netherlands, received research support from Eli Lilly & Co, Merck Sharp & Dohme, Novo Nordisk and Sanofi Aventis. 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