Glucagon-like peptide-1-based therapies and cardiovascular
Upcoming SlideShare
Loading in...5
×
 

Like this? Share it with your network

Share

Glucagon-like peptide-1-based therapies and cardiovascular

on

  • 2,514 views

 

Statistics

Views

Total Views
2,514
Views on SlideShare
2,513
Embed Views
1

Actions

Likes
0
Downloads
58
Comments
0

1 Embed 1

http://www.slideshare.net 1

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Glucagon-like peptide-1-based therapies and cardiovascular Document Transcript

  • 1. review article Diabetes, Obesity and Metabolism 13: 302–312, 2011. © 2011 Blackwell Publishing Ltdarticlereview Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control P. Anagnostis1 , V. G. Athyros2 , F. Adamidou1 , A. Panagiotou1 , M. Kita1 , A. Karagiannis2 & D. P. Mikhailidis3 1 Endocrinology Clinic, Hippokration Hospital, Thessaloniki, Greece 2 Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece 3 Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK Type 2 diabetes mellitus is a well-established risk factor for cardiovascular disease (CVD). New therapeutic approaches have been developed recently based on the incretin phenomenon, such as the degradation-resistant incretin mimetic exenatide and the glucagon-like peptide-1 (GLP-1) analogue liraglutide, as well as the dipeptidyl dipeptidase (DPP)-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, which increase the circulating bioactive GLP-1. GLP-1 exerts its glucose-regulatory action via stimulation of insulin secretion and glucagon suppression by a glucose-dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actions are mediated through GLP-1 receptors (GLP-1Rs), although GLP-1R-independent pathways have been reported. Except for the pancreatic islets, GLP-1Rs are also present in several other tissues including central and peripheral nervous systems, gastrointestinal tract, heart and vasculature, suggesting a pleiotropic activity of GLP-1. Indeed, accumulating data from both animal and human studies suggest a beneficial effect of GLP-1 and its metabolites on myocardium, endothelium and vasculature, as well as potential anti-inflammatory and antiatherogenic actions. Growing lines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP-4 inhibitors compared with placebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether these agents actually decrease CVD outcomes remains to be confirmed by large randomized placebo-controlled trials. This review discusses the role of GLP-1 on the cardiovascular system and addresses the impact of GLP-1-based therapies on CVD outcomes. Keywords: adipose tissue, antidiabetic drug, cardiovascular disease, exenatide, GLP-1, incretins, lipid-lowering therapy, liraglutide Date submitted 26 September 2010; date of first decision 27 October 2010; date of final acceptance 11 November 2010 Introduction specific receptors on β-pancreatic cells [3,5]. GIP and GLP-1 seem to be responsible for about 50% of postprandial insulin Type 2 diabetes mellitus (T2DM) is a chronic disease character- secretion [3]. Furthermore, GLP-1 has been shown to stimu- ized by insulin resistance and progressive decline in pancreatic late proliferation and neogenesis of β cells and to inhibit their β-cell function [1]. It has long been recognized that orally apoptosis [3,5]. GLP-1 receptors (GLP-1Rs) are also present on administered glucose is a stronger insulinotropic stimulus than α-pancreatic cells, whereas GIP receptors are expressed mainly intravenous glucose, suggesting a modulation of plasma glucose on β cells. GLP-1 suppresses glucagon secretion by α cells, by the gastrointestinal system [2]. The mediators of this phe- while GIP stimulates it [3,6]. Apart from the pancreatic islets, nomenon are gut-derived hormones, termed incretins, which GLP-1Rs are present in several other tissues including central are released in response to ingested nutrients, mainly glucose, (hypothalamus) and peripheral nervous systems, gastrointesti- and stimulate insulin secretion by β cells of the pancreas [3]. nal tract, lung and heart [3,5,7]. As a result, GLP-1 exerts The incretin effect seems to be significantly impaired in T2DM further beneficial actions on glucose metabolism by mediating due to a reduced secretion of these hormones, accelerated satiety at the hypothalamic level leading to reduced food intake metabolism or defective responsiveness to their action [4]. and weight loss, and by delaying stomach emptying through The main members of the incretin family are glucagon- the vagus nerve [3,5,7]. like peptide-1 (GLP-1) and glucose-dependent insulinotropic GLP-1 derives from the same gene that encodes glucagon, polypeptide (GIP). GLP-1 derives from the L cells of the distal and is a product of the catalytic action of the protein convertase intestine, while GIP is released from the K cells of the proximal PC1/3 on proglucagon in the enteroendocrine cells [8]. In α- intestine. They both stimulate insulin secretion by binding with pancreatic cells, proglucagon is cleaved to glucagon via protein convertase PC2. However, under certain conditions, islet α cells do express PC1/3 and liberate GLP-1 from proglucagon [9]. Correspondence to: Dr. Panagiotis Anagnostis, Endocrinology Clinic, Hippokration Hospital, 49 Konstantinoupoleos Str, Thessaloniki 54 642, Greece. The active form of GLP-1 is GLP-1(7-36) [3,9]. GLP-1 is rapidly E-mail: anagnwstis.pan@yahoo.gr degraded by the enzyme dipeptidyl dipeptidase-4 (DPP-4) to
  • 2. DIABETES, OBESITY AND METABOLISM review articleinactive GLP-1(9-36), leading to the short circulating half-life studies, although mainly with regard to microvascular com-time for GLP-1 of 2 min. The kidneys also play a role in the plications. In particular, the United Kingdom Prospectiveclearance of GLP-1 from the circulation [3,9,10]. Diabetes Study (UKPDS) showed a 16% risk reduction The recognition and better understanding of the physiol- for myocardial infarction (MI) by intensive glucose contrology and pathophysiology of the incretin phenomenon has led in patients with T2DM (although of marginal significance,to the development of incretin-based therapeutic approaches p = 0.052) [19], which remained significant (p = 0.01) into T2DM. These include the degradation-resistant GLP-1R the 10-year poststudy monitoring period [20]. In a similaragonists and the inhibitors of DPP-4 activity [9]. There are way, two recent studies, the Action to Control Cardiovascularcurrently two GLP-1R agonists that have been approved by the Risk in Diabetes (ACCORD) and the Action in Diabetes andFood and Drugs Administration (FDA) and used clinically to Vascular Disease: Preterax and Diamicron Modified Releasedate: exenatide and liraglutide. Exenatide is the synthetic form Controlled Evaluation (ADVANCE) evaluated the potentialof exendin-4, an incretin mimetic that is present in the saliva benefits of intensive glucose control [HbA1c targets ≤6% (orof the Gila monster (Heloderma suspectum) [11]. Exenatide 42 mmol/mol) and ≤6.5% (or 48 mmol/mol), respectively] ondisplays 53% sequence homology to mammalian GLP-1 and cardiovascular disease (CVD). In the ACCORD study, non-is resistant to DPP-4 action, due to the presence of glycine as fatal MI occurred less often in the intensive glucose controlthe second amino acid, resulting in a longer circulating half- group, although the study was terminated early due to higherlife time (2.4 h) [12,13]. Experimental and clinical trials have mortality rates in this group of patients [21]. On the other hand,shown that exenatide exerts many of the glucoregulatory effects the ADVANCE trial showed a small but significant reductionof GLP-1, such as enhancement of glucose-dependent insulin in the incidence of both macro- and microvascular eventsrelease, inhibition of glucagon secretion and reduction of food with intensive glucose lowering [hazard ratio (HR), 0.90; 95%intake and satiety. It is administered subcutaneously and has confidence interval (CI), 0.82–0.98; p = 0.01], mainly due tobeen associated with reductions in fasting and postprandial glu- improvement of nephropathy [22]. These studies indicated thecose concentrations, and haemoglobin A1c (HbA1c) (1–2% or importance of the early intervention by achieving low glu-11–22 mmol/mol), combined with weight loss [12,13]. Recent cose targets in patients with lower baseline HbA1c, no priordata also suggest more beneficial effects of the long-acting history of coronary artery disease (CAD) and shorter historyrelease form of exenatide at a dose 2 mg once weekly in terms of diabetes. Moreover, in patients with type 1 DM strongerof glucose regulation with the same weight reduction compared associations between glucose control and reduction in the ratewith exenatide 10 μg BID [14] (Table 1). of CVD events (42%, p = 0.02) were shown in the Diabetes Liraglutide has recently been approved for the treatment Control and Complications Trial (DCCT), followed-up forof T2DM, expresses 97% homology to natural GLP-1 and its a mean 17-year period in the observational Epidemiology ofresistance to degradation by DPP-4 is achieved through its Diabetes Interventions and Complications (EDIC) study [23].binding to serum albumin, which prolongs its half-life time GLP-1R agonists affect not only fasting but also postprandialto 12 h. It is administered subcutaneously once daily at a hyperglycaemia [12,13]. The effect of GLP-1 on postprandialdose of 0.6, 1.2 or 1.8 mg [9,12,15]. GLP-1R agonists can be blood glucose is mediated through its inhibition of gastricadministered either as a monotherapy or adjuvant to met- emptying and concomitant glucose absorption and by post-formin, sulphonylureas or thiazolidinediones, when optimal prandial insulin response [24]. Postprandial hyperglycaemiaglycaemic control is not achieved with these agents [16]. Other has been strongly associated with CVD events and, in addi-GLP-1R agonists in development are albiglutide, taspoglutide tion, it is regarded as a more important CVD risk factor(Ro1583), AVA0010, CJC-1134-PC, NN9535, LY2189265 and than fasting glucose levels [25,26]. Many mechanisms for thisLY2428757 [12] (Table 1). relationship have been proposed, such as increased oxidative The DPP-4 inhibitors, including vildagliptin, sitagliptin, stress, abnormal vascular reactivity, hypercoagulability andsaxagliptin and the novel alogliptin, linagliptin and duto- endothelial dysfunction [27].gliptin, suppress the DPP-4 activity by 80% and cause atwofold increase in circulating bioactive GLP-1 and GIP levelsin humans [9,12,15,17,18]. They reduce fasting and postpran- Cardioprotective Effects of GLP-1dial plasma glucose, have neutral effect on weight and can beadministered either as monotherapy or in combination with Data From Animal Studies. Apart from this indirect effect ofother antidiabetic drugs. The benefit of DPP-4 inhibitors is their GLP-1 on CVD outcomes through achievement of euglycaemia,ease of administration, as they are taken orally, whereas cur- accumulating evidence from both experimental and clinicalrently available GLP-1R agonists require injection [9,15,17,18] studies suggests a direct influence on myocardium as well. As(Table 1). mentioned earlier, GLP-1Rs have been detected in the rodent The present review considers the pleiotropic actions of GLP- and human heart, as well as in regions of the brain involved in1 on the cardiovascular system and the impact of GLP-1 agonist autonomic function, and, therefore, central or peripheral GLP-administration on cardiovascular risk factors and outcomes. 1R signalling may transduce direct and indirect cardiovascular effects of circulating GLP-1 [28,29]. All these GLP-1Rs in different tissues have similar if not identical ligand-bindingGLP-1 and Myocardium capacity and their sequence seems to be homologous to theThe beneficial effect of glucose control on cardiovascular out- sequences of the family of G-protein receptors for severalcomes has long been shown by large randomized-controlled endocrine peptides such as glucagon, secretin, calcitonin,Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01345.x 303
  • 3. review article DIABETES, OBESITY AND METABOLISMTable 1. Incretin-based therapies currently available or in development.Compound Current status Structure DosageExenatide Available 53% Sequence homology to mammalian Twice daily, at doses of 5 or 10 μg GLP-1, glycine as a second amino acid Long-acting release form (once weekly, at a dose of 2 mg)Liraglutide Available 97% Sequence homology to human Once daily at a dose of 0.6, 1.2 or GLP-1, with a single substitution of 1.8 mg arginine for lysine in position 34Albiglutide In development Two tandem-linked copies of a modified 30–50 mg once weekly human GLP-1 sequence within the large human serum albumin MoleculeTaspoglutide (Ro1583) In development GLP-1-based molecule that contains 20–30 mg once weekly aminoisobutyric acid substitutions at positions 8 and 35AVA0010 In development Modified exendin-4 molecule with 5–30 μg once or twice daily additional lysine residues at the carboxy terminalCJC-1134-PC In development Recombinant human serum albumin- 1.5–3 mg once or twice weekly exendin-4-conjugated proteinNN9535 In development GLP-1 analogue 0.1–1.6 mg once weeklyLY2189265 In development GLP-1 analogue 0.25–3 mg once weeklyLY2428757 In development Pegylated 0.5–17.6 mg once weekly GLP-1 moleculeSitagliptin Available DPP-4 inhibitor 25–100 mg once dailyVildagliptin Available DPP-4 inhibitor 50 mg twice dailySaxagliptin Available DPP-4 inhibitor 5–10 mg once dailyAlogliptin In development DPP-4 inhibitor 12.5–25 mg once dailyLinagliptin In development DPP-4 inhibitor 2.5–5 mg once dailyDutogliptin In development DPP-4 inhibitor 200–400 mg once dailyDPP-4, dipeptidyl dipeptidase-4; GLP-1, glucagon-like peptide type-1.growth hormone-releasing hormone (GHRH), parathyroid Further animal studies showed additional benefits of GLP-1hormone and vasoactive intestinal peptide (VIP) [29]. on myocardial metabolism in ischaemic conditions. In an open- In experimental rat studies, GLP-1 infusions resulted in chest porcine heart model, the infusion of rGLP-1 decreasedincreased heart rate and blood pressure (BP). This inotropic pyruvate and lactate concentrations both in normoxic condi-and chronotropic effect is mediated through Fos-signalling tions and during ischaemia and reperfusion. However, it did notin several autonomic control sites in the brain regions and significantly affect the extent of tissue necrosis [36]. In an in vivoin the adrenal medulla [30,31]. However, other investigators rabbit model of myocardial ischaemia/reperfusion, the GLP-1failed to confirm such haemodynamic effects in pigs [32], analogue fused to non-glycosylated human transferrin (GLP-while others reported negative inotropic effects of GLP-1 on 1-Tf) limited myocardial loss, either given prior to myocardialrat cardiomyocytes in vitro [33]. On the other hand, it has ischaemia or at the onset of reperfusion [37]. The results ofbeen shown that mice with genetic deletion of GLP-1R display this study suggest a cardioprotective effect of GLP-1 perhapsreduced heart rate, elevated left ventricular (LV) end-diastolic due to antiapoptotic properties. Indeed, GLP-1 limits apoptosispressure and impaired LV contractility and diastolic func- in both β cells and myocytes via activation of cyclic adeno-tion after insulin administration, indicating a direct role of sine monophosphate (cAMP) and phosphoinositide 3-kinaseGLP-1 on the myocardium [34]. Accordingly, 48-h infusion of (PI3-K) by binding with GLP-1Rs [38,39]. PI3-K activationrecombinant GLP-1 (rGLP-1) in dogs with advanced dilated has been associated with myocardial protection in the settingcardiomyopathy led to significant improvements in LV func- of ischaemic/reperfusion injury [40] and myocardial precon-tion (increased stroke volume and cardiac output and decreased ditioning [41]. The lack of GLP-1 effect on infarct size that wasLV end-diastolic pressure) and systemic vascular resistance. observed in the former study [36] may be attributed to the factThis amelioration in LV dysfunction was associated with that the investigators did not employ an inhibitor of DPP-4,an increased insulin-independent myocardial glucose uptake, as GLP-1-Tf has a much longer half-life (27 h in rabbits) thanindependent of the insulinotropic effects of GLP-1, as well natural GLP-1 [37]. Indeed, the conjunction of GLP-1 withas decreased plasma norepinephrine and glucagon levels [35]. valine pyrrolidide, a potent inhibitor of DPP-4, added beforeThe different haemodynamic effects of GLP-1 observed in these myocardial ischaemia in rats, reduced MI size both in vitrostudies may be partly because of the differences in dose, method and in vivo [39]. Furthermore, 24-h continuous i.v. infu-of delivery or species. sion of GLP-1 after coronary artery occlusion and subsequent304 Anagnostis et al. Volume 13 No. 4 April 2011
  • 4. DIABETES, OBESITY AND METABOLISM review articlereperfusion attenuated postischaemic regional contractile dys- class II–III heart failure of ischaemic aetiology receiving 48-hfunction in normal conscious dogs [42]. GLP-1 seems also to rGLP-1 (0.7 pmol/kg/min). Despite the absence of major car-reduce infarct size in rats, when given either prior to ischaemia diovascular effects, minor increases in heart rate and diastolic(as a preconditioning mimetic) or directly at reperfusion [43]. BP during GLP-1 infusion were noticed [57]. In a recent large In terms of pharmacological intervention, both GLP-1R retrospective study, exenatide twice daily was compared withagonists and DPP-4 inhibitors have shown to exert cardiopro- other glucose-lowering agents in terms of their impact on CVDtective effects on myocardial survival after MI in animal studies. events. Despite the higher rates of CAD, obesity, hyperlipi-Specifically, exenatide has shown strong infarct-limiting action daemia, hypertension and/or other comorbidities at baseline,and improved systolic and diastolic cardiac functions after exenatide-treated patients were less likely to have a CVDischaemia–reperfusion injury in rat and porcine heart mod- event than non-exenatide-treated ones (HR: 0.81, 95% CI:els [44–47]. Furthermore, intraperitoneal administration of 0.68–0.95; p = 0.01). Furthermore, exenatide-treated patientsliraglutide in mice before coronary artery occlusion reduced showed lower rates of CVD-related hospitalization (HR: 0.88,infarct size and cardiac rupture and improved cardiac out- 95% CI: 0.79–0.98; p = 0.02) and all-cause hospitalizationput [48]. However, others did not confirm these findings for (HR: 0.94, 95% CI: 0.91–0.97; p < 0.001) than those notliraglutide in a porcine ischemia–reperfusion model. In this having received exenatide [58].study, liraglutide was injected subcutaneously (as in humans) Emerging data also indicate a cardioprotective role of DPP-4before ligation of the left anterior descending artery. Com- inhibitors in humans. In particular, sitagliptin administrationpared with controls, liraglutide had no effect on infarct size at a single dose of 100 mg in patients with CAD and pre-nor on cardiac output and, in addition, the heart rate was served LV function enhanced LV response to stress, attenuatedsignificantly higher in liraglutide-treated pigs [49]. These dif- postischaemic stunning and improved global and regional LVferences may be attributed to the dosing regimen, the different performance compared with placebo [59]. Encouraging resultsanalogue, the timing of treatment and the species to which have also been published recently from an interim analysis ofit was administrated. Larger animal models such as pigs are a phase III randomized placebo-controlled trial regarding theprobably more predictive of results in humans [50]. As far as granulocyte colony-stimulating factor (G-CSF)-based stem cellDPP-4 inhibitors are concerned, sitagliptin seemed to improve mobilization in combination with sitagliptin in patients afterfunctional recovery from ischaemia–reperfusion in mice and acute MI. During the first 6 weeks of follow-up, sitagliptin alongpresented similar cardioprotection with genetic deletion of with G-CSF seems to be quite safe and effective for myocardialDPP-4 [51]. Sitagliptin has also been associated with a reduc- regeneration and may constitute a new therapeutic option intion in infarct size in these experimental models [52]. the future [60].Data From Human Studies. All these promising data have alsobeen reproduced in human studies. In particular, in a pilot study Proposed Mechanismsof six patients with diabetes and New York Heart Association The exact mechanisms underlying this cardioprotective effect(NYHA) class II–III congestive heart failure of ischaemic of GLP-1 have not been fully elucidated. First of all, GLP-1aetiology, subcutaneous infusion of 3–4 pmol/kg/min of rGLP- increases myocardial insulin sensitivity [35], as well as myocar-1 for 72 h showed a trend towards improvement of systolic and dial glucose uptake independently of plasma insulin levels [61].diastolic cardiac functions at rest and during exercise [53]. In Moreover, the survival of cardiac myocytes is mediated byanother study of 12 patients with (NYHA) class III/IV heart inhibition of apoptosis via cAMP and PI3-K pathways, afterfailure, a 5-week infusion of rGLP-1 (2.5 pmol/kg/min) added binding with GLP-1Rs [38,39]. The next mediator is Akt,to standard therapy improved variables of LV function, such a serine-threonine kinase, the activation of which has beenas ejection fraction, maximum myocardial ventilation oxygen shown to attenuate cardiomyocyte death, to restore regionalconsumption and 6-min walk test, as well as quality of life [54]. wall thickening after myocardial ischaemia and to improveSimilarly, i.v. infusion (1.5 pmol/kg/min) of rGLP-1 for 72 h survival of preserved cardiomyocytes [62]. Furthermore, thein 11 subjects with LV dysfunction after MI and angioplasty activation of the antioxidant gene, heme oxygenase-1 (HO-1),led to reduced hospital stay and improved global and regional through GLP-1R [63] reduces fibrosis and LV remodelling andLV wall motion scores. These favourable outcomes remained restores LV function after MI [64]. HO-1 acts via inductiondetectable even several weeks after hospital discharge [55] and of nuclear factor-E2-related factor (Nrf)2 gene expression andwere noticed in patients with or without diabetes, indicating nuclear translocation and subsequent stimulation of Akt [65].that GLP-1 may act on the cardiovascular system independently Other cardioprotective mediators are glycogen synthase kinaseof glycaemic control [54,55]. In all these studies rGLP-1 was (GSK)-3β, Bcl-2 family proteins [66] and PPARs-β andwell tolerated [53–55]. -δ [67]. Similar benefits in terms of myocardial function were noticed Liraglutide has been shown to enhance the activity of Aktin patients receiving GLP-1 (1.5 pmol/kg/min) before and after and to suppress GSK-3β, an Akt substrate. It may also increasecoronary artery bypass grafting (CABG). Compared with the the levels of PPAR-β/δ and Nrf2 in the mouse heart [48].control group, they needed fewer inotropic and vasoactive Furthermore, in this animal model, liraglutide induced mRNAinfusions postoperatively to achieve the same haemodynamic and protein levels of HO-1 and reduced cleaved caspase 3 [48],result and presented arrhythmias less frequently [56]. How- a type of aspartate-specific cysteine protease, the activation ofever, these favourable outcomes were not confirmed in a which is also associated with the induction of cardiac cell apop-recent study of 20 patients without diabetes and with NYHA tosis [68]. Exenatide seems also to use the same pathways inVolume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01345.x 305
  • 5. review article DIABETES, OBESITY AND METABOLISMTable 2. Proposed pathogenic mechanisms for glucagon-like peptide GLP-1(9-36) improved LV function and increased myocar-(GLP)-1 cardioprotection. dial glucose uptake [71]. Noticeably, another experimental rat model evaluating the effects of GLP-1(7-36) on the cardiovascu- lar system and elucidating the role of GLP-1(9-36) showed thatPathogenic mechanisms GLP-1(7-36) infusion was characterized by regional haemody-Achievement of fasting and postprandial euglycaemia namic effects including tachycardia, hypertension, renal andIncreased myocardial glucose uptake mesenteric vasoconstriction, whereas GLP-1(9-36) did notActivation of cAMP and concomitant PIK-3 and PKA display any cardiovascular actions [72].antiapoptotic pathwaysActivation of AktActivation of antioxidant gene HO-1Nrf2 gene expression (through HO-1) GLP-1 and Atherosclerosis (Vasculature,Activation of PPAR-β and -δ Endothelium, Inflammation)Suppression of GSK-3βInhibition of caspase-3 It is well documented that diabetes is associated with endothelialGLP-1R-independent pathway role of GLP-1(9-39) dysfunction [73]. Emerging lines of evidence show an addi-Beneficial effects on endothelium tional benefit of GLP-1 on the endothelium. Indeed, except Increased activity of NO. for cardiomyocytes, GLP-1R expression has been detected NO-independent vasodilation through GLP-1 on endothelial and vascular smooth muscle cells (SMCs), Inhibition of monocyte/macrophage accumulation as well as on macrophages and monocytes [70,74]. Previ- Anti-inflammatory effects Inhibition of atherosclerosis ous animal studies have shown that GLP-1 can induce an endothelial-dependent relaxation of pulmonary artery vesselcAMP, cyclic adenosine monophosphate; GLP-1R, GLP-1 receptor; GSK, rings [75,76], an effect that is NO dependent [76]. NO is aglycogen synthase kinase; HO-1, heme oxygenase-1; NO, nitric oxide; Nrf2, well-known vasodilatory endothelium-derived factor [77]. Ofnuclear factor-E2-related factor; PI3-K, phosphoinositide 3-kinase; PKA, note, GLP-1(9-36) appeared to improve the survival of humanprotein kinase A; PPAR, peroxisome proliferator-activated receptor. aortic endothelial cells after ischaemia–reperfusion [69]. These actions were also exerted through the NOS pathway [68]. Nev- ertheless, some investigators observed a vasodilatory effect oforder to exert its cardioprotective action. Specifically, exenatide GLP-1 independently of NO, indicating clearly a direct actiontreatment increases myocardial phosphorylated Akt and Bcl-2 on vascular SMC via its GLP-1R [78] (Table 3).expression levels and inhibits the expression of active caspase Another pathogenic link between diabetes and atheroscle-3 [44]. In terms of DPP-4 cardioprotective pathways, sitagliptin rosis is the increased formation of advanced glycation-endseems to reduce infract size in ischaemia–reperfusion animal products (AGEs). AGEs and their receptors play a key rolemodels via cAMP-dependent activation of protein kinase A in the vascular damage in patients with diabetes [79]. On the(PKA) [52] (Table 2). other hand, GLP-1 may have an impact on this process as Remarkably, these effects of GLP-1 were not shown in it has been shown to protect from the deleterious effects ofanimals with genetic deletion of GLP -1R, a fact that in AGEs on human umbilical vein endothelial cells, through thecombination with the increased cAMP and reduced apop- inhibition of AGE receptor gene expression on these cells [80].tosis in cardiomyocyte cultures indicates a GLP-1R-dependent Remarkably, in T2DM patients with CAD, rGLP-1 infusionsaction [46]. Nevertheless, GLP-1 action is also mediatedthrough GLP-1R-independent pathways. In particular, as men-tioned earlier, under the influence of DPP-4, GLP-1(7-36) Table 3. Glucagon-like peptide (GLP)-1 and atherosclerosis.amide is degraded to the inactive N-terminally truncatedmetabolite GLP-1(9-36) amide, which does not interact with Related tissues Proposed mechanismsthe known GLP-1R [3,69]. Data from isolated mouse heart Endothelium Expression of GLP-1 receptorsmodels show that GLP-1(9-36) exerts a vasodilatory effect NO-dependent actionthrough a GLP-1R-independent mechanism via the formation Upregulation of NOSof cyclic guanosine monophosphate (cGMP) by nitric oxide Inhibition of AGE receptor gene(NO) which, in turn, is produced under the action of nitric expressionoxide synthase (NOS) [70]. In this study, native GLP-1, as well Inhibition of expression of TNF-α, VCAM-1 and PAI-1as the synthetic analogue exendin-4 [which is DPP-4 resis- Vascular smooth muscle cells Expression of GLP-1 receptorstant and therefore cannot be metabolized to GLP-1(9-36)], Increased flow-mediated vasodilationimproved LV functional recovery after ischaemia–reperfusion Macrophages Expression of GLP-1 receptorsinjury. However, for animals lacking GLP-1Rs, this action was Inhibition of macrophage accumulationevident only for GLP-1 and not for exendin-4 [70]. Moreover, through cAMP/PKA pathwaysGLP-1 and not GLP-1(9-36) displayed a direct inotropic action Monocytes Expression of GLP-1 receptorsvia GLP-1R in the mouse heart and vasculature [70]. The AGE, advanced glycation-end product; cAMP, cyclic adenosine monophos-GLP-1R-independent role of GLP-1(9-36) for the cardiovascu- phate; NO, nitric oxide; NOS, nitric oxide synthase; PAI-1, plasminogenlar system was further indicated from a study of conscious activator inhibitor type-1; PKA, protein kinase A; TNF-α, tumour necrosisdogs with dilated cardiomyopathy, in which infusions of factor-α; VCAM-1, vascular cell adhesion molecule-1.306 Anagnostis et al. Volume 13 No. 4 April 2011
  • 6. DIABETES, OBESITY AND METABOLISM review article(at a dose of 2 pmol/kg/min) significantly increased flow- GLP-1 and Arterial Hypertensionmediated vasodilation (FMD) in the brachial artery compared Conflicting data exist with respect to the effects of GLP-1with placebo [81]. FMD highly correlates with endothelial on BP in rats. Although some studies have showed mod-dysfunction in the coronary circulation [82] and is also con-sidered to be NO mediated [83]. Furthermore, GLP-1 infusion est increases in BP and heart rate [30,31], in salt-sensitiveenhanced acetylcholine-mediated vasodilation in non-diabetic, rodent models GLP-1 treatment has shown antihypertensive,normotensive non-smokers, an effect that was abolished after cardioprotective and renoprotective actions [95,96]. The mainco-administration of glyburide (but not glimepiride). These mechanism for the latter seems to be a natriuretic and diureticdata indicate also a potential modulatory role of sulphony- effect of GLP-1, due to inhibition of Na+ reabsorption in thelurea receptor subunit on GLP-1Rs in the endothelial cells proximal tubule [97] or attenuation of angiotensin II-inducedand a selectivity of KATP channel inhibition amongst different phosphorylation of extracellular signal-regulated kinase-1/2sulphonylurea agents [84]. in renal cells [96]. Noticeably, increased cardiac output with There are also data about the impact of GLP-1R agonists and no BP changes has also been reported in rats, suggestingDPP-4 inhibitors on endothelial function and CVD biomarkers. that GLP-1 may cause peripheral vasodilatation [98]. As men-Exendin-4 has been shown to prevent homocysteinaemia- tioned earlier, endothelial-dependent vasorelaxation by GLP-1induced endothelial dysfunction in rats with diabetes [85]. in experimental studies comprises another mechanism of BPExenatide may also attenuate intimal hyperplasia of carotid lowering [75,76]. This vasorelaxation may be mediated throughartery (a surrogate marker of CVD [86]) in insulin-resistant NO pathways or may be NO independent and mediated viarats independently of glucose regulation and food intake. In cAMP/PKA-mediated hyperpolarization [99]. In calves, GLP-this study, exenatide was associated with a non-significant 1 was haemodynamically neutral [100], whereas in isolatedupregulation of NOS and reduction of the proinflammatory porcine ileal arteries it produced a dose-dependent vasodilatorytranscriptional nuclear factor-κB (NF-κB) [87]. In another effect [101]. Antihypertensive, cardioprotective and renopro-experimental model, it also reduced monocyte/macrophage tective effects have also been reported for exenatide analogueaccumulation in the arterial wall, by inhibiting the inflam- AC3174 in a salt-sensitive rat model [102].matory response in macrophages through cAMP/PKA path- In humans, small pilot studies in patients with heart failureways [74]. In this study, exenatide attenuated the mRNA showed a slight increase in diastolic blood pressure (DBP) afterexpression of tumour necrosis factor (TNF)-α, and mono- GLP-1 infusions [53,57], despite a trend towards a decreasecyte chemoattractant protein-1 (MCP-1), which have also in systolic blood pressure (SBP) [53]. On the other hand,been associated with atherosclerosis [74]. Of note, indirect in a study of patients with T2DM, GLP-1 (at a dose of 2.4anti-inflammatory effects for exenatide can be also speculated pmol/kg/min, for 48-h continuous infusion) showed a ten-by its effect on adiponectin, a well-known insulin-sensitizing dency to decrease both SBP and DBP compared to saline, withand antiatherogenic adipokine [88]. In particular, in cultures of no significant effect on heart rate [103]. However, these studiesadipocytes, exenatide increased adiponectin mRNA expression were too small for safe conclusions.via the GLP-1R–PKA pathway [89] (Table 3). Nonetheless, encouraging data have emerged from larger Beneficial effects on markers of endothelial dysfunction and studies with GLP-1 analogues. A double-blind 24-weekincreased CVD risk have also been observed for liraglutide. placebo-controlled trial in T2DM patients na¨ve to antidiabetic ıSpecifically, in cultured human vascular endothelial cells, drugs showed a significant reduction in both SBP and DBP withliraglutide inhibited the expression of TNF-α and the exenatide (5 or 10 μg BID) compared with placebo [104]. Exe-hyperglycaemic-mediated induction of expression of vascular natide (5 μg BID for 4 weeks followed by 10 μg BID) showedcell adhesion molecule-1 (VCAM-1) and plasminogen activator also a trend towards lowering 24-h, day-time and night-timeinhibitor type-1 (PAI-1) [90,91]. Noticeably, in another study SBP, with a neutral effect on DBP and heart rate, when addedof cultured human umbilical vein endothelial cells, liraglutide to metformin and/or thiazolidinedione for 12 weeks in anotherincreased NO production and suppressed NF-κB activation. placebo-controlled trial of T2DM [105]. Studies of longer dura-Liraglutide also reduced TNF-α-induced MCP-1, VCAM-1 tion of exenatide (at a dose of 10 μg BID for 82 weeks up toand intercellular adhesion molecule-1 (ICAM-1) mRNA 3.5 years while continuing other antidiabetic medications suchexpression. These effects were mediated by the AMP-activated as metformin and/or sulphonylurea) suggest also improve-protein kinase, which occurs through a signalling pathway ments in DBP [106] or both SBP and DBP [107]. A recentindependent of cAMP [92]. study pooling data from six trials, including 2171 subjects with An additional effect of liraglutide on inflammatory process a follow-up of at least 6 months, tried to compare the effects ofhas emerged, as it tended to reduce the levels of high-sensitivity exenatide on BP with those of insulin or placebo. The authorsC-reactive protein (hsCRP) in patients with T2DM in a dose- showed greater reductions in SBP with exenatide than withdependent way [91]. It is well known that elevated hsCRP has placebo mainly in patients with abnormally high baseline SBPbeen associated with an increased risk for atherosclerosis and levels. No differences between these groups were noticed inCVD [93]. Similar inhibitory effects on VCAM-1 and hsCRP terms of DBP [108]. The main mechanism for this antihyper-have also been reported for exenatide [74,94]. Favourable tensive effect of exenatide seems to be related to weight loss (as iteffects on endothelial function have also been reported for is well known that weight reduction exerts beneficial outcomessitagliptin, mainly through induction of NOS activity, and to a on hypertension [109]) notwithstanding the aforementionedgreater extent compared with pioglitazone [52] (Table 3). natriuretic and vasodilatory effects of GLP-1.Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01345.x 307
  • 7. review article DIABETES, OBESITY AND METABOLISM Similar favourable effects on both SBP and DBP have also significantly decreased TG, TC, LDL-C, non-HDL and total-been reported for liraglutide, either as a monotherapy (at a to-HDL cholesterol (9–16%), although it led to a smallersingle dose of 0.65, 1.25 or 1.9 mg) [110] or in combination with increase in HDL cholesterol (+4 vs. +9%) [123]. No data existmetformin and thiazolidinediones (1.2 or 1.9 mg daily) [111], on the effect of sitagliptin on postprandial lipaemia in humans.compared with placebo [110,111] or with sulphonylurea (1.2 However, it must be stated that in an animal model sitagliptinor 1.9 mg daily) [112]. Regarding the role of DPP-4 inhibitors reduced postprandial apoB48 and triacylglycerol accumulationon BP, sitagliptin (at a dose of 50 or 100 mg BID) has been to a similar extent than exendin-4 [124]. The exact mecha-associated with small but significant reductions (2–3 mmHg) nisms underlying the postprandial lipid reduction by DPP-4in 24-h ambulatory SBP and DBP compared with placebo, inhibitors and GLP-1R agonists are not clarified. It seems,although this study involved patients without diabetes [113]. however, that GLP-1R signalling plays a key role in the con-However, the exact effect of DPP-4 inhibitors on BP needs trol of intestinal lipoprotein synthesis and secretion, beyondto be better elucidated, as experimental data suggest also an weight reduction [124]. Finally, in an open-label prospectiveenhancement of the vasoconstrictor role of angiotensin II in trial assessing the LDL-C-lowering effects of sitagliptin, cole-kidneys by sitagliptin [114]. sevelam and rosiglitazone, sitagliptin (as well as rosiglitazone), in contrast to colesevelam, did not exert any beneficial effect on LDL-C [125].GLP-1 and Lipid MetabolismThree placebo-controlled studies tried to evaluate the impact Conclusionsof exenatide on lipid parameters [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipopro- Emerging evidence suggests some pleiotropic actions of GLP-1tein cholesterol (HDL-C) and triglycerides (TG)] in patients on the cardiovascular system, either directly through GLP-on metformin alone [115], sulphonylurea alone [116] or met- 1Rs on the myocardium, endothelium and vasculature or viaformin plus sulphonylurea [117]. At week 30, no significant the GLP-1R-independent actions of GLP-1(9-36). Experimen-differences were observed in these studies for either the exe- tal data from animal and human studies indicate inotropicnatide group or placebo in terms of TC, LDL-C, HDL-C, TG and vasodilatory effects of GLP-1, increased myocardial glu-or apolipoprotein B (apoB) concentrations [115–117]. Never- cose uptake, improvement of endothelial function, reduction in infarct size (when given either prior to injury or at thetheless, in an open-label 82-week extension of these studies, point of reperfusion), as well as potential anti-inflammatoryexenatide treatment at 10 μg BID led to significant improve- and antiatherogenic actions. Based on these data, the GLP-1Rments in HDL-C (mean increase of 4.6 mg/dl from baseline) agonists seem to exert a cardioprotective role either directlyand TG levels (mean reduction of 38.6 mg/dl from baseline). via the aforementioned pathways or indirectly by improvingThe greatest improvements in lipid profile were observed in CVD risk factors beyond hyperglycaemia, such as hypertensionsubjects with the greatest weight reduction [107]. Furthermore, and dyslipidaemia. These mechanisms deserve further research.when a subset of this cohort was followed-up for 3.5 years, Although the exact mechanisms have not been fully elucidated,exenatide as adjunctive therapy to metformin and/or sulpho- these encouraging lines of evidence remain to be verified in largenylurea significantly ameliorated all lipid parameters compared prospective randomized placebo-controlled trials with optimalwith baseline. In particular, it resulted in 12% reduction in TG, doses of GLP-1R agonists and possibly DPP-4 inhibitors in5% reduction in TC and 6% in LDL-C, whereas it induced order to determine their impact on CVD risk and associatedan increase in HDL-C of 24% [106]. Exenatide has also been variables.associated with a decrease in postprandial TG and apoB48levels (a component of chylomicrons, rich in triacylglyceroland produced after fat ingestion [118]) compared with insulin Conflict of Interestglargine [119] or placebo [120]. Postprandial lipaemia is highly This review was written independently. The authors did notassociated with insulin resistance and leads LDL-C and HDL-C receive financial or professional help with the preparation of themetabolism to a more atherogenic direction in patients with manuscript. The authors have given talks, attended conferencesT2DM [118]. Significant reductions in TG and TC and in and participated in advisory boards and trials sponsored byinsulin dosage requirement have also been reported retrospec- various pharmaceutical companies. P. A., V. G. A., A. K. andtively for exenatide (5 μg BID) when added to insulin or oral D. P. M. designed the study. F. A. and A. P. conducted andhypoglycaemic agents [94,121]. collected data. F. A., M. K. and D. P. M. analysed the study. Regarding the impact of liraglutide on lipids, it has been P. A. wrote the manuscript.associated with a significant reduction in TG levels (up to 22% All the authors have no competing interest to disclose.at the dose of 1.9 mg daily, compared with placebo), although itdid not exert any significant change on TC, LDL-C, HDL-C andapoB [110]. Few data exist for the effect of DPP-4 inhibitors on Referenceslipids. There is evidence that vildagliptin (50 mg BID) reduces 1. Fonseca VA. Defining and characterizing the progression of type 2postprandial plasma TG and chylomicron apoB48 compared diabetes. Diabetes Care 2009; 32(Suppl. 2): S151–156.with placebo, through reduction of intestinally derived TG. 2. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oralHowever, in this study it presented minimal effects on fasting and intravenous glucose administration. J Clin Endocrinol Metab 1964;lipid levels [122]. Compared with rosiglitazone, vildagliptin 24: 1076–1082.308 Anagnostis et al. Volume 13 No. 4 April 2011
  • 8. DIABETES, OBESITY AND METABOLISM review article 3. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999; 20: 22. ADVANCE Collaborative Group. Intensive blood glucose control and 876–913. vascular outcomes in patients with type 2 diabetes. N Engl J Med ¨ 4. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in 2008; 358: 2560–2572. type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29: 46–52. 23. Nathan DM, Cleary PA, Backlund JY et al. Diabetes Control and Compli- cations Trial/Epidemiology of Diabetes Interventions and Complications 5. Tomas E, Habener JF. Insulin-like actions of glucagon-like peptide-1: a (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and dual receptor hypothesis. Trends Endocrinol Metab 2010; 21: 59–67. cardiovascular disease in patients with type 1 diabetes. N Engl J Med 6. Meier JJ, Gallwitz B, Siepmann N et al. Gastric inhibitory polypeptide 2005; 353: 2643–2653. (GIP) dose-dependently stimulates glucagon secretion in healthy human 24. Deane AM, Nguyen NQ, Stevens JE et al. Endogenous glucagon-like subjects at euglycaemia. Diabetologia 2003; 46: 798–801. peptide-1 slows gastric emptying in healthy subjects, attenuating 7. Abbott CR, Monteiro M, Small CJ et al. The inhibitory effects of peripheral postprandial glycemia. J Clin Endocrinol Metab 2010; 95: 215–221. administration of peptide YY(3-36) and glucagon-like peptide-1 on food 25. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for intake are attenuated by ablation of the vagal-brainstem-hypothalamic cardiovascular disease in type 2 diabetes: the epidemiological evidence. pathway. Brain Res 2005; 1044: 127–131. Diabetologia 2001; 44: 2107–2114. ´ 8. Rouille Y, Martin S, Steiner DF. Differential processing of proglucagon by 26. Cavalot F, Petrelli A, Traversa M et al. Postprandial blood glucose is a the subtilisin-like prohormone convertases PC2 and PC3 to generate stronger predictor of cardiovascular events than fasting blood glucose either glucagon or glucagon-like peptide. J Biol Chem 1995; 270: in type 2 diabetes mellitus, particularly in women: lessons from the 26488–26496. San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab 2006; 91: 9. Wideman RD, Kieffer TJ. Mining incretin hormone pathways for novel 813–819. therapies. Trends Endocrinol Metab 2009; 20: 280–286. 27. Brownlee M. The pathobiology of diabetic complications: a unifying 10. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 mechanism. Diabetes 2005; 54: 1615–1625. by human plasma in vitro yields an N-terminally truncated peptide that 28. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995; ribonucleic acid encoding the rat glucagon-like peptide 1 receptor. 80: 952–957. Endocrinology 1996; 137: 2968–2978. 11. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and 29. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for characterization of exendin-4, an exendin-3 analogue, from Heloderma glucagon-like peptide 1: brain, heart and pancreatic forms have the same suspectum venom. Further evidence for an exendin receptor on dispersed deduced amino acid sequences. FEBS Lett 1995; 358: 219–224. acini from guinea pig pancreas. J Biol Chem 1992; 267: 7402–7405. 30. Barragan JM, Rodriguez RE, Blazquez E. Changes in arterial blood pressure 12. Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes and heart rate induced by glucagon-like peptide-1-(7–36 amide) in rats. mellitus. Nat Rev Endocrinol 2009; 5: 262–269. Am J Physiol 1994; 266: E459–E466. 13. Gentilella R, Bianchi C, Rossi A, Rotella CM. Exenatide: a review from 31. Yamamoto H, Lee CE, Marcus JN et al. Glucagon-like peptide-1 receptor pharmacology to clinical practice. Diabetes Obes Metab 2009; 11: stimulation increases blood pressure and heart rate and activates 544–556. autonomic regulatory neurons. J Clin Invest 2002; 110: 43–52. 14. Buse JB, Drucker DJ, Taylor KL et al; for the DURATION-1 Study Group. 32. Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ. Glucagon-like peptide DURATION-1: exenatide once weekly produces sustained glycemic control 1 undergoes differential tissue-specific metabolism in the anesthetized and weight loss over 52 weeks. Diabetes Care 2010; 33: 1255–1261. pig. Am J Physiol 1996; 271: E458–E464. 15. Montanya E, Sesti G. A review of efficacy and safety data regarding 33. Vila Petroff MG, Egan JM, Wang X, Sollott SJ. Glucagon-like peptide 1 the use of liraglutide, a once-daily human glucagon-like peptide 1 increases cAMP but fails to augment contraction in adult rat cardiac analogue, in the treatment of type 2 diabetes mellitus. Clin Ther 2009; myocytes. Circ Res 2001; 89: 445–452. 31: 2472–2488. 34. Gros R, You X, Baggio LL et al. Cardiac function in mice lacking the 16. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American glucagon-like peptide-1 receptor. Endocrinology 2003; 144: 2242–2252. Association of Clinical Endocrinologists/American College of Endocrinol- 35. Nikolaidis LA, Elahi D, Hentosz T et al. Recombinant glucagon-like ogy consensus panel on type 2 diabetes mellitus: an algorithm for peptide-1 increases myocardial glucose uptake and improves left glycemic control. Endocr Pract 2009; 15: 540–559. ventricular performance in conscious dogs with pacing-induced dilated 17. Neumiller JJ, Wood L, Campbell RK. Dipeptidyl peptidase-4 inhibitors for cardiomyopathy. Circulation 2004; 110: 955–961. the treatment of type 2 diabetes mellitus. Pharmacotherapy 2010; 30: 36. Kavianipour M, Ehlers MR, Malmberg K et al. Glucagon-like peptide-1 463–484. (7-36) amide prevents the accumulation of pyruvate and lactate in the 18. Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Sitagliptin in ischemic and non-ischemic porcine myocardium. Peptides 2003; 24: clinical practice: a new approach in the treatment of type 2 diabetes. 569–578. Expert Opin Pharmacother 2008; 9: 1705–1720. 37. Matsubara M, Kanemoto S, Leshnower BG et al. Single dose GLP-1-Tf 19. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose ameliorates myocardial ischemia/reperfusion injury. J Surg Res 2011; control with sulphonylureas or insulin compared with conventional 165: 38–45. treatment and risk of complications in patients with type 2 diabetes 38. Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like peptide-1 promotes (UKPDS 33). Lancet 1998; 352: 837–853. DNA synthesis, activates phosphatidylinositol 3-kinase and increases 20. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow- transcription factor pancreatic and duodenal homeobox gene 1 (PDX- up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 1) DNA binding activity in b (INS-1)-cells. Diabetologia 1999; 42: 359: 1577–1589. 856–864. 21. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of 39. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: peptide 1 can directly protect the heart against ischemia/reperfusion 2545–2559. injury. Diabetes 2005; 54: 146–151.Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01345.x 309
  • 9. review article DIABETES, OBESITY AND METABOLISM 40. Hausenloy DJ, Yellon DM. New directions for protecting the heart against patients with heart failure. Am J Physiol Heart Circ Physiol 2010; 298: ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage H1096–H1102. Kinase (RISK)-pathway. Cardiovasc Res 2004; 61: 448–460. 58. Best JH, Hoogwerf BJ, Herman WH et al. Risk of cardiovascular disease 41. Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning events in patients with type 2 diabetes prescribed the GLP-1 receptor activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ agonist exenatide twice daily or other glucose-lowering therapies: a Res 2000; 87: 309–315. retrospective analysis of the LifeLinkTM Database. Diabetes Care 2011; 42. Nikolaidis LA, Doverspike A, Hentosz T et al. Glucagon-like peptide- 34: 90–95. 1 limits myocardial stunning following brief coronary occlusion and 59. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by reperfusion in conscious canines. J Pharmacol Exp Ther 2005; 312: sitagliptin improves the myocardial response to dobutamine stress and 303–308. mitigates stunning in a pilot study of patients with coronary artery 43. Bose AK, Mocanu MM, Carr RD, Yellon DM. Glucagon like peptide-1 is disease. Circ Cardiovasc Imaging 2010; 3: 195–201. protective against myocardial ischemia/reperfusion injury when given 60. Theiss HD, Brenner C, Engelmann MG et al. Safety and efficacy of either as a preconditioning mimetic or at reperfusion in an isolated rat SITAgliptin plus GRanulocyte-colony-stimulating factor in patients heart model. Cardiovasc Drugs Ther 2005; 19: 9–11. suffering from acute myocardial infarction (SITAGRAMI-Trial)—rationale, 44. Sonne DP, Engstrøm T, Treiman M. Protective effects of GLP-1 analogues design and first interim analysis. Int J Cardiol 2010; 145: 282–284. exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in 61. Bhashyam S, Fields AV, Patterson B et al. Glucagon-like peptide-1 rat heart. Regul Pept 2008; 146: 243–249. increases myocardial glucose uptake via p38alpha MAP kinase-mediated, 45. Timmers L, Henriques JP, de Kleijn DP et al. Exenatide reduces infarct nitric oxide-dependent mechanisms in conscious dogs with dilated size and improves cardiac function in a porcine model of ischemia and cardiomyopathy. Circ Heart Fail 2010; 3: 512–521. reperfusion injury. J Am Coll Cardiol 2009; 53: 501–510. 62. Matsui T, Tao J, del Monte F et al. Akt activation preserves cardiac 46. Ku HC, Chen WP, Su MJ. GLP-1 signaling preserves cardiac function in function and prevents injury after transient cardiac ischemia in vivo. endotoxemic Fischer 344 and DPP4-deficient rats. Naunyn Schmiede- Circulation 2001; 104: 330–335. bergs Arch Pharmacol 2010; 382: 463–474. 63. Yin F, Liu JH, Zheng XX, Guo LX. GLP-1 receptor plays a critical role in 47. Brown SB, Libonati JR, Selak MA, Shannon RP, Simmons RA. Neonatal geniposide-induced expression of heme oxygenase-1 in PC12 cells. Acta exendin-4 leads to protection from reperfusion injury and reduced rates Pharmacol Sin 2010; 31: 540–545. of oxidative phosphorylation in the adult rat heart. Cardiovasc Drugs Ther 64. Liu X, Pachori AS, Ward CA et al. Heme oxygenase-1 (HO-1) inhibits 2010; 24: 197–205. postmyocardial infarct remodeling and restores ventricular function. 48. Noyan-Ashraf MH, Momen MA, Ban K et al. GLP-1R agonist liraglutide FASEB J 2006; 20: 207–216. activates cytoprotective pathways and improves outcomes after 65. Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase- experimental myocardial infarction in mice. Diabetes 2009; 58: 975–983. 1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated 49. Kristensen J, Mortensen UM, Schmidt M, Nielsen PH, Nielsen TT, transcriptional control of nuclear respiratory factor-1. Circ Res 2008; Maeng M. Lack of cardioprotection from subcutaneously and preischemic 103: 1232–1240. administered liraglutide in a closed chest porcine ischemia reperfusion 66. Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S, Sollott SJ. Role of model. BMC Cardiovasc Disord 2009; 9: 31. glycogen synthase kinase-3beta in cardioprotection. Circ Res 2009; 104: 50. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA. 1240–1252. Myocardial protection at a crossroads: the need for translation into 67. Burkart EM, Sambandam N, Han X et al. Nuclear receptors PPAR- clinical therapy. Circ Res 2004; 95: 125–134. beta/delta and PPARalpha direct distinct metabolic regulatory programs ´ 51. Sauve M, Ban K, Momen MA et al. Genetic deletion or pharmacological in the mouse heart. J Clin Invest 2007; 117: 3930–3939. inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes 68. Narula J, Pandey P, Arbustini E et al. Apoptosis in heart failure: release of after myocardial infarction in mice. Diabetes 2010; 59: 1063–1073. cytochrome c from mitochondria and activation of caspase-3 in human 52. Ye Y, Keyes KT, Zhang C et al. The myocardial infarct size-limiting effect cardiomyopathy. Proc Natl Acad Sci U S A 1999; 96: 8144–8149. of sitagliptin is PKA-dependent, whereas the protective effect of 69. Ban K, Kim KH, Cho CK et al. Glucagon-like peptide (GLP)-1(9-36)amide- pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ mediated cytoprotection is blocked by exendin(9-39) yet does not require Physiol 2010; 298: H1454–H1465. the known GLP-1 receptor. Endocrinology 2010; 151: 1520–1531. ´ 53. Thrainsdottir I, Malmberg K, Olsson A, Gutniak M, Ryden L. Initial 70. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. experience with GLP-1 treatment on metabolic control and myocardial Cardioprotective and vasodilatory actions of glucagon-like peptide function in patients with type 2 diabetes mellitus and heart failure. Diab 1 receptor are mediated through both glucagon-like peptide 1 Vasc Dis Res 2004; 1: 40–43. receptor-dependent and -independent pathways. Circulation 2008; 117: 54. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon- 2340–2350. like peptide-1 infusion improves left ventricular ejection fraction and 71. Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP- functional status in patients with chronic heart failure. J Card Fail 2006; 1 mediates myocardial glucose uptake and improves left ventricular 12: 694–699. performance in conscious dogs with dilated cardiomyopathy. Am J Physiol 55. Nikolaidis LA, Mankad S, Sokos GG et al. Effects of glucagon-like peptide- Heart Circ Physiol 2005; 289: H2401–H2408. 1 in patients with acute myocardial infarction and left ventricular 72. Gardiner SM, March JE, Kemp PA, Bennett T, Baker DJ. Possible involve- dysfunction after successful reperfusion. Circulation 2004; 109: 962–965. ment of GLP-1(9-36) in the regional haemodynamic effects of GLP-1(7- 56. Sokos GG, Bolukoglu H, German J et al. Effect of glucagon-like peptide-1 36) in conscious rats. Br J Pharmacol 2010; 161: 92–102. (GLP-1) on glycemic control and left ventricular function in patients 73. Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in undergoing coronary artery bypass grafting. Am J Cardiol 2007; 100: diabetes mellitus: molecular mechanisms and clinical implications. Rev 824–829. Endocr Metab Disord 2010; 11: 61–74. 57. Halbirk M, Nørrelund H, Møller N et al. Cardiovascular and metabolic 74. Arakawa M, Mita T, Azuma K et al. Inhibition of monocyte adhesion effects of 48-h glucagon-like peptide-1 infusion in compensated chronic to endothelial cells and attenuation of atherosclerotic lesion by a310 Anagnostis et al. Volume 13 No. 4 April 2011
  • 10. DIABETES, OBESITY AND METABOLISM review article glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010; anti-inflammatory action in endothelial cells. Diabetologia 2010; 53: 59: 1030–1037. 2256–2263. 75. Golpon HA, Puechner A, Welte T, Wichert PV, Feddersen CO. Vasorelaxant 93. Haffner SM. The metabolic syndrome: inflammation, diabetes mellitus, effect of glucagon-like peptide-(7-36)amide and amylin on the and cardiovascular disease. Am J Cardiol 2006; 97: 3–11. pulmonary circulation of the rat. Regul Pept 2001; 102: 81–86. 94. Viswanathan P, Chaudhuri A, Bhatia R, Al-Atrash F, Mohanty P, Dan- ¨ ¨ 76. Richter G, Feddersen O, Wagner U, Barth P, Goke R, Goke B. GLP-1 dona P. Exenatide therapy in obese patients with type 2 diabetes stimulates secretion of macromolecules from airways and relaxes mellitus treated with insulin. Endocr Pract 2007; 13: 444–450. pulmonary artery. Am J Physiol Lung Cell Mol Physiol 1993; 265: 95. Yu M, Moreno C, Hoagland KM et al. Anti-hypertensive effect of L374–L381. glucagons-like peptide 1 in Dahl salt-sensitive rats. J Hypertens 2003; 77. Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell 21: 1125–1135. Cardiol 1999; 31: 51–60. 96. Hirata K, Kume S, Araki S et al. Exendin-4 has an anti-hypertensive effect ¨ ¨ 78. Nystrom T, Gonon AT, Sjoholm A, Pernow J. Glucagon-like peptide-1 in salt-sensitive mice model. Biochem Biophys Res Commun 2009; 380: relaxes rat conduit arteries via an endothelium-independent mechanism. 44–49. Regul Pept 2005; 125: 173–177. 97. Moreno C, Mistry M, Roman RJ. Renal effects of glucagon-like peptide in 79. Chen J, Song M, Yu S et al. Advanced glycation endproducts alter rats. Eur J Pharmacol 2002; 434: 163–167. functions and promote apoptosis in endothelial progenitor cells through 98. Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP. receptor for advanced glycation endproducts mediate overexpression of Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic cell oxidant stress. Mol Cell Biochem 2010; 335: 137–146. function and prolongs survival in the spontaneously hypertensive, heart 80. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Glucagon-like peptide-1 failure-prone rat. Circ Heart Fail 2008; 1: 153–160. (GLP-1) inhibits advanced glycation end product (AGE)-induced up- 99. Green BD, Hand KV, Dougan JE, McDonnell BM, Cassidy RS, Grieve DJ. regulation of VCAM-1 mRNA levels in endothelial cells by suppressing GLP-1 and related peptides cause concentration-dependent relaxation of AGE receptor (RAGE) expression. Biochem Biophys Res Commun 2010; rat aorta through a pathway involving KATP and cAMP. Arch Biochem 391: 1405–1408. Biophys 2008; 478: 136–142. ¨ 81. Nystrom T, Gutniak MK, Zhang Q et al. Effects of glucagon-like peptide-1 100. Edwards C, Edwards A, Bloom S. Cardiovascular and pancreatic endocrine on endothelial function in type 2 diabetes patients with stable coronary responses to glucagon-like peptide-1 (7-36) amide in the conscious calf. artery disease. Am J Physiol Endocrinol Metab 2004; 287: E1209–E1215. Exp Physiol 1997; 82: 709–716. 82. Anderson TJ, Uehata A, Gerhard MD et al. Close relation of endothelial 101. Hansen L, Hartmann B, Mineo H, Holst JJ. Glucagon-like peptide-1 function in the human coronary and peripheral circulations. J Am Coll secretion is influenced by perfusate glucose concentration and by a Cardiol 1995; 26: 1235–1241. feedback mechanism involving somatostatin in isolated perfused porcine ¨ 83. Ingelsson E, Syvanen AC, Lind L. Endothelium-dependent vasodilation in ileum. Regul Pept 2004; 118: 11–18. conduit and resistance vessels in relation to the endothelial nitric oxide 102. Liu Q, Adams L, Broyde A, Fernandez R, Baron AD, Parkes DG. The synthase gene. J Hum Hypertens 2008; 22: 569–578. exenatide analogue AC3174 attenuates hypertension, insulin resistance, 84. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Benefi- and renal dysfunction in Dahl salt-sensitive rats. Cardiovasc Diabetol cial effects of GLP-1 on endothelial function in humans: dampening by 2010; 9: 32. glyburide but not by glimepiride. Am J Physiol Endocrinol Metab 2007; 103. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion 293: E1289–E1295. of glucagon-like peptide 1 lowers plasma glucose and reduces appetite 85. Goyal S, Kumar S, Bijjem KV, Singh M. Role of glucagon-like peptide-1 in in type 2 diabetic patients. Diabetes Care 1999; 22: 1137–1143. vascular endothelial dysfunction. Indian J Exp Biol 2010; 48: 61–69. 104. Moretto TJ, Milton DR, Ridge TD et al. Efficacy and tolerability of exenatide 86. Hodis HN, Mack WJ, LaBree L et al. The role of carotid arterial intima- monotherapy over 24 weeks in antidiabetic drug-naive patients with type media thickness in predicting clinical coronary events. Ann Intern Med 2 diabetes: a randomized, double-blind, placebo-controlled, parallel- 1998; 128: 262–269. group study. Clin Ther 2008; 30: 1448–1460. 87. Murthy SN, Hilaire RC, Casey DB et al. The synthetic GLP-I receptor 105. Gill A, Hoogwerf BJ, Burger J et al. Effect of exenatide on heart rate and agonist, exenatide, reduces intimal hyperplasia in insulin resistant rats. blood pressure in subjects with type 2 diabetes mellitus: a double-blind, Diab Vasc Dis Res 2010; 7: 138–144. placebo-controlled, randomized pilot study. Cardiovasc Diabetol 2010; 88. Athyros VG, Tziomalos K, Karagiannis A, Anagnostis P, Mikhailidis DP. 9: 6. Should adipokines be considered in the choice of treatment of obesity- 106. Klonoff DC, Buse JB, Nielsen LL et al. Exenatide effects on diabetes, related health problems? Curr Drug Targets 2010; 11: 122–135. obesity, cardiovascular risk factors and hepatic biomarkers in patients 89. Kim Chung le T, Hosaka T, Yoshida M et al. Exendin-4, a GLP-1 receptor with type 2 diabetes treated for at least 3 years. Curr Med Res Opin agonist, directly induces adiponectin expression through protein kinase 2008; 24: 275–286. A pathway and prevents inflammatory adipokine expression. Biochem 107. Blonde L, Klein EJ, Han J et al. Interim analysis of the effects of exenatide Biophys Res Commun 2009; 390: 613–618. treatment on A1C, weight and cardiovascular risk factors over 82 weeks 90. Liu H, Dear AE, Knudsen LB, Simpson RW. A long-acting glucagon-like in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab peptide-1 analogue attenuates induction of plasminogen activator 2006; 8: 436–447. inhibitor type-1 and vascular adhesion molecules. J Endocrinol 2009; 108. Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on 201: 59–66. systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens ` 91. Courreges JP, Vilsbøll T, Zdravkovic M et al. Beneficial effects of once-daily 2010; 23: 334–339. liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular 109. Neter JE, Stam BE, Kok FJ et al. Influence of weight reduction on blood risk biomarkers in patients with type 2 diabetes. Diabet Med 2008; 25: pressure: a meta-analysis of randomized controlled trials. Hypertension 1129–1131. 2003; 42: 878–884. 92. Hattori Y, Jojima T, Tomizawa A et al. A glucagon-like peptide-1 (GLP- 110. Vilsbøll T, Zdravkovic M, Le-Thi T et al. Liraglutide, a long-acting human 1) analogue, liraglutide, upregulates nitric oxide production and exerts glucagon-like peptide-1 analog, given as monotherapy significantlyVolume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01345.x 311
  • 11. review article DIABETES, OBESITY AND METABOLISM improves glycemic control and lowers body weight without risk of ¨ 118. Mero N, Syvanne M, Taskinen MR. Postprandial lipid metabolism in hypoglycaemia in patients with type 2 diabetes. Diabetes Care 2007; 30: diabetes. Atherosclerosis 1998; 141(Suppl. 1): S53–55. 1608–1610. ´ 119. Bunck MC, Corner A, Eliasson B et al. One-year treatment with exenatide111. Zinman B, Gerich J, Buse JB et al; LEAD-4 Study Investigators. Efficacy vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and and safety of the human glucagon-like peptide-1 analog liraglutide in oxidative stress. Atherosclerosis 2010; 212: 223–229. combination with metformin and thiazolidinedione in patients with type 120. Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD. Improve- 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32: 1224–1230. ment of postprandial endothelial function after a single dose of exenatide112. Garber A, Henry R, Ratner R et al; LEAD-3 (Mono) Study Group. Liraglutide in individuals with impaired glucose tolerance and recent-onset type 2 versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a diabetes. Diabetes Care 2010; 33: 1028–1030. randomised, 52-week, phase III, double-blind, parallel-treatment trial. 121. Bhushan R, Elkind-Hirsch KE, Bhushan M, Butler WJ, Duncan K, Mar- Lancet 2009; 373: 473–481. rioneaux O. Improved glycemic control and reduction of cardiometabolic113. Mistry GC, Maes AL, Lasseter KC et al. Effect of sitagliptin, a dipeptidyl risk factors in subjects with type 2 diabetes and metabolic syndrome peptidase-4 inhibitor, on blood pressure in nondiabetic patients with treated with exenatide in a clinical practice setting. Diabetes Technol mild to moderate hypertension. J Clin Pharmacol 2008; 48: 592–598. Ther 2009; 11: 353–359.114. Tofovic DS, Bilan VP, Jackson EK. Sitagliptin augments angiotensin II- ¨ ¨ 122. Matikainen N, Manttari S, Schweizer A et al. Vildagliptin therapy reduces induced renal vasoconstriction in kidneys from rats with the metabolic postprandial intestinal triglyceride-rich lipoprotein particles in patients syndrome. Clin Exp Pharmacol Physiol 2010; 37: 689–691. with type 2 diabetes. Diabetologia 2006; 49: 2049–2057.115. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects 123. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of exenatide (exendin-4) on glycemic control and weight over 30 weeks of vildagliptin and rosiglitazone monotherapy in patients with type 2 in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; diabetes: a 24-week, double-blind, randomized trial. Diabetes Care 2007; 28: 1092–1100. 30: 217–223.116. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 124. Hsieh J, Longuet C, Baker CL et al. The glucagon-like peptide 1 receptor is Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control essential for postprandial lipoprotein synthesis and secretion in hamsters over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. and mice. Diabetologia 2010; 53: 552–561. Diabetes Care 2004; 27: 2628–2635. 125. Rigby SP, Handelsman Y, Lai YL, Abby SL, Tao B, Jones MR. Effects of117. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin- colesevelam, rosiglitazone, or sitagliptin on glycemic control and lipid 4) on glycemic control over 30 weeks in patients with type 2 diabetes profile in patients with type 2 diabetes mellitus inadequately controlled treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: by metformin monotherapy. Endocr Pract 2010; 16: 53–63. 1083–1091.312 Anagnostis et al. Volume 13 No. 4 April 2011