Glucagon-like peptide-1-based therapies and cardiovascular


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Glucagon-like peptide-1-based therapies and cardiovascular

  1. 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: degraded by the enzyme dipeptidyl dipeptidase-4 (DPP-4) to
  2. 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. 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. 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. 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. 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. 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 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
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