Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
Glucagon-like peptide 1 receptor agonists and cardiovascular risk in type 2 diabetes: a clinical perspective M. Fisher Glasgow Royal Infirmary, University of Glasgow, Glasgow, UK
Diabetes is associated with the development of premature atherosclerotic disease, including coronary heart disease and acute coronary syndromes. A late consequence of this process is the development of chronic heart failure, which contributes to the increased cardiovascular (CV) morbidity and mortality associated with diabetes. Reduction of cholesterol with statins and intensive blood pressure control significantly reduce vascular events in people with diabetes. Intensive treatment of glycaemia reduces microvascular complications, especially retinopathy and nephropathy, but has only a modest effect in reducing macrovascular complications. Attention has therefore focused on individual antidiabetic drugs or drug classes to determine if these have effects in reducing CV events beyond the reduction of blood glucose. Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of injected therapies that enhance the incretin effect, increasing insulin release from the pancreas and reducing glucagon production. They also have a central effect, increasing satiety, and in routine clinical use are associated with reductions in body weight. Another possibly beneficial effect of these drugs is a slight but significant reduction in systolic blood pressure. Data from cohort studies have indicated no increase in CV events with GLP-1 receptor agonists, and perhaps some reductions in CV events. The safety and possible CV benefit of these drugs is now being tested in large, multicentre, randomized, placebo-controlled trials. Keywords: cardiovascular disease, GLP-1, macrovascular disease, microvascular disease, type 2 diabetes Date submitted 3 June 2014; date of first decision 21 June 2014; date of final acceptance 14 August 2014
Introduction Cardiovascular (CV) disease is a common cause of morbidity and mortality in people with type 2 diabetes, with myocardial infarction (MI) and chronic heart failure the leading causes of death and disability [1], and the largest contributor to the direct and indirect costs of diabetes [2]. For people with type 2 diabetes, there is an increased risk of poor prognosis after CV events [3] and compared with people without diabetes, a higher risk of mortality at similar levels of coronary artery disease [4]. Hyperglycaemia correlates directly with the increased CV risk, aligning with the accepted view that hyperglycaemia and insulin resistance are key players in the development of atherosclerosis and its complications [5]. It is hypothesized that metabolic abnormalities cause overproduction of reactive oxygen species and that these play a major role in precipitating diabetic vascular disease via endothelial dysfunction and inflammation [5]. Further characterization of reactive oxygen species-generating pathways may open doors to novel therapeutic strategies against vascular complications for people with diabetes [5], but at present the routine management of those with diabetes must pay close attention to the methods that provide the maximum reduction in CV events, such as blood pressure lowering or the use of statins. Attenuation of the CV risk in people with diabetes requires a comprehensive understanding of the impact of different Correspondence to: Prof. Miles Fisher, Glasgow Royal Infirmary, University of Glasgow, 84 Castle Street, Glasgow G4 0SF, UK. E-mail: [email protected]
glucose-lowering strategies. With the exception of metformin in the UK Prospective Diabetes Study [6], treatment with antidiabetic drugs has generally not been associated with reducing CV risk, and has been neutral at best, or apparently detrimental in the case of rosiglitazone [7]. Large prospective intervention trials [the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [8], the Action in Diabetes and Vascular Disease (ADVANCE) study [9], and the Veterans Affairs Diabetes Trial (VADT) [10]] have shown no beneficial effect of intensive glucose control on primary CV endpoints in type 2 diabetes. These findings confirm that the relationship between glucose control and CV outcomes is complex; intensive efforts to reduce hyperglycaemia may have negative effects on the CV system, which may be directly related to the mode of drug action. A simple discovery made 50 years ago – that glucose taken orally induces a greater insulin response than when taken parenterally and known as the incretin effect – has led to the development of a class of drugs that may directly modulate the CV risk profile of people with type 2 diabetes [11]. A key finding is that increased levels of glucagon-like peptide 1 (GLP-1) or agonism of the GLP-1 receptor can exert positive effects on the CV system and hints at a role for these agents in the context of CV protection in this high-risk population. The recent demonstration in mice that GLP-1 receptor activation promotes the secretion of atrial natriuretic peptide (ANP) with an associated reduction of blood pressure confirms the importance of the gut–heart axis in the action of GLP-1 receptor agonists (Figure 1) [12].
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Figure 1. A mechanism of blood pressure reduction in mice via glucagon-like peptide 1 (GLP-1) receptor agonist-mediated atrial natriuretic peptide (ANP) activation. In mice, ANP mediates GLP-1-stimulated urinary sodium secretion and vascular smooth muscle relaxation and blood pressure reduction. Adapted with permission from Ref. [12]. cAMP, cyclic adenosine monophosphate; cGMP, guanosine monophosphate; LDCV, large dense core vesicle; Epac2, exchange protein directly activated by cAMP 2.
The GLP-1 receptor agonists are being increasingly used in clinical practice, both in conjunction with oral antidiabetic drugs and basal insulin. This is unsurprising because their physiologically-based mechanism of action of glucoregulation results in improved glycaemic control, without the concomitant risk of hypoglycaemia and with a reduction in body weight through retardation of gastric emptying and suppression of appetite. The number of approved agents continues to expand with the recent launch of lixisenatide (Lyxumia , Sanofi, Paris, France) [13]. GLP-1 receptor agonists are now the subject of a large programme of CV outcome studies [14]. In this context, a review of the current knowledge of GLP-1 receptor agonists’ effects on CV-related clinical variables is timely.
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Methods PubMed, Embase and clinical trials databases were searched for the period January 2003 to May 2013 for approved GLP-1 receptor agonists (exenatide, liraglutide and lixisenatide). Abstracts published at the Congresses of the American Diabetes Association for the period 2008–2013 and European Association for the Study of Diabetes (EASD) for the period 2008–2012 were searched. PubMed and Google Scholar were searched for references to these GLP-1 receptor agonists. Hand-searches of bibliographies of journal articles were performed to identify additional references of interest. Relevant references were identified and examined, and data extracted if relevant.
Characteristics and Pharmacokinetics of GLP-1 Receptor Agonists Four GLP-1 receptor agonists are approved for the treatment of type 2 diabetes. Exenatide (Byetta ; Bristol Myers Squibb-AstraZeneca EEIG, Uxbridge, UK) is a synthetic form of exendin-4, a 39-amino-acid peptide isolated from the saliva of the Gila monster that shows 53% homology to native GLP-1 [15]. It has a short half-life of 2.4 h [16] and is approved for
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twice-daily dosing. A long-acting-release (LAR) formulation of exenatide (Bydureon ; Bristol Myers Squibb-AstraZeneca EEIG) has more recently been approved that comprises exenatide embedded within microspheres of a biodegradable medical polymer and allows once-weekly dosing [17]. Liraglutide (Victoza ; Novo Nordisk, Bagsværd, Denmark) is a modified version of human GLP-1. A C-16 acyl chain is linked to amino acid 20 via a 𝛾-glutamic acid spacer, and the lysine at position 28 has been exchanged for an arginine residue [18]. The addition of the acyl chain allows liraglutide to associate with albumin, prolonging its half-life to 11–15 h and making this long-acting molecule suitable for once-daily dosing. Liraglutide was approved in Europe in 2009 and in the USA in 2010 [19]. Lixisenatide (Lyxumia; Sanofi) is a synthetic, modified version of exendin-4. It is a 44-amino-acid peptide that differs from exendin-4 by the deletion of the penultimate proline residue and the addition of six lysine residues at the C-terminus [20]. The resulting poly(A) tail induces an 𝛼-helix structure that stabilizes the peptide. The half-life of lixisenatide is approximately 3 h and is approved for once daily dosing. Lixisenatide has a strong binding affinity for the GLP-1 receptor, with receptor-binding studies showing lixisenatide to have a median inhibitory concentration for the human GLP-1 receptor of 1.4 nM, which is approximately four times the equivalent value for native GLP-1 of 0.35 nM, and seemingly stronger than the affinities of exenatide (0.55 nM) and liraglutide (0.11 nM) [21], although no direct comparisons of receptor-binding affinities are available.
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Effect of GLP-1 Receptor Agonists on CV Risk Factors Blood Glucose Levels The glycaemic efficacy of GLP-1 receptor agonists has been extensively investigated in randomized controlled trials and assessed by meta-analysis. In a meta-analysis of studies in people with type 2 diabetes, from mean
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baseline glycated haemoglobin (HbA1c) values of 7.4–10.3% (57–89 mmol/mol), the highest maintenance doses of exenatide twice daily and liraglutide once daily were associated with changes from baseline in mean HbA1c of −1.1 to −1.6% (−12 to −17.5 mmol/mol) [22]. A network meta-analysis compared exenatide LAR with liraglutide once daily (1.2 and 1.8 mg). The estimated mean differences in HbA1c versus placebo were −1.1, −1.0 and −1.2% (−12, −10.9 and −13.2 mmol/mol) respectively [23]. For lixisenatide, evidence from the ‘GLP-1 agonist AVE0010 in patients with type 2 diabetes mellitus for glycaemic control and safety evaluation’ (GetGoal) phase III randomized trial programme found mean HbA1c reductions of −0.7 to −1.0% (−7.7 to −10.9 mol/mol) from baseline [23–34]. Although ostensibly operating through the same mechanism of action – agonism of the GLP-1 receptor – differences in the pharmacokinetics and pharmacodynamic characteristics of the different GLP-1 receptor agonists translate into differential effects on daily glucose profiles that may have significance for CV risk. Randomized, head-to-head comparisons suggest that the glycaemic efficacy of long-acting GLP-1 receptor agonists, in particular liraglutide, is related predominantly to its effect on reducing fasting plasma glucose [35]. For the short-acting agonists, exenatide twice daily and lixisenatide once daily, a more pronounced modulation of prandial glucose rises is apparent. This effect is most marked with lixisenatide, which has shown reductions in 2-h postprandial glucose as high as −8 mmol/l in randomized trials [33]. This postprandial effect may have relevance if the potentially deleterious impact of postprandial dysglycaemia on oxidative stress and atherothrombosis is considered [36].
Body Weight One of the CV benefits of GLP-1 receptor agonist treatment is a reduction in body weight, consistently reported in clinical studies, which appears to be attributable to a reduction in food intake, mainly determined by a direct hypothalamic effect, and retarded gastric emptying, mediated via the autonomic nervous system [37,38]. A number of meta-analyses have quantified the weight loss associated with GLP-1 receptor agonist treatment. Body weight decreased by −3.31 kg compared with active control, and by −1.22 kg compared with placebo in a meta-analysis of liraglutide and exenatide twice daily studies [39], and a wider analysis of GLP-1 receptor agonists that included studies of lixisenatide and albiglutide, reported an overall reduction in body mass index (BMI) at 6 months versus placebo of −1.0 kg/m2 [40]. A more detailed reviewing of body weight reductions from baseline showed that, across its pivotal phase III studies, exenatide twice daily reduced body weight by −1.6 to −2.8 kg [41–43], with reductions of up to 8 kg in other studies [44]. Exenatide once-weekly appears to have similar effects on body weight to those of exenatide twice daily, reducing weight by −2.0 to −3.7 kg across the DURATION studies [45–50]. Liraglutide reduced body weight by −1.0 to −3.2 kg in the Liraglutide Effect and Action in Diabetes (LEAD) 2–6 studies [51–55]. By contrast, body weight changes were minimal in the LEAD 1 study in which participants received a sulphonylurea in
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combination with liraglutide or rosiglitazone [56]. Weight loss from baseline with lixisenatide was −0.2 to −3.0 kg in studies in which participants did not receive insulin; in combination with insulin, weight loss ranged from −0.4 to −1.8 kg in two studies and there was a weight gain of +0.3 kg in combination with insulin glargine [24–34].
Blood Pressure The recent elucidation that activation of GLP-1 receptors, located exclusively in a trial of cardiomyocytes, leads to secretion of ANP and a resultant reduction in blood pressure is an important step in fully understanding the consistent antihypertensive findings in GLP-1 receptor studies in people with type 2 diabetes [12]. A meta-analysis of liraglutide and exenatide (twice daily and LAR) studies (n = 32 studies), showed significant systolic blood pressure reductions of −1.79 mmHg compared with placebo and −2.39 mmHg compared with active control. The reductions in diastolic blood pressure (−0.54 mmHg compared with placebo and −0.50 mmHg compared with active control) were not statistically significant [39]. For lixisenatide, a phase II dose-finding study reported decreases in systolic blood pressure of −2 to −9 mmHg and systolic blood pressure of −2 to −4 mmHg [57], but no other details of the exact blood pressure changes were reported from the whole GetGoal programme.
Heart Rate There is evidence from phase III trials to show a consistent increase in heart rate associated with treatment with exenatide twice daily, LAR and liraglutide. In studies that investigated exenatide twice daily, increases of about two beats per minute (bpm) were reported [49,58]. Exenatide once-weekly increased heart rate by 1.5–4 bpm [47–49] and liraglutide increased heart rate by 2–4 bpm [53,54,56]. These findings are mirrored in a meta-analysis, with an overall increase in heart rate of 1.9 bpm versus placebo and 1.9 bpm versus active control. The reporting of pooled meta-analysis findings for heart rate for exenatide twice daily, exenatide LAR and liraglutide reflects a perception that the observed heart rate increase is a class effect, but this view remains unconfirmed. The heart rate effect was more evident for liraglutide and exenatide LAR than for exenatide twice daily in the meta-analysis, and this was confirmed in a direct comparison of exenatide twice daily and liraglutide, which found a marginal increase in heart rate with exenatide (0.7 bpm) and a significantly greater increase with liraglutide (3.3 bpm) [55]. In a phase II pharmacodynamic comparison of lixisenatide and liraglutide, lixisenatide decreased heart rate by 3.6 bpm but with liraglutide, there was a 5.3 bpm increase [57]. In the GetGoal studies reported to date, no increase in heart rate associated with lixisenatide treatment versus placebo has been reported. It has been suggested that the differences in heart rate are a manifestation of the differences in GLP-1 receptor activation, with continuous activation with liraglutide and exenatide LAR associated with the heart rate effect [35]. The publication of data on the effects of new GLP-1 receptor agonists, such as albiglutide, on heart rate will make a further contribution to this debate.
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review article Lipid Profiles Incretin-based therapies are thought to improve intestinal lipoprotein metabolism via direct effects, by reducing gastric emptying, increasing insulin secretion or enhancing chylomicron clearance [59]. Exenatide twice daily and LAR have been shown to have potentially beneficial effects on lipid profiles, decreasing total cholesterol and low-density lipoprotein (LDL) cholesterol while marginally increasing high-density lipoprotein (HDL) cholesterol [47,49,60–62]. In LEAD-4 and LEAD-6, liraglutide decreased total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and free fatty acids and increased very-low-density lipoprotein cholesterol [53,55]. No information on the effects of lixisenatide on lipid profiles has yet been published. Further studies are required to fully establish the effect of GLP-1 receptor agonists on lipid profiles and to determine the mechanism of action.
QT Interval Alterations Demonstrating no drug-induced changes in the heart rate-corrected QT (QTc) interval is a prerequisite in the approval process of a new drug [63]. For exenatide twice daily, surveillance of exenatide twice daily post-marketing events reported by Amylin Pharmaceuticals, representing more than 1.5 million patient-years of exposure, did not show an association between exenatide treatment and QT prolongation or pro-arrhythmic events [64]; however, at a therapeutic dose in healthy subjects, although time-matched QTc was not prolonged, there was a correlation between increasing plasma concentrations and changes in QTc that was sufficiently robust for the US Food and Drug Administration (FDA) to request additional data. The further data were derived from a substudy of DURATION-1, which found that continuous exposure to exenatide using the LAR formulation did not show this correlation [65]. A QT study of therapeutic doses of liraglutide in healthy subjects also found there was no prolongation of the QT interval [66]. QT findings with lixisenatide have not yet been reported from the phase III programme, although no clinically significant changes according to 12-lead electrocardiogram measurements were observed in a phase II dose-finding study with lixisenatide [67].
Effects on CV Outcomes: Retrospective Analyses With regulatory requirements mandating that CV safety is assessed before market approval, there is considerable interest in pooled analyses of CV safety, in particular reviewing major adverse CV events (MACE) such as CV mortality, stroke, MI, acute coronary syndrome (ACS) and revascularization procedures. A retrospective analysis of the ‘LifeLink’ database was performed to determine whether exenatide reduced the relative incidence of CV disease events (MI, ischaemic stroke or coronary revascularization) [68]. A total of 39 275 people treated with exenatide twice daily were compared with 381 218 people treated with other glucose-lowering therapies. Despite having a higher level of previous ischaemic heart disease, obesity, hyperlipidaemia, hypertension and/or other
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comorbidities at baseline, those treated with exenatide were less likely to have a CV disease event [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68–0.95; p = 0.01], and had lower rates of CV disease-related hospitalization (HR 0.88; 95% CI 0.79–0.98; p = 0.02) and all-cause hospitalization (HR 0.94; 95% CI 0.91–0.97; p < 0.001) compared with the control participants. In an analysis of 12 studies of exenatide twice daily that included 2316 people with 1072 patient-years of exposure, comparison with 1629 people exposed to comparators (insulin or placebo) for 780 patient-years found the risk of primary MACE with exenatide was 0.70 (95% CI 0.38–1.31), suggesting that there is a lower risk of MACE with exenatide [69]. A pooled analysis of 15 phase II and III studies was conducted to determine the rate of CV death, MI and stroke with liraglutide relative to comparator drugs (metformin, glimepiride, rosiglitazone, insulin glargine or placebo). In 4257 people exposed to liraglutide for 2882 patient-years and 2381 people exposed to the comparator drugs for 1486 patient-years, the incidence ratio for MACE was 0.73 (95% CI 0.38–1.41), also suggesting a lower risk of MACE with liraglutide [70]. A number of meta-analyses have investigated the incidence of MACE with GLP-1 receptor agonists as a class rather than as individual molecules. A meta-analysis including 36 trials, of which 20 reported at least one MACE endpoint, reported an odds ratio (OR) of MACE of 0.74 (95% CI 0.50–1.08; p = 0.12) with GLP-1 receptor agonists (exenatide twice daily, LAR and liraglutide) versus comparators [71]. A significant reduction of CV events was observed with GLP-1 receptor agonists compared with placebo (OR 0.459; 95% CI 0.255–0.826; p = 0.009), but not compared with active comparators (OR 1.054; 95% CI 0.633–1.756; p = 0.839). A recent network meta-analysis of 45 studies (investigating exenatide, liraglutide, lixisenatide, albiglutide and other GLP-1 receptor agonists in development – taspoglutide and dulaglutide) included 15 883 people and reported an OR of 0.70 (95% CI 0.40–1.22; p = 0.204) for CV safety (CV mortality, ischaemic heart disease, non-fatal heart failure and stroke) with GLP-1 receptor agonists versus placebo, and an OR of 1.06 (95% CI 0.65–1.74; p = 0.807) versus the active comparators [72]. These analyses all suggest that GLP-1 receptor agonists may reduce MACE by 25–30% compared with placebo.
Prospective CV Outcomes Studies Long-term, prospective CV outcome trials are being conducted to examine the effect of GLP-1 receptor agonists on CV outcomes (Figure 2). For lixisenatide, an interim analysis of the ELIXA (Evaluation of Cardiovascular Outcomes in patients with Type 2 Diabetes After Acute Coronary syndrome) study formed part of the regulatory submission to the FDA in late 2012. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial will investigate the impact on CV endpoints of adding exenatide LAR to usual care compared with placebo in people with type 2 diabetes stable on oral antidiabetic drugs [73]. The primary outcome is the composite endpoint of CV-related death, non-fatal MI or non-fatal stroke. A total of 9500 people are expected to be enrolled with a follow-up of at least 5.5 years. Results are expected in 2017.
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Figure 2. Cardiovascular outcome trials of glucagon-like peptide 1 (GLP-1) receptor agonists. ACS, acute coronary syndrome; CVD, cardiovascular disease; ELIXA, Evaluation of Cardiovascular Outcomes in patients with Type 2 Diabetes after Acute Coronary syndrome; EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results.
In the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial (Figure 2), the effect of long-term liraglutide on CV events compared with placebo will be determined in >9300 people with type 2 diabetes and other risk factors for CV disease [74]. The primary endpoint for that study is the time from randomization to the first occurrence of the composite outcome of CV death, non-fatal MI or non-fatal stroke, over a time period of 60 months. The study is expected to be reported in 2016. The first large CV study expected to be reported is ELIXA [75]. This study is designed to show that lixisenatide can reduce CV morbidity and mortality relative to placebo in people with type 2 diabetes who have experienced an ACS event. The primary composite endpoint is CV death, non-fatal MI, non-fatal stroke and hospitalization for unstable angina, and the study is a superiority study. Participants will be followed for approximately 4 years, and approximately 6000 people will be enrolled. Results are expected in 2014/2015, and this will be the first study to investigate the effects of a GLP-1 receptor agonist in people at high risk who have experienced an ACS event. If lixisenatide can reduce the rate of recurrent events in these people at high risk, this may represent a welcome treatment option in this growing patient group.
Discussion CV disease is the most significant complication of diabetes and CV outcomes are an important finding for new diabetes drugs to fulfil the CV safety requirement before regulatory approval. For most established diabetes medications, improved glycaemia assessed by the surrogate marker of HbA1c implies a macrovascular benefit, but recent large outcomes trials show the complexity of the relationship between glycaemia and CV risk. There is considerable anticipation about the potential benefits of GLP-1 receptor agonists because of their favourable profile. Current evidence confirms that treatment of type 2 diabetes
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with GLP-1 receptor agonists has beneficial effects on CV variables that are independent of the primary prescribing indication of glucose-lowering. These effects include reducing body weight, lowering blood pressure and improving lipid profiles. In addition, retrospective analyses and meta-analyses suggest that GLP-1 receptor agonists may reduce the risk of CV events, such as heart failure and MI, and may even improve survival. The mechanism of blood pressure lowering has now been elucidated in mice; it is mediated via activation of GLP-1 receptors that are localized exclusively in the cardiac atria and promote the secretion of ANP with a corresponding reduction of blood pressure [12]. Because of this mechanism, blood pressure lowering is likely to be a class effect, but that is not clearly the case with heart rate changes. The differences seen in heart rate effect reported between the different GLP-1 receptor agonists do seem to suggest a differential effect, with those that exert continuous activation through extended half-lives manifesting this potentially undesirable effect. One important consideration is the accuracy of measurement of this secondary outcome in the clinical studies, often measured with a short sampling interval. Without full 24-h ambulatory monitoring, it is difficult to know if there is a mechanistic basis to the different findings. The disclosure of heart rate data from the GetGoal and HARMONY phase III programmes for lixisenatide and albiglutide, respectively, will give further insight, and definitive findings for exenatide, liraglutide and lixisenatide will be expected from the clinical outcomes studies. Ultimately, it is the findings from the clinical outcomes studies that will be most informative and help shape the evolving position of the GLP-1 receptor agonist class in the type 2 diabetes treatment paradigm. Similar studies on outcomes are being undertaken for other antidiabetic therapies. The results of the CV outcome studies with saxagliptin (SAVOR-TIMI 53) [76] and alogliptin (EXAMINE) [77] have recently been published. In both studies, the primary outcomes were similar for the active and placebo groups, excluding any increase in events but failing to show any benefit, and as an aside, also providing
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review article ancillary findings on pancreatic safety. In the SAVOR-TIMI 53 trial, the use of saxagliptin was associated with an increase in hospitalization for heart failure. This endpoint was not reported in the principal publication of the results from EXAMINE. This finding was unexpected by the investigators, and further analysis of heart failure events from SAVOR-TIMI 53 (already initiated by the FDA [78]), EXAMINE, and other ongoing trials of DPP-4 inhibitors will be required. This also means that heart failure data for exenatide, liraglutide and lixisenatide will be closely scrutinized. The characteristics of the participants recruited to LEADER and EXSCEL were similar to those of the SAVOR-TIMI 53 participants, while the ELIXA trial studied those who have had a recent ACS. These, and other CV safety trials in diabetes, should provide information to guide the treatment of people with diabetes across the CV spectrum, from primary prevention, through stable coronary disease and after ACS, to end-stage chronic heart failure.
Acknowledgements Search and editorial assistance in the preparation of this manuscript was provided by Aidan McManus, PhD CMPP of Edge Medical Communications, funded by Sanofi.
Conflict of Interest The author has received lecture fees and been paid for advisory work by Eli Lilly, Novo Nordisk, Sanofi, Astra Zeneca and GSK.
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11. Plutzky J. The incretin axis in cardiovascular disease. Circulation 2011; 124: 2285–2289. 12. Kim M, Platt MJ, Shibasaki T et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 2013; 19: 567–575. 13. Elkinson S, Keating GM. Lixisenatide: first global approval. Drugs 2013; 73: 383–391. 14. Sivertsen J, Rosenmeier J, Holst JJ, Vilsboll T. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol 2012; 9: 209–222. 15. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992; 267: 7402–7405. 16. Kolterman OG, Buse JB, Fineman MS et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082–3089. 17. Kim D, MacConell L, Zhuang D et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 2007; 30: 1487–1493. 18. Knudsen LB, Nielsen PF, Huusfeldt PO et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 2000; 43: 1664–1669. 19. Ahren B. GLP-1 for type 2 diabetes. Exp Cell Res 2011; 317: 1239–1245. 20. Werner U, Haschke G, Herling AW, Kramer W. Pharmacological profile of lixisenatide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul Pept 2010; 164: 58–64. 21. Thorkildsen C, Neve S, Larsen BD, Meier E, Petersen JS. Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice. J Pharmacol Exp Ther 2003; 307: 490–496. 22. Aroda VR, Henry RR, Han J et al. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther 2012; 34: 1247–1258. 23. Scott DA, Boye KS, Timlin L, Clark JF, Best JH. A network meta-analysis to compare glycaemic control in patients with type 2 diabetes treated with exenatide once weekly or liraglutide once daily in comparison with insulin glargine, exenatide twice daily or placebo. Diabetes Obes Metab 2013; 15: 213–223. 24. Fonseca VA, Alvarado-Ruiz R, Raccah D et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care 2012; 35: 1225–1231. 25. Seino Y, Akane T, Niemoller E, Sakaki T. Long-term safety of once-daily (QD) lixisenatide in Japanese patients with type 2 diabetes (T2DM): GetGoal-Mono Japan. J Diabetes Investig 2012; 3(Suppl. 1Abstract PCS-30-5). 26. Ahren B, Leguizamo Dimas A, Miossec P, Saubadu S, Aronson R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care 2013; 36: 2543–2550. 27. Yu Pan C, Han P, Liu X et al. Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: A randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia). Diabetes Metab Res Rev 2014; DOI: 10.1002/dmrr.2541. 28. Bolli GB, Munteanu M, Dotsenko S et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med 2014; 31: 176–184. 29. Rosenstock J, Raccah D, Koranyi L et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013; 36: 2945–2951.
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30. Rosenstock RE, Hanefeld M, Shamanna P et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications 2014; 28: 386–392. 31. Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab 2013; 15: 1000–1007. 32. Riddle MC, Aronson R, Home P et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care 2013; 36: 2489–2496. 33. Seino Y, Min KW, Niemoeller E, Takami A, Investigators EG-LAS. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab 2012; 14: 910–917. 34. Riddle MC, Forst T, Aronson R et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes Care 2013; 36: 2497–2503. 35. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728–742. 36. O’Keefe JH, Bell DS. Postprandial hyperglycemia/hyperlipidemia (postprandial dysmetabolism) is a cardiovascular risk factor. Am J Cardiol 2007; 100: 899–904.
review article 48. Russell-Jones D, Cuddihy RM, Hanefeld M et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 2012; 35: 252–258. 49. Blevins T, Pullman J, Malloy J et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301–1310. 50. Buse JB, Nauck M, Forst T et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381: 117–124. 51. Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90. 52. Garber A, Henry R, Ratner R et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373: 473–481. 53. Zinman B, Gerich J, Buse JB et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met + TZD). Diabetes Care 2009; 32: 1224–1230. 54. Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met + SU): a randomised controlled trial. Diabetologia 2009; 52: 2046–2055.
37. Hayes MR, De Jonghe BC, Kanoski SE. Role of the glucagon-like-peptide-1 receptor in the control of energy balance. Physiol Behav 2010; 100: 503–510.
55. Buse JB, Rosenstock J, Sesti G et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39–47.
38. Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR. The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology 2012; 62: 1916–1927.
56. Marre M, Shaw J, Brandle M et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med 2009; 26: 268–278.
39. Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open 2013; 3 pii: e001986.
57. Kapitza C, Forst T, Coester HV, Poitiers F, Ruus P, Hincelin-Méry A. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab 2013; 15: 642–649.
40. Monami M, Dicembrini I, Marchionni N, Rotella CM, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Exp Diabetes Res 2012; 2012: 672658. 41. Buse JB, Henry RR, Han J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628–2635.
58. Buse JB, Bergenstal RM, Glass LC et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011; 154: 103–112. 59. Farr S, Adeli K. Incretin-based therapies for treatment of postprandial dyslipidemia in insulin-resistant states. Curr Opin Lipidol 2012; 23: 56–61.
42. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092–1100.
60. Moretto TJ, Milton DR, Ridge TD et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2008; 30: 1448–1460.
43. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083–1091. 44. Derosa G, Maffioli P, Salvadeo SA et al. Exenatide versus glibenclamide in patients with diabetes. Diabetes Technol Ther 2010; 12: 233–240.
61. Davies MJ, Donnelly R, Barnett AH, Jones S, Nicolay C, Kilcoyne A. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab 2009; 11: 1153–1162.
45. Drucker DJ, Buse JB, Taylor K et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240–1250.
62. DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care 2010; 33: 951–957.
46. Bergenstal RM, Wysham C, Macconell L et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010; 376: 431–439.
63. Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Rockville: Department of Health and Human Services, Food and Drug Administration, 2005.
47. Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010; 375: 2234–2243.
64. Darpö B, Sager P, MacConell L et al. Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects. Br J Clin Pharmacol 2013; 75: 979–989.
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65. Sager P, Darpö B, Han J et al. Exenatide once weekly did not affect the QTc interval in patients with type 2 diabetes. Diabetes 2011; 60(A294(Abstract 1070-P)).
72. Sun F, Yu K, Wu S et al. Cardiovascular safety and glycemic control of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus: a pairwise and network meta-analysis. Diabetes Res Clin Pract 2012; 98: 386–395.
66. Chatterjee DJ, Khutoryansky N, Zdravkovic M, Sprenger CR, Litwin JS. Absence of QTc prolongation in a thorough QT study with subcutaneous liraglutide, a once-daily human GLP-1 analog for treatment of type 2 diabetes. J Clin Pharmacol 2009; 49: 1353–1362.
73. Exenatide study of cardiovascular event lowering trial (EXSCEL): a trial to evaluate cardiovascular outcomes after treatment with exenatide once weekly in patients with type 2 diabetes mellitus. 2010. Available from URL: http://clinicaltrials.gov/ct2/show/NCT01144338. Accessed 28 April 2013.
67. Ratner RE, Rosenstock J, Boka G, Investigators DRIS. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med 2010; 27: 1024–1032.
74. Marso SP, Poulter NR, Nissen SE et al. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J 2013; 166: 823–830.
68. Best JH, Hoogwerf BJ, Herman WH et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care 2011; 34: 90–95. 69. Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol 2011; 10: 22. 70. Marso SP, Lindsey JB, Stolker JM et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Diab Vasc Dis Res 2011; 8: 237–240. 71. Monami M, Cremasco F, Lamanna C et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp Diabetes Res 2011; 2011: 215764.
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75. Evaluation of cardiovascular outcomes in patients with type 2 diabetes after acute coronary syndrome during treatment with AVE0010 (lixisenatide) (ELIXA). 2010. Available from URL: http://clinicaltrials.gov/ct2/show/NCT01147250. Accessed 28 April 2014. 76. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317–1326. 77. White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327–1335. 78. U.S Food and Drug Administration. Drug Safety Communication. FDA Drug Safety Communication: FDA to review heart failure risk with diabetes drug saxagliptin (marketed as Onglyza and Kombiglyze XR). Available from URL: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM385315.pdf. Accessed 12 February 2014.
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Glucagon-like peptide 1 receptor agonists and cardiovascular risk in type 2 diabetes: a clinical perspective M. Fisher Glasgow Royal Infirmary, University of Glasgow, Glasgow, UK
Diabetes is associated with the development of premature atherosclerotic disease, including coronary heart disease and acute coronary syndromes. A late consequence of this process is the development of chronic heart failure, which contributes to the increased cardiovascular (CV) morbidity and mortality associated with diabetes. Reduction of cholesterol with statins and intensive blood pressure control significantly reduce vascular events in people with diabetes. Intensive treatment of glycaemia reduces microvascular complications, especially retinopathy and nephropathy, but has only a modest effect in reducing macrovascular complications. Attention has therefore focused on individual antidiabetic drugs or drug classes to determine if these have effects in reducing CV events beyond the reduction of blood glucose. Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of injected therapies that enhance the incretin effect, increasing insulin release from the pancreas and reducing glucagon production. They also have a central effect, increasing satiety, and in routine clinical use are associated with reductions in body weight. Another possibly beneficial effect of these drugs is a slight but significant reduction in systolic blood pressure. Data from cohort studies have indicated no increase in CV events with GLP-1 receptor agonists, and perhaps some reductions in CV events. The safety and possible CV benefit of these drugs is now being tested in large, multicentre, randomized, placebo-controlled trials. Keywords: cardiovascular disease, GLP-1, macrovascular disease, microvascular disease, type 2 diabetes Date submitted 3 June 2014; date of first decision 21 June 2014; date of final acceptance 14 August 2014
Introduction Cardiovascular (CV) disease is a common cause of morbidity and mortality in people with type 2 diabetes, with myocardial infarction (MI) and chronic heart failure the leading causes of death and disability [1], and the largest contributor to the direct and indirect costs of diabetes [2]. For people with type 2 diabetes, there is an increased risk of poor prognosis after CV events [3] and compared with people without diabetes, a higher risk of mortality at similar levels of coronary artery disease [4]. Hyperglycaemia correlates directly with the increased CV risk, aligning with the accepted view that hyperglycaemia and insulin resistance are key players in the development of atherosclerosis and its complications [5]. It is hypothesized that metabolic abnormalities cause overproduction of reactive oxygen species and that these play a major role in precipitating diabetic vascular disease via endothelial dysfunction and inflammation [5]. Further characterization of reactive oxygen species-generating pathways may open doors to novel therapeutic strategies against vascular complications for people with diabetes [5], but at present the routine management of those with diabetes must pay close attention to the methods that provide the maximum reduction in CV events, such as blood pressure lowering or the use of statins. Attenuation of the CV risk in people with diabetes requires a comprehensive understanding of the impact of different Correspondence to: Prof. Miles Fisher, Glasgow Royal Infirmary, University of Glasgow, 84 Castle Street, Glasgow G4 0SF, UK. E-mail: [email protected]
glucose-lowering strategies. With the exception of metformin in the UK Prospective Diabetes Study [6], treatment with antidiabetic drugs has generally not been associated with reducing CV risk, and has been neutral at best, or apparently detrimental in the case of rosiglitazone [7]. Large prospective intervention trials [the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [8], the Action in Diabetes and Vascular Disease (ADVANCE) study [9], and the Veterans Affairs Diabetes Trial (VADT) [10]] have shown no beneficial effect of intensive glucose control on primary CV endpoints in type 2 diabetes. These findings confirm that the relationship between glucose control and CV outcomes is complex; intensive efforts to reduce hyperglycaemia may have negative effects on the CV system, which may be directly related to the mode of drug action. A simple discovery made 50 years ago – that glucose taken orally induces a greater insulin response than when taken parenterally and known as the incretin effect – has led to the development of a class of drugs that may directly modulate the CV risk profile of people with type 2 diabetes [11]. A key finding is that increased levels of glucagon-like peptide 1 (GLP-1) or agonism of the GLP-1 receptor can exert positive effects on the CV system and hints at a role for these agents in the context of CV protection in this high-risk population. The recent demonstration in mice that GLP-1 receptor activation promotes the secretion of atrial natriuretic peptide (ANP) with an associated reduction of blood pressure confirms the importance of the gut–heart axis in the action of GLP-1 receptor agonists (Figure 1) [12].
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Figure 1. A mechanism of blood pressure reduction in mice via glucagon-like peptide 1 (GLP-1) receptor agonist-mediated atrial natriuretic peptide (ANP) activation. In mice, ANP mediates GLP-1-stimulated urinary sodium secretion and vascular smooth muscle relaxation and blood pressure reduction. Adapted with permission from Ref. [12]. cAMP, cyclic adenosine monophosphate; cGMP, guanosine monophosphate; LDCV, large dense core vesicle; Epac2, exchange protein directly activated by cAMP 2.
The GLP-1 receptor agonists are being increasingly used in clinical practice, both in conjunction with oral antidiabetic drugs and basal insulin. This is unsurprising because their physiologically-based mechanism of action of glucoregulation results in improved glycaemic control, without the concomitant risk of hypoglycaemia and with a reduction in body weight through retardation of gastric emptying and suppression of appetite. The number of approved agents continues to expand with the recent launch of lixisenatide (Lyxumia , Sanofi, Paris, France) [13]. GLP-1 receptor agonists are now the subject of a large programme of CV outcome studies [14]. In this context, a review of the current knowledge of GLP-1 receptor agonists’ effects on CV-related clinical variables is timely.
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Methods PubMed, Embase and clinical trials databases were searched for the period January 2003 to May 2013 for approved GLP-1 receptor agonists (exenatide, liraglutide and lixisenatide). Abstracts published at the Congresses of the American Diabetes Association for the period 2008–2013 and European Association for the Study of Diabetes (EASD) for the period 2008–2012 were searched. PubMed and Google Scholar were searched for references to these GLP-1 receptor agonists. Hand-searches of bibliographies of journal articles were performed to identify additional references of interest. Relevant references were identified and examined, and data extracted if relevant.
Characteristics and Pharmacokinetics of GLP-1 Receptor Agonists Four GLP-1 receptor agonists are approved for the treatment of type 2 diabetes. Exenatide (Byetta ; Bristol Myers Squibb-AstraZeneca EEIG, Uxbridge, UK) is a synthetic form of exendin-4, a 39-amino-acid peptide isolated from the saliva of the Gila monster that shows 53% homology to native GLP-1 [15]. It has a short half-life of 2.4 h [16] and is approved for
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twice-daily dosing. A long-acting-release (LAR) formulation of exenatide (Bydureon ; Bristol Myers Squibb-AstraZeneca EEIG) has more recently been approved that comprises exenatide embedded within microspheres of a biodegradable medical polymer and allows once-weekly dosing [17]. Liraglutide (Victoza ; Novo Nordisk, Bagsværd, Denmark) is a modified version of human GLP-1. A C-16 acyl chain is linked to amino acid 20 via a 𝛾-glutamic acid spacer, and the lysine at position 28 has been exchanged for an arginine residue [18]. The addition of the acyl chain allows liraglutide to associate with albumin, prolonging its half-life to 11–15 h and making this long-acting molecule suitable for once-daily dosing. Liraglutide was approved in Europe in 2009 and in the USA in 2010 [19]. Lixisenatide (Lyxumia; Sanofi) is a synthetic, modified version of exendin-4. It is a 44-amino-acid peptide that differs from exendin-4 by the deletion of the penultimate proline residue and the addition of six lysine residues at the C-terminus [20]. The resulting poly(A) tail induces an 𝛼-helix structure that stabilizes the peptide. The half-life of lixisenatide is approximately 3 h and is approved for once daily dosing. Lixisenatide has a strong binding affinity for the GLP-1 receptor, with receptor-binding studies showing lixisenatide to have a median inhibitory concentration for the human GLP-1 receptor of 1.4 nM, which is approximately four times the equivalent value for native GLP-1 of 0.35 nM, and seemingly stronger than the affinities of exenatide (0.55 nM) and liraglutide (0.11 nM) [21], although no direct comparisons of receptor-binding affinities are available.
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Effect of GLP-1 Receptor Agonists on CV Risk Factors Blood Glucose Levels The glycaemic efficacy of GLP-1 receptor agonists has been extensively investigated in randomized controlled trials and assessed by meta-analysis. In a meta-analysis of studies in people with type 2 diabetes, from mean
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baseline glycated haemoglobin (HbA1c) values of 7.4–10.3% (57–89 mmol/mol), the highest maintenance doses of exenatide twice daily and liraglutide once daily were associated with changes from baseline in mean HbA1c of −1.1 to −1.6% (−12 to −17.5 mmol/mol) [22]. A network meta-analysis compared exenatide LAR with liraglutide once daily (1.2 and 1.8 mg). The estimated mean differences in HbA1c versus placebo were −1.1, −1.0 and −1.2% (−12, −10.9 and −13.2 mmol/mol) respectively [23]. For lixisenatide, evidence from the ‘GLP-1 agonist AVE0010 in patients with type 2 diabetes mellitus for glycaemic control and safety evaluation’ (GetGoal) phase III randomized trial programme found mean HbA1c reductions of −0.7 to −1.0% (−7.7 to −10.9 mol/mol) from baseline [23–34]. Although ostensibly operating through the same mechanism of action – agonism of the GLP-1 receptor – differences in the pharmacokinetics and pharmacodynamic characteristics of the different GLP-1 receptor agonists translate into differential effects on daily glucose profiles that may have significance for CV risk. Randomized, head-to-head comparisons suggest that the glycaemic efficacy of long-acting GLP-1 receptor agonists, in particular liraglutide, is related predominantly to its effect on reducing fasting plasma glucose [35]. For the short-acting agonists, exenatide twice daily and lixisenatide once daily, a more pronounced modulation of prandial glucose rises is apparent. This effect is most marked with lixisenatide, which has shown reductions in 2-h postprandial glucose as high as −8 mmol/l in randomized trials [33]. This postprandial effect may have relevance if the potentially deleterious impact of postprandial dysglycaemia on oxidative stress and atherothrombosis is considered [36].
Body Weight One of the CV benefits of GLP-1 receptor agonist treatment is a reduction in body weight, consistently reported in clinical studies, which appears to be attributable to a reduction in food intake, mainly determined by a direct hypothalamic effect, and retarded gastric emptying, mediated via the autonomic nervous system [37,38]. A number of meta-analyses have quantified the weight loss associated with GLP-1 receptor agonist treatment. Body weight decreased by −3.31 kg compared with active control, and by −1.22 kg compared with placebo in a meta-analysis of liraglutide and exenatide twice daily studies [39], and a wider analysis of GLP-1 receptor agonists that included studies of lixisenatide and albiglutide, reported an overall reduction in body mass index (BMI) at 6 months versus placebo of −1.0 kg/m2 [40]. A more detailed reviewing of body weight reductions from baseline showed that, across its pivotal phase III studies, exenatide twice daily reduced body weight by −1.6 to −2.8 kg [41–43], with reductions of up to 8 kg in other studies [44]. Exenatide once-weekly appears to have similar effects on body weight to those of exenatide twice daily, reducing weight by −2.0 to −3.7 kg across the DURATION studies [45–50]. Liraglutide reduced body weight by −1.0 to −3.2 kg in the Liraglutide Effect and Action in Diabetes (LEAD) 2–6 studies [51–55]. By contrast, body weight changes were minimal in the LEAD 1 study in which participants received a sulphonylurea in
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combination with liraglutide or rosiglitazone [56]. Weight loss from baseline with lixisenatide was −0.2 to −3.0 kg in studies in which participants did not receive insulin; in combination with insulin, weight loss ranged from −0.4 to −1.8 kg in two studies and there was a weight gain of +0.3 kg in combination with insulin glargine [24–34].
Blood Pressure The recent elucidation that activation of GLP-1 receptors, located exclusively in a trial of cardiomyocytes, leads to secretion of ANP and a resultant reduction in blood pressure is an important step in fully understanding the consistent antihypertensive findings in GLP-1 receptor studies in people with type 2 diabetes [12]. A meta-analysis of liraglutide and exenatide (twice daily and LAR) studies (n = 32 studies), showed significant systolic blood pressure reductions of −1.79 mmHg compared with placebo and −2.39 mmHg compared with active control. The reductions in diastolic blood pressure (−0.54 mmHg compared with placebo and −0.50 mmHg compared with active control) were not statistically significant [39]. For lixisenatide, a phase II dose-finding study reported decreases in systolic blood pressure of −2 to −9 mmHg and systolic blood pressure of −2 to −4 mmHg [57], but no other details of the exact blood pressure changes were reported from the whole GetGoal programme.
Heart Rate There is evidence from phase III trials to show a consistent increase in heart rate associated with treatment with exenatide twice daily, LAR and liraglutide. In studies that investigated exenatide twice daily, increases of about two beats per minute (bpm) were reported [49,58]. Exenatide once-weekly increased heart rate by 1.5–4 bpm [47–49] and liraglutide increased heart rate by 2–4 bpm [53,54,56]. These findings are mirrored in a meta-analysis, with an overall increase in heart rate of 1.9 bpm versus placebo and 1.9 bpm versus active control. The reporting of pooled meta-analysis findings for heart rate for exenatide twice daily, exenatide LAR and liraglutide reflects a perception that the observed heart rate increase is a class effect, but this view remains unconfirmed. The heart rate effect was more evident for liraglutide and exenatide LAR than for exenatide twice daily in the meta-analysis, and this was confirmed in a direct comparison of exenatide twice daily and liraglutide, which found a marginal increase in heart rate with exenatide (0.7 bpm) and a significantly greater increase with liraglutide (3.3 bpm) [55]. In a phase II pharmacodynamic comparison of lixisenatide and liraglutide, lixisenatide decreased heart rate by 3.6 bpm but with liraglutide, there was a 5.3 bpm increase [57]. In the GetGoal studies reported to date, no increase in heart rate associated with lixisenatide treatment versus placebo has been reported. It has been suggested that the differences in heart rate are a manifestation of the differences in GLP-1 receptor activation, with continuous activation with liraglutide and exenatide LAR associated with the heart rate effect [35]. The publication of data on the effects of new GLP-1 receptor agonists, such as albiglutide, on heart rate will make a further contribution to this debate.
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review article Lipid Profiles Incretin-based therapies are thought to improve intestinal lipoprotein metabolism via direct effects, by reducing gastric emptying, increasing insulin secretion or enhancing chylomicron clearance [59]. Exenatide twice daily and LAR have been shown to have potentially beneficial effects on lipid profiles, decreasing total cholesterol and low-density lipoprotein (LDL) cholesterol while marginally increasing high-density lipoprotein (HDL) cholesterol [47,49,60–62]. In LEAD-4 and LEAD-6, liraglutide decreased total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and free fatty acids and increased very-low-density lipoprotein cholesterol [53,55]. No information on the effects of lixisenatide on lipid profiles has yet been published. Further studies are required to fully establish the effect of GLP-1 receptor agonists on lipid profiles and to determine the mechanism of action.
QT Interval Alterations Demonstrating no drug-induced changes in the heart rate-corrected QT (QTc) interval is a prerequisite in the approval process of a new drug [63]. For exenatide twice daily, surveillance of exenatide twice daily post-marketing events reported by Amylin Pharmaceuticals, representing more than 1.5 million patient-years of exposure, did not show an association between exenatide treatment and QT prolongation or pro-arrhythmic events [64]; however, at a therapeutic dose in healthy subjects, although time-matched QTc was not prolonged, there was a correlation between increasing plasma concentrations and changes in QTc that was sufficiently robust for the US Food and Drug Administration (FDA) to request additional data. The further data were derived from a substudy of DURATION-1, which found that continuous exposure to exenatide using the LAR formulation did not show this correlation [65]. A QT study of therapeutic doses of liraglutide in healthy subjects also found there was no prolongation of the QT interval [66]. QT findings with lixisenatide have not yet been reported from the phase III programme, although no clinically significant changes according to 12-lead electrocardiogram measurements were observed in a phase II dose-finding study with lixisenatide [67].
Effects on CV Outcomes: Retrospective Analyses With regulatory requirements mandating that CV safety is assessed before market approval, there is considerable interest in pooled analyses of CV safety, in particular reviewing major adverse CV events (MACE) such as CV mortality, stroke, MI, acute coronary syndrome (ACS) and revascularization procedures. A retrospective analysis of the ‘LifeLink’ database was performed to determine whether exenatide reduced the relative incidence of CV disease events (MI, ischaemic stroke or coronary revascularization) [68]. A total of 39 275 people treated with exenatide twice daily were compared with 381 218 people treated with other glucose-lowering therapies. Despite having a higher level of previous ischaemic heart disease, obesity, hyperlipidaemia, hypertension and/or other
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comorbidities at baseline, those treated with exenatide were less likely to have a CV disease event [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68–0.95; p = 0.01], and had lower rates of CV disease-related hospitalization (HR 0.88; 95% CI 0.79–0.98; p = 0.02) and all-cause hospitalization (HR 0.94; 95% CI 0.91–0.97; p < 0.001) compared with the control participants. In an analysis of 12 studies of exenatide twice daily that included 2316 people with 1072 patient-years of exposure, comparison with 1629 people exposed to comparators (insulin or placebo) for 780 patient-years found the risk of primary MACE with exenatide was 0.70 (95% CI 0.38–1.31), suggesting that there is a lower risk of MACE with exenatide [69]. A pooled analysis of 15 phase II and III studies was conducted to determine the rate of CV death, MI and stroke with liraglutide relative to comparator drugs (metformin, glimepiride, rosiglitazone, insulin glargine or placebo). In 4257 people exposed to liraglutide for 2882 patient-years and 2381 people exposed to the comparator drugs for 1486 patient-years, the incidence ratio for MACE was 0.73 (95% CI 0.38–1.41), also suggesting a lower risk of MACE with liraglutide [70]. A number of meta-analyses have investigated the incidence of MACE with GLP-1 receptor agonists as a class rather than as individual molecules. A meta-analysis including 36 trials, of which 20 reported at least one MACE endpoint, reported an odds ratio (OR) of MACE of 0.74 (95% CI 0.50–1.08; p = 0.12) with GLP-1 receptor agonists (exenatide twice daily, LAR and liraglutide) versus comparators [71]. A significant reduction of CV events was observed with GLP-1 receptor agonists compared with placebo (OR 0.459; 95% CI 0.255–0.826; p = 0.009), but not compared with active comparators (OR 1.054; 95% CI 0.633–1.756; p = 0.839). A recent network meta-analysis of 45 studies (investigating exenatide, liraglutide, lixisenatide, albiglutide and other GLP-1 receptor agonists in development – taspoglutide and dulaglutide) included 15 883 people and reported an OR of 0.70 (95% CI 0.40–1.22; p = 0.204) for CV safety (CV mortality, ischaemic heart disease, non-fatal heart failure and stroke) with GLP-1 receptor agonists versus placebo, and an OR of 1.06 (95% CI 0.65–1.74; p = 0.807) versus the active comparators [72]. These analyses all suggest that GLP-1 receptor agonists may reduce MACE by 25–30% compared with placebo.
Prospective CV Outcomes Studies Long-term, prospective CV outcome trials are being conducted to examine the effect of GLP-1 receptor agonists on CV outcomes (Figure 2). For lixisenatide, an interim analysis of the ELIXA (Evaluation of Cardiovascular Outcomes in patients with Type 2 Diabetes After Acute Coronary syndrome) study formed part of the regulatory submission to the FDA in late 2012. The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial will investigate the impact on CV endpoints of adding exenatide LAR to usual care compared with placebo in people with type 2 diabetes stable on oral antidiabetic drugs [73]. The primary outcome is the composite endpoint of CV-related death, non-fatal MI or non-fatal stroke. A total of 9500 people are expected to be enrolled with a follow-up of at least 5.5 years. Results are expected in 2017.
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Figure 2. Cardiovascular outcome trials of glucagon-like peptide 1 (GLP-1) receptor agonists. ACS, acute coronary syndrome; CVD, cardiovascular disease; ELIXA, Evaluation of Cardiovascular Outcomes in patients with Type 2 Diabetes after Acute Coronary syndrome; EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results.
In the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial (Figure 2), the effect of long-term liraglutide on CV events compared with placebo will be determined in >9300 people with type 2 diabetes and other risk factors for CV disease [74]. The primary endpoint for that study is the time from randomization to the first occurrence of the composite outcome of CV death, non-fatal MI or non-fatal stroke, over a time period of 60 months. The study is expected to be reported in 2016. The first large CV study expected to be reported is ELIXA [75]. This study is designed to show that lixisenatide can reduce CV morbidity and mortality relative to placebo in people with type 2 diabetes who have experienced an ACS event. The primary composite endpoint is CV death, non-fatal MI, non-fatal stroke and hospitalization for unstable angina, and the study is a superiority study. Participants will be followed for approximately 4 years, and approximately 6000 people will be enrolled. Results are expected in 2014/2015, and this will be the first study to investigate the effects of a GLP-1 receptor agonist in people at high risk who have experienced an ACS event. If lixisenatide can reduce the rate of recurrent events in these people at high risk, this may represent a welcome treatment option in this growing patient group.
Discussion CV disease is the most significant complication of diabetes and CV outcomes are an important finding for new diabetes drugs to fulfil the CV safety requirement before regulatory approval. For most established diabetes medications, improved glycaemia assessed by the surrogate marker of HbA1c implies a macrovascular benefit, but recent large outcomes trials show the complexity of the relationship between glycaemia and CV risk. There is considerable anticipation about the potential benefits of GLP-1 receptor agonists because of their favourable profile. Current evidence confirms that treatment of type 2 diabetes
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with GLP-1 receptor agonists has beneficial effects on CV variables that are independent of the primary prescribing indication of glucose-lowering. These effects include reducing body weight, lowering blood pressure and improving lipid profiles. In addition, retrospective analyses and meta-analyses suggest that GLP-1 receptor agonists may reduce the risk of CV events, such as heart failure and MI, and may even improve survival. The mechanism of blood pressure lowering has now been elucidated in mice; it is mediated via activation of GLP-1 receptors that are localized exclusively in the cardiac atria and promote the secretion of ANP with a corresponding reduction of blood pressure [12]. Because of this mechanism, blood pressure lowering is likely to be a class effect, but that is not clearly the case with heart rate changes. The differences seen in heart rate effect reported between the different GLP-1 receptor agonists do seem to suggest a differential effect, with those that exert continuous activation through extended half-lives manifesting this potentially undesirable effect. One important consideration is the accuracy of measurement of this secondary outcome in the clinical studies, often measured with a short sampling interval. Without full 24-h ambulatory monitoring, it is difficult to know if there is a mechanistic basis to the different findings. The disclosure of heart rate data from the GetGoal and HARMONY phase III programmes for lixisenatide and albiglutide, respectively, will give further insight, and definitive findings for exenatide, liraglutide and lixisenatide will be expected from the clinical outcomes studies. Ultimately, it is the findings from the clinical outcomes studies that will be most informative and help shape the evolving position of the GLP-1 receptor agonist class in the type 2 diabetes treatment paradigm. Similar studies on outcomes are being undertaken for other antidiabetic therapies. The results of the CV outcome studies with saxagliptin (SAVOR-TIMI 53) [76] and alogliptin (EXAMINE) [77] have recently been published. In both studies, the primary outcomes were similar for the active and placebo groups, excluding any increase in events but failing to show any benefit, and as an aside, also providing
doi:10.1111/dom.12380 5
review article ancillary findings on pancreatic safety. In the SAVOR-TIMI 53 trial, the use of saxagliptin was associated with an increase in hospitalization for heart failure. This endpoint was not reported in the principal publication of the results from EXAMINE. This finding was unexpected by the investigators, and further analysis of heart failure events from SAVOR-TIMI 53 (already initiated by the FDA [78]), EXAMINE, and other ongoing trials of DPP-4 inhibitors will be required. This also means that heart failure data for exenatide, liraglutide and lixisenatide will be closely scrutinized. The characteristics of the participants recruited to LEADER and EXSCEL were similar to those of the SAVOR-TIMI 53 participants, while the ELIXA trial studied those who have had a recent ACS. These, and other CV safety trials in diabetes, should provide information to guide the treatment of people with diabetes across the CV spectrum, from primary prevention, through stable coronary disease and after ACS, to end-stage chronic heart failure.
Acknowledgements Search and editorial assistance in the preparation of this manuscript was provided by Aidan McManus, PhD CMPP of Edge Medical Communications, funded by Sanofi.
Conflict of Interest The author has received lecture fees and been paid for advisory work by Eli Lilly, Novo Nordisk, Sanofi, Astra Zeneca and GSK.
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