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Editorial Liraglutide and Cardiometabolic Effects: More than Just Another Antiobesity Drug? Niki Katsiki1, Georgios A. Christou2 and Dimitrios N. Kiortsis2,* 1 nd
2 Propedeutic Department of Internal Medicine, Medical School, Aristotle University, Thessaloniki, Greece; 2Laboratory of Physiology, Medical School, University of Ioannina, Ioannina, Greece
We recently reviewed the role of liraglutide (3.0 mg) in obesity treatment [1]. Since then, the Satiety and Clinical Adiposity-Liraglutide Evidence in Nondiabetic and Diabetic people (SCALE) Obesity and Prediabetes study, the largest (n= 3731) randomized controlled trial investigating the use of liraglutide (3.0 mg) in obesity, was published [2]. Briefly, patients were randomly assigned in a 2:1 ratio to liraglutide 3.0 mg once-daily or placebo as an adjunct to diet and exercise [2]. Patients (78.5% women) were non-diabetics (61.2% had prediabetes as defined by the American Diabetes Association [3]) with a mean body mass index (BMI = 38.3 ± 6.4 Kg/m2).
Dimitrios N. Kiortsis
After 56 weeks of treatment, patients on liraglutide lost significantly more weight compared with the placebo group (– 5.4% difference; 95% confidence interval – 5.8 to – 5.0%; p < 0.001) [2]. Similarly, the percentages of patients achieving at least 5% or > 10% weight loss were significantly higher in the liraglutide group (63.2 and 33.1%, respectively) compared with placebo (27.1 and 10.6%, respectively; p < 0.001 for all comparisons). Notably, missing values in the SCALE Obesity and Prediabetes study were imputed with the use of the last-observation-carried-forward (LOCF) method for measurements made after baseline. The LOCF method is one of the most commonly used approaches for dealing with dropout data. In the LOCF method, the outcome variable for a dropout subject is the change from baseline to the last observed response [4]. This assumes that the outcome remains frozen in time after the point a subject drops out. In this aspect, the greater magnitude of dropout in the placebo arm (36%) compared with the liraglutide arm (28%) in the SCALE Obesity and Prediabetes study possibly results in the overestimation of the weight loss effect of liraglutide compared with placebo, given the expected further weight loss of the individuals who withdrew from the study if they had not dropped out. Liraglutide 3.0 mg/day also led to significantly greater improvements in several cardiometabolic parameters [BMI, waist circumference, fasting glucose and insulin, glycated haemoglobin, total cholesterol, serum triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic and diastolic blood pressure and serum levels of high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1) and adiponectin] [2]. Of note, several continuous variables expressed as mean ± standard deviation (SD) had the SD > mean (e.g. for hsCRP, PAI-1, adiponectin, urinary albumin:creatinine ratio, fibrinogen and insulin). These variables may not be normally distributed (e.g. urinary albumin:creatinine ratio in the placebo group was 3.6±627.2 mg/g) and may have been better expressed as median (range). Apart from LDL-C, small dense LDL (sdLDL) particles are related to increased cardiovascular disease (CVD) risk [5-7]. Liraglutide was reported to decrease sdLDL-C levels [8]. In the SCALE Obesity and Prediabetes study [2], TG levels were significantly reduced and HDL-C levels were significantly increased following liraglutide 3.0 mg/day treatment. This improvement in atherogenic dyslipidaemia may also be accompanied by a fall in the proportion of sdLDL-C to LDL-C [5-7]. However, the authors did not measure sdLDL-C levels. Similarly, postprandial lipaemia (PPL) may be another CVD risk predictor [9,10]. Liraglutide up to 1.8 mg/day was shown to reduce PPL [11, 12]. In the SCALE Obesity and Prediabetes study [2], PPL was not reported. Metabolic syndrome (MetS) is a cluster of hypertension, dyslipidaemia, insulin resistance and/or central obesity associated with increased CVD risk [13, 14]. Based on a joint interim statement of several scientific societies published in 2009 [15], MetS diagnostic criteria include elevated blood pressure, waist circumference, TG and fasting glucose as well as low HDL-C levels. In the SCALE Obesity and Prediabetes study [2], liraglutide 3.0 mg/day significantly improved all these cardiometabolic factors. In this context, it would be useful to assess the impact of liraglutide 3.0 mg/day on MetS prevalence in this study. Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, has been related to increased CVD risk [1618]. Elevated liver enzyme activities were also linked to raised CVD morbidity and mortality [19]. NAFLD treatment, although not yet established, is multifactorial including lifestyle changes, hypolipidaemic, antihypertensive, antiobesity and antidiabetic drugs [20-22]. Liraglutide 0.9-1.8 mg/dl was reported to improve biochemical and/or histological features of NAFLD/ nonalcoholic steatohepatitis (NASH) [23-25]. No data on NAFLD were reported in the SCALE Obesity and Prediabetes study. Elevated serum uric acid (SUA) levels have been associated with increased vascular risk [26, 27]. No data exists for liraglutide effects on SUA levels. Chronic kidney disease (CKD) stage 3, as assessed by estimated glomerular filtration rate (eGFR) 1875-6212/16 $58.00+.00
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30-60 mL/min/1.73 m2, is related to CVD morbidity and mortality [28-30]. Therefore, in terms of CVD risk, it would be interesting to evaluate if any eGFR changes occurred in the SCALE Obesity and Prediabetes study [2]. However, the significant overestimation of true GFR by the relevant estimated values in obese individuals should be taken into account [31]. The beneficial liraglutide-related effects on glucose control were greater in patients with prediabetes than those without. Furthermore, at the end of the study (56 weeks), fewer patients on liraglutide had prediabetes and type 2 diabetes compared with the placebo group [2]. Statins are known to increase the risk of new-onset diabetes (NOD) [32, 33]. In contrast, ezetimibe and fibrates may improve glucose metabolism [34]. In the SCALE Obesity and Prediabetes study [2], there were patients on lipid-lowering drugs (although the authors do not specify which). Based on the observed liraglutide-related beneficial impact on glucose metabolism, it would have been interesting to also evaluate its effect on statin-induced NOD. It follows that, if liraglutide 3.0 mg was shown to prevent this drug-related NOD, this would have important clinical implications in statin-treated patients. Side effects (mainly nausea and diarrhoea), with mild to moderate severity, were more common in the liraglutide-treated patients compared with placebo. Hypoglycaemias were more frequent in the liraglutide group compared with placebo (11.9 vs. 3.3% for all events; 1.3 vs. 1.0% for spontaneously reported; 3.6 vs. 0.8% for those reported at fasting plasma glucose visit and 8.3 vs. 1.4% for those reported at oral glucose tolerance test visit, respectively) (see appendix) [2]. However, the authors do not report any statistics with regard to hypoglycaemias. We performed Chi-square test (with Yates correction) that showed a significant difference in all hypoglycaemic events between the 2 groups (p < 0.0001). None of these hypoglycaemic events was serious or required third-party assistance. Resting heart rate (HR) was also slightly increased in the liraglutide group [2.5±9.8 vs 0.1±9.5 beats per min (bpm), respectively; p < 0.001]. The upregulation of HR by liraglutide appears to occur within the first few weeks and then reaches a plateau. Glucagon-like peptide-1 (GLP-1) receptors are found in the myocytes of the sinoatrial node, thus possibly explaining the increased HR observed with liraglutide administration [35]. However, studies investigating the direct effect of liraglutide on the automatism of the sinoatrial node are lacking. It should be noted that elevated HR (with no lower threshold reported) has been associated with an increased risk for coronary atherosclerosis, CVD morbidity (especially heart failure) and mortality as well as with total mortality [36, 37]. The reported association between the elevation of HR and CVD events are possibly attributed at least in part to the downregulation of the Parasympathetic Nervous System (PNS) and/or upregulation of the Sympathetic Nervous System (SNS) [37]. Importantly, the presumed mechanism of HR upregulation by liraglutide involves the activation of GLP-1 receptors in the sinoatrial node and thus exposes the heart to a lower cardiovascular stress compared with the modulation of PNS and SNS, which can also lead to proarrhythmia, increased inotropy and elevation of blood pressure [38]. From this point of view the prognostic significance of the upregulation of HR by liraglutide should be differentiated from the one of other antiobesity drugs, which increase HR through adrenergic activation, such as phentermine/topiramate, naltrexone/bupropion and sibutramine. Nevertheless, the elevation of HR by liraglutide may be an important consideration for the achievement of the target HR in obese patients with coronary artery disease. Other antiobesity drugs have also been shown to increase HR including the combination of phentermine and topiramate extended release [39, 40] (mean increase 1.3 and 1.7 bpm on the 7.5/46 and 15/92 mg dose, respectively [41]) and the 32 mg naltrexone/360 mg bupropion combination (increase up to 2 bpm) [42, 43]. Sibutramine, despite its beneficial metabolic effects [44], was found to raise HR in the Sibutramine Cardiovascular Outcomes (SCOUT) trial (mean differences compared with placebo were from 2.2 to 3.7 bpm) [45]. In this study, sibutramine treatment was also associated with an increased risk for CVD morbidity, a finding that led to its withdrawal from the market. In contrast, lorcaserin has not been reported to affect HR [46]. Hypocaloric diet plus orlistat has been shown to induce greater decrease in HR compared with hypocaloric diet plus placebo, which could be attributed to the greater orlistat-induced weight loss, rather than to a direct effect of orlistat on sinoatrial node automatism [47, 48]. Night-time HR changes may be even more strongly associated with inflammation [49]. The clinical implications of drug-related changes in HR remain to be established. However, for liraglutide, any disadvantage related to the increased HR may be more than compensated for by the beneficial effects described above. In another recent study, 3-months treatment of liraglutide in non-diabetic obese individuals significantly improved binge eating as well as obesity, glucose and lipid parameters but also increased plasma ghrelin levels compared with placebo [50]. Ghrelin is a gut hormone involved in appetite control [51] and its levels may be affected by antidiabetic drugs including liraglutide (at the dose of 1.2 mg/day) [52, 53]. Therefore, it would have been useful to measure ghrelin levels in the recently published SCALE Obesity and Prediabetes study. Overall, the findings of the SCALE Obesity and Prediabetes study are in accordance with both previous and current reviews on the efficacy, safety and tolerability of liraglutide for the management of obesity [54-59]. Importantly, the number of participants (n = 3731) in the SCALE Obesity and Prediabetes study permits to reach relatively firm conclusions regarding the safety of liraglutide 3.0 mg for a treatment period of 56 weeks. Taking into account that antiobesity drugs are not usually be taken for many years, the long term safety of this treatment should be investigated (e.g. by studies and surveillance programmes) for the detection of potential adverse effects after the cessation of liraglutide 3.0 mg treatment, rather than through extended studies using liraglutide 3.0 mg therapy. In conclusion, liraglutide 3.0 mg/day seems a promising antiobesity agent exerting beneficial metabolic effects. Future studies may further explore its impact on several cardiometabolic risk factors such as SUA, eGFR, sdLDL, PPL, MetS and NAFLD as well as on HR. Therefore, its long term efficacy and safety remains to be established.
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COMPETING INTEREST This editorial was written independently. The authors did not receive financial or professional help with the preparation of the manuscript. NK has given talks, attended conferences and participated in trials sponsored by Amgen, Astra Zeneca, Libytec, Novo Nordisk, MSD and Novartis. GAC declares that he has no conflict of interest. DNK has given talks, attended conferences and participated in trials sponsored by Amgen, Angelini, MSD, BGP, ELPEN and Unipharma. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
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Dimitrios N Kiortsis Professor of Physiology Laboratory of Physiology, Medical School University of Ioannina 45110 Ioannina, Greece Phone: 0030 2651007551 Fax: 0030 2651007850 E-mail:
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