Ergophysiological evaluation of heart failure patients with reduced ejection fraction undergoing exercise-based cardiac rehabilitation: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aims to explore in heart failure (HF) patients with reduced ejection fraction (EF) undergoing exercise-based cardiac rehabilitation the following: 1) the comparison of temporal changes between peak oxygen uptake (VO2peak) and first ventilatory threshold (VO2VT1), 2) the association of VO2peak and VO2VT1 changes with physiological factors, and 3) the differential effects of continuous aerobic exercise (CAE) and interval training (IT) on VO2peak and VO2VT1. METHODS: A systematic literature search was conducted in PubMed, CENTRAL, and Scopus. Inclusion criteria were 1) original research articles using exercise-based cardiac rehabilitation, 2) stable HF patients with reduced EF, 3) available values of VO2peak and VO2VT1 (in mL/kg/min) both at baseline and after exercise training with comparison between these time points. RESULTS: Among the 30 eligible trials, 24 used CAE, 5 IT, and one CAE and IT. Multivariable meta-regression with duration of exercise training and percentage of males as independent variables and the change in VO2peak as a dependent variable showed that the change in VO2peak was negatively associated with duration of exercise training (coefficient=-0.061, p=0.027), implying the possible existence of a waning effect of exercise training on VO2peak in the long term. Multivariable meta-regression demonstrated that both age (coefficient=-0.140, p<0.001) and EF (coefficient=-0.149, p<0.001) could predict the change in VO2VT1, whereas only age (coefficient=-0.095, p=0.022), but not EF (coefficient = 0.082, p = 0.100), could predict the change in VO2peak. The posttraining peak respiratory exchange ratio, as an index of maximum effort during exercise testing, correlated positively with the change in VO2peak (coefficient=-0.021, p=0.044). The exercise-induced changes of VO2peak (p = 0.438) and VO2VT1 (p = 0.474) did not differ between CAE and IT groups. CONCLUSIONS: Improvement of endurance capacity during cardiac rehabilitation may be detected more accurately with the assessment of VO2VT1 rather than VO2peak.

Effects of Hypoglycemia on Cardiovascular Function in Patients with Diabetes.

Hypoglycemia is common in patients with type 1 and type 2 diabetes (T1D, T2D), treated with insulin or sulfonylureas, and has multiple short- and long-term clinical implications. Whether acute or recurrent, hypoglycemia significantly affects the cardiovascular system with the potential to cause cardiovascular dysfunction. Several pathophysiological mechanisms have been proposed linking hypoglycemia to increased cardiovascular risk, including hemodynamic changes, myocardial ischemia, abnormal cardiac repolarization, cardiac arrhythmias, prothrombotic and proinflammatory effects, and induction of oxidative stress. Hypoglycemia-induced changes can promote the development of endothelial dysfunction, which is an early marker of atherosclerosis. Although data from clinical trials and real-world studies suggest an association between hypoglycemia and cardiovascular events in patients with diabetes, it remains uncertain whether this association is causal. New therapeutic agents for patients with T2D do not cause hypoglycemia and have cardioprotective benefits, whereas increasing the use of new technologies, such as continuous glucose monitoring devices and insulin pumps, has the potential to reduce hypoglycemia and its adverse cardiovascular outcomes in patients with T1D.

An echocardiographic study of acute, progressive cardiac changes following a 246 km running race.

We describe the case of an ultra-marathon runner who finished first the "Spartathlon", a 246 km running race. The finishing time was the second fastest time ever in "Spartathlon". After finishing the race, the athlete suffered non-cardiac syncope and was administered intravenously 3 L of fluids for 5 hours. He underwent two echocardiographic assessments, one immediately after the finish of the race and the second 5 h later. Post-exercise fluid administration led to an increase in dimensions of all cardiac cavities, accompanied by a decrease in left ventricular (LV) end-diastolic interventricular septum thickness and posterior wall thickness of 0.1 cm. Dimensions and the respiratory profile of inferior vena cava improved after the race, reflecting alleviation of exercise-related hypovolaemia. Additionaly, LV global longitudinal strain improved, but right ventricular (RV) systolic function continued to deteriorate, mainly due to impairment of basal and medial RV free wall longitudinal strain. Study of this case offers a unique model for understanding the successive changes of cardiac structure and function following an ultra-marathon running race.

Unraveling the role of resistin, retinol-binding protein 4 and adiponectin produced by epicardial adipose tissue in cardiac structure and function: evidence of a paracrine effect.

PURPOSE: Adipokines produced by adipose tissue have been found to be involved in the pathophysiology of metabolic and cardiovascular diseases. We aimed to investigate the relationships of resistin, retinol-binding protein 4 (RBP4) and adiponectin produced by epicardial adipose tissue with coronary artery disease (CAD) and cardiac structure and function. METHODS: Forty-one non-diabetic males scheduled for cardiothoracic surgery were examined. Anthropometric measurements, echocardiography, coronary angiography, and blood analysis were performed preoperatively. We measured the serum levels of resistin, RBP4, and adiponectin and their mRNA expression in thoracic subcutaneous adipose tissue and two epicardial adipose tissue samples, one close to left anterior descending artery (LAD) (resistin-LAD, RBP4-LAD, adiponectin-LAD), and another close to the right coronary artery (RCA) (resistin-RCA, RBP4-RCA, adiponectin-RCA). RESULTS: Left ventricular (LV) ejection fraction correlated negatively with adiponectin-LAD (rho = - 0.390, p = 0.025). The ratio of early to late diastolic transmitral flow velocity, as an index of LV diastolic function, correlated negatively with resistin-LAD (rho = - 0.529, p = 0.024) and RBP4-LAD (rho = - 0.458, p = 0.049). There was no difference in epicardial adipose tissue mRNA expression of resistin, RBP4, and adiponectin between individuals with CAD and those without CAD. When we compared the individuals with CAD in the LAD with those without CAD in the LAD, there was no difference in resistin-LAD, RBP4-LAD, and adiponectin-LAD. There was no difference in resistin-RCA, RBP4-RCA, and adiponectin-RCA between the individuals with CAD in the RCA and those without CAD in the RCA. CONCLUSION: Elevation of epicardial adipose tissue mRNA expression of adiponectin was associated with LV systolic dysfunction, while that of both resistin and RBP4 was linked to LV diastolic dysfunction.

The Associations of Dietary Vitamin K Intake and Circulating Vitamin 25(OH)D with Serum Lipoprotein Levels: The Vitamin Deficiency Matters.

A synergistic interplay between vitamins K and D appears to exist. We aimed to investigate for the first time whether the associations of dietary vitamin K intake and circulating 25(OH)D with serum lipoprotein levels are influenced by the existence of deficiency of either or both vitamins K and D. Sixty individuals [24 males, 36(18-79) years old] were examined. Vitamin deficiency of K1 and D were defined as vitamin K1 intake/body weight (BW)<1.00 µg/kg/day and circulating 25(OH)D<20 ng/ml, respectively. In individuals with vitamin K1 deficiency, the vitamin K1 intake/BW correlated positively with high density lipoprotein-cholesterol (HDL-C) (r=0.509, p=0.008) and negatively with serum triglycerides (TG) (r=-0.638, p=0.001), whereas circulating 25(OH)D correlated negatively with TG (r=-0.609, p=0.001). In individuals with vitamin D deficiency, the vitamin K1 intake/BW correlated positively with HDL-C (r=0.533, p=0.001) and negatively with TG (r=-0.421, p=0.009), while circulating 25(OH)D correlated negatively with TG (r=-0.458, p=0.004). The above-mentioned associations of vitamin K1 intake/BW and circulating 25(OH)D with serum lipoproteins were not detected in individuals without vitamin K1 deficiency or the ones without vitamin D deficiency. The vitamin K2 intake/BW correlated negatively with low density lipoprotein-cholesterol (LDL-C) (r=-0.404, p=0.001). In conclusion, the associations of vitamin K1 intake with TG and HDL-C and of circulating 25(OH)D with TG were more pronounced in individuals with deficiency of either or both vitamins K1 and D. Increased dietary vitamin K2 intake was associated with decreased LDL-C.

Prolonged QT Interval in Athletes: Distinguishing between Pathology and Physiology.

BACKGROUND: The physiological QT prolongation in athletes is expected to widen the gray zone between physiology and pathology of QT, increasing the diagnostic challenges encountered in athletes with QT prolongation. SUMMARY: According to international recommendations for electrocardiogram in athletes, further evaluation for long QT syndrome (LQTS) is indicated in male athletes with corrected QT (QTc) ≥470 ms and in female athletes with QTc ≥480 ms. Apart from QTc ≥500 ms, diagnostic challenges arise in borderline cases of QTc prolongation, where further clinical investigations are needed to be performed to clarify whether LQTS exists. Clinical diagnostic investigations, including exercise testing, are more readily available, convenient, and easily interpretable, as well as less costly than genetic testing for LQTS. The main findings on exercise testing that are suggestive of LQTS can be the paradoxical prolongation of QTc during exercise and QTc ≥480 ms at fourth min of recovery. KEY MESSAGES: Exercise testing appears to have an important role in the diagnostic evaluation of athletes with prolonged QT interval, when genetic testing is not available.

The role of cardiac computed tomography in pre-participation screening of mature athletes.

The overwhelming majority of sports-related sudden cardiac deaths in mature athletes is attributed to coronary artery disease (CAD). Coronary plaques of mature athletes appear to be more calcified compared to sedentary individuals and thus may be more stable and less likely to be associated with an acute coronary event. Cardiac computed tomography (CT), including unenhanced CT for coronary artery calcium scoring (CACS) and contrast-enhanced coronary CT angiography, is characterized by very high negative predictive value to rule out CAD. Cardiac CT has been shown to have additional diagnostic value for detection of CAD in athletes over and above exercise electrocardiogram. Moreover, measurement of CACS possibly enables a more precise cardiovascular risk stratification of mature athletes. The main advantage of cardiac CT is its noninvasive nature. Although cardiac CT appears to increase the overall cost of cardiac examinations, this additional cost is much lower than the cost of unnecessary invasive coronary angiographies that would be performed in case of false positive results of exercise electrocardiograms. Radiation exposure may not be a major concern for the application of this modality to pre-participation screening of athletes, since recent technical advancements have resulted in low radiation dose of cardiac CT.Highlights Coronary computed tomography angiography can be used in pre-participation screening of mature athletes to increase the negative predictive value for excluding coronary artery disease.The identification of coronary artery calcium score = 0 in an athlete can improve risk stratification, since this athlete can be reasonably managed as an individual with low cardiovascular risk.

Impact of a 246 Km ultra-marathon running race on heart: Insights from advanced deformation analysis.

Although previous studies suggest that prolonged intense exercise such as marathon running transitorily alters cardiac function, there is little information regarding ultramarathon races. Aim of this study was to investigate the acute impact of ultra-endurance exercise (UEE) on heart, applying advanced strain imaging. Echocardiographic assessment was performed the day before and at the finish line of "Spartathlon": A 246 Km ultra-marathon running race. 2D speckle-tracking echocardiography was performed in all four chambers, evaluating longitudinal strain (LS) for both ventricles and atria. Peak strain values and temporal parameters adjusted for heart rate were extracted from the derived curves. Out of 60 participants initially screened, 27 athletes (19 male, age 45 ± 7 years) finished the race in 33:34:27(28:50:38-35:07:07) hours. Absolute values of right (RV) and left ventricular (LV) LS (RVLS -22.9 ± 3.6 pre- to -21.2 ± 3.0% post-, p=0.04 and LVLS -20.9 ± 2.3 pre- to -18.8 ± 2.0 post-, p=0.009) slightly decreased post-race, whereas atrial strain did not change. RV and LV LS decrease was caused mainly by strain impairment of basal regions with apical preservation. Inter-chamber relationships assessed through RV/LV, LV/LA, RV/RA and RA/LA peak values' ratios remained unchanged from pre to post-race. Finally, UEE caused an extension of the systolic phase of cardiac cycle with concomitant diastole reduction (p<0.001 for all strain curves). Conclusively, ventricular LS strain as well as effective diastolic period slightly decreased, whereas atrial strain and inter-chamber relationships remained unchanged after running a 246-km-ultra-marathon race. These changes may be attributed to concomitant pre- and afterload alterations following UEE.

Exploring the Anthropometric, Cardiorespiratory, and Haematological Determinants of Marathon Performance.

AIM: We aimed to investigate the main anthropometric, cardiorespiratory and haematological factors that can determine marathon race performance in marathon runners. METHODS: Forty-five marathon runners (36 males, age: 42 ± 10 years) were examined during the training period for a marathon race. Assessment of training characteristics, anthropometric measurements, including height, body weight (n = 45) and body fat percentage (BF%) (n = 33), echocardiographic study (n = 45), cardiopulmonary exercise testing using treadmill ergometer (n = 33) and blood test (n = 24) were performed. We evaluated the relationships of these measurements with the personal best marathon race time (MRT) within a time frame of one year before or after the evaluation of each athlete. RESULTS: The training age regarding long-distance running was 9 ± 7 years. Training volume was 70 (50-175) km/week. MRT was 4:02:53 ± 00:50:20 h. The MRT was positively associated with BF% (r = 0.587, p = 0.001). Among echocardiographic parameters, MRT correlated negatively with right ventricular end-diastolic area (RVEDA) (r = -0.716, p < 0.001). RVEDA was the only independent echocardiographic predictor of MRT. With regard to respiratory parameters, MRT correlated negatively with maximum minute ventilation indexed to body surface area (VEmax/BSA) (r = -0.509, p = 0.003). Among parameters of blood test, MRT correlated negatively with haemoglobin concentration (r = -0.471, p = 0.027) and estimated haemoglobin mass (Hbmass) (r = -0.680, p = 0.002). After performing multivariate linear regression analysis with MRT as dependent variable and BF% (standardised ß = 0.501, p = 0.021), RVEDA (standardised ß = -0.633, p = 0.003), VEmax/BSA (standardised ß = 0.266, p = 0.303) and Hbmass (standardised ß = -0.308, p = 0.066) as independent variables, only BF% and RVEDA were significant independent predictors of MRT (adjusted R2 = 0.796, p < 0.001 for the model). CONCLUSIONS: The main physiological determinants of better marathon performance appear to be low BF% and RV enlargement. Upregulation of both maximum minute ventilation during exercise and haemoglobin mass may have a weaker effect to enhance marathon performance. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT04738877.

A critical review of the effects of vitamin K on glucose and lipid homeostasis: its potential role in the prevention and management of type 2 diabetes.

In recent years, our knowledge regarding the physiological role of vitamin K has expanded beyond regulation of coagulation to include many other aspects of human health. In the present review, we aimed to evaluate the existing evidence for beneficial effects of vitamin K on type 2 diabetes and components of the metabolic syndrome as risk factors for cardiovascular disease. Increased dietary intake of vitamin K has been linked to lower incidence of type 2 diabetes mellitus (T2DM), possibly through its enhancement of insulin production and sensitivity. Additionally, higher plasma levels of vitamin K1 have been associated with lower T2DM risk and decreased insulin resistance, and supplementation trials also suggest a positive influence of vitamin K on glucose regulation. Vitamin K might also beneficially affect serum lipids and lipid metabolism. However, the available data remain controversial. Additionally, different studies use different approaches to assess vitamin K status owing to the absence of a generally accepted marker, which further complicates data evaluation. In conclusion, vitamin K possibly improves glucose and lipid metabolism and could be an emerging target in the context of prevention and control of T2DM, insulin resistance, and dyslipidemia.

The impact of demographic, anthropometric and athletic characteristics on left atrial size in athletes.

The structural adaptations of the "athlete's heart" include left atrial (LA) enlargement. A literature search was performed based on PubMed listings up to November 2, 2019 using "athletes AND left atrium," "athletes AND LA," "sports AND left atrium," "sports AND LA," "exercise AND left atrium," and "exercise AND LA" as the search terms. Eligible studies included those reporting the influence of demographic, anthropometric and athletic characteristics on LA size in athletes. A total of 58 studies were included in this review article. Although LA volume has been reported to be greater in males compared to females when indexed for body surface area (BSA), there was no difference between sexes. The positive association between LA size and age in athletes may reflect the increase in body size with maturation in nonadult athletes and the training age of endurance athletic activity in adult athletes. Caucasian and black athletes have been demonstrated to exhibit similar LA enlargement. The positive association of LA size with lean body mass (LBM) possibly accounts for the relationship of LA size with BSA. LA enlargement has been reported only in endurance-trained, but not in strength-trained athletes. LA size appears to increase with an increase in both the volume and intensity of endurance training. LA size correlates independently with the training age of endurance athletes. The athlete's characteristics that independently determine LA size include LBM, endurance training, and training age.

The regulation of serum resistin levels in metabolically healthy and unhealthy obese individuals.

PURPOSE: We have recently demonstrated that absolute counts of circulating proinflammatory monocytes were lower in obese patients without metabolic syndrome (MS) (metabolically healthy obese, MHO) compared with those with MS (metabolically unhealthy obese, MUO), but higher compared with healthy lean controls (MHL). We hypothesized that circulating resistin, a cytokine secreted by white blood cells (WBC), is involved in obesity-related low-grade inflammation. The aim of this study was to (a) determine serum resistin levels among MUO and MHO subjects and (b) investigate the role of circulating WBC subsets as potential determinants of resistin. METHODS: Study participants were 58 obese (33 MUO, 25 MHO) and 25 MHL individuals. Serum levels of resistin, high-sensitivity C-reactive protein (hsCRP), and absolute counts of circulating WBC subpopulations were determined. Comparisons were sex- and age-adjusted. RESULTS: Serum resistin levels in MHL were lower compared with those of obese (p = 0.041), but similar to those of MHO (p = 0.856) individuals. Both resistin (p = 0.005) and absolute neutrophil count (NeuA) (p = 0.025) were higher in MUO compared with MHO. The difference in resistin levels between obese and MHL individuals disappeared after adjustment for NeuA. Resistin correlated positively with absolute total monocyte count (p = 0.037) in MHL and with body mass index (BMI) (p = 0.023), hsCRP (p = 0.022), and NeuA (p = 0.044) in obese subjects. Resistin association with ΒΜΙ disappeared after adjustment for hsCRP, while association with hsCRP disappeared after further adjustment for NeuA. CONCLUSION: Circulating resistin was higher in MUO compared with MHO. The increased secretion of resistin by the greater number of neutrophils in the former may have contributed to this regulation.

High Tolerability of Pitavastatin Therapy: A Case Report of Comparison with other Statins.

INTRODUCTION: Myopathy is possibly the most clinically relevant statin-induced side effect. CASE PRESENTATION: We report a case of a 63-year-old healthy male with mixed dyslipidemia. He developed bilateral myalgia of the forearms with fluvastatin 40 mg/day, pravastatin 20 mg/day, and combination of atorvastatin 10 mg and ezetimibe 10 mg/day. The only hypolipidemic treatment that was tolerable was the combination of pitavastatin 1 mg and ezetimibe 10 mg/day. DISCUSSION: Pitavastatin demonstrated less potential for the development of myalgia compared to the so far considered most tolerable statins (i.e., fluvastatin and pravastatin). All the tested statins were used at the lowest approved dose for clinical use. CONCLUSION: The combination of pitavastatin 1 mg and ezetimibe appears to be a promising treatment choice for individuals who are intolerant to statin therapy due to muscle complaints.

Exploring the determinants of the cardiac changes after ultra-long duration exercise: The echocardiographic Spartathlon study.

AIM: The investigation of the pathophysiological determinants of cardiac changes following ultra-long duration exercise. METHODS: Twenty-seven runners who finished a 246 km running race were examined both before and after the finish of the race. Examinations included echocardiography and measurement of body weight and blood biochemical parameters. RESULTS: Exercise increased left ventricular end-diastolic interventricular septum thickness (LVIVSd) (p < 0.001) and posterior wall thickness (LVPWTd) (p = 0.001) and right ventricular end-diastolic area (p = 0.005), while reduced tricuspid annular plane systolic excursion (TAPSE) (p = 0.004). A minor decrease in the peak absolute values of both left ventricular (from -20.9 ± 2.3% to -18.8 ± 2.0%, p = 0.009) and right ventricular (from -22.9 ± 3.6% to -21.2 ± 3.0%, p = 0.040) global longitudinal strains occurred. There was decrease in body weight (p < 0.001) and increase in both circulating high-sensitivity troponin I (p = 0.028) and amino-terminal pro-B type natriuretic peptide (NT-proBNP) (p = 0.018). The change in the sum of LVIVSd and LVPWTd correlated negatively with percentage change of body weight (r = -0.416, p = 0.049). The only independent determinant of post-exercise NT-proBNP was pulmonary artery systolic pressure (r = 0.797, p = 0.002). Post-exercise NT-proBNP correlated positively with percentage changes of basal (RVbas) (r = 0.582, p = 0.037) and mid-cavity (RVmid) (r = 0.618, p = 0.043) right ventricular diameters and negatively with percentage change of TAPSE (r = -0.720, p = 0.008). Similar correlations with RVbas, RVmid and TAPSE were found for pulmonary artery systolic pressure. Post-exercise high-sensitivity troponin I correlated negatively with percentage change of body weight (r = -0.601, p = 0.039), but was not associated with any cardiac parameter. CONCLUSION: The main cardiac effects of ultra-long duration exercise were the decrease in left ventricular end-diastolic dimensions and increase in left ventricular wall thickness, as well as minimal dilatation and alteration in systolic function of right ventricle, possibly due to the altered exercise-related right ventricular afterload.

Metabolically Healthy Obesity Is Characterized by a Proinflammatory Phenotype of Circulating Monocyte Subsets.

Background: Obesity is associated with macrophage infiltration in adipose tissue that induces insulin resistance and contributes to the development of metabolic syndrome (MS). The aim of this study was to investigate whether circulating monocyte subsets (macrophage precursors) differ among obese subjects with MS [metabolically unhealthy obese (MUO)], obese subjects without MS [metabolically healthy obese (MHO)], and metabolically healthy lean (MHL) individuals. Methods: Fifty-eight obese (33 MUO, 25 MHO) and 25 MHL individuals participated in the study. Absolute blood counts of classical (Mon1A), intermediate (Mon2A), and nonclassical (Mon3A) monocyte subsets were measured by flow cytometry. Results: Increased proinflammatory monocyte counts (Mon2A, Mon3A) were observed in obese compared with MHL individuals (P = 0.001 and P = 0.017 respectively). Mon2A count in MHO was lower compared with that in MUO subjects (P = 0.036) but higher compared with MHL controls (P = 0.032). Mon2A was positively associated with serum triglyceride levels (r = 0.328, P = 0.023) and mean blood pressure (BP) (r = 0.457, P = 0.001) in obese subjects. Among MS components, only the presence of elevated BP (≥130/85 mmHg) was independently associated with increased Mon2A in obese subjects (P < 0.001). Conclusions: Absolute counts of proinflammatory monocytes were lower in metabolically healthy compared with MUO individuals, but higher compared with healthy lean controls. The presence of low-grade inflammation suggests that "metabolically healthy" obesity is not a benign condition. ClinicalTrials.gov identifier: NCT03241394.

Indirect clinical markers for the detection of anabolic steroid abuse beyond the conventional doping control in athletes.

Growing analytical challenges have arisen for the detection of misuse of androgenic anabolic steroids (AAS) in athletes the last years. Therefore, consideration of additional indirect markers can substantially aid the efforts to detect AAS abuse in athletes. Moreover, this approach can also help physicians to suspect AAS abuse when treating athletes. Laboratory markers highly indicative of AAS abuse in athletes include the considerable downregulation of high density lipoprotein-cholesterol, elevation of haematocrit or serum γ-glutamyl transpeptidase levels and for males reduced serum levels of both luteinizing hormone and follicle-stimulating hormone. Moreover, physical signs suggestive of current AAS abuse are hypertension, apparent changes in behaviour making the athlete more irritable and aggressive and the sudden appearance of acne vulgaris in an adult athlete with no recent history of acne, while testicular atrophy and gynecomastia raise suspicion of current or past AAS abuse in male athletes.

Semaglutide as a promising antiobesity drug.

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a long elimination half-life, allowing subcutaneous (sc) administration once per week. Both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) recently approved once-weekly sc semaglutide for the treatment of type 2 diabetes mellitus (T2DM). The weight loss efficacy of once-weekly sc semaglutide appears to be superior compared with the other once-weekly GLP-1 RAs in patients with T2DM. Semaglutide was recently evaluated as an antiobesity drug in a phase II dose-finding trial, which demonstrated superior weight loss efficacy of once daily sc semaglutide compared with both placebo and once daily 3.0 mg liraglutide in patients with obesity but without T2DM. The magnitude of semaglutide-induced weight loss in this study exceeded the criteria of both the EMA and FDA for antiobesity drugs, and there were no safety concerns, indicating the eligibility of once daily sc semaglutide as a future antiobesity drug.