Prevalence of Baseline Cardiac Arrhythmias in Participants with Overweight or Obesity in Phase 1 Clinical Trials: Analysis of 24-Hour Holter Electrocardiogram Recordings.

Although estimates of the prevalence of cardiac arrhythmias in healthy volunteers exist, there is a lack of baseline data in other specific populations, such as people living with overweight and obesity, who are increasingly involved in clinical trials. This study investigated the baseline prevalence of arrhythmias in participants with overweight or obesity in 2 phase 1 trials of weight management medications (NCT03661879, NCT03308721). Participants aged 18-55 years, without a history of cardiovascular disease, and with body mass index (BMI) of 25.0-39.9 kg/m2 , were screened for abnormalities in vital signs, electrocardiogram (ECG) recordings, and electrolytes. Baseline 24-hour ECG (Holter) data were collected and manually reviewed by a cardiologist. The primary endpoint was the proportion of participants with ≥1 episode of the predefined cardiac arrhythmias. Continuous 12-lead ECG data were obtained from 207 participants. Most arrhythmias occurred in <3% of participants. Atrioventricular blocks and other potentially malignant arrhythmias were uncommon. There were no associations with age, sex, or BMI. Prevalence of atrioventricular blocks, nonsustained ventricular tachycardia, and other potentially malignant arrhythmias mirrored those reported in healthy participants with normal weight. In clinical trials of weight management medication, knowledge of the baseline prevalence of arrhythmias in people with overweight and obesity may inform trial eligibility criteria, improve on-trial decisions, and could be useful in discussions with health authorities. Baseline Holter readings and real-time ECG telemetry monitoring should be considered in such trials if arrhythmia risk is intrinsic to the molecule, or when signals have been observed in preclinical studies.

Pharmacokinetics and tolerability of semaglutide in people with hepatic impairment.

AIMS: To investigate whether the pharmacokinetic characteristics of semaglutide were altered in people with hepatic impairment, assessed using Child-Pugh criteria, vs those with normal hepatic function. METHODS: In this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ClinicalTrials.gov ID NCT02210871), four groups of participants with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n = 7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞ ). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-group ratio (hepatic impairment/normal function) was within the interval 0.70 to 1.43. RESULTS: Semaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal function of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal function 1.02 (90% CI 0.93, 1.12), and severe impairment/normal function 0.97 (90% CI 0.84, 1.12). The maximum plasma semaglutide concentration (Cmax ) did not appear to be influenced by hepatic function, with mild impairment/normal function treatment ratios of 0.99 (90% CI 0.80, 1.23), moderate impairment/normal function 1.02 (90% CI 0.88, 1.18) and severe impairment/normal function 1.15 (90% CI 0.89, 1.48; sensitivity analysis excluding one extreme semaglutide concentration: 1.05 [90% CI 0.88, 1.25]). In all, 10 participants reported 12 mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed. CONCLUSIONS: Semaglutide exposure did not appear to be affected by hepatic impairment, suggesting that dose adjustment may not be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.

Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity.

AIM: To investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, 2-period, crossover trial. Subjects with obesity (N = 30) received once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, or placebo. After each 12-week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed. RESULTS: Semaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC0-5h ]; estimated treatment difference: glucose -1.34 mmol h/L [-2.42, -0.27]; insulin -921 pmol h/L [-1461, -381]; C-peptide -1.42 nmol h/L [-2.33, -0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First-hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC0-1h ; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide-treated subjects. Overall gastric emptying (AUC0-5h ) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively). CONCLUSION: Semaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first-hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.

Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.

AIM: The aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide. MATERIALS AND METHODS: This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed. RESULTS: After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (-1255 kJ; P < .0001) and during the subsequent evening meal ( P = .0401) and snacks ( P = .0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (-3036 kJ; P < .0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass. CONCLUSION: After 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide-induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy-dense foods.