INS and obesity due to melanocortin 4 receptor deficiency: Moreover, the four multicentric and multinational Rimonabant In Obesity (RIO) trials showed that treatment with a CB1 antagonist in humans resulted in a reduction in body weight and waist circumference, along with improvements in several cardiometabolic risk factors such as triglyceride levels, fasting insulin, glycated hemoglobin (HbA1c), and blood pressure, accompanied by favourable increases in HDL cholesterol and adiponectin concentrations [32,33,34,35].