Tesofensine – what is it and how does it work?
Tesofensine, also known as NS2330, is technically classified as a presynaptic serotonin–noradrenaline–dopamine reuptake inhibitor. Its pharmacological action leads to the inhibition of the reabsorption of these neurotransmitters by the central nervous system, resulting in reduced feelings of hunger. This compound primarily acts as an appetite suppressant while also influencing fat oxidation and resting energy expenditure. Additionally, Tesofensine exhibits a modulating effect on dopamine within specific brain regions, impacting the pleasure sensation associated with food consumption.
Originally developed for Alzheimer’s and Parkinson’s disease by a Danish company called NeuroSearch, Tesofensine’s efficacy in these neurological conditions proved inconclusive. However, during initial trials, weight loss appeared as a consistent effect, particularly in overweight or obese individuals. Consequently, research shifted towards investigating Tesofensine’s potential in obesity treatment.
The most important mechanism of action related to Tesofensine is its influence on dopamine. Dopamine, a neurotransmitter pivotal in modulating feelings of satisfaction and pleasure, undergoes significant alterations in signaling patterns with prolonged overeating, leading to severe behavioral changes, including eating more. Altered dopamine signaling is associated with weight gain, obesity, and glucose intolerance, with a substantial proportion of obese individuals exhibiting reduced dopamine receptor density.
Clinical Studies
Several studies have been done on Tesofensine. One of the most relevant Phase 2b clinical trials reported in The Lancet showed significant weight loss over a six-month period across different Tesofensine doses. Patients improved in insulin sensitivity, increased energy expenditure at rest, and enhanced fat oxidation. Subsequent Phase 3 studies further confirmed Tesofensine’s efficacy in reducing body weight, visceral fat, and improving glucose metabolism. Patients lost an average of 28lbs on a 1 mg dose, 25 on a 0.5 mg dose and 15lbs on a 0.25 mg dose, compared with a 4.8lbs loss in the placebo group. All participants were instructed to follow a diet with a 300 kcal deficit and to increase their physical activity gradually to 30-60 minutes of exercise per day. Additionally, patients also displayed:
- Improved insulin sensitivity and higher metabolism of sugars, which may be helpful for patients at risk of type II diabetes.
- Reduced appetite within a 14-day period, higher levels of satiety and less desire to eat out of plan.
- After 14 days, an increase in resting energy expenditure of 6% was measured and this directly linked to Tesofensine as any external factors were ruled out as possible causes.
- Increase in fat oxidation and consequent reduction in fat tissue. The 24-hour fat oxidation rates increased by 15% alongside with a reduction in protein oxidation.
Outcomes and benefits
- Reduction in body weight overall if not eating in excess
- Decreased body fat and visceral fat
- Lower levels of very-low-density lipoprotein (VLDL) and triglycerides
- Improved insulin sensitivity and regulation of glucose metabolism
- Potential reversal of early type 2 diabetes
Regarding side effects, Tesofensine is well-tolerated with minimal adverse effects, similar to placebo. While there may be a slight increase in heart rate, there is no significant effect on blood pressure at therapeutic doses.
The clinical safety data from over 20 trials involving approximately 1,600 patients taking Tesofensine for up to a year provides robust safety evidence. Additionally, Tesofensine has received FDA approval for the treatment of obesity.
Common side effects observed in recent trials include dry mouth, insomnia, tachycardia, constipation, nausea, diarrhea, and transient increases in blood pressure and heart rate.
In conclusion, Tesofensine is a powerful and effective therapeutic option for obesity treatment, with a potent mechanism of action capable of inducing weight loss and improving metabolic parameters listed in this article. Without a doubt, Tesofensine holds the potential to address the needs of individuals looking to lose some weight, struggling with obesity and associated metabolic disorders (even type 2 diabetes), all with minimal and very manageable side effects.
