• The epidemic explosion of obesity is engulfing the entire globe. With future projection by the World Obesity Federation predicting that very soon almost half of the world’s population will be overweight or obese.
• Obesity is not just about how much one weighs, it is the impact of excess adipose tissue (fat) on an individual’s health.
• Obesity is a ‘disease’, the same as diabetes, hypertension, dyslipidemia etc., requiring a long-term, planned treatment. It should be considered a journey, and not a destination. 
• People suffering from obesity are at an increased risk of 229+ health risks/complications.
• These can be easily explained by the 4 ‘M’ complications:
  1. ‘M’etabolic: diabetes; hypertension; cholesterol; fatty liver etc.
  2. ‘M’echanical: knee pain, back pain, hyperacidity, snoring/sleep apnoea etc.
  3. ‘M’ental: self-esteem, social/personal/professional performance, altered self image etc.
  4. ‘M’onetary: healthcare expenditure.
• One of the most cost-effective interventions in healthcare is weight management, which, when compared to other health interventions, provides early opportunities to prevent a wide range of health conditions and diseases, potentially protecting the body's functions and systems.
• Obesity is not just a simple mathematical equation involving excess calorie consumption and decreased calorie expenditure.
• Genetic predisposition explains 40%-60% of the reasons for excess weight.
• Numerous genes predisposing an individual to obesity are located in the brain, and a lot of them directly modulate hunger/eating patterns of an individual. 
• Calorie restriction (diet) through nutritional intervention is the most important determinant of weight loss.
• Compared to diet, increased calorie expenditure (exercise/fitness) contributes less to weight loss. However, fitness is directly and strongly related to an enhanced quality of life and longevity.
• Diet control and appetite management are two major obstacles in achieving weight loss. These challenges often lead to ineffective weight loss and subsequent weight regain, making them the most prevalent reasons for unsuccessful weight management.
• Most of the failures in weight management happen during the weight maintenance period.
• Hedonic hunger and pleasure eating are major contributors to the obesity epidemic and must be addressed for effective and lasting weight loss. 
• Until recently, addressing hedonic hunger or pleasure eating were considered impossible by both healthcare providers and patients.

Pharmacotherapy, or drug therapy, for weight loss is one of the most important and effective pillars of weight loss. Most of the successful medications for weight loss act by altering appetite/hunger, of these, most have either been withdrawn from the market because of their side effects or the absence of regulatory approval for use in India. 

However, recently, ‘Semaglutide’, a drug primarily approved for its effectiveness in the management of Type-2 diabetes (Rybelsus/Ozempic), has now been approved for the management of weight because of its outstanding weight loss benefit even in patients without Type-2 diabetes (Wegovy). Semaglutide is proving to be a game changer not just because of its efficacy in weight loss, but also multifactorial risk reduction. Across the globe, obesity care physicians and people suffering from obesity, both, are sharing their excitement and enthusiasm around Semaglutide and the results achieved.

Semaglutide belongs to a class of drugs known as glucagon-like peptide-1 (GLP-1) receptor agonists. Oral Semaglutide gains its novelty by being the first-in-class protein molecule (drug) to be successfully administered by the oral route.

Let’s understand the role of this ‘wonder drug’: 

1. How does Semaglutide cause weight loss? 

1. The drug mimics the natural hormone GLP-1, which is produced by the gut.
2. Its primary target for weight loss is the brain.
3. It acts on the appetite/hunger centres in the brain.
4. By reducing appetite or hunger it leads to reduced calorie intake and hence weight loss—an important driver for weight gain in most cases—with patients’ often saying “I just don’t feel like eating”.
5. Not only does this drug reduce hunger, it also reduces food cravings. Interestingly, most people who lose weight while taking Semaglutide report a major reduction in their attraction to calorie-dense foods, including sweets, fast foods, etc; they are just not attracted to these foods anymore. Patients say, “I just don’t like to eat the foods that I used to love eating or couldn’t do without”.
6. A reduction in hunger and cravings for calorie-dense foods makes compliance with the prescribed nutrition plan easier.
7. Another mechanism contributing to weight loss is reduced gastric (stomach) emptying. Patients are likely to feel fuller and satiated with less food intake and stay satiated for longer periods of time. Patients often report, “My tummy feels full with very little food and stays full for longer time”.
8. Emerging data from trials and even clinical practice on use of Semaglutide shows that patients report increasing aversion to alcohol and/or tobacco due to the drug's effect on brain centres. Therefore, it is possible that the medication might reduce these two major health risks—drinking and smoking.

1. Other health benefits of Semaglutide:

1. Reduced abdominal obesity.
2. Reduces fasting blood insulin level and also reduces insulin resistance. 
3. It provides excellent and durable blood glucose control--HbA1c reduction in patients with type-2 diabetes mellitus.
4. It has a blood pressure-lowering effect, both systolic and diastolic.
5. Beneficial effects on lipid profile through reduced triglycerides and increased good cholesterol count.
6. Its cardiovascular safety is well documented, and evidence indicates it may help reduce the occurrence of heart attacks in people with obesity, both with and without type-2 diabetes.
7. Semaglutide use is associated with a lesser chance of developing brain stroke.
8. A recent trial investigating the kidney protection potential of Semaglutide was prematurely stopped because of very early achievement of outcomes.
9. Ongoing trials of Semaglutide in neurodegenerative diseases , such as Alzheimer’s, add to the health benefits of the drug.
10. Semaglutide directly and indirectly benefits patients with fatty liver disease or NAFLD.

1. Approval and availability of Semaglutide in India: 
   1. Oral Semaglutide: Approved and available in India for use in type-2 diabetes and obesity ONLY; 3 mg; 7 mg and 14 mg.
   2. Injectable Semaglutide: 
      1. Ozempic (once a week, 1 mg): Not approved or available in India. 
      2. Wygovy (once a week, 2.4 mg): Approved for weight loss in case of obesity without type-2 diabetes, currently not-available.
2. Common side-effects:
   1. Nausea, vomiting would be the most common side effects of Semaglutide in clinical practice. 
   2. Loose motions are rare, but are a common reason for not being able to tolerate the drug. 
   3. Headache not responding to conventional pain medicines.
   4. More information is available in the section on absolute and relative contraindications.

1. How to minimise side effects of Semaglutide:

1. All patients must be informed about the possible common side effects of the drug.
2. The drug must always be started at the lowest possible dose, for example 3 mg for oral Semaglutide.
3. The dose should be gradually increased after 4 weeks, as per the pack insert. In clinical practice, we may delay the dose increase if the patient experiences more than expected side effects.
4. Small, frequent meals can be recommended.
5. Maintaining proper hydration is important.
6. Avoiding fatty/oily meals is key.
7. To alleviate nausea, patients can have apples, crackers, mint, or ginger-based drinks 30 minutes after GLP-1 RAs.
8. Antacids may be prescribed temporarily to counter the nausea and vomiting.

1. Semaglutide is not to be prescribed in the following situations:
   1. Type-1 diabetes
   2. Pancreatitis history
   3. Presence of gall bladder stones
   4. Moderate to severe retinal/macular disease in patients with type-2 diabetes
   5. Presence of family or personal history of Medullary thyroid cancer or MEN 2 syndrome 
   6. Patients with gastroparesis

In conclusion, Semaglutide a ‘game changer’ or ‘wonder drug’ is promising not just for effective and durable weight loss in most patients, but is also backed by robust scientific evidence of providing excellent control over blood sugar, blood pressure and lipid parameters with potential protection of vital organs, including the heart, liver, kidney. Finally, choosing the right patients and clinical situations for prescribing Semaglutide and avoiding ‘off label’ or ‘over the counter’ usage is vital to realizing the true potential of Semaglutide for the health of patients.