Obesity – A Burning Problem: Need for an Effective Pill!

Obesity is a common problem in our Valley dwellers. In a study conducted by Gauri Kaul Foundation we found it to be present in 25.4 % of the rural population of 6 districts in the valley. The impression gained from our Gauri Heart Centre is again that at least one third of our urban population is obese.

Obesity is defined by the Obesity Society as a medical condition, often considered as disease in which excess body weight has accumulated to such an extent that it negatively affects health. People with a body mass index (BMI) over 30 Kg/m2 are by definition obese.

It is a major cause of disability and is associated with several diseases, especially cardiovascular diseases (heart attacks, strokes and heart failure), Type 2 diabetes, obstructive sleep apnoea (OSA), certain types of cancers and osteo-arthritis. It has several socio-economic, individual and environmental causes.

New Weightloss Therapies?

The traditional methods of losing weight by adopting a healthy life style by reducing calorie intake, plenty of fruits and vegetables and regular burning of calories by exercise in any form which is equivalent to walking more than 8000 steps per day are very important. However, there is a large percentage of persons who are not able to adhere to this for the long term or are unable to reduce significant weight by these measures alone.

Bariatric surgery which involves making changes in the digestive tract surgically is a method reserved for extreme cases of obesity where the BMI is more than 40 kg/m2 or more than 35 kg/m2 with concomitant diseases like diabetes, heart related issues which could be reduced by it. It is extremely effective and leads to a weight reduction up to 25% and is associated with reduction in vascular events, cancers and liver disorders associated with fatty liver. Being a surgical procedure, its adoption is very low in general and this surgery has significant morbidity too.

Drugs for producing Weight Loss

This is what the world looks for and medical research is continuing to look for the ideal drug which at least match the results of bariatric surgery. A plethora of drugs came in like Amphetamines, Fenfluramines, Sibutramine, Rimonabant and Orlistat, most of the drugs proved unsafe and resulted in serious problems and have been withdrawn with the exception of Orlistat which consumed three times a day acts by preventing absorption of fat. Besides its side effects like abdominal cramps, passing gas and oily stools the weight loss achieved is very modest, at best 5% over 12 weeks when combined with dietary measures with enough exercise.

A New Generation of Weight Reducing Drug

Semaglutide( Ozempac, Wegovy, Rybelsus)

Tirzepatide (Mounjaro)

Both these agents are GLP1 analogues. Tirzepatide, has additional GIP effect making it a dual action agent.  These were developed for the management of diabetes and it was noted that the regular administration would lead to significant up to 20 % weight reduction. Ozempac / wegovy and Mounjaro are injectable agents, while Rybelsus is an oral agent.

In a comparative study Tirzepatide showed a better weight loss and lower blood sugar levels as compared to semaglutide.

These agents basically work by imitating an intestinal hormone that stimulates insulin production, lowering your appetite and making you feel full.  These additionally act on several organs of the body.

The author is the National lead investigator for the international study SELECT in which semaglutide was given to patients with previous vascular events (heart attacks, strokes etc) associated with overweight (BMI 27 kg/m2) without them having diabetes. It was compared to a matching placebo (dummy injection). The topline results which have just been announced show the patients who got the active injection had significant reduction in vascular events along with a significant loss of weight.

He is also the lead investigator of SURPASS-CVOT study in which tirzepatide has been tested against dulaglutide (another GLP1 analogue) in overweight persons, diabetes and previous vascular disease. The results are likely in 2024-25.

Injection semaglutide has become a rage in USA and is being used by a very large population. Novo Nordisk is serving hundreds of thousands of US patients with Wegovy and the demand continues to outpace the increased production. It is approved by US FDA as a safe weight losing drug. On the other hand, Mounjaro (Tirzapetide) is not approved for this indication but is being used as an off-label indication. These injections produce up to 15 to 20 % wight loss in 15 months’ time with a rapid onset. Thus an 80 Kg person can expect to lose 16 kgs and become 64 kgs.

Oral Rybelsus (Semaglutide) is freely available in India in three strengths 3, 7 and 14 mgs for the management of obese diabetics and is also being used as an off-label agent for weight reduction.  It is a path breaking technology of converting a peptide into a pill. The downside is that a very few patients tolerate the recommended 14 mgs dose and the weight loss is not comparable to the injectable variety. More data needs to come regarding its efficacy whereas its injectable version is a proven entity.

Still To Come and in Pipeline:

A number of oral agents with a dual mode of action (GLP analogues and GIP) orforglipron and triple mode of action (GLP analogue,GIP and glucagon receptors) retatrutride are in the pipeline with an estimated weight loss up to 24% which makes them at least equivalent to bariatric surgery

Take Home Message

Obesity is a common problem in our milieu with at least one quarter of our population suffers from it. It is the mother of cardiovascular diseases, diabetes,OSA, certain cancers and osteo-arthritis. Although life style modification is mandatory it is often not effective in improving the outcomes.

Bariatric surgery is very effective but not accepted by most, being a surgical procedure. Drugs have been the most sought-after answer. A plethora of agents came but till recently were fraught with serious side effects and new medical problems. The recent availability of drugs like semaglutide, tirzapetide have been shown to be safe and very effective. A few more agents like orforglipron and retatrutride which act by multiple mechanisms are likely to hit the market soon with results as effective as bariatric surgery.

 These drugs have a bright future but there is a key challenge of making them affordable and accessible to the underserved populations that carry the highest burden of disease.

The author is Padmashree and founder of Gauri Kaul Foundation