New evidence-based guidelines have been released recommending long-term pharmacologic therapy for adults with obesity who do not respond adequately to lifestyle interventions alone. Which antiobesity medications received an AGA endorsement? Must read for general practitioners.

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Around 39% of the world's adults were overweight in 2014 (Body Mass Index [BMI] 25–29.9 kg/m2 or obese (BMI > 29.9 kg/m2), a number that has doubled since 1975. In 1975, just 6.4% of women and 3.2% of men were obese; by 2014, those numbers had climbed to 14.9% and 10.8%, respectively. The demographic and epidemiological transitions from declining mortality and fertility to an increase in lifestyle-related disorders have coincided with the rising incidence of overweight and obesity in emerging nations like India.

In India, the rate at which people are becoming overweight or obese is higher than anywhere else in the world. For example, the percentage of women who are overweight rose from 8.4% in 1998 to 15.5% in 2015, while the percentage who are obese went from 2.2% to 5.1% over the same time period. In tandem with this rapid expansion, the prevalence of non-communicable illnesses has also increased significantly.

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Case example

A 68-year-old patient was referred for cardiometabolic risk management because of his obesity, T2DM, CKD, and IHD. He has a body mass index of 38 and a waist circumference of 108 centimetres; his blood pressure is 146/88 and his heart rate is 72 beats per minute. He is now on a drug regimen that includes: metoprolol 50 mg OD, aspirin, metformin 1000 mg bd, atorvastatin 80 mg, and duloxetine 20 mg od. Which medicine for the chronic management of obesity would be preferable, in addition to SGLT2inhibitor, for the advantages to the cardiovascular and renal systems?

1. Orlistat
2. Phentermine/topiramate ER
3. Liraglutide 3mg
4. Naltrexone/bupropion ER

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How should one decide on an obesity treatment?

New evidence-based recommendations from the American Gastroenterological Association (AGA) suggest that persons who are overweight and do not react effectively to lifestyle changes alone should undergo long-term pharmaceutical medication.

Obesity therapy has evolved over the last several years. With this first-of-its-kind guidance, clinicians and their adult patients who have trouble losing weight and keeping it off with lifestyle modifications alone will have precise information to work with. These drugs are intended to combat a medical illness, not a behavioural one. Lifestyle changes alone are not always successful in treating obesity. Improvements in weight-related conditions such as joint pain, diabetes, fatty liver, and hypertension are possible with the use of medicines to aid in weight reduction.

Medications listed below, in combination with changes in lifestyle, were suggested as first treatments:

• Semaglutide 2.4 mg
• Phentermine-topiramate ER
• Liraglutide 3 mg
• Naltrexone-bupropion ER

The AGA advised against using orlistat owing to its low expected weight reduction effectiveness and high likelihood of treatment abandonment due to unwanted side effects.

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Recommendation 1

Things to think about when putting it into practice

Anti-obesity medications often need long-term usage; thus, the choice of medicine or intervention should be based on the individual's clinical profile and requirements, which may include but are not limited to comorbidities, patient preferences, costs, and access to the treatment.

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Recommendation 2

Things to think about when putting it into practice

1. Semaglutide 2.4 mg may be preferred above other authorised anti-obesity medications for the long-term treatment of obesity in most individuals due to the size of the net benefit.
2. Semaglutide is an authorised medication for type 2 diabetes and has glucoregulatory advantages as well.
3. Semaglutide's side effects, which include nausea and vomiting, may be due to its potential to slow stomach emptying. These unwanted effects may be lessened with gradual dosing.
4. The elevated danger of pancreatitis and gallbladder illness has been linked to the use of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs).

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Recommendation 3

Things to think about when putting it into practice

1. It has been shown that liraglutide, in addition to being effective against type 2 diabetes, also has glucoregulatory advantages.
2. Potential side effects of liraglutide include a slowed emptying of the stomach, which may cause sickness. These unwanted effects may be lessened with gradual dosing.
3. The risk of developing pancreatitis and gallstones when using liraglutide has been shown.

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Recommendation 4

Things to think about when putting it into practice

1. Patients who also suffer from migraines may benefit more from using phentermine-topiramate ER since topiramate is a good migraine headache treatment.
2. Patients with a history of cardiovascular disease and uncontrolled hypertension should not use Phentermine-topiramate ER.
3. It has been shown that topiramate may cause birth defects. It is important to encourage women of reproductive age to routinely utilise reliable forms of contraception.
4. Phentermine-containing drugs need careful monitoring of vital signs, including blood pressure and heart rate.

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Recommendation 5

Things to think about when putting it into practice

1. Naltrexone and bupropion ER may be useful in treating obesity in individuals who are also trying to quit smoking and in people who are experiencing depression.
2. Patients with a history of seizure disorders should not use naltrexone-bupropion ER, and those who are at risk for seizures should use it cautiously.
3. It is not recommended to use naltrexone-bupropion ER together with any opiate drugs.
4. After the first 12 weeks of therapy with naltrexone-bupropion ER, regular monitoring of blood pressure and heart rate is recommended.

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Recommendation 6

Things to think about when putting it into practice

Individuals who choose to use orlistat should also take a daily multivitamin. Supplements containing fat-soluble vitamins (A, D, E, and K) should be taken at least 2 hours apart from orlistat.

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Recommendation 7

Things to think about when putting it into practice

1. The Food and Drug Administration has authorised phentermine monotherapy for temporary usage (12 weeks). As weight loss is a long-term process, however, many doctors prescribe phentermine for periods of time beyond the recommended 12 weeks.
2. Patients who have had a history of heart problems should not use phentermine.
3. When using phentermine, it's important to keep an eye on vital signs including blood pressure and heart rate.

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Recommendation 8

Things to think about when putting it into practice

1. For temporary usage, the FDA has authorised diethylpropion monotherapy (12 weeks). Diethylpropion is only approved for a 12-week course of treatment, but because of the chronic nature of weight control, many doctors prescribe it for much longer.
2. Patients who have a preexisting heart condition should not use diethylpropion.
3. As with any medication, diethylpropion should have its effects evaluated regularly.

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Recommendation 9

The Gelesis100 oral superabsorbent hydrogel has been recommended for usage only within the confines of a clinical study due to the AGA's recognition of a "knowledge gap" about its use.

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Coming back to the case example

Liraglutide, a GLP-1 analogue that has shown promise in treating type 2 diabetes mellitus (T2DM), is now authorised as a weight reduction drug when taken at a daily dosage of 3 mg. When compared to the placebo group, participants in the SCALE diabetes study lost an average of 4% of their body weight and had a drop in their HbA1c) of 1%. When it comes to cardiometabolic risk markers like lipids and blood pressure, liraglutide consistently improves at all dosages while causing a modest rise in heart rate. Though there were few events and large confidence intervals, a pooled post hoc analysis of phase 3 studies containing 3 mg of liraglutide revealed a prospective cardiovascular benefit.

In this patient with known ascvd and CKD3, the other drugs are not preferable for decreasing CV risk but might be investigated. Though orlistat has been found to be safe for people with cardiovascular disease and decreases risk factors for cardiovascular disease, it has not been proven to prevent cardiovascular events and is not as helpful for glycemic management or renal benefits in this population. Patients with preexisting cardiovascular disease should exercise care while using sympathomimetic drugs like phentermine or the combo drug phentermine/topiramate ER. Although it has not been shown that phentermine/topiramate ER is safe for the heart, evidence from phase 3 studies is promising.

Multiple cardiometabolic markers improved in conjunction with weight reduction with naltrexone/bupropion ER, while blood pressure remained consistently higher than placebo. The cardiovascular safety of naltrexone/bupropion ER has not been established despite the fact that a study was launched with promising early findings, although with a significant dropout rate.

Disclaimer- This article was originally published on 8th february 2023.The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.