INTRODUCTION:

A person's body mass index is deemed obese (BMI > 30 kg/m² or BMI > 25kg/m²). Globally, the illness is becoming more and more of a public health emergency.¹In North India, the prevalence of coronary heart disease is 7–10%. Although in South India, it can reach 14 percent. Datafrom the National Health and Nutrition Examination Survey (NHANES, 1999–2000) indicate that 14% of teenagers are severely overweight or obese (≥95th percentile) and about 30% of adolescents are at risk for being overweight (≥85th percentile but <95th percentile).^2,3 Men typically store fat in their bellies, but premenopausal women store it in their hips and thighs.

Women's fat storage patterns resemble men's following menopause, which occurs approximately at age 50. Obesity and particularly abdominal obesity are linked to a higher risk of morbidity, including lipid abnormalities, insulin resistance, systemic inflammation, and other conditions that cause cardiovascular disease. Based on these parameters, 40% of women and 12% of men in the nation have abdominal obesity. As compared to men, women are more obsessed.^4,5 Two anti-obesity medications have received FDA approval, and more are being developed. FDA-approved AOMs include combination medication therapy, liraglutide, orlistat, phentermine/topiramate, and naltrexone/bupropion. Treatment options for obesity were focused on the proper behavioral approach, which changed nutrition and increased physical activity. There are studies assessing the efficacy of several diets, including ketogenic and Mediterranean diets and extremely low-calorie diets. It has been shown that this kind of diet, which has balanced amounts of the major nutrients—carbs, proteins, and fats can be used to treat obesity by creating a negative energy balance.^6,7 Otherwise, for those who are obese and either have diabetes mellitus or not. Two innovative glucose-lowering medications are sodium co-transporter 2 inhibitors (SGLT-2in) and glucagon-like peptide-1 receptor agonists (GLP-1RAs). These two drug classes don't work better for glycemic management, but they do lessen body edema and lower the risk of cardiovascular disease through separate mechanisms. Liraglutide 3mg and Semaglutide 2.4mg are two GLP-1RAs that the FDA has approved for use in obese people who have perhaps one or more weight-connected chronic conditions. Randomized controlled trials (RCTs) comparing GLP-1RAs or SGLT-2is with placebo have been conducted recently in a large number of fatty patients with or without diabetes mellitus.⁸ Pancreaticpolypeptide (PP), which functions as a potent anorexigenic hormone that successfully regulates energy homeostasis and food intake, may help anti-obesity treatments because of their high amino acid sequenceaffinity. Diabetes mellitus, Cushing syndrome, hypothyroidism, and polycystic ovarian syndrome are the most prevalent conditions that play a part in gaining weight and becoming obese. Obesity and depression are strongly correlated according to recent research.^9,10

CARDIOVASCULAR DISEASE RISK AND OBESITY:

The body of confirmation associated obesity to a higher risk of cardiovascular disease is growing. The rates of adult morbidity and death are increased by obesity and its comorbidities, hypertension, and glucose intolerance. However, there is a connection between increased obesity and cardiovascular disease in those with average BMIs of 25 to 30kg/m². First off, there is evidence linking obesity to several major risk factors for atherosclerosis, such as insulin resistance (T2DM), elevated triglyceride and low-high density lipoprotein cholesterol concentration, hypertension, and atherogenic dyslipidemia. Additionally linked to an increased risk of death from cardiac diseases is the metabolic condition. The comprehensive risks ratios for heart disease mortality in individuals with metabolism syndrome were 2.26 in men and 2.78 in women respectively, according to the study.^11,12Themajority of cases of IHD (ischemic heart disease) are due to a reduction in coronary blood flow caused by obstructive atherosclerotic disease.¹³Atherosclerosis generally occurs when the fatty, yellow-coloured plaques i.e. (atheromas) build up on the artery walls, narrowing the arteries and restricting the flow of blood.¹⁴

1) Pharmacological treatment goals for obesity (Including Several Drug Combinations):

a) BELVIQ:

Phase 3 clinical studies of the phentermine + topiramate combination were conducted after lorcaserin-induced weight loss. Under the results of the clinical trials for "behavioral modification and lorcaserin for obesity" (BLOOM) and “second study management of obesity" (BLOOSOM), the patient under investigation did not have diabetes. In the meanwhile, each patient got a lifestyle modification and either a placebo or lorcaserin. It indicates that patients losing weight on FDA-approved doses of 10 mg twice a day lost almost 3% more weight than those on a placebo.¹⁵

b) TOPIRAMATE PLUS PHENTERMINE:

Combining phentermine and topiramate reduces body weight and improves the cardiac illness risk variable. A range of dosages for this drug combination therapy have been examined, ranging from "3 mg phentermine plus 23 mg topiramate (low dose)" to "15mg phentermine plus 92 mg topiramate (high dose)". On the other hand, phentermine acts as a central sympathomimetic, increasing the release of dopamine, non-epinephrine, and serotonin. Topiramate functions as a gamma-aminobutyric acid (GABA) agonist, glutamine inhibition, and carbonic anhydrase inhibitory agent. For patients with an initial BMI of at least 30kg/m² or 27 kg/m² in the occurrence that certainly one or more complications linked to weight exist and other metabolic conditions, this combination has been authorized by the Food and Drug administration of the United States. When compared to other medications such as a combination of Naltrexone with bupropion, liraglutide, Belviq, and orlistat, the all-inclusive dosage of 7.5mg + 46mg of topiramate and phentermine is the most effective for weight reduction.^15,16However, since phentermine is not yet obtainable in India, topiramate is the only medication used to treat obesity abroad.¹⁷

C) SEMAGLUTIDE:

The FDA-approved semaglutide has been used for long-term assessment of weight in adults who are overweight. A health problem such as elevated cholesterol levels, increased blood pressure, and diabetes mellitus combined with a minimal calorie diet and increased exercise. A glucagon-like peptide-1 receptor agonist is semaglutide. It replicates the actions of the body's natural glucagon-like peptide-1 production. By promoting insulin production and inhibiting glucagon release, GLP-1 aids in the regulation of blood sugar levels. The American Diabetes Association (ADA) further recommends that GLP-1RAs lower the risk of severe adverse cardiac events (major atherosclerotic events) in individuals with T2DM and existing atherosclerotic coronary artery disease to a similar extent.¹⁸ When semaglutide was compared to other long-acting GLP-1 RAs, it was found to be superior in terms of total weight reduction.¹⁹

D) NALTREXONE PLUS BUPROPION:

The FDA has approved bupropion and naltrexone for different indications. Bupropion is a dopamine and non-epinephrine reuptake inhibitor that is licensed for depression, seasonal affective disorders, and quitting smoking. Researchers have looked into bupropion 300–400 mg/day as a monotherapy for overweight and obese people. Over six to twelve months, bupropion resulted in an average of 3.4% placebo-stimulated weight loss.^20,21 Initially, Phase 2 clinical case studies compared individual monotherapy (NB) or placebo with Naltrexone Plus Bupropion (NB) up to 24 to 48 weeks to help obese people lose weight. Studies have shown that combination therapies result in greater weight loss than separate monotherapies. Furthermore, there is a link between Naltrexone and bupropion and a decrease in both total and abdominal body fat. Phase 2 results showed that weight loss started as early as four weeks and continued not less than 56 weeks. When a fixed combination of naltrexone plus bupropion sustained-release (SR) in the doses of 32mg + 360mg per day has been used. In a meta-analysis, 55% of patients who received bupropion plus naltrexone lost 5% of their body mass, compared to 23% of those who received a placebo. Compared to placebo, participants treated with this combination (NB) lost an additional 5 kg of weight after a year of follow-up. For many patients with uncontrolled hypertension, it is contraindicated.^22,23 The moderately high cholesterol profile suggests a somewhat beneficial combination of bupropion and naltrexone for raising HDL cholesterol. The cardiometabolic risk profile may benefit little or somewhat from weight loss medication.²⁴ For nearly a decade, bupropion has been a lethal medication and has been combined with naltrexone for extended periods.²⁵

2) Non-pharmacological therapies (lifestyle interventions) for obesity:

a) PHYSICAL ACTIVITY OR EXERCISE:

Weight reduction is the primary goal for exercising in addressing the issues of gaining weight. To this end, the National Academy of Science's Institute of Medicine published a recommendation that calls for 60 minutes/day for a week instead of moderate-intensity exercise without modifying caloric intake. The positive effects of workouts for obese people include altered metabolism, such as better liver function, and hormone functioning, such as greater sensitivity to insulin and leptin, and elevated levels of the hunger hormone ghrelin. The stomach and small intestine are the main organs that release the peptide hormone ghrelin into the bloodstream, which stimulates appetite. It's the cause of weight gain.^26,27 A lower body weight should be achieved by eating a diet low in calories and getting 200–300 minutes of physical activity each week. Studies have indicated that longer-term weight loss is more likely to occur when exercise levels are higher. A patient can exercise most easily and effectively by walking. We advise patients to work for at least 40 minutes a day because this kind of activity improves heart patients' conditions and has more benefits.^28,29 A moderate-intensity walking program initiated following gaining weight with extremely low-energy diets promotes weight reduction and improves metabolic health associated with obesity sustainability.³⁰

b) DIET:

Several food choices the best diet is libitum, which allows patients to eat freely as long as they stay within physician-recommended calorie limits. However, variations in calories, the desired pace of shedding pounds, and the stage of medical management may be necessary depending on the population being treated and the severity of obesity. The diet needs to limit sweets and oils and prioritize foods high in fiber, fruits, and vegetables. A low-calorie diet offers at least 1000 calories per day. However, most low-calorie diets offer less than 800 calories per day. 90% of patients in the majority of clinical trials who followed extremely minimal consumption of calories lost 20 pounds or more, than 50% lost 40 pounds or more, in the first four to six months of the diet.²⁹ While long-term diet experiments have not demonstrated a definite superiority of one diet over another in terms of average weight loss, there is a significant amount of unique variation. Within each diet group, there are numerous anecdotalsuccess stories for a variety of weight loss diets.³¹ The consumption of 200 grams per day of low-fat dairy products is linked to a 25%, 7%, and 12% reduction in the risk of being overweight or obese.³²Thecare of obese individuals requires nutritional surveillance since it improves patient adherence to dietary supplements and keeps them from gaining weight back.³³

A population intervention or exposure, comparison, outcomes, and time procedure, or PI/PECOT, was used to systematically address overweight and obesity utilizing BMI classifications (more than 25 kg/m2 or greater than 30 kg/m2), and mandatory concomitant conditions. The subsequent measures are taken into consideration:

1). Substituting macronutrients (with all possible regimens with high, low, or extremely low carbs, foods rich in protein, or keto meals).

2). Conduct investigations on fat composition. The quantity of saturated fats, monounsaturated fats, polyunsaturated fatty acids (n-3 or n-6 PUFAs), and fish oils was used to characterize the quality of fat.

3). Food-focused diets, either with or without calorie restriction (such as those that emphasize whole grains, legumes, nuts, seeds, fruits, vegetables, and dairy products).

4). Dietary patterns, including low-glycemic load diets, Mediterranean diets (MED), vegan diets, and the dietary approach to cease (DASH) diet, can be followed by calorie restriction.³⁴

c) BEHAVIORAL MODIFICATION:

Using self-monitoring techniques (such as keeping track of food intake, exercising, or changing weight), managing stress, controlling stimuli (such as eating with smaller plates or away from the television), and receiving social support,0 especially from family and relatives are important components of behavioral modification.³⁵

Table.1 Various Anti-Obesity Drugs are used in Obesity with Cardiovascular Disease (CVD).^3,4,15,17

Drug Name	Usual dose mg/day	Mode of action	Indication	Contraindications	Adverse events	Route of Administration
Phentermine plus topiramate	15mg/ 92mg (ones a day)	Non- epinephrine agonist/ GABA agonist, glutamate antagonist	For those suffering from coronary artery disease, type 2 diabetes, hypertension or raised cholesterol	Patient with chronic Malabsorption syndrome or cholestasis, pregnancy, breastfeeding.	Elevation in heart rate, mood, sleep disturbance, acidity, paresthesia, and sleeplessness.	Oral
Naltrexone plus bupropion	4mg/90mg (2 tablets twice a day)	Opioid receptor agonist- non-epinephrine- dopamine reuptake inhibitor.	Reduced calorie diet, hypertension and type -2 diabetes	Chronic opioid use, pregnancy, Bulimia or anorexia nervosa, barbiturates and antiseizures.	Nausea, constipation headache, insomnia diarrhoea, slip disorder, dry mouth.	Oral
Semaglutide	2.4mg (weekly)	2.4mg (weekly)	Type-2 diabetes diet and improve glycaemic control.	pregnancy along with type 2 numerous endocrine neoplasia syndrome or medullary thyroid carcinoma	Nausea, abdominal pain, diarrhoea, constipation, headache, vomiting	Subcutaneous
Belviq	10mg (twice a day)	acts to suppress appetite by activating The region of the hypothalamus in particular contains 5-HT2c receptors in the brain's nervous system.	High cholesterol, calorie restrictions and weight related comorbidities.	Pregnancy, excipients and breastfeeding	Fatigue, back pain, dizziness, memory deficit, hyperprolactinemia	Oral

CONCLUSION:

Obesity and being overweight are linked to mortality and cardiovascular disease. A few lifestyle changes, like dietary adjustments, exercise, and dietary modifications, as well as bariatric surgery, can lessen weight loss and enhance cardiac results. Combining exercise and diet into lifestyle modifications that help lose body weight was an extra effective way to reach the desired reduction in calories goals rather than just diet and exercise. Pharmacotherapy or anti-obesity medications have a larger potential to enhance heart health, which is mostly associated with obesity. To assess the positive aspects and difficulties of these medicines, cardiovascular outcomes are also required. It is important to assess every patient.

CONFLICT OF INTEREST:

There is no conflict of interest.

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Received on 25.12.2023 Modified on 08.03.2024

Res. J. Pharmacology and Pharmacodynamics. 2024;16(2):114-118.

DOI: 10.52711/2321-5836.2024.00020