Recent Advances and Outcomes of Obesity Management

**Chapter 6**

## Novel Anti-Obesity Pharmacotherapies

*Firas Ghomraoui and Gitanjali Srivastava*

#### **Abstract**

Obesity is a global disease that causes or exacerbates many severe weight-related complications such as diabetes, cardiovascular disease, and fatty liver. Though there are concerted efforts to combat this disease through several means, lifestyle therapy is still considered the mainstay treatment for obesity. Unfortunately, patients with obesity respond either modestly or unfavorable to lifestyle intervention alone. Although the classical definition of an AOM is a medication that can help reduce at least 5% of body weight over a period of 3 months, the more novel agents have far surpassed that. There are presently six major FDA-approved medications: orlistat, phentermine monotherapy, phentermine-topiramate, naltrexone-bupropion, liraglutide 3.0 mg, and semaglutide 2.4 mg. Great strides have been made in the development of more novel agents, particularly those that affect either the gut hormones controlling satiety or certain pancreatic hormones. In this chapter, we will discuss current and upcoming novel AOMs available to treat and manage obesity. We will explore the novel endocrine peptides that are presently market accessible and how treating to target is feasible in the new era of obesity medicine. Further clinical trials must be conducted to pave the way for safer and more effective agents with greater access and affordability.

**Keywords:** anti-obesity medications, medical weight loss, weight management, type 2 diabetes, amylin, pramlintide, semaglutide, liraglutide

#### **1. Introduction**

Obesity is a worldwide growing disease that causes or exacerbates weight-related medical conditions contributing to a growing economic burden on many of the healthcare systems around the world. Various diseases have been found to be caused primarily by obesity, including type 2 diabetes mellitus (T2DM), obstructive sleep apnea (OSA), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and multiple cancers (namely liver, kidney, and gynecological cancers) [1]. As per the World Health Organization (WHO), obesity is categorized by Body Mass Index (BMI) of 30 and above, with overweight being between 25 and 30 [2]. Further classification as per the Center for Disease Control (CDC) guidelines include mild obesity (BMI between 30 and 35), moderate obesity (BMI between 35 and 40), and severe obesity (BMI more than 40) [3]. As per the WHO, as of 2016, there are 1.9 billion people who were classified as overweight around the world, with an extra 650

million with obesity [2]. This trend has been ballooning on an alarming rate with an incline in overweight and obesity rates, especially among children and adolescents from 4–18% globally between the years 1975 and 2016 [2].

Due to the rising prevalence and the major health consequences of obesity, there are unsurmountable efforts to combat this rising epidemic. Whereas adjunctive lifestyle therapy coupled with pharmacotherapy or surgical intervention remains a mainstay regimen for obesity treatment, several factors could impede clinically significant weight loss goals, rendering the journey tough for the majority of patients, including physical limitations due to injury (a possible consequence of obesity itself, nonetheless), socioeconomic status, and psychological factors. Therefore, focus on management has shifted towards a more wholesome approach that includes multidisciplinary intervention (dietary, exercise physiology, and clinical psychology referrals) to address barriers to care and other factors pertaining to decreased access to care. Furthermore, the advent of novel agents for treatment of obesity and subsequent Food and Drug Administration (FDA) approval to several of these agents recently have propelled these medications to the forefront of the fight against this debilitating disease.

As per the National Institutes of Health (NIH), the most updated guidelines to initiate medical treatment for obesity include a BMI that is greater than 30 or a BMI that is greater than 27 with a concurrent co-morbidity, such as T2DM or hypertension [4]. There are several definitions to what one considers significant weight loss. Weight loss at a total of 5% or more of baseline weight over a period of 3 months is considered clinically significant as per current studies, though more novel pharmacotherapies have now surpassed these goals [4]. Currently, there are six agents that are FDA approved for weight loss: orlistat, phentermine monotherapy, phentermine-topiramate, liraglutide 3.0 mg, naltrexone-bupropion, and (most recently) semaglutide 2.4 mg [5].

#### **2. Older-generation AOMs**

Orlistat, the first and oldest agent, is a pancreatic and gastric lipase inhibitor. One large prospective study done in 2004 showed a mean reduction in weight of 5.8 kg in patients taking orlistat compared to placebo (3 kg) over a period of 4 years [6]. However, its use has significantly decreased over the years to the well-documented side effects, which include kidney injury and kidney stones secondary to increase calcium oxalate formation in the renal tubules [7]. Phentermine-topiramate is the second FDA-approved medication and is consistent of a combination of phentermine, a central norepinephrine-releasing stimulant drug, and topiramate, an anti-migraine and anticonvulsant medication. One such randomized clinical trial, the SEQUEL study, showed an average of 9.3% and 10.5% reduction in weight in phenterminetopiramate half and full dose, respectively, compared to placebo (1.8%) over a period of 2 years [8]. Furthermore, the same study showed a reduction in diabetes development along with less side effects (which might include constipation, parathesias, and dry mouth) of this medication observed if administered over a longer period [8]. Naltrexone-bupropion (NB) is a combination medication consistent of naltrexone, and opioid antagonist medication, with bupropion, an anti-depressant medication [9]. A post-hoc analysis conducted by le Roux CW et al. in 2022 analyzing several clinical trials pertaining to this medication showed a consistent weight loss trajectory of 5–10% in all the patients taking NB compared to placebo [10].

*Novel Anti-Obesity Pharmacotherapies DOI: http://dx.doi.org/10.5772/intechopen.110685*



#### **Table 1.**

*Older generation and Novel\* anti-obesity pharmacotherapy summary.*

With greater understanding of the pathophysiology behind obesity, there have been gargantuan strides towards newer, more efficacious, and safer medications to induce weight loss compared to the medications in the older generation category. One such category of medications that are also FDA approved for weight loss include the Glucagonlike Peptide-1 (GLP-1) agonists. These medications, originally designed to be antidiabetic medications, have shown consistent weight loss potential upon their use, even in non-diabetic patients [11]. As of this moment, the FDA has approved two medications of this category for weight loss: liraglutide and semaglutide. However, there are several barriers that could limit the use of these medications, most notably related to the cost of these medications and variable insurance coverage that patients could carry (**Table 1**).

#### **3. Novel AOMs**

#### **3.1 Liraglutide and Semaglutide**

Liraglutide is a daily injection and, at 3.0 mg daily, is used for weight loss (as opposed to 1.8 mg daily for T2DM management) [12]. A randomized clinical trial, conducted by Pi-Sunyer X et al. back in 2015, showed a total of 63.2% and 33.1% of all the participants losing at least 5% and 10% of their body weight, respectively as compared to placebo (27.1% and 10.6%, respectively) [12]. Furthermore, another study showed the odds of maintaining those rates of weight loss tripled with liraglutide

*Novel Anti-Obesity Pharmacotherapies DOI: http://dx.doi.org/10.5772/intechopen.110685*

vs. placebo [13]. Semaglutide is a similar medication from the same drug family but is administered as a weekly injection compared to liraglutide. This is currently the newest FDA-approved medication at 2.4 mg weekly injection. There are currently five clinical trials that looked at the efficacy of this medication for weight management in comparison to placebo that have been performed (named STEP 1–5) [14]. The latest clinical trial, named STEP 5, looked at the use of semaglutide 2.4 mg weekly for sustained long-term weight loss in patients who do not have T2DM over a 2-year period. In this trial, the patients who took semaglutide for weight loss reported a mean change in body weight of −15.3% compared to the placebo group (−2.6%; P < 0.0001) [15]. The most reported side effects with this medication were gastrointestinal symptoms, such as nausea and reflux (**Table 1**) [15].

#### **3.2 Tirzepatide**

Tirzepatide, a weekly-injectable medication that agonizes both the GLP-1 receptors and the glucose-dependent insulinotropic polypeptide (GIP). It was first developed as an anti-diabetic medication and has shown great efficacy of lowering HbA1c as was demonstrated in the SURPASS trials but was found to greatly induce weight loss too [16]. In fact, the latest SURPASS trial (named SURPASS-5) showed a mean body weight change from baseline of −5.4 kg, −7.5 mg, −8.8 mg, and 1.6 kg with tirzepatide 5 mg, 10 mg, 15 mg, and placebo, respectively, over a period of 40 weeks [16]. However, the most impactful clinical trial was just published recently by Jastreboff AM et al. In this trial, 2539 patients who were obese or overweight with one co-morbidity (excluding T2DM), were randomized into tirzepatide and placebo groups over 72 weeks. The results were quite spectacular, with a mean weight change of −20.9% on the highest dose of tirzepatide (15 mg weekly) compared to placebo (−3.1%; P < 0.001) [17]. Furthermore, 91% of those taking the highest dose of tirzepatide reported a more than 5% weight loss from baseline compared to placebo (35%; P < 0.001), fitting the criteria for clinically significant weight loss [17]. The most reported side effects mimic those of the GLP-1 agonists [17].

#### **3.3 Cagrilintide**

In addition to the gut hormones controlling satiety (such as GLP-1 and GIP), there are studies pertaining to mimicking pancreatic hormones such as amylin. Cagrilintide is a long-acting amylin analogue that is administered as a weekly injection [18]. In a randomized clinical trial performed by Lau DCW et al., patients who were either obese or overweight with one co-morbidity (excluding T2DM) were randomized into groups of cagrilintide, liraglutide, and placebo over a 26-week period. The patients who took cagrilintide (at maximum dose of 4.5 mg weekly) were shown consistently to experience higher weight loss (10.8%) in comparison to the liraglutide 3 mg daily group (9%) and placebo (3%); p < 0·001 and p-0.03 respectively [18]. The most reported side effects with this medication include gastrointestinal symptoms such as nausea, constipation, and diarrhea [18].

Moreover, there has been growing interest in combinatory AOMs for greater efficacy and synergy and/or additive effects. Dual-action incretin cagrilintide + semaglutide 2.4 mg was most notably shown in a study conducted by Enebo LB et al. as recently as 2021 [19]. In this robust clinical trial, 96 patients were randomized to groups of cagrilintide at various doses vs. placebo (semaglutide 2.4 mg being given to all participants). The results were promising; the mean percentage bodyweight

reduction was greater with cagrilintide 1.2 and 2.4 mg than with placebo over 20 weeks (15.7% weight reduction for cagrilintide 1.2 mg, 17·1% for cagrilintide 2.4 mg vs. 9.8% in the placebo groups). The side effects reported were mostly gastrointestinal symptoms by a third of the participants, with glycemic parameters improving in all groups [19]. Given the new findings in the literature pertaining to the latter medications, it is only a matter of time before tirzepatide, cagrilintide, and other combinations join the growing list of weight loss medications that are approved by the FDA for an obesity indication.

#### **3.4 Setmelanotide**

Another novel medication has achieved an orphan indication for rare genetic obesity. Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is one such example that acts upon energy homeostasis through the leptin-melanocortin pathway [20]. This medication is used to treat mono-genic obesity primarily, such as the ones that are due to congenital leptin receptor (LEPR) deficiency, a bi-allelic mutation causing a deficiency in pro-opiomelanocotin (POMC) deficiency or proprotein covertase subtilisin/kexin type 1 (PCSK1) deficiency [20]. Several phase 3 global clinical trials with setmelanotide reported consistent weight loss of more than 10% of the original body weight, with side effects being mostly hyperpigmentation followed by nausea and vomiting [20].

#### **3.5 Updated bariatric surgery considerations**

Presently, the most common bariatric surgery procedures performed are the vertical sleeve gastrectomy (VSG) and the Roux-en-Y gastric bypass surgery (RYGB). Both procedures are effective for weight reduction and treatment of type 2 DM, as several studies showed, with RYGB being superior to VSG in both aspects (although RYGB carried higher risk) [21, 22]. Recently, updated bariatric surgery guidelines were published by Eisenberg D et al. in 2022, thirty-one years after the previous guidelines [23]. The newer guidelines lower bariatric surgery criteria in patients to a BMI greater than 35 (irrespective of whether they have co-morbidities or not) or a BMI greater than 30 with a diagnosis of metabolic syndrome and significantly remove barriers to treatment [23]. These latest bariatric surgery guidelines stem from the clearer understanding of the underpinnings of energy metabolism and scientific progress leading to necessary revision of the original guidelines [23]. While bariatric surgery is able to achieve 30–35% weight loss, novel AOMs can be utilized as adjunctive pharmacotherapy pre- or post-operatively to target weight gain [24]. Thus, combinatory novel AOMs coupled with surgical intervention are likely to garner more evidence in the future.

#### **3.6 Weight-related therapeutic targets**

As we make scientific progress with >15% weight loss, improvement, or remission in metabolic dearrangements such as fatty liver, T2DM, and cardiovascular disease can now be feasible. Anti-diabetes medications, such as semaglutide, liraglutide, and the newer tirzepatide were serendipitously found to be novel AOMs. Consequential reduction in hemoglobin A1c levels occur with the use of these agents in patients with dual obesity-diabetes diagnosis. Several studies have been conducted comparing different agents with regards to their efficacy of lowering A1c targets; in one trial,

#### *Novel Anti-Obesity Pharmacotherapies DOI: http://dx.doi.org/10.5772/intechopen.110685*

tirzepatide was shown to be superior to semaglutide over a 40-week period (−2.24 percentage points vs. −1.86 percentage points respectively) [25]. Furthermore, another area of highlighted focus is cardiovascular disease where risk reduction is paramount [26–28]. There is now heavy focus on GLP-1s for such a role, as evidenced by the PIONEER, SELECT, and SUSTAIN trials. One trial evaluated the role of oral semaglutide with regards to cardiovascular outcomes, with overall reduction of cardiovascular events in the patients taking oral semaglutide vs. placebo (although statistically significant only for non-inferiority of oral semaglutide vs. placebo throughout the study) [28]. Additionally, non-alcoholic fatty liver disease (NAFLD) is a complication with growing incidence around the world, ostensibly tied to the rise of obesity. Again, GLP-1 s have shown great efficacy in this realm, as one metaanalysis of several clinical trials spanning several GLP-1 agents showcased an overall reduction of both absolute percentage of hepatic fat and serum liver enzymes over a median period of 26 weeks [29]. All in all, in addition to weight reduction, there are innumerable health benefits being observed because of the growing use of these novel anti-obesity medications.

#### **3.7 Obesity medical devices**

In addition to AOMs and surgical weight loss options, there are different anti-obesity medical devices. One such device is called Plenity, an oral, nonsystemic, superabsorbent hydrogel that has shown to reduce a mean weight loss of 6.4% compared to 4.4% in the placebo group over a 24-week period [30]. Another device that has been studied showcased a 3.68–4.52% drop in total body weight [31]. Further studies with regards to medical devices are underway to pave way for their wider introduction to combat this global epidemic.

### **4. Conclusion**

In conclusion, there are great strides being made in the pharmacotherapeutic management of obesity, as a response to the growing dangers of obesity. Previously, clinically significant weight loss was thought to be greater than 5% or more; however, we are now entering a new era of obesity medicine where >15% might be the new target for weight loss intervention. With novel obesity pharmacotherapy in the horizon, greater awareness and more solid recognition of this malady as a disease requires unique attention from a socio-economic and policy-making level (involving the patient, the insurance companies, and the governing bodies) in order to ensure non-discriminatory access at reasonable prices.

### **Author details**

Firas Ghomraoui1,4 and Gitanjali Srivastava1,2,3,4\*

1 Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University School of Medicine, Nashville, TN, USA

2 Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA

3 Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA

4 Vanderbilt Weight Loss Center, Vanderbilt University Medical Center, Nashville, TN, USA

\*Address all correspondence to: gitanjali.srivastava@vumc.org

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 7**

## The Role of Dietary Interventions in the Management of Obesity

*Asad Ullah, Muhammad Jamil and Johar Jamil*

#### **Abstract**

The epidemic of obesity is taking over many parts of the world. The etiology of obesity is multifactorial; however, disordered energy balance regulation is a central feature. Obesity is managed by lifestyle changes alone or in combination with pharmacotherapy or bariatric surgery. Diet is an essential part of the primary and secondary prevention of obesity. Various dietary patterns have successfully induced acute weight loss, but no diet stands apart from others. Most agree that an ideal weight loss diet should be nutritionally adequate, safe, effective, affordable, and culturally admissible. Creating a negative energy balance is the underpinning theme across weight loss diets. Despite early weight loss, most individuals struggle to maintain weight long-term. Weight gain occurs due to a complex interaction of physiological, environmental, and psychological factors. Long-term weight management is influenced by lifelong conformity to low energy diet, lifestyle changes and ongoing support from family, friends, and healthcare professionals. Strategies should be implemented at the population level to prevent obesity. Policymakers, schools, businesses, healthcare providers, community leaders and individuals must unite at local, national, and international levels to fight the epidemic of obesity.

**Keywords:** low fat diet, low carbohydrate diet, Mediterranean diet, weight loss, fasting

#### **1. Introduction**

Obesity is a complex chronic disease with abnormal or excessive body fat that impairs health, increases the risk of long-term medical complications, and reduces life span. Obesity is associated with diabetes mellitus, hypertension, cardiovascular disorders, neurological conditions, e.g., Alzheimer's dementia, fatty liver disease, and certain cancers.

The prevalence of obesity has almost tripled globally between 1975 and 2016 [1]. It has reached to epidemic level and is expected to grow in the foreseeable future.

Patients with body mass index (BMI) >25 kg/m<sup>2</sup> or high abdominal girth (men >102 cm and women >88 cm) should consider weight loss. Other factors, such as a family history of obesity, fat distribution, obesity-associated comorbidities, and cardiovascular risk factors, influence obesity management.

Setting a weight loss goal is the first step. It should be realistic, achievable, and reasonable. Weight loss could be divided into two phases, i.e., initial rapid weight loss (up to 6 months) and slow maintenance phase (lifelong). Diet plays a substantial


#### **Table 1.**

*Advantages of 10 kg weight loss.*

role in the early phase of weight loss. Research shows that a modest 5–10% weight loss improves lipid profile, glycemic control, and blood pressure [2] (**Table 1**). It is clinically safe and achievable; hence most weight loss programs aim for 5–10% weight loss in the acute phase.

Weight maintenance is more challenging. Adherence to a low-fat diet and regular physical activity determine success.

Lifestyle modification (including diet, stress management, sleep, and physical exercise) is the first line of treatment for class I (BMI 30–34.9 kg/m2 ) & class II (BMI 35–39.5 kg/m2 ) obesity. Most agree that diet plays a fundamental role in the etiology of obesity. The modern diet is rich in refined carbohydrates, animal fats, salt, additives, preservatives, and ultra-processed foods. All these attributes drive weight gain and obesity. Therefore, modifying diet alone or combined with other interventions could prevent or treat obesity.

Public health and social marketing shape the dietary patterns of the public. The current focus is on selecting healthy food and eating less. Unfortunately, this has created a misconception that calorie restriction is the only or main factor responsible for weight loss. Indeed, weight loss needs calorie restriction, but the mechanics of weight loss are far more complex than just calorie restriction.

#### **2. Nutritional strategies for weight loss**

Clinical and commercial weight loss programs have successfully used various dietary patterns. A common theme among weight loss diets is setting up a negative energy balance. Most weight loss programs target 0.5 to 1 kilogram weight loss per week. A calorie deficit of 500 per day or 3500 per week is sufficient to achieve this target. The recommended calorie intake for a patient is calculated by first calculating the resting metabolic rate and multiplying it by an appropriate physical activity factor to get the calories for weight maintenance. Then subtract calories to induce weight loss. A fixed-calorie diet is a relatively easy alternate approach. It recommends a predetermined daily calorie intake based on the calorie level, which caused weight loss in clinical trials.

After deciding the daily calorie intake limits the next step is to choose the appropriate diet. Patients and families should be actively involved in selecting the weight loss diet to ensure success.


**Table 2.**

*Common dietary approaches for weight loss.*

**Table 2** summarizes some of the commonly used weight loss diets.

#### **2.1 Macronutrient-based approaches for weight loss**

The human diet comprises macronutrients, micronutrients, dietary fiber, and water. The macronutrients, i.e., carbohydrates, fat, and protein, are energy sources. Fat is the most energy-dense macronutrient and contains 9 kcal/gram. Carbohydrates and protein provide ~4 kcal/gram.


#### **Table 3.**

*Macronutrient reference values for the healthy population.*

Dietary reference intake (DRI) provides reference values of nutrients in healthy populations. **Table 3** demonstrates the daily requirements of macronutrients for healthy individuals [3].

Macronutrient-based calorie-restricted diets have variable macronutrient composition. Keeping energy constant, increasing one macronutrient will result in a compensatory reduction of another macronutrient. For instance, a low carbohydrate diet will have relatively high fat and protein content.

#### *2.1.1 Low-fat diet*

A low-fat diet provides 20–25% of energy from fat, and a very low-fat diet yields 10–20% of energy from fat. The proponents of a low-fat diet hypothesize that reducing the most calorie-dense macronutrient, i.e., fat, could result in weight loss. However, this relationship is not as straightforward as it sounds. Epidemiologic data show increased body weight despite a reduction in overall fat intake.

A meta-analysis comparing low-fat and regular-fat diets reported greater weight loss (3–5 kg) in individuals with a 10% or more reduction in dietary fat intake [4]. Another review showed a dose-dependent decrease in weight with a low-fat diet. Every 1% reduction in fat was associated with 0.28 kg weight loss [5]. However, another meta-analysis failed to show a difference in weight loss with reduced and normal-fat diets [6].

Indeed high-fat intake is associated with weight gain; however, the weight loss effect is unclear within the low-fat range (<30% of total energy). A systematic review reported higher weight loss in higher fat quartiles within the low-fat range [7]. Weight loss achieved with a low-fat diet is comparable to other weight loss diets.

A low-fat diet is associated with reduced triglyceride levels. However, triglycerides could increase if high glycemic index (GI) carbohydrates replace fat. Interestingly, low GI carbohydrates or mono/polyunsaturated fat do not increase triglycerides [8].

It is a challenge to maintain a very low-fat diet long term.

#### *2.1.2 Low-carbohydrate diet*

This diet yield <45% of daily calorie intake from a carbohydrate source. But there is a lack of consensus on the exact amount of carbohydrates, making it difficult to compare outcomes of studies.

The low-carbohydrate intake suppresses insulin secretion, which decreases fat storage (carbohydrate-insulin model). The higher protein content enhances satiating and higher metabolic burn (200–300 kcal) due to the thermogenic effect. Although unproven, some also argue that the calories from proteins are less prone to be stored as fat than the equivalent caloric intake from a carbohydrate source.

#### *The Role of Dietary Interventions in the Management of Obesity DOI: http://dx.doi.org/10.5772/intechopen.111529*

A meta-analysis of 38 studies shows greater weight loss with a low carbohydrate diet than a high carbohydrate diet (16.9 vs. 1.9 kg respectively). However, randomized cross-over and randomized controlled trials did not report a significant difference in weight loss between low and high carbohydrate diet [9].

Carbohydrate-restricted diet enhances satiety and is easy to follow. Studies show increased insulin sensitivity and improvement in glycemic control with a high-fat diet [10]. Evidence confirms the benefits of a low-carbohydrate diet in type II diabetes mellitus [11]. They are famous for rapid weight loss, especially the ketogenic version.

Adverse effects include fatigue, nausea, halitosis, muscle cramps, dizziness, and headache. Most low-carbohydrate diets limit fruit and vegetables, which increases the risk of micronutrient deficiency, e.g., vitamin A, B1, B6, E, folic acid, calcium, potassium, and dietary fiber. Moreover, adherence to a very low-carbohydrate diet is a challenge.

Studies have raised concerns about increased cardiovascular risks with a low-carbohydrate diet, especially if the saturated fat intake is high. A meta-analysis confirmed an increase in low-density lipoprotein with a low carbohydrate diet, although high-density lipoprotein and triglycerides improved [12]. The high protein content of this diet could increase urinary calcium excretion, leading to osteoporosis. Renal impairment could ensue due to high acid load [13]. Gout could occur due to high purine content.

#### *2.1.3 Ketogenic diet*

Also called the keto diet is a very low carbohydrate diet that allows 20–50 grams of carbohydrates per day and induces ketosis. The ketogenic diet suppresses insulin secretion, thus switching the energy source from glucose to fat. The body attempts to keep glucose levels at an appropriate level through gluconeogenesis. However, as the body's ability to synthesize glucose declines, fat is mobilized and utilized to produce ketones through ketogenesis, which meet the body's energy demands. Ketosis suppresses appetite, food cravings and hunger [14], thus encouraging rapid weight loss. Notably, nutritional ketosis does not cause metabolic acidosis [15] as opposed to diabetic ketoacidosis.

Keto diets are popular in the weight loss industry but do not have full support from the medical community due to their side effects. **Table 4** shows the two commonly used ketogenic diets and their macronutrient contents.

A meta-analysis of 14 randomized trials with 12 months or more follow-up reported greater weight loss with a very low carbohydrate ketogenic diet [WMD: 0.91 kg (95% CI: −1.65 to −0.17) p = 0.47] compared to a low-fat diet [16].

Besides weight loss, the ketogenic diet has a therapeutic role in diseases such as epilepsy, non-alcoholic steatohepatitis, Alzheimer's disease, polycystic ovary syndrome, acne and certain cancers [17]. The exact mechanisms of therapeutic actions of the ketogenic diet are not fully understood; however, **Table 5** [17] illustrates the suggested mechanisms.


**Table 4.** *Composition of ketogenic diets.*


#### **Table 5.**

*Proposed therapeutic mechanisms of keto diets in various medical conditions.*

The long-term safety of the keto diet is yet to be confirmed. Epidemiological data correlate a low carbohydrate diet with high mortality [18]. The high-fat content of the keto diet is a concern. It adversely affects the gut microbiome, brain function, cardiovascular health, and metabolic profile. Furthermore, compliance with the ketogenic diet is a challenge.

The Keto diet should be used cautiously with sodium-glucose transporter 2 (SGLT2) inhibitors in diabetic patients [19] due to the risk of metabolic acidosis.

Most of the macronutrient-based dietary approaches result in significant weight loss in the short term. No macronutrient distribution has shown a meaningful advantage over others regarding weight loss or cardiometabolic benefits. POUND LOST study [20] compared four diets with macronutrient permutations in obese adults (BMI 25–40 (kg/m2 ) in a free-living setting. Body weight and body fat (total, visceral, hepatic, and subcutaneous fat) were measured at 6 and 24 months. Regardless of the macronutrient composition, most participants lost body fat (12.4%), lean mass (3.5%), visceral fat (16.1%), subcutaneous fat (13.6%) and abdominal fat (13.8%) at 6 months. The critical determinants for weight loss were low-calorie density and high fiber intake. The structured eating patterns might have also contributed to weight loss. At 24 months, most participants regained 40% of the lost weight with no difference between the diets.

Quality of the macronutrients is equally crucial for health benefits. Eco-Atkin study [21] randomly assigned 47 overweight adults with hyperlipidemia to either a low carbohydrate (26%) vegan diet with high protein (31%) and fat (43%) from gluten, soya, vegetable oils and nuts or high carbohydrate lacto-ovo vegetarian diet (58% carbohydrate, 25% fat & 16% protein). Weight loss at 4 weeks was similar in both groups; however, total cholesterol, high-density lipoprotein ratio (−8.1%), low-density lipoprotein (−8.7%) and apolipoproteins B: A1 ratio (−9.6%) were significantly lower in the low carbohydrate group. Blood pressure was also lower in the low-carbohydrate vegan group. Twenty-three patients completed 6 months of follow-up in a freeliving setting. Study participants lost further weight in both groups (−6.9 vs. −5.8 kg respectively). Lipid markers declined in both groups but more in the low carbohydrate

vegan group than in the comparator group. This study highlighted the weight loss and cardiovascular benefits of a vegan diet over a vegetarian diet. Similarly, the Prospective Urban Rural Epidemiology (PURE) study reported low non-cardiovascular and allcause mortality in individuals with high fruit, vegetable, and legume intake [22].

In clinical studies, restrictive dietary approaches show weight loss in the short term; however, increased hunger and dissatisfaction reduce their effectiveness and long-term sustainability.

#### **2.2 Balanced low-calorie diets patterns**

This approach focuses on the whole diet rather than targeting a specific macronutrient. Besides acute weight loss, it has beneficial cardiometabolic effects independent of weight loss. They are more satisfying and have a better consumer acceptance profile. Therefore, long-term compliance is better. A few common balanced macronutrient dietary patterns are discussed below.

#### *2.2.1 Mediterranean diet pattern*

The Mediterranean diet is popular in the Mediterranean basin but is adopted worldwide due to its favorable effects on cardiovascular risks and weight loss. Some of the longest-living people in the world have consumed the Mediterranean diet. Its ingredients are not homogeneous and vary from region to region. However, it is primarily a plant-based diet, which promotes a high intake of local fruit, vegetables, unrefined grains, nuts, legumes, and olive oil. Fermented dairy products, fish, and red wine are allowed in moderation, while a low intake of meat and meat products is recommended. Mediterranean diet is rich in dietary fiber, micronutrients, antioxidants, monounsaturated and omega-3 polyunsaturated fats. It is low in saturated fat. It offers more food diversity than restrictive diets.

Studies show contradictory results about the weight loss outcomes of Mediterranean diet. A systematic review of 21 epidemiologic studies provided mixed results regarding the effects of the Mediterranean diet on weight loss [23]. The mixed results could be due to heterogeneity, varied comparators, and inconsistent follow-up periods. A recent systematic review [24] of 5 randomized trials reported moderate weight loss (−3.8 to −10.1 Kg) beyond 12 months using the Mediterranean diet. The weight loss was superior to the low-fat diet but equal to the low-carbohydrate and American Diabetes Association diet. Further studies are needed to clarify the role of the Mediterranean diet in weight loss.

Regardless of weight loss, the antioxidant and anti-inflammatory properties of the Mediterranean diet have beneficial effects on the cardiometabolic profile. Some experts believe that the anti-atherogenic effect is related to bioactive constituents in Olive oil (esp. extra virgin oil) [25] rather the mono-unsaturated fat. PREvención con DIeta MEDiterránea (PREDIMED) study is the largest randomized controlled trial designed to assess the cardiovascular benefits of the Mediterranean diet [26]. The study randomly assigned 7447 participants with cardiovascular disease risk factors but no diagnosis of cardiovascular disease into three groups. Group 1 was assigned to a Mediterranean diet enriched with extra virgin olive oil (MD + EVOO), group 2 had a Mediterranean diet with nuts (MD + nuts) and group 3 was prescribed a low-fat diet. No restrictions were placed on energy intake. The unadjusted hazard ratio for the cardiovascular event was 0.70 (95% CI: 0.53–0.91) in MD + EVOO and 0.7 (95% CI:0.53–0.94) in MD + nuts compared to the control group. The risk of developing

diabetes mellitus was lower in the MD groups. In June 2018, the PREDIMED study was retracted and republished due to errors in the randomization. However, study results and overall conclusion remained unchanged after re-analysis.

#### *2.2.2 Dietary approach to stop hypertension (DASH) diet*

DASH dietary pattern was introduced in the 1990s to prevent and treat hypertension. It advocates the intake of fresh fruit, vegetables, low or fat-free dairy and nuts. DASH diet recommends lower sodium intake (<1.5 g/day) and discourages using saturated fat and sweetened beverages.

A meta-analysis of the DASH diet reported a reduction in systolic and diastolic blood pressure by −7.4 and −4.4 mm Hg, respectively, compared to the comparator [27].

Besides its blood pressure-lowering effect, several studies have highlighted the favorable effects of the DASH diet on lipid profile, blood glucose and insulin resistance. It correlates with lower colorectal cancer risk and improved celiac and diverticular disease [28]. A meta-analysis of 13 studies revealed the weight loss effects of the DASH diet [29]. The weighted mean difference was −1.42 kg (95% CI: −2.03 to −0.82) in 8–24 weeks. The weight loss effect was more pronounced with a low-calorie DASH diet in obese individuals.

#### *2.2.3 Portfolio pattern*

It is a modified plant-based diet with cholesterol-lowering foods such as olive oil, nuts, legumes, pulses, barley, oats, psyllium, etc. Its role in weight loss is not clear.

#### *2.2.4 Nordic pattern*

It was launched in 2004 and comprised the traditional diet consumed in Nordic countries. It encourages the use of fruit, vegetables, spices, seafood, and unsaturated oils (Canola oil), while processed foods and red meat are discouraged.

A randomized study reported a mean weight loss of −4.7 kg with an ad libitum Nordic diet compared to −1.5 kg with an average Danish diet [30].

#### *2.2.5 Vegetarian pattern*

It is a heterogeneous diet emphasizing the consumption of plant-based food (e.g., fruit, vegetables, seeds, legumes etc.). A vegetarian diet is classified depending on the restrictions applied, but avoiding meat is a constant feature. Vegans avoid any food of animal origin, lacto-vegetarians can take dairy products, and lacto-ovo-vegetarians can take dairy and eggs.

The vegetarian diet is rich in polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), minerals, fiber, antioxidants, and plant sterols. All these ingredients favorably influence lipid profile and cardiovascular risks. The low-calorie density of vegetarian food encourages weight loss.

Multiple studies have shown weight loss with vegetarian diet [31].

#### *2.2.6 Low glycemic index dietary pattern*

The glycemic index is the blood glucose response to a defined amount of carbohydrate (50 grams) in a test food relative to a reference food (usually white bread).

#### *The Role of Dietary Interventions in the Management of Obesity DOI: http://dx.doi.org/10.5772/intechopen.111529*

The GI was primarily developed for managing diabetes mellitus; however, it has earned popularity in weight management.

Low GI foods positively modify blood glucose levels, insulin levels, blood pressure and lipid profile. Studies show an association between low GI food with higher weight loss (−1 to 3 kg) compared to other energy-restricted diets in the short term [32].

#### *2.2.7 Paleolithic pattern*

It is also called the 'old stone age' or 'caveman diet'. This pattern is based on the diet practiced by our ancestors 2 million years ago. Its ingredients vary from region to region but generally allow vegetable, fruit, pasture-raised or grass-fed meat, fish, poultry, and nuts. At the same time, processed foods, grains, legumes, and dairy are restricted.

The Paleolithic diet is nutritious; however, compliance is challenging due to the elimination of commonly consumed beverages and foods. Limited available research showed improved insulin sensitivity, lipid profile, weight loss and an association with lower frequency of certain cancers [33, 34].

#### **2.3 Low-calorie dietary pattern**

A low-calorie diet (LCD) allows 900–1200 kcal/day. LCD is popular for achieving rapid weight loss in a short time; however, weight regain is a concern. A systematic review reported a mean weight loss of 7–13 kg at 14 weeks [35]. The weight loss declined to 6–7 kg at 12 months and 3.5 kg at 2 yr. Most individuals were close to the pre-intervention weight at 5 yr., highlighting the difficulty in maintaining weight long-term. Interestingly, men attain higher weight loss with LCD than women (11.8 vs. 10.3% respectively) [36].

Furthermore, sustaining LCD is challenging due to its restrictive nature and low energy content. These diets pose the risk of micronutrient deficiency. Therefore, it should be supplemented with either multivitamins or fortified food.

The very low-calorie diet (VLCD) provides <900 kcal/day. It is best preserved for those with acute threatening health risks from obesity and where rapid weight loss could improve the outcomes. VLCD is used briefly before bariatric surgery to reduce the risk of complications.

Weight loss with VLCD is more impressive than with LCD. Ninety per cent of the patients accomplish more than 10% weight loss with VLCD vs. 60% of the patients with LCD. Weight loss slows substantially after 12 weeks due to a low resting metabolic rate and declining voluntary energy expenditure. Like LCD, the weight loss is more in men than in women (2–2.5 kg vs. 1.5–2 kg/week). Adding behavioral therapy and exercise to VLCD increases weight loss [37]. Studies show that VLCD could help in maintaining weight [37].

The Diabetes remission clinical trial (DiRECT) trial reported a high likelihood of diabetes mellitus remission with VLCD at 1 & 2 yr. follow-ups [38].

Some experts fear that the rapid weight loss with VLCD will follow rapid weight gain. But studies do not support this hypothesis [39].

VLCD is administered in a liquid formula based on milk or egg protein. It is supplemented with vitamins, fatty acids, and electrolytes to compensate for micronutrient deficiency. The protein content of VLCD is high (0.8–1.5 g/kg) to counter the lean mass loss.


#### **Table 6.**

*Side effects and complications of VLCD.*

**Table 6** summarizes the side effects of VLCD. Patients on VLCD therapy require close metabolic monitoring and should be administered only under the supervision of physicians with experience in this area.

VLCD is contraindicated in patients with a history of cardiovascular diseases, cardiac conduction abnormalities, recent myocardial infarction, type I diabetes mellitus, renal disease, hepatic disorders, burns, and pregnant or lactating women. Behavioral contraindications include acute psychiatric illness, substance abuse, major depression, bulimia nervosa, and bipolar disorder. Caution should be exercised if used in the elderly and pediatric population.

#### **2.4 Food-based approaches**

These dietary approaches recommend using specific foods such as fruit, vegetables, pulses (lentils, chickpeas, peas & beans etc.), nuts, whole grains, and dairy products. Evidence shows that these foods have a role in weight loss, maintaining body weight, and reducing cardiovascular risks.

#### **2.5 FAD diets**

The FAD diet is marketed as a quick fix for rapid weight loss in a short period. It is administered as a very restrictive diet or eating a few foods in an unusual pattern, such as eating only tomatoes. Such programs often make unreasonable claims that are not based on scientific evidence. A FAD diet could be harmful and should be discouraged.

#### **2.6 Intermittent energy restriction**

Fasting has been used for health benefits since the 5th Century BC [40]. In modern medicine, fasting in obesity management goes back to 1960s. Unfortunately, it went out of fashion due to serious adverse events. However, it has re-emerged as a therapeutic option recently. Besides weight loss, calorie restriction enhances insulin sensitivity, improves blood pressure, and reduces cardiovascular risks in animals. Furthermore, fasting correlates with cancer prevention and increased life expectancy in pre-clinical studies. The exact mechanisms for these changes are not fully understood. One hypothesis is the upregulation of the Sirtuins (SIRTs) signaling pathway. Sirtuin 1 (SIRT1) is an intra-nuclear molecule which deacetylates transcription factors involved in longevity and stress management. Calorie restriction upregulates SIRT1, which, in turn, reduces inflammation and increases insulin sensitivity [41]. SIRT1 reduces fat storage and resets the hormones linked with age pacing via the proliferator-activated receptor gamma pathway [42].

Fasting could be total prolonged fasting (TPF) or intermittent fasting (IF). TPF involves going without food for days. It is counterproductive for weight loss due to a compensatory decline in metabolic rate and physical activity. Moreover, it is associated with severe lean mass and micronutrient deficiency.

Intermittent fasting (IF) offers a sustainable and healthy alternative. It consists of fast and feast windows. Few or no calories are ingested during the fast, followed by ad libitum eating. IF is not a diet as such instead; it is about the timing of eating. In other words, any diet could be intercalated with IF.

Three common forms of IF are a 5:2 diet, alternate day fasting and time-restricted feeding (TRF). The 5:2 diet entails two fasts and five ad libitum feeding days per week. Alternate day fasting involves a day of fasting followed by an ad libitum eating day. TRF is the most popular form of IF. It implies an 8–10 hr. daytime feeding window followed by a 14–16 hr. fast (including overnight fast). The supporters of TRF hypothesize that eating food late at night may disrupt circadian rhythm, hormonal balance, glucose tolerance, reduce resting energy expenditure, and alter body temperature rhythms. Therefore, changing the eating time may improve the metabolism.

Fasting can reduce body weight by multiple mechanisms, i.e., calorie restriction, ketogenesis, interfering with the gut microbiome and establishing a feeding routine. A study compared a 5:2 diet with continuous energy restriction (1200–1500 kcal/day). The weight loss was comparable in the two groups (−6.8 ± 6.4 kg vs. −5.0 ± 7.1 kg, respectively) [43]. Another review of 40 studies reported that the IF caused 7–11 pounds of weight loss over 10 weeks; however, it was not superior to continuous energy restriction [44]. Furthermore, the adaptative responses to weight loss with IF were not different from continuous energy restriction.

Fasting remains an option in managing obesity, but further research is required.

#### **2.7 Non-dieting approach**

The traditional weight loss dietary approaches are predominately restrictive and fail to support weight maintenance. Non-dieting lifestyle approach is a popular alternative to the conventional weight-focused approach. The proponents of this weightneutral approach believe that health is the outcome of behaviors independent of body weight. It focuses on a meaningful and fulfilling lifestyle. In a non-dieting program, food intake is guided by internal body cues, e.g., hunger and satiety [45], rather than external signals, such as meal time or events. Patients are encouraged to accept and respect their body size/shape at any weight. Health at Every Size (H@ES) is a program based on this philosophy. Besides intuitive eating, cognitive behavioral therapy and reasonable levels of physical activity administered in a non-restrictive way are other essential elements of H@ES.

Although the non-dieting approach is weight neutral, some studies have reported weight loss with this pattern. A randomized study compared a non-dieting eating pattern (1800 kcal/day) to a restrictive diet (1200 kcal/day). Weight loss was less in the non-dieting group than in the comparator group initially. However, at 12 months, greater weight loss was observed in the non-dieting group (10 vs. 4.5 Kg) than in the comparator [46]. Other studies revealed contradictory results; therefore, further research is needed.

The non-dieting approach has limitations and is not suitable for everyone. It is contraindicated in obese individuals fond of high-fat or high-sugar foods, those with extreme hunger signals, who consider eating large portions normal, and who lack the comprehension of healthy nutrition.

The non-dieting approach improves eating-related psychological disorders such as binge eating, depression, anxiety, and poor self-image [47].

#### **3. Practical dietary interventions for weight loss**

Regardless of the weight loss dietary approach, the following interventions could assist in achieving sustainable weight loss. It is essential to incorporate these strategies into daily routines to achieve the desired results.

#### **3.1 Replacing high for low energy density foods**

Studies show that people eat a consistent amount of food regularly. Therefore, diminishing the calorie density will lower the energy intake while eating satisfying meals.

The food energy density could be reduced by adding water-rich foods such as vegetables and non-starchy fruit. Another approach is reducing fat by using low-fat versions, e.g., grilled meat instead of fried meat or low-fat milk instead of full-fat dairy, without restricting the portion size. Besides quantity, the quality of fat also matters. Most dietary guidelines recommend substituting trans and saturated fat with monounsaturated and polyunsaturated fat.

Utilizing low-calorie dense foods at different meal courses could also help achieve sustainable weight loss. Studies indicate that selecting a large portion of low-energy-density food in the first course (starters) promotes satiety and helps lower the total calorie intake, e.g., low-calorie-dense salads and broth-based soups. Most of the energy intake occurs during the main course. Substituting high-calorie dense foods with low-calorie dense foods in entrée could support weight loss.

Food portion is another variable which influences energy intake. The larger the portion size, the higher the energy intake.

In a nutshell, reducing calorie density and controlling portion size promote weight loss.

#### **3.2 Increasing satiety and adequate nutrients intake**

#### *3.2.1 Protein and fiber for fullness and satiety*

An effective weight loss diet should satisfy hunger and induce satiety. Protein is the most satiating macronutrient. Protein intake reduces food intake and decreases the likelihood of snacking. Furthermore, protein preserves lean mass while on a lowcalorie diet. It, in turn, keeps up basal metabolic rate supporting weight loss.

Dietary fiber comes from plant-based foods, but humans cannot fully digest dietary fiber. The undigested fiber confers a sense of fullness. Studies show that dietary fiber has a role in weight loss. Besides weight loss, it also has a role in preventing cardiovascular diseases, diabetes mellitus, stroke, and cancer (esp., bowel cancers) [48].

Dietary fiber exists in two forms, i.e., insoluble and soluble viscous forms. Insoluble fiber adds bulk to stool but does not impact the cardiometabolic profile. Soluble viscous fiber (found in oats, psyllium, barley, fruit, and vegetables) improves the cardiometabolic profile and glycemic control. DRI recommends an intake of 25–38 g of mixed fiber per day.

#### *3.2.2 Reducing or eliminating the use of ultra-proceed foods*

Ultra-processed food goes through multiple industrial processes (milling, molding) and has added ingredients which compromise its nutritional value. They are high in salt, sugar, and fat but deficient in fiber and micronutrients. For example, ice cream, chocolate, soft drinks, fries, sweetened breakfast cereals etc.

Several studies correlate the consumption of ultra-processed food with weight gain, risk of type II diabetes mellitus, cardiovascular diseases, cancers, depression, and overall mortality [49]. High glycemic load, poor nutritional value, displacement of healthful foods and poor gut-neuronal satiety signaling are some reasons for poor health outcomes.

A cohort study with almost 9 years of follow-up reported a 26% greater risk of weight gain in the higher quartile (6.1 servings/day) of ultra-processed food consumers compared to the lower quartile (1.5 servings/day) [50]. Eliminating or reducing ultra-processed food will support healthy weight and reduce the risk of diseases associated with such foods.

#### *3.2.3 Using low calories beverages and water*

Sugar-sweetened beverages (SSBs) add empty calories. It encourages weight gain by stimulating insulin secretion and probably activating the dopaminergic reward system in the brain. SSBs increase the risk of insulin resistance and cardiovascular risks independent of weight gain. The incidence of type II diabetes mellitus is higher among SSB consumers. Fruit drinks, sodas, sweetened carbonated drinks, cordials, sports drinks, and flavored drinks are examples of SSBs. Fruit juices are considered healthy and have nutrients; however, they are calorie dense and could cause weight gain if consumed in higher quantities.

Studies report a direct dose-response correlation between SSBs and long-term weight gain [51].

Substituting water or low-calorie sweetened beverages (tea, coffee, sparkling water etc.) for SSBs may promote healthy weight by reducing total calorie intake.

#### *3.2.4 Substituting non-nutritive sweeteners for nutritive sweeteners*

Nutritive sweeteners (NS) contain calories and promote weight gain; non-nutritive sweeteners (NNS) were introduced to replace NS.

NNS has zero or few calories. Logically, NNS use will reduce energy intake and weight. However, studies show mixed results. Prospective cohort studies report weight gain and increased risk of type II DM with NNS, while randomized controlled trials show beneficial effects of NNS on weight and type II DM [52]. This divide in studies conclusions is likely due to study design and differences in the controls. Controls in prospective studies are free living, and additional variables are not controlled for, while randomized trials control for additional variables. Further research is needed to provide insights into the benefits or harms of NNS.

#### **4. Healthy dietary patterns tools**

Selecting the right portion size is a challenge for most people. There is a need for tools that could guide the public in choosing the appropriate portion size.

Meal replacement (MR) or pre-packaged food is one such tool. It contains fixed calories (typically 200–300 kcal/serving). MR is available in various forms, such as snack bars, frozen meals, or shakes. It could be employed as a partial (as part of a lowcalorie diet) or total meal replacement (as part of a very low-calorie diet).

In the first three to 4 months, partial meal replacement achieves 10–12% weight loss [53]. Systematic reviews and meta-analyses have demonstrated the efficacy of MR in achieving greater weight loss with partial meal replacement compared to conventional weight loss diets. MR has favorable effects on type II diabetes mellitus. The DiRECT study confirmed a 20-fold higher remission of diabetes mellitus at 12 months with total liquid meal replacement [38].

Portion control tools such as plates, bowels, serving spoons, cups, scales etc., could help limit food quantity; however, studies show these measures are insufficient. Poor compliance is a significant problem. Educating patients about proportion size is more effective. My Plate campaign is an example of a portion control education tool. It was launched by the United States Department of Agriculture (USDA) to promote healthy eating. It is an online tool which guides individuals about what and how much to eat.

Smartphone applications (apps) can support weight loss. Quite a few apps are already available in the market. Apps make weight loss activities measurable (by collecting data such as food intake, physical activity, distance traveled, sleep quality, heart rate, stress levels etc.), giving the consumer more control. The efficacy of apps in weight loss is controversial. Further studies are needed to validate their use in weight management. Apps could be used as an adjunct to other weight loss measures.

#### **5. Maintaining weight loss**

Many people succeed in losing weight, but only a few manage to keep it off. Some individuals regain a substantial amount of weight within 2 years, and most will retrieve all the weight lost in 5 yr. [54].

Why is weight maintenance so difficult? The initial rapid weight loss is followed by protective homeostatic changes, which resist further weight loss. Orixigenic hormone (ghrelin) increases while anorexigenic hormones (cholecystokinin, leptin, amylin, peptide YY and glucagon-like peptide 1) decrease [55]. Furthermore, the resting metabolic rate declines with weight loss. The muscles become more efficient in conserving energy. The net result of these changes is increased appetite and reduced energy expenditure resulting in weight gain [56]. Motivation drops as weight loss hits a plateau. The problem is further complicated by the easy availability of calorie-dense food and disinhibited eating habits.

Weight maintenance cannot be achieved only with diet; It requires a more holistic approach, including diet, physical activity, behavioral changes, and psychological support. Adherence to a low-calorie density diet and lifestyle modification are the keys to long-term success.

Research shows that individuals with ongoing support from friends, family, and healthcare professionals do better than those without help. The technology could be utilized to support sustainable weight loss. Genomics could help in selecting the appropriate diet for the right patient.

#### *The Role of Dietary Interventions in the Management of Obesity DOI: http://dx.doi.org/10.5772/intechopen.111529*

The National Weight Control Registry (NWCR) findings are an invaluable resource for weight maintenance. NWCR was established in 1994 to determine the characteristics of successful weight loss maintainers [57]. The database prospectively tracks over 10,000 individuals who have lost 30 pounds or more [mean 66 pounds (30–300 pounds)] and maintained it for at least 1 yr. [mean 5.5 yr. (1–66 yr)] [58].

The database has certain limitations. Firstly, it is not a prevalence study, and the sample is not random. Therefore, the results could not be extrapolated to the general population. Secondly, the participants self-identify themselves as eligible for the registry. Most of the information is self-reported, which is liable to bias. Thirdly, 80% of the participants are predominantly white females. Their mean age ranges between 45 and 49 yr. Despite its limitations, many studies support the NWCR findings.

The critical lessons learnt from the NWCR database are as follows: NWCR participants lost weight utilizing various interventions in the acute phase; however, there is limited variability in the strategies used for weight maintenance. Most consumed low fat (<30%), high carbohydrate and low energy diet to keep the weight off.

More than 90% of the participants used physical activity and diet to maintain weight. Most individuals do regular exercise (average 1 hour per day). Studies have revealed that physical activity preserves lean body mass regardless of weight loss which helps maintain a higher metabolic rate. Regular physical activity could also be a biomarker for compliance with other positive lifestyle modifications.

Seventy-eight per cent of the participants reported eating breakfast regularly. How breakfast contributes to sustainable weight loss is not clear. Perhaps eating breakfast may be more satiating than eating late in the day. Eating breakfast is correlated with lower BMI [59].

Almost all participants of NWCR weigh themselves at least weekly, and some even more frequently. Identifying increasing weight can act as an early warning sign that feeds back to institute corrective and preventative measures.

The dietary pattern of weight maintainers is consistent over the weekdays, weekends, and vacations all over the year.

Almost two-thirds of the individuals in NWCR spent less time in front of the television screen than the average American adult (*≤* 10 hours vs. 28 hours per week). Watching TV is a passive activity, and most people also eat while watching TV. It is unclear what part of the energy balance contributes to weight gain, but watching TV is an independent marker of weight status regardless of the reason.

There are some exceptions to the behaviors mentioned above. Four per cent of the NWCR participants do not take breakfast; some individuals (<10%) take a low carbohydrate diet, and 9% do little or no exercise to maintain weight.

#### **6. Conclusions**

Obesity is a chronic disease which is associated with increased morbidity and mortality. The prevalence of obesity has increased globally.

It is managed by lifestyle modification alone or in combination with medications or surgery. Diet is an integral part of the primary and secondary prevention of obesity. There is no consensus on the best dietary approach for weight loss. However, most agree that an ideal weight loss diet should be culturally acceptable, palatable, satiating, low-energy-dense, nutritious, affordable, and sustainable. Most dietary guidelines recommend a high intake of whole grains, legumes, fresh fruit, vegetables, and nuts. Moderate consumption of unprocessed meat, eggs, and milk is encouraged, while refined sugars, high sodium, trans fat, and processed foods are discouraged. Patient and family involvement is essential in selecting the right diet plan for better compliance.

Most patients can achieve 5–10% weight loss with diet, but few can maintain it over an extended period. Management goals for weight maintenance are different; here, the emphasis is on long-term compliance with low calorie-dense, low-fat diet, physical activity, behavioral change, and psychosocial support.

Besides managing obesity at an individual level, tackling it at a population level is necessary. The existing measures for controlling obesity are inadequate. The public and private sectors need to step in and play their role. Weight management programs should be built into job plans, especially for high-risk jobs. Schools should embed healthy eating and physical activity in the curriculum. Food laws should promote healthy eating and exercise. There is room for improvement in the marketing regulations of unhealthy foods and drinks.

#### **Acknowledgements**

I would like to express my special thanks to my parents, wife, and children, who supported me in completing this work.

#### **Conflict of interest**

"The authors declare no conflict of interest." This work is not funded.

#### **Notes/thanks/other declarations**

None.

*The Role of Dietary Interventions in the Management of Obesity DOI: http://dx.doi.org/10.5772/intechopen.111529*

#### **Author details**

Asad Ullah1 \*, Muhammad Jamil<sup>2</sup> and Johar Jamil3

1 University of Liverpool, Liverpool, UK

2 Retired General Practitioner, Peshawar, Pakistan

3 University of Swabi, Swabi, Pakistan

\*Address all correspondence to: drasadullah99@hotmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 8**

## Metabolic Outcomes in Obese Patients after Bariatric Embolization of the Left Gastric Vessel

*Zaira Dzhamutdinovna Ramazanova, Alexander Sergeevich Ametov and Evgeniya Yurievna Pashkova*

#### **Abstract**

The prevalence of overweight and obesity is growing rapidly in the modern world. Currently more than 600 million people are obese, over 2 billion people are overweight. By 2025, according to World Health Organization experts (WHO), the number of people with obesity will increase almost twofold and will make from 30 to 50 percent of the population in economically developed countries. Embolization of the left gastric artery is an innovative, minimally invasive method of treating obesity, which allows to reduce body weight six months after its implementation by 17–18% on average. This technique, long used in emergency medicine as a method to stop gastric bleeding, has a new potential in the treatment of obesity. In this manuscript we present a pilot study examining the effects of bariatric embolization of the left gastric artery on the parameters of fat and carbohydrate metabolism in obese patients. We also present a case report illustrating the weight loss and the metabolic benefits of the left gastric artery embolization.

**Keywords:** embalization of the left gastic artery, obesity, grelin, leptin, high-molecular adiponectin

#### **1. Introduction**

Obesity has become the modern day epidemic affecting both developed and developing countries.

Data from numerous studies indicate that obesity has adverse metabolic effects on human health and is major cause for the development of diabetes mellitus, malignant neoplasms, cardiovascular diseases, as well as degenerative joint diseases, infertility, fatty liver disease, among others [1].

Obesity treatment comprises lifestyle interventions, including diet therapy, increased physical activity, psychotherapy as well as pharmacotherapy, and traditional bariatric surgery. It should be noted that the effectiveness of the conservative methods of treating obesity is quite limited compared to the results of bariatric surgery aimed at weight loss.

Bariatric surgery is by far the most effective strategy for achieving long-term weight loss. The use of bariatric surgery is justified in persons suffering from morbid obesity (body mass index above 40 kg/m2 ), and in persons suffering from type 2 diabetes or other obesity-associated diseases - with an index over 35 kg/m2 . These surgical indications are particularly important given the lack of efficacy of conservative methods of treatment [2], Currently, the following types of bariatric surgery are most commonly used: gastric banding, sleeve gastroplasty, biliopancreatic bypass surgery and gastric bypass surgery [3].

Despite the fact that there is irrefutable evidence of the effectiveness of bariatric surgery over conservative methods of treating obesity, such operations like any surgical intervention, has many potential complications, and other health risks for patients and, moreover, surgical interventions do not always provide the desired results. These limitations of the current surgical interventions led to the emergence of new approaches in the fight against obesity, which would occupy their niche between standard bariatric surgery and conservative methods of treatment [4].

Bariatric embolization of the left gastric artery (ELGA), used for more than 40 years in emergency surgery to stop gastrointestinal bleeding, now is used as an innovative intervention of obesity management. During ELGA manipulation polyvinyl alcohol microspheres are introduced through the radial or femoral artery with a microcatheter, which subsequently creates ischemia of the gastric fundus that leads to the desired outcome: a decrease in the level of the hunger hormone ghrelin and a subsequent decrease in appetite [5].

The ghrelin hormone, the structure and function of which was first described by Kojima et al. in 1999, the 28th amino acid peptide that is produced by the endocrine cells lining the fundus of the stomach, remains today one of the known hormones that stimulates appetite. It is known that the level of ghrelin increases significantly during fasting and decreases after eating [6].

Ghrelin, having a powerful orexigenic effect and playing an important role in weight regulation, is a promising therapeutic target in bariatric surgery. Several studies [7–11] have demonstrated a significant decrease in weight as well as in ghrelin level after left gastric artery embolization [3, 12]. Thus, the definitive role of ghrelin in weight loss in obese patients after bariatric embolization is evident [3, 12, 13].

However, such studies have only examined the effect of bariatric embolization on body weight and ghrelin levels in obese patients. In this study we aim to evaluate not only weight reduction and ghrelin level after ELGA, but also to assess how changes in the level of the hunger hormone affect other hormones that regulate energy homeostasis and how to achieve weight stabilization after the initial weight loss with ELGA.

**The aim** of the current study is to evaluate the effect of bariatric embolization of the left gastric artery on the parameters of fat and carbohydrate metabolism in obese patients.

#### **2. Materials and methods**

A pilot study was conducted in the City Clinical Hospital n.a. S.P. Botkin in the Department of Endocrinology No. 59, which included 23 patients (10 men and 13 women, mean age 40.2 ± 10.6 years) with a diagnosis of morbid obesity (BMI > 40 kg/m2 ) and obesity of the 2nd degree (BMI > 35 kg/m2 ). In order to reduce body weight all the patients underwent surgical intervention in the form of bariatric embolization of the left gastric artery with polyvinyl alcohol microparticles 300–500

#### *Metabolic Outcomes in Obese Patients after Bariatric Embolization of the Left Gastric Vessel DOI: http://dx.doi.org/10.5772/intechopen.112054*

microns. Preoperative preparation included computed tomography of the aorta and its branches with contrast and administration of proton pump inhibitors.

During ELGA that is performed without anesthesia by transradial or transfemoral access, catheterization and angiography of the celiac trunk and left gastric artery were performed, followed by slow introduction of polyvinyl alcohol spherical particles with a diameter of 300–500 microns into the artery which led to the embolization of the left gastric artery. The duration of surgery is from 20 minutes to 1 hour.

The research work was approved at a meeting of the ethics committee of the Federal State Budgetary Educational Institution of Higher Education, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia dated on January 16, 2018 No 1.

Prior to the initiation of the study, each patient signed a written informed consent to participate in the study. All the patients before and after the bariatric embolization underwent an anthropometric examination including measurement of height, body weight, calculation of BMI, waist circumference (WC) as well as laboratory work including the determination of adiponectin, ghrelin and leptin. To assess carbohydrate metabolism, fasting plasma glucose, glycated hemoglobin, insulin, and HOMA-ir were also determined.

The severity of insulin resistance was determined using the HOMA-ir index, which was calculated using the formula HOMA-ir = (fasting glycemia (mmol/l) × IRI (immunoreactive insulin) (μU/ml))/22.5. The duration of the observation was 6 months, after which a follow up examination was carried out.

SPSS® statistical software version 21 was used to analyze our study data. The Wilcoxon test was used to assess the difference between the indicators before and after ELGA. Paired interrelations of indicators were determined by Pearson's rank correlation coefficient. The critical significance level (p) in the study was taken equal to 0.01. The results of the study are presented as M ± m, where M is the average value and m is the error of the mean.

#### **3. Results**

Preliminary results showed that 6 months after the bariatric embolization of the left gastric artery, a statistically significant decreases in all anthropometric parameters were observed: body weight decreased from 138 ± 33.2 kg to 114 ± 26 kg (18.5%, p < 0.001), BMI from 47.4 ± 9.3 kg/m2 to 38.1 ± 7.4 kg/m<sup>2</sup> (19.6%, p < 0.001), WC index from 130.4 ± 9.7 cm to 115 ± 10.3 cm (9%, p = 0.01).

After ELGA, patients experienced a decrease in the hunger hormone and changes in the secretion of adipose tissue hormones. Previous studies have noted a decrease in weight and ghrelin level after ELGA [5, 6, 12]. Thus, the level of ghrelin decreased from 20.23 ± 4.6 to 2.09 ± 0.93 femtomol/μl (90% p < 0.001). The level of leptin, which is secreted in proportion to adipose tissue, decreased from 23.3 ± 4.9 ng/ml to 10.5 ± 3.7 ng/ml. (54% p < 0.001). At the same time, a correlation analysis was carried out between the change of body weight and the level of ghrelin, which has a positive correlation with the weight of patients after bariatric embolization (r = 0.329, p < 0.01).

In this study, the level of adiponectin was determined, which, according to the literature, is a key and universal marker of metabolic health [14]. It is known that the level of adiponectin is reduced in patients with visceral obesity and tends to increase with decreasing body weight [15]. The results of our study confirm these literature data: for example, 6 months after bariatric embolization, patients showed a


*BMI, body mass index; WC, waist circumference etc.; HbA1C, glycated hemoglobin; Homa-ir, homeostasis model assessment of insulin resistance.*

#### **Table 1.**

*The dynamics of the studied parameters in patients with obesity before and after ELGA.*

statistically significant increase in the average level of adiponectin from 22.5 ± 8.1 μg/ ml to 42.4 ± 11 μg/ml (88.4%, p < 0.001).

As an example, we performed a correlation analysis between the change of adiponectin and body weight. Adiponectin negatively correlated with body weight of patients, the correlation coefficient after 6 months was (r = −0.389, p < 0.01). After ELGA, a positive change of carbohydrate metabolism was revealed.

The mean fasting glucose level initially before ELGA was 6.7 ± 0.9 mmol/l and by the sixth month it decreased to 5.3 ± 0.7 mmol/l (p < 0.001), the mean HbA1 level with an initial value of 6.2 ± 0.85% 6 months after the intervention showed a significant decrease to 5.5 ± 0.56% (p < 0.001), insulin initially −15.6 ± 7.7 μU/ml, after six months it decreased to 8.1 ± 0.7 μU/ml (p < 0.001), HOMA-IR index initially −4.5 ± 1.2, after 6 months of observation: −1.9 ± 0.32 (p < 0.001). The dynamics of the studied parameters of patients is presented in **Table 1**.

#### **4. Discussion**

Currently, the available therapeutic options as well as the surgical interventions to combat obesity are not fully effective. Several emerging therapeutic alternatives, are being evaluated in search of new, highly effective, yet safe methods of treating obesity.

Bariatric embolization of the left gastric artery appears to be an attractive therapeutic alternative that might become one of the most successful strategies in the fight against obesity while allowing control of energy consumption, affecting fat metabolism and significantly reducing the level of ghrelin, the hunger hormone.

The preliminary results of our pilot study, despite a small cohort of patients and the absence of a control group, showed that subjects who underwent bariatric embolization demonstrated a statistically significant weight loss 6 months after it was carried out by an average of 18–19%, a decrease in BMI, which was accompanied by

*Metabolic Outcomes in Obese Patients after Bariatric Embolization of the Left Gastric Vessel DOI: http://dx.doi.org/10.5772/intechopen.112054*

a decrease in ghrelin by 90% and leptin by 54%, which are secreted in proportion to body fat mass.

It should be noted that previous studies evaluated only the changes of body weight measured in kg, BMI and ghrelin levels, but in our work we further evaluated other metabolic parameters and demonstrated how the level of ghrelin, which is the main underlying cause of weight loss in bariatric embolization, is associated with changes in other hormones that regulate energy homeostasis such as leptin, adiponectin [3, 12–14].

We also demonstrated at 6th month of observation, patients had a statistically significant increase in the average values of adiponectin by 84%, which has a negative correlation with body weight. An increase in the level of adiponectin was accompanied by a regression of metabolic changes in obese patients six months after the bariatric embolization, a decrease in body weight, an improvement in the sensitivity of peripheral tissues to insulin with the restoration of all parameters of carbohydrate metabolism and the prevention of many metabolic diseases, one of which is type 2 diabetes mellitus.

After the embolization of the left gastric artery in obese patients by 6 month, we demonstrated significant improvements in all indicators of carbohydrate metabolism: fasting glucose, HbA1c, insulin, HOMA-ir index.

While, future studies with long-term patients' follow-up will be required, our piolt data showed that bariatric embolization can become the very effective therapeutic intervention for obesity management in the short term, allowing not only to reduce body weight, but also to normalize carbohydrate metabolism and restore the hormonal function of adipose tissue.

Finally, we would like to present a clinical case of a patient who underwent embolization of the left gastric artery in order to reduce body weight.

**Clinical case №1.** Patient X., aged 48, was admitted to the Department of Endocrinology No 59 of the City Clinical Hospital n.a. S.P. Botkin with complaints of overweight, general weakness, fatigue, severe thirst, dry mouth and shortness of breath after walking a distance of less than 500 m.

Patient reported significant weight gain in 2011 after an accident resulting in left leg fracture which limited his physical activity. Subsequently, the patient noted an increase in weight of 10 kg per year. In 2016 he was diagnosed type 2 diabetes mellitus and oral hypoglycemic therapy with vildagliptin at a dosage of 50 mg was prescribed, followed by the addition of metformin at a dosage of 1000 mg twice a day. Also, the patient's condition was aggravated by arterial hypertension with an episodic increase to 220/120 mmHg, which he has been suffering from for 25 years.

On examination: height 178 cm, body weight 136 kg, BMI 42.9 kg/m<sup>2</sup> .

On auscultation of the heart, the tones were muffled, rhythmic, no murmurs were heard, blood pressure was 140/85 mm Hg, the heart rate was 76 beats per minute. The frequency of respiratory movements was 16 per minute, with auscultation of the lungs, vesicular breathing was carried out in all parts of the lungs, there was no wheezing. The abdomen was enlarged due to subcutaneous fat, on the lateral surfaces of which striae were noted.

Biochemical profile revealed an increase in fasting glucose to 9.58 mmol/ml, glycated hemoglobin – 7.5%; insulin – 23.2 mU/l; C-peptide was 1642 pmol/l; HOMA-IR index (Homeostasis Model Assessment of Insulin Resistance) = 9.8; HOMA-β = 160.5. There were also high levels of uric acid up to 470 μmol/l, triglycerides up to 5.8 mmol/l, total cholesterol up to 6.7 mmol/l, LDL up to 3.5 mmol/l.

Ultrasound examination of the hepatobiliary system showed hepatomegaly, diffuse changes in the liver and pancreas of a lipomatous-fibrous nature.

The patient also underwent esophagogastroscopy, which revealed no contraindications to bariatric embolization of the left gastric artery.

Preoperative workup included ECG, echocardiography, radiography of the chest organs, ultrasound of the arteries and veins of the lower extremities, ultrasound examination of the kidneys and adrenal glands.

The patient was diagnosed with morbid obesity (BMI = 42.9 Kg/m2 ). Diabetes mellitus type 2. The target level of glycated hemoglobin was less than 7%. Arterial hypertension of stage 3, a very high risk of cardiovascular complications. Dyslipidemia IIb. Hyperuricemia. Non-alcoholic fatty liver disease.

The indications for surgical treatment were determined for the patient, and subsequently, computed tomography of the aorta and its branches with contrast was performed to determine the anatomical variant of the gastric blood supply. Preparation for bariatric embolization also included the administration of the proton pump inhibitor drugs omeprozole 20 mg twice a day and sucralfate 1 g four times a day for a week before surgery.

In a planned manner in December 2017 in order to reduce body weight, the patient underwent surgical intervention in the form of X-ray endovascular bariatric embolization of the left gastric artery. The duration of the operation was 1 hour 10 minutes.

On the third day after the intervention, gastroscopy was performed, according to which no possible ischemic complications from the gastric mucosa were detected.

The examination of the patient before bariatric embolization, and after three days, 1 month, 3 and 6 months included the determination of body weight, BMI (Kg/m<sup>2</sup> ), fasting glucose, glycated hemoglobin, insulin, C-peptide, HOMA-IR, HOMA-β, as well as the level of ghrelin, leptin and high molecular weight adiponectin.

The results of the study showed that by the end of the first month after ELGA, the patient's weight decreased by 8% and amounted to 125 kg, by 3 months - by 11.7% (120 kg), by 6 months - by 17% (112 kg), and after a year body weight compared with baseline data decreased by 20.5% and amounted to 108 kg against 136 kg of initial weight. By the end of the 6th month of observation, BMI decreased to 35.3 kg/m2 (−18.4% of the initial), and a year later decreased to 34 kg/m2 (−20.7% of the initial).

It should be noted that we observed a decrease in the level of ghrelin and leptin by 6 months after ELGA and also should be especially emphasized, the significant increase in the level of high-molecular-weight adiponectin, which is a recognized universal marker of metabolic health (**Table 2**).


#### **Table 2.**

*Changes in weight and hormonal profile in a patient with morbid obesity after ELGA.*

*Metabolic Outcomes in Obese Patients after Bariatric Embolization of the Left Gastric Vessel DOI: http://dx.doi.org/10.5772/intechopen.112054*


#### **Table 3.**

*Changes of carbohydrate metabolism parameters in a patient with morbid obesity after bariatric embolization.*


#### **Table 4.**

*The dynamics of lipid profile parameters in an obese patient before and after ELGA.*

The analysis of the parameters of carbohydrate metabolism after surgery showed a stable positive trend in the form of a stable decrease in fasting glycemia after 6 months to 4.8 mmol/l (−49.4% of the initial), the level of glycated hemoglobin to 6.1% (−18.6% of baseline), decrease in insulin to 7.5 μIU/ml (−67.6% of baseline) and C-peptide to 3.2 ng/ml34% of baseline), decrease in HOMA-IR to 1.6 (−75, 3% of the initial) and HOMA-β up to 115(+51%) (**Table 3**).

By the end of the sixth month of follow-up after surgery, we also obtained a significant decrease in the patient's uric acid level to 367 μmol/l (−21.9% of the baseline), a decrease in total cholesterol to 3.17 mmol/l (−52.5% of the baseline), as well as LDL up to 1.86 (−46.8%) and triglycerides up to 2.13 mmol/l (−63% of the baseline) (**Table 4**).

#### **Author details**

Zaira Dzhamutdinovna Ramazanova1 \*, Alexander Sergeevich Ametov1 and Evgeniya Yurievna Pashkova1,2

1 Department of Endocrinology, Federal State Budgetary Educational Institution of Further Professional Education "Russian Medical Academy of Continuous Professional Education" of the Ministry of Healthcare of the Russian Federation, Russia

2 Department of Endocrinology, Botkin Hospital, Moscow, Russia

\*Address all correspondence to: zaira.ramazanova.92@list.ru

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Metabolic Outcomes in Obese Patients after Bariatric Embolization of the Left Gastric Vessel DOI: http://dx.doi.org/10.5772/intechopen.112054*

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