Novel Anti-Obesity Pharmacotherapies

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.

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 phentermine-topiramate 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].

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 Glucagon-like Peptide-1 (GLP-1) agonists. These medications, originally designed to be anti-diabetic 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).

Drug	Mechanism of action	Administration	Mean weight loss observed	Contraindications	ADRs
Orlistat	Pancreatic and gastric lipase inhibitor	120 mg orally three times/day	5.8 kg	Gallstones, malabsorption syndromes	Flatulence, diarrhea, bloating, kidney stones
Phentermine Monotherapy	Sympathomimetic amine	8 mg (short acting) 2–3 times/day, 15 mg once daily, 37.5 mg once daily	(10.0 +/− 1.2 kg)	History (hx) of cardiovascular disease, uncontrolled HTN, uncontrolled anxiety or bipolar disorder (manic type), MAOI use within the last 14 days	Insomnia, increased jitteriness, constipation, dry mouth
Phentermine/topiramate	Combination of sympathomimetic amine and anti-epileptic medication	Start with 3.75/23 mg; orally once daily for; 14 days; increase to; 7/46 mg once daily; and monthly titration; upwards to achieve; weight loss	9.3%–10.5% mean weight reduction	Glaucoma, hyperthyroidism, or MAOI use within 14 days	Dyspepsia, insomnia, constipation, dry mouth
Naltrexone/bupropion	Combination of opioid antagonist and antidepressant	Naltrexone 8 mg with bupropion 90mg; titrate upwards to two tablets twice daily	5–10% mean weight reduction	Seizure disorders, anorexia or bulimia nervosa, chronic opioid use, MAOI use within the past 14 days	GI symptoms, headaches, dry mouth
Liraglutide*	GLP-1 receptor agonist	Starts at 0.6 mg daily subcutaneous injection for 7 days, then up titrate by 0.6 mg daily every 7 days to reach maximum dose of 3 mg daily	Around 10% mean weight reduction	Family or personal hx of medullary thyroid cancer or multiple endocrine neoplasia (MEN)-2 syndrome	Nausea, diarrhea, hypoglycemia, decreased appetite, abdominal pain, suicidal ideation
Semaglutide*	GLP-1 receptor agonist	Start with 0.25 mg weekly subcutaneous injection, then up titrate every 4 weeks until maximum dose of 2.4 mg weekly	15.3% mean weight reduction	Family or personal hx of medullary thyroid cancer or multiple endocrine neoplasia (MEN)-2 syndrome	Nausea, diarrhea, hypoglycemia, decreased appetite, abdominal pain, suicidal ideation
Tirzepatide*	Dual GLP-1 and GIP agonist	Start with 2.5 mg weekly subcutaneous injection, then up titrate by 2.5 mg weekly every 4 weeks until maximum dose of 15 mg weekly	20.9% mean weight reduction	Family or personal hx of medullary thyroid cancer or multiple endocrine neoplasia (MEN)-2 syndrome	Nausea, diarrhea, hypoglycemia, decreased appetite, abdominal pain, suicidal ideation
Cagrilintide*	Amylin analogue	Maximum dose of 4.5 mg weekly	10.8% mean weight reduction		Hypoglycemia
Cagrilintide-Semaglutide*	Combination of amylin analogue and a GLP-1 agonist	1.2 mg–2.4 mg weekly of cagrilintide with 2.4 mg weekly semaglutide	15.7–17.1% weight reduction	Family or personal hx of medullary thyroid cancer or multiple endocrine neoplasia (MEN)-2 syndrome	Nausea, diarrhea, hypoglycemia, decreased appetite, abdominal pain, suicidal ideation

Table 1.

Older generation and Novel* anti-obesity pharmacotherapy summary.

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 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, 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, 27, 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 meta-analysis 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.