Impact on Cardiovascular Health of Using Phentermine/Topiramate in Combination With Laparoscopic Sleeve Gastrectomy in Super Obesity.

INTRODUCTION: Management of patients with BMI≥50 kg/m2 is challenging. In previous work, pre and postoperative pharmacotherapy with phentermine/topiramate plus laparoscopic sleeve gastrectomy (PT + SG) promoted greater weight loss than sleeve gastrectomy (SG) alone at 24 mo postoperatively. This current secondary analysis studied the impact of PT + SG on blood pressure (BP), heart rate, and antihypertensive usage. METHODS: Patients with BMI≥50 kg/m2 planning to have SG (n = 13) were recruited from 2014 to 2016, at an academic medical center in Winston-Salem, North Carolina, for this open-label trial. Participants took phentermine/topiramate (PT; 7.5/46-15/92 mg/d) for ≥3 mo preoperatively and 24 mo postoperatively. The control group (n = 40) underwent SG during the same time frame. We used mixed models for BP and heart rate to compare PT + SG versus SG alone over time, adjusted for age, sex, and initial BP. RESULTS: By 24 mo postoperatively the model adjusted changes in systolic blood pressure/diastolic blood pressure (SBP/DBP) (mm Hg) were -24.44 (-34.46,-14.43)/-28.60 (-40.74,-16.46) in the PT + SG group versus -11.81 (-17.58,-6.05)/-13.89 (-21.32,-6.46) in the control group (SBP P = 0.02; DBP P = 0.03). At baseline 8 (61.5%) participants in the PT + SG arm and 22 (55.0%) in the control group used antihypertensives. Excluding patients lost to follow-up (n = 3), by 24 mo postoperatively, none of the PT + SG participants were on antihypertensives compared to 14 (41.2%) in the control group (P = 0.01). CONCLUSIONS: Patients with BMI≥50 kg/m2 treated with PT + SG had greater improvement in BP with no use of antihypertensive medication at 24 mo postoperatively versus SG alone, where 41% continued medication use. Larger trials are required to evaluate this.

A narrative review of approved and emerging anti-obesity medications.

Background: Recently, many drugs have been approved for halting overweight and obesity-few types of research shifted to using Anti-obesity medications (AOM) solely for well-being and shape-keeping. Objective: This narrative review's objective was to explore the use of AOM in relation to their medical indications, efficacy, and cardiovascular safety. Methods and materials: We have conducted a narrative review of the literature on approved/non-approved AOM used for obesity and overweight. We have shed light on the emerging trials of therapies and evolving remedies. Results: Recently, there has been an enormous change in the use of AOM with high consumption that deserves extensive surveillance for the long-term consequences and impact on social, mental, and physical health. Nearly six AOMs and combined therapy are approved by the Food and Drug Administration. The recent guidelines for obesity management have shifted the focus from weight loss to goals that the patient considers essential and toward targeting the root cause of obesity. Conclusion: The use of AOM increased enormously despite its sometimes-dubious safety and ineffectiveness. The public and medical professionals should be vigilant to the real-world benefits of anti-obesity drugs and their achieved effectiveness with an improved safety profile.

Drugs for Treating Obesity.

Older medications approved for chronic weight management (orlistat, naltrexone/bupropion, liraglutide 3 mg and, in the USA, phentermine/topiramate) have not been widely adopted by health care providers. Those medications produce only modest additional weight loss when used to augment lifestyle intervention. However, semaglutide 2.4 mg weekly has recently emerged and produces much more weight loss - on average 15% weight loss at 1 year. Semaglutide's enhanced efficacy and that its class (GLP-1 receptor analogs) is well-known may result in more clinicians adopting pharmacotherapy. Furthermore, the first dedicated cardiovascular outcome trial powered for superiority testing an anti-obesity medication (SELECT) is underway with semaglutide 2.4 mg. A positive outcome will further promote the concept that weight management should be a primary target for cardiometabolic disease control. In phase 3, tirzepatide and cagrilintide/semaglutide combination are showing promise for even greater weight loss efficacy. Another recently approved medication takes a personalized medicine approach; setmelanotide is approved as a therapy for those with some of the ultra-rare genetic diseases characterized by severe, early onset obesity. This chapter reviews the currently available and anticipated medications for chronic weight management as well as those approved for the genetic and syndromic obesities.

Pharmacotherapy of obesity: An update.

Several pharmacological approaches to controlling body weight have been developed over the last decades, albeit with limited success. Currently available agents include centrally acting appetite suppressants and peripherally acting compounds. Efficacy and safety of these agents in the clinical setting require a difficult balance. Further strategies including multiagonists able to simultaneously target multiple actors involved in obesity initiation and expansion such as the glucagon receptor family are under investigation. The results of recent clinical trials are encouraging and highlight emerging compounds as potential game changers. In view of the rising prevalence of obesity and the associated burden of comorbidities worldwide, and compared with other areas of pharmacological intervention, we feel that the field of obesity has been affected by therapeutic inertia. Of note, obesity may also affect the response to concomitant medications such as low-dose aspirin. Lessons from withdrawn agents such as the cannabinoid receptor antagonist rimonabant include developing compounds with a more targeted action profile (i.e., central vs peripheral, or antagonist versus inverse agonist) as well as careful selection of patients based on individual risk factors. We anticipate that the expanding knowledge base and clinical testing will result in improved outcomes for patients with obesity in the near future.

Medication use for the treatment of diabetes in obese individuals.

Obesity is a major cause of type 2 diabetes and may complicate type 1 diabetes. Weight loss for obese individuals with diabetes has many health benefits, often leads to improvement in glucose control and sometimes, in type 2 diabetes, near normalisation of abnormal glucose metabolism. Weight loss is difficult to maintain and attempts to lose weight may be undermined by some diabetes treatments such as sulfonylureas, thiazolidinediones and insulin. Whilst lifestyle support should be the primary approach to aid individuals who wish to lose weight, pharmacological approaches can also be considered. These include choosing glucose-lowering drugs or drug combinations that are weight neutral or result in weight loss or prescribing drugs that are specifically approved as anti-obesity medication. Given that some of the newer glucose-lowering medications that cause weight loss, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), are also being used or considered for use as anti-obesity drugs, it seems that the distinction between glucose-lowering medication and weight loss medication is becoming blurred. This review discusses the main pharmacological approaches that can be used to support weight loss in individuals with diabetes.

Health-related quality of life in two randomized controlled trials of phentermine/topiramate for obesity: What mediates improvement?

PURPOSE: Phentermine/topiramate combination therapy resulted in significant weight loss and improvements in cardiometabolic risk factors in patients with obesity/overweight in two published 56-week randomized, placebo-controlled trials (EQUIP and CONQUER). The purpose of the current study was to examine whether phentermine/topiramate is also associated with greater improvements in health-related quality of life (HRQOL) and whether HRQOL improvements are solely attributable to weight reduction. METHODS: Patients in EQUIP (n = 751) had a body mass index (BMI) ≥ 35 with no obesity-related comorbidity. Patients in CONQUER (n = 1623) had a BMI ≥ 27 and ≤ 45 and at least two obesity-related comorbid conditions. HRQOL was assessed with Impact of Weight on Quality of Life-Lite (IWQOL-Lite) and Medical Outcomes Study Short Form (SF-36) (CONQUER only). RESULTS: Significant improvements in both obesity-specific and physical HRQOL were observed at 56 weeks in both trials (p < .0001). In EQUIP, BMI reduction fully mediated improvements in IWQOL-Lite total score (p < .0001). In CONQUER, both BMI reduction (all p values < .0001) and change in depressive symptoms (all p values < .025) were significant mediators of improved IWQOL-Lite total score and SF-36 Physical Component Summary score. Gender, psychiatric history, and baseline triglycerides moderated these relationships. CONCLUSIONS: Both trials demonstrated that treatment with phentermine/topiramate improved HRQOL compared with placebo. Although reduction in BMI accounted for the majority of improvements in obesity-specific and physical HRQOL, decrease in depressive symptoms was also a significant mediator. Results highlight the predominance of weight reduction as a key factor in improving HRQOL in obesity.

Review of Pharmacologic Weight Loss Medications in a Patient-Centered Medical Home.

Background: Per the Centers for Disease Control, 78 million adults were classified as obese in the United States in 2009 to 2010. Lifestyle modifications and pharmacologic treatment are appropriate options to combat obesity. Objectives: The primary objective of the study was to assess change in body weight after 12 weeks in patients seen at a family medicine patient-centered medical home (PCMH) who were prescribed Food and Drug Administration-approved weight loss medications. Methods: A retrospective medical record review was used to evaluate weight loss in adult patients with office visits at the PCMH. Adult patients were eligible for inclusion in the study if prescribed a Food and Drug Administration approved weight loss medication between July 1, 2013, and March 31, 2014, and had at least one weight documented during a follow-up visit 12 weeks after the initial prescription. Results: Of the 27 patients identified for study inclusion, 22 (81.5%) were prescribed phentermine. The remaining 5 (18.5%) patients were prescribed phentermine/topiramate ER. After 12 weeks of pharmacologic therapy, the median change in body weight was -3.7 kg (range = -16.8 to 5.5 kg) regardless of medication taken. This correlates to a -1.4 kg/m2 (range = -15.7 to 4.2 kg/m2) median change in body mass index. Twelve patients (44.4%) lost at least 5% of their body weight during the study period. Conclusions: In our study population, we observed a median weight loss of 3.7 kg over 12 weeks while utilizing weight loss medications. Unfortunately, other lifestyle-modification services offered through the PCMH were not consistently utilized.

Pharmacotherapy for weight loss: the cardiovascular effects of the old and new agents.

WHAT IS KNOWN AND OBJECTIVE: Obesity affects approximately one-third of the American population, and its prevalence continues to increase. It is a significant risk factor for cardiovascular diseases and contributes to increased healthcare costs and mortality. The objective is to review the current literature on the cardiovascular effects of weight loss pharmacotherapy agents. METHODS: Literature was accessed through MEDLINE/PubMed (up to April 2013) using the search terms obesity, weight loss, pharmacotherapy, cardiovascular adverse effects and cardiovascular side effects. References of the articles identified and www.clinicaltrials.gov were also reviewed. Relevant guidelines, review articles, clinical trials, meta-analyses, case series, FDA documentation and prescribing information were included and limited to English language articles. RESULTS AND DISCUSSION: With the newly FDA-approved weight loss pharmacotherapy, treatment options for obesity are more diverse. However, safety concerns, including adverse cardiovascular effects, have played a significant role in the history of weight loss pharmacotherapy and will likely play a role in the future of the new agents, lorcaserin and phentermine/topiramate, as well. WHAT IS NEW AND CONCLUSION: Long-term cardiovascular outcomes studies with and without high-risk cardiovascular patients are still needed for both lorcaserin and phentermine/topiramate before these agents can be recommended in these patient populations. It is yet to be determined whether modest weight loss benefit of these new agents outweighs the cardiovascular risks.

Novel Anti-obesity Therapies and their Different Effects and Safety Profiles: A Critical Overview.

Obesity has become an epidemic and a worldwide problem and its treatment is ever-evolving. Apart from diet and exercise, medication and surgery are other options. After disappointing side effects of various obesity drugs, new treatments showed promising results. This review discusses the following anti-obesity drugs: liraglutide, semaglutide, tirzepatide, orlistat, as well as the phentermine/topiramate and bupropion/naltrexone combinations. These drugs have been approved by the Food and Drug Administration (FDA) for weight reduction except for tirzepatide which is still under evaluation. Efficacy and tolerable safety profiles of some of these drugs contribute to the management of obesity and reduce the complications associated with this chronic disease.

Dilated Cardiomyopathy: Beware of Diet Drugs Slimming the Heart.

There have been rare reports of dilated cardiomyopathy from chronic use of phentermine/topiramate, although very limited data are available. Phentermine is an atypical amphetamine analog that has been contraindicated in patients with a history of cardiovascular disease. We present a case of nonischemic dilated cardiomyopathy in the setting of chronic phentermine/topiramate use, which is the most likely cause of her dilated cardiomyopathy.

Which is the optimal antiobesity agent for patients with nonalcoholic fatty liver disease?

Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population worldwide. Obesity is a major risk factor for development and progression of NAFLD and weight loss is an effective intervention for the management of NAFLD. However, few patients achieve substantial and sustained weight loss with lifestyle measures. Therefore, antiobesity agents are frequently considered in patients with NAFLD but there are limited data on their safety and efficacy. In the present review, we discuss the role of antiobesity agents in the management of NAFLD. All approved antiobesity agents appear to reduce transaminase levels and to improve steatosis in patients with NAFLD. However, their effects on fibrosis are less well studied and whether they affect liver-related outcomes, including progression to cirrhosis and hepatocellular cancer, is unknown. The glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, appear to represent a first-line option in obese patients with NAFLD and type 2 diabetes mellitus (T2DM) since they induce considerable weight loss and have been extensively studied in patients with T2DM. However, more studies are needed to evaluated their effects on liver-related and cardiovascular outcomes in patients with NAFLD, particularly in those without T2DM.

Anti-obesity pharmacotherapy for treatment of pediatric type 2 diabetes: Review of the literature and lessons learned from adults.

Type 2 diabetes mellitus (T2DM) in adolescents is a more rapidly progressive disease, associated with earlier and higher rates of microvascular complications than in adults. As obesity is a significant risk factor for T2DM development and progression, the American Diabetes Association (ADA) recommends anti-obesity medications (AOMs) as adjuvant therapy for adults with both T2DM and overweight/obesity. In adults, the addition of AOMs to a diabetes regimen can improve glycemic control, reduce weight, and decrease anti-diabetes medication use. The ADA recommends considering bariatric surgery for adolescents with T2DM who have a BMI >35 kg/m2, but did not mention the use of AOMs in their 2022 updated guidelines. Currently, there are three FDA-approved AOMs available for chronic use in adolescents with obesity. Other medications are used in an "off-label" fashion for appetite suppression and BMI reduction. As additional AOMs are being developed and FDA-approved for the pediatric population, new treatment options with novel mechanisms of action will become available for adolescents with T2DM and obesity. In this review, we will discuss the evidence for the use of AOMs in the treatment of T2DM in adolescents, including lessons learned from the adult T2DM literature.

A Rare Case of Phentermine-Induced Nonischemic Cardiomyopathy.

Obesity is a global epidemic with steadily increasing prevalence in most countries. Weight loss is generally challenging for patients to tackle in the face of the temptation to overeat and avoid physical activity. Hence, clinicians and patients alike are likely to steer toward the use of anorexigens. We report the case of a 33-year-old female with no significant cardiac history who presented with dyspnea, productive cough, and chest pressure for one month and was diagnosed with new-onset heart failure with a reduced ejection fraction secondary to prolonged phentermine use. The authors aim to highlight phentermine's potential for precipitating heart failure, even in a young, relatively healthy person, especially with a growing obese population. Ultimately, healthy weight loss can be achieved by implementing dietary changes and encouraging adequate physical activity, as the World Health Organization (WHO) recommended. Anorectic drugs may be employed for short-term use. Further research concerning the long-term side effects of phentermine may avert the prescriber and patient from abusing this drug.

FDA-Approved Pharmacotherapy for Weight Loss Over the Last Decade.

Obesity is a recently defined illness whose diagnosis and treatment continue to be stigmatized. Currently, due to lifestyle changes brought on by technological advancements and the wide availability and affordability of high-calorie foods, millions of people around the world suffer from obesity and/or its sequelae. Finding adequate prevention and treatment options would therefore lead to massive improvements in the duration and quality of life of affected individuals. In this review, we searched the PubMed database for studies exploring the safety and efficacy of the five medications currently approved by the FDA for the treatment of obesity. We included only studies pertaining to adult patients that have been published between 2012 and 2022. We found evidence that all the drugs analyzed such as orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, and semaglutide appear to be effective in inducing weight loss, with the suggestion that semaglutide may have superior efficacy. However, a massive obstacle in developing treatment guidelines remains the lack of prolonged studies monitoring the long-term safety and efficacy of obesity medications. Nevertheless, in patients at risk of complications from obesity, the benefits of losing fat mass may outweigh the potential side effects associated with these medications and clinicians should prescribe whichever of the FDA-approved pharmacotherapy they deem most appropriate for the patient's specific set of circumstances.

Anti-Obesity Drugs: Long-Term Efficacy and Safety: An Updated Review.

As a chronic and relapsing disease, obesity negatively impacts the health of men to a greater extent than that of women, with a higher risk of cardiovascular disease. Since lifestyle modifications alone are often challenging and limited for the maintenance of weight reduction, pharmacotherapy should be considered in a timely manner for obese men or overweight patients with weight-related comorbidities. Recent advances in anti-obesity drugs have enabled the potential of achieving clinically significant weight loss. Increasing evidence has shown that behavior-based interventions with one of these medications can result in greater weight loss than that elicited by usual care conditions. Data from most recent meta-analyses showed that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranges from 2.9% to 6.8%; phentermine/topiramate (-6.8%) liraglutide (-5.4%), naltrexone/bupropion (-4.0%), lorcaserin (-3.1%), and orlistat (-2.9%). However, they have a high cost and may cause adverse outcomes depending on the individual. Very recently, on February 13, 2020, the US Food and Drug Administration requested withdrawal of lorcaserin from the market because a safety clinical trial showed an increased occurrence of cancer. Therefore the decision to initiate drug therapy in obese individuals should be made after the benefits and risks are considered. Thereafter, treatment should be tailored to specific patient subpopulations depending on their chronic conditions, comorbidities, and preferences. Herein, we provide an overview of the latest developments in weight loss medications, which may serve as one of the strategies for long-term obesity control.

Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand?

PURPOSE OF REVIEW: As a chronic and relapsing disease, obesity impairs metabolism and causes cardiovascular diseases. Although behavioral modification is important for the treatment of obesity, it is difficult to achieve an ideal weight or sustain the process of long-term weight loss. Therefore, the obesity control guidelines strongly recommend lifestyle interventions along with medical treatment for patients who are overweight. There is sufficient evidence supporting that pharmacotherapy in combination with behavior-based interventions can result in significant weight loss and improved cardiometabolism. RECENT FINDINGS: Recent meta-analyses of new anti-obesity drugs and their weight-loss efficacy have shown that the overall placebo-subtracted weight reduction (%) for at least 12 months ranged from 2.9 to 6.8% for the following drugs: phentermine/topiramate (6.8%), liraglutide (5.4%), naltrexone/bupropion (4.0%), orlistat (2.9%), and lorcaserin (3.1%). However, very recently, on February 13, 2020, the US Food and Drug Administration (FDA) ordered the withdrawal of lorcaserin from markets, as a clinical trial to assess drug safety showed an increased risk of cancer. Currently, the anti-obesity medications that have been approved by the FDA for chronic weight management are orlistat, phentermine/topiramate, naltrexone/bupropion, and liraglutide. However, they are costly and may have adverse effects in some individuals. Therefore, drug therapy should be initiated in obese individuals after weighing its benefits and risks. One of the strategies for long-term obesity control is that anti-obesity medications should be tailored for specific patients depending on their chronic conditions, comorbidities, and preferences.

Current Long-Term Pharmacotherapies for the Management of Obesity.

Obesity is a serious and growing worldwide health challenge associated with type 2 diabetes mellitus, cardiovascular disease, osteoarthritis, some cancers, sleep apnea, asthma, and nonalcoholic fatty liver. The Korean Society for the Study of Obesity recommends that pharmacotherapy should be considered when intensive lifestyle modifications fail to achieve a weight reduction in obese patients with a body mass index ≥25 kg/m2. Long-term medications for obesity have traditionally fallen into two major categories: centrally acting anorexiant medications and peripherally acting medications, such as orlistat. In this paper, we provide an overview of the anti-obesity medications currently available for the long-term and individualized treatment of obesity.

Anorectic state of obesity medications in the United States. Are leaner times ahead?

Introduction: Obesity is considered to be a chronic disease. Currently there are five prescription-only medications on the US market for the long-term management of obesity. However, these medications are underutilized by obese or overweight individuals seeking medical assistance for weight management.Areas covered: This special report provides an overview of the emerging obesity pharmacotherapies based on the data available from recruiting and active phase II/III trials from a registry of clinical trials. The authors also give their expert opinion and provide their future perspectives on the treatment of obesity based on what is known.Expert opinion: Despite obesity being a chronic condition affecting 40% of the US population, there is a low demand for obesity medications in the US market. Although the potential obesity medications that are currently being investigated in phase II/III clinical trials are promising, it is unclear whether the future pharmacotherapies will be enough to meet the health care need.

Obesity: The New Global Epidemic Pharmacological Treatment, Opportunities and Limits for Personalized Therapy.

BACKGROUND: The increase in global obesity rates over the past three decades has been remarkable, a true epidemic, both in developed and in developing countries. The projections, based on current trends, suggest an increase in the prevalence of obesity at 60% in adult men, 40% in adult women and 25% in children in 2050. Given the limitations of lifestyle and surgery interventions bariatric, drug therapy approaches for the treatment of obesity, therefore become important options. AIM: The purpose of this review is a review of the literature, based on research on MEDLINE until 2019, on the possible pharmacological options in the treatment of obesity. RESULTS: Currently, the FDA has approved several molecules for the treatment of obesity, both in monotherapy and in combination. Pharmacological monotherapies focus mainly on a single protein target and include orlistat, lorcaserin and liraglutide while the combination molecules propose a multitarget approach and include phentermine/topiramate and naltrexone/bupropion. All the approved drugs showed, in the different studies, a weight reduction of at least 5%, compared to placebo, in 52 weeks of observation. Phentermine-topiramate and liraglutide have been associated with the highest probability of at least 5% weight loss. Liraglutide and naltrexone-bupropion had the lowest rates of therapy discontinuation due to adverse events. CONCLUSION: The drugs, associated with the standard diet and/or exercise protocols, represent a good therapeutic opportunity to allow not only weight loss but also to reduce the risk of developing diseases caused by obesity, particularly cardiovascular diseases, and to maintain the set objectives over time. However, future research on the pharmacological treatment of obesity should encourage greater personalization of therapy, given the differences in safety, efficacy and response to therapy, in the different subpopulations of patients with obesity.

Gender-related issues in the pharmacology of new anti-obesity drugs.

Four new medicines-liraglutide, lorcaserin, bupropion/naltrexone, and phentermine/topiramate-have been recently added to the pharmacological arsenal for obesity treatment and could represent important tools to manage this epidemic disease. To achieve satisfactory anti-obesity goals, the use of these new medicines should be optimized and tailored to specific patient subpopulations also by applying dose adjustments if needed. In the present review, we posit that gender could be among the factors influencing the activity of the new obesity drugs both because of pharmacokinetic and pharmacodynamic factors. Although evidence from premarketing clinical studies suggested that no dose adjustment by gender is necessary for any of these new medicines, these studies were not specifically designed to identify gender-related differences. This observation, together with the strong theoretical background supporting the hypothesis of a gender-dimorphic response, strongly call upon an urgent need of new real-life data on gender-related difference in the pharmacology of these new obesity drugs.