June 1, 2023

A critical review of the manuscript: Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults published in Lancet 2011; 377: 1341-52.

Welcome to iforum rx where we explore the evidence that informs ambulatory care pharmacy practice today’s presentation is regarding the article effects of low dose controlled release phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults published in the lancet april of 2011. our presenter is diane hadley

A pgy2 ambulatory care pharmacy practice resident at the university of maryland school of pharmacy over the last 20 years there has been a dramatic increase in the prevalence of obesity in the united states according to the cdc every state in the u.s had a 20 or higher prevalence of obesity in 2010 and a dozen states had a 30 or higher prevalence rate why is

This important well obesity can result in a number of health-related complications especially related to cardiovascular health it has an established link to diabetes hypertension and dyslepidemia which collectively increase the risk of mi and cva what can be done to decrease these risks and treat obesity diet and exercise are the mainstays of treatment but what

Pharmacologic agents are available for the management of obesity this timeline of obesity pharmacotherapy was adapted from the journal of obesity medications for weight loss date back to the 1930s but many therapies have been restricted or withdrawn from the market due to the potential for serious adverse effects in october 2010 just three months after this chart was

Published cerbutamine or meridia was also withdrawn following the publication of the scout trial this rtc showed a 1.4 percent absolute risk increase in cardiovascular events with cerbutamine compared to placebo as clinicians we are left wondering if and when it is safe to recommend pharmacotherapy for weight loss one of the newest agents to receive fda approval

For weight loss is the combination of phentermine and topiramate the medication branded under the name kusemia is marketed by vivus in july 2012 the fda approved kusemia for short-term weight loss in patients with a bmi of 30 or greater it is also indicated in patients with a bmi of 27 or greater plus one weight related co-morbidity including hypertension type 2

Diabetes or dyslipidemia kusemia was approved with a risk evaluation and mitigation strategy or rems which consists of a medication guide advising patients about important safety information and elements to assure safe use such as including prescriber training and pharmacy certification vivas was also required to conduct a long-term cardiovascular outcomes trial to

Assess the risk of cardiovascular outcomes like mi and cva two major clinical practice guidelines address the management of obesity the nhlbi obesity education initiative guidelines and the 2005 american college of physician clinical guidelines for obesity management both recommend lifestyle modifications including diet exercise and behavioral therapy as first line

Treatment there are a few differences as well for example the nhlbi guidelines consider the use of pharmacologic therapy for weight loss in patients with an earlier stage of obesity compared with the acp guidelines also nhlbi guidelines do not mention the use of antidepressant medications for the treatment of obesity while the acp guidelines include antidepressant

Agents as a therapeutic option for weight loss before we proceed further in the presentation we’re going to stop for a clinical checkpoint according to the nhlbi obesity education initiative guidelines what is a cut off for the definition of a class 1 obesity is it a 25 to 29.9 kilograms per meter squared is it b 30 to 34.9 kilograms per meter squared is it c

35 to 39.9 kilograms per meter squared or d greater than 40 kilograms per meter squared and the answer is b 30 to 34.9 kilograms per meter squared the conquer trial was a double-blind placebo-controlled phase 3 trial which was conducted in a multi-center fashion within the u.s this study randomized patients in a two to one to two fashion favoring the placebo and

The higher dose of phentermine topiramate the authors noted this randomization purposely to highlight the benefits risk ratio between the placebo and the higher dose of fentamine topiramate in addition to pharmacotherapy patients were given the learn manual a weight loss guide centered on the five aspects of behavioral modification lifestyles exercise attitudes

Relationships and nutrition follow-up occurred at baseline two weeks and four weeks during drug titration and then monthly thereafter the primary outcomes included mean percentage change in body weight and proportion of patients with a five percent or greater percentage of weight loss secondary outcomes included weight loss proportion of patients with a 10 or

Greater weight loss changes in waist measurement and other efficacy variables including bmi blood pressure lipids glycemic parameters and other surrogate markers the inclusion criteria for the trial appropriately included all patients with bmis that were classified from overweight to morbidly obese they also included all patients that are at high risk for metabolic

Syndrome they appropriately excluded patients that are on diabetic therapies that could affect weight such as the sulfonylureas that could cause weight gain insulin which can also cause weight gain and tcds which could cause fluid retention baseline characteristics were similar among groups with an average age of 51 years old and an average bmi in the class to

Obesity range of note the majority of patients were caucasian women with abdominal obesity amine hemoglobin a1c of 5.9 percent and a mean ldl cholesterol of 120 milligrams per deciliter more than half of the study population had three or more obesity related comorbidities including hypertension pre-diabetes diabetes or dyslipidemia in the intention to treat arm

Of the trial both of the doses of phentermine topiramate had impressive reduction in weight loss of about 18 pounds for the low dose group and 22 pounds for the high dose group compared to only three pounds for the placebo group in addition the intention to treat arms showed that a large majority of patients reached a five percent weight loss in the per

Protocol portion of the trial impressive weight loss was achieved despite the relatively high dropout rate of about 38 percent the highest percentage of dropouts was seen in the placebo group however both of the phentermine and topiramate groups also noted significant dropout rates the low dose group lost about 22 pounds and the high dose group lost about 28

Pounds statistically significant differences were noted in several of the secondary outcomes but clinically meaningful differences were only noted for waist circumference and systolic blood pressure the decrease in waist circumference was approximately two inches greater for the low dose a phantomy to a pyramid group and 2.7 inches greater in the high dose group

Compared to placebo in addition the systolic blood pressure decreased by 2.3 millimeters of mercury in the low dose group and 3.2 millimeters of mercury in the high dose group compared to placebo there were a number of statistically significant differences in the incidence of adverse effects between the placebo and phentermine topiramate treated patients the most

Common side effects associated with phenterminetopiramate included dry mouth paresthesias and constipation a slight increase in heart rate was also noted in the high dose fentamine topiramate group limitations of the conquer trial included poor representation of male subjects and high-risk minority groups a significant number of study subjects were also lost to

Follow-up however the trial did show that treatment with phentermine topiramate resulted in clinically meaningful weight loss in a high-risk population would like to welcome our panelist dr cena haynes who is coming to us from palm beach atlantic university gregory school of pharmacy she is a professor and an associate dean and also dr phillip rogers who’s the

Professor at the university of north carolina chapel hill assistant dean of pharmacy practice partnerships so thank you both for taking the time out of your busy schedules to talk about what can we give patients for pharmacotherapy for weight loss so my first question that i’m going to pose to both of you is i think we could all agree that lifestyle modification

Is really the best approach to weight loss but under what circumstance would each of you recommend pharmacotherapy for weight loss you know obviously yes we do consider lifestyle modification and to be paramount in really any whether you’re going to use pharmacotherapy or not patients can’t lose sight of the fact that they still do need to focus on lifestyle

Modification and i think in clinical practice we’ve often seen the patient given a trial of it i would say that three months should be a reasonable amount of time to at least see some weight loss some might argue for shorter or longer periods of time but i think at that point is where most clinicians making a decision to whether the patient needs extra help and

To me those patients that might be on other drugs that might be causing weight gain you know despite their best efforts and intentions to lose weight if they’re on medicines that are causing them to gain weight such as insulin and so forth they may be someone i’d have a lower threshold for helping with some pharmacotherapy because i know it’s very difficult for

Them to lose weight i would recommend pharmacotherapy in patients who have a significant amount of weight to lose that have tried the three to six months of lifestyle modification and i certainly feel pharmacotherapy is warranted in patients who i believe are candidates for bariatric surgery i think bariatric surgery is certainly becoming more of a popular option

For a wider array of patients and it has really great outcomes but some people are not candidates for it either financially or clinically and these drugs can be helpful to those patients although maybe not certainly not as as effective i think that you both brought up some really good points about when we can consider patients for uh weight loss pharmacotherapy

So based on the results of the conquer trial do you think the combination of phentermine and to pyramid should be considered as the drug of choice for weight loss and what are some strengths and weaknesses that you see in the study i would consider this a drug of choice unless it’s contraindicated this was an agent that has been evaluated for two years which is

Longer than other agents i do feel we need to realize the degree of weight loss that we have overall with pharmacotherapy is modest at best and in terms of some of the weaknesses of this study subjects were primarily middle-aged white women and few elderly patients which while these patients have cardio metabolic risk factors the subjects enrolled did not really

Represent what i feel is the complexity and severity of concurrent disease states that i see in practice and then in terms of some of the strengths you know definitely this combination help patients lose 10 of their body weight or what was an average i think of 24 pounds in a year and the fda right now looks at a 5 weight loss benchmark when they’re looking to

Approve agents for obesity management and this study did see that cardiometabolic risk factors improved they talked about the reductions in of course systolic blood pressure diastolic blood pressure triglycerides c reactive protein patients fasting glucose and total cholesterol with an improvement in hdl so i think that was the strength of the study i’ll comment

On my thoughts on drug of choice i guess my inclination would be to to utilize a single drug therapy at first the evidence for this combination is is is getting very compelling given the conker study but i think that given the side effects that have been of some concern i think due to the just the longer clinical experience that we’ve got with drugs like phentermine

Alone as well as orostat i might be more tempted to offer a patient that initially and if if there’s good effects seen with that or we need enhanced effects then moving on to this agent although i think for patients who are morbidly obese or have had problems with losing weight with other agents in the past and going directly to this agent certainly could be a

An option the strengths that i liked in the conquer trial was its duration i was really pleased to see them include at least a more expansive inclusion of patients certainly less restrictive exclusion criteria than we see in most previous obesity studies many obesity studies in the past have been criticized for studying the what we might call the healthy obese

Population the ones that have very few complications of their of their disease for weaknesses obviously the trial suffered from not having an active comparator we simply had lifestyle modification and placebo that was unfortunately not really well described in the paper i do agree the elderly were poorly represented here which is going to be a a greater problem as

The population ages and then also this trial was limited in its assessment of cognitive dysfunction that it really only looked at what was referred to as disturbance of attention i actually agree with phil on his last comment related to psychiatric disturbances in terms of a weakness of this study people with clinically significant depression were actually removed

From the study you know we need more information in order to determine if this agent could be used in patients who have mood disorders or suffer from depression which we often do see in patients who are obese now what about other agents like lyric glutathide that we know can have a side effect of weight loss would you ever consider these agents for weight loss

In patients who don’t have diabetes i would consider that a possible solution for some of these individuals i would probably limit their use to only those patients who have known pre-diabetes as we might call it or multiple risk factors for developing diabetes i do agree with phil there are trials underway to investigate the effects of exenatide and laraglotide

In non-diabetes patients with obesity and actually pcos and we have such few agents to use long term i think this class certainly has a promising utility as monotherapy or as part of a multi-factorial approach in treating our patients with diabetes and obesity and i would consider using exenatide or regulation in a patient with pre-diabetes or impaired glucose

Tolerance over this agent we’ve been discussing however unfortunately some of the same issues that limit the use of currently approved weight loss therapy like side effects contraindications and even third party coverage and cost will probably affect the glp one agent’s use as well i think it’s going to be a very kind of interesting next couple of years in terms

Of the field of obesity pharmacotherapy thank you both very much for your time i really appreciate it and your insight and clinical perspective the combination of phentermine to pyramid or qsemia is an important addition to the pharmacological treatments for obesity treatment can result in significant weight loss among patients who are overweight or obese of

Note phenterminetopiramate therapy may increase heart rate and the risk on heart attacks or strokes is yet to be determined therefore kyusemia is not recommended in patients with recent or unstable cardiovascular disease or stroke the medication should be also avoided in pregnancy due to the risk of birth defects the fda recommends that women of child bearing

Age receive contraception and monthly pregnancy tests while taking the medication the drug should also be avoided in patients with comorbid glaucoma or hypothyroidism in order to ensure safe use kusemia and compliance with the rem strategy the medication can only be prescribed by certified providers who have completed an online training program and can only be

Dispensed by certified pharmacies additional information about provider certification program and certified pharmacies can be found on the qsemia website thank you for taking the time to listen to my presentation of the conquer trial and have a great day thank you for viewing this capticast and for your comments this broadcast was brought to you by iforumrx

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Transcribed from video
The CONQUER Study – Phentermine plus Topiramate for Weight Loss _ Body Health And Weight Management By BH WM