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Study Overview
Objective. To examine whether an early response (or non-response) to lorcaserin therapy predicts ≥ 5% weight loss achieved at 1 year.
Study design. Secondary analysis of data collected in 3 placebo-controlled blinded randomized trials.
Setting and participants. This study relied upon data collected as part of 3 separate phase 3 clinical trials of lorcaserin, a weight loss drug and selective serotonin 2c (5-HT2c) agonist. The first study, “Behavioral Modification and Lorcaserin for Overweight and Obesity Management” (BLOOM; n = 3182) enrolled overweight (with at least 1 comorbidity) or obese (no comorbidity needed) adult patients (18–65 yr) without diabetes, to determine the safety and efficacy of lorcaserin. The second trial, “Behavioral Modification and Lorcaserin Second Study of Obesity Management” (BLOSSOM; n = 4008) enrolled a similar population as BLOOM. For both BLOOM and BLOSSOM, patients were randomly assigned to receive either lorcaserin (10 mg po bid) or placebo for a 1-year period, and all patients received advice and instruction in exercise goals (at least 30 min/day) and caloric intake (600 kcal less than recommended for weight maintenance for that individual) necessary to promote weight loss. The third trial, BLOOM-DM (n = 604) focused on overweight or obese diabetic patients, but otherwise was similar in methodology to BLOOM and BLOSSOM. All studies took place in multiple US academic and private medical centers and were funded by Arena Pharmaceuticals. For the current analysis, the investigators used data from these trials and classified participants as either “responders” or “non-responders” based on each participant’s early weight loss response to either lorcaserin or placebo.
Main outcome measures. The investigators used area under the curve for the receiver operating characteristic (AUC for ROC) analysis to determine whether an early weight loss response to lorcaserin or placebo predicted a patient’s longer-term (52-week) weight loss. Several steps were used to conduct these analyses.
First, the investigators needed to determine what amount of weight loss at which of several early time-points would qualify a participant as a “responder” to either drug or placebo. They compared weight lost at weeks 2, 4, 8 and 12, using AUC for ROC analysis to identify the appropriate “responder” or “non-responder” cut-points, and classified all participants with data points in these early weeks as such. Second, all of the early responder and non-responder participants with 52-week weight data were then classified as to whether or not they had achieved at least a 5% weight loss at the end of the study. AUC for ROC analysis was again used to determine whether this early categorization was predictive of final study response. In addition to looking at early response as predictive of final weight loss, the investigators also examined the response/non-response variable’s ability to predict other health outcomes, including changes in lipid levels, blood pressure, and, for type 2 diabetic participants, changes in glycemic control (fasting plasma glucose [FPG] and HgbA1c). Finally, the investigators examined the incidence of adverse events in the different groups as well.
Results. The investigators identified a 4.6% weight loss by week 12 on lorcaserin or placebo as the optimal cut-point for determining whether a participant was a “responder” or “non-responder” (“W12R” or “W12NR”). This cut-point had an AUC (95% CI) of 0.849 (0.828–0.870) for predicting ≥ 5% weight loss at 52 weeks, with a positive predictive value (PPV) of 0.855 and negative predictive value (NPV) of 0.740, thus optimizing specificity and sensitivity of the time/weight cut-point compared to those at weeks 2, 4, or 8. Given the need for practical clinical recommendations, however, the investigators used a cut-point of 5% weight loss by week 12 to determine response/non-response for the health outcome analyses. The breakdown of responders vs. non-responders was as follows: For the pooled BLOOM/BLOSSOM participants, there were 1251 lorcaserin-recipient responders and 1286 lorcaserin-recipient non-responders (about 40% of those randomized to lorcaserin were “responders”). Among placebo recipients, there were 541 early responders and 1852 non-responders (about 17% of those randomized to placebo were “responders”). For the diabetic BLOOM-DM participants, the ratios were similar although slightly less favorable, with only about 30% (n = 78) of lorcaserin patients classified W12 responders (139 non-responders), and 10% (n = 25) of placebo patients as W12 responders (192 non-responders).
The lorcaserin and placebo groups in BLOOM and BLOSSOM were similar to one another, with overall mean (SD) age of 43.8 (11.6) years for lorcaserin and 44.0 (11.4) years for placebo. The vast majority of participants in these 2 trials were female (81.7% in lorcaserin arms, 81.0% in placebo), and the majority were non-Hispanic white (67.6% in lorcaserin and 66.2% in placebo). The mean (SD) baseline body mass index (BMI, kg/m2) was 36.1 (4.3) for lorcaserin and 36.1 (4.2) for placebo. The BLOOM-DM participants were also similar in the lorcaserin and placebo arms, although they were older (mean age, 53.2 years lorcaserin, 52 years placebo), and more likely to be female (53.5% lorcaserin, 54.4% placebo). Otherwise, the BLOOM-DM participants were similar on reported demographic characteristics to those in the other 2 trials.
Importantly, however, for all 3 trials there were differences in demographic characteristics between those participants characterized as responders and those characterized as non-responders. Amongst the nondiabetic participants in the BLOOM and BLOSSOM studies, responders (to both lorcaserin and placebo) were more likely to be non-Hispanic white (as opposed to African American or Hispanic participants, who were more likely to be non-responders), and responders were older than non-responders. Interestingly, for the diabetics in the BLOOM-DM trial, the responder/non-responder differences were less pronounced, although the responders were still slightly more likely to be non-Hispanic white and older, particularly for placebo.
Among BLOOM and BLOSSOM participants who received lorcaserin, mean weight loss at 52 weeks was 10.8% among W12Rs and only 2.7% among W12NRs. A similar pattern was observed in the BLOOM and BLOSSOM placebo participants; W12Rs averaged 9.5% weight loss at 52 weeks, versus just 1.1% in W12NRs. Among diabetics receiving lorcaserin in the BLOOM-DM study, weight loss at 1 year was 9.1% in W12Rs versus 3.1% in W12NRs. Similarly, in placebo-recipients in BLOOM-DM, weight loss at 1 year was 7% for W12Rs and 1.3% for W12NRs. When the weight loss at 1 year was categorized in terms of whether or not participants achieved at least 5% or 10% weight loss, once again early responders to either lorcaserin or placebo had higher rates of achieving both thresholds. Namely, 85.5% of nondiabetic W12Rs had achieved or maintained 5% weight loss at week 52, while only 26% of the W12NRs ultimately did so. Seventy percent of diabetic W12Rs to lorcaserin had ≥ 5% weight loss at week 52 and 25.2% of W12NRs did. The pattern of prediction for achieving 10% weight loss at week 52 was even more pronounced, with, for example, 49.8% of nondiabetic W12Rs having lost at least 10% of their starting weight at 1 year, versus just 4.7% of W12NRs.
When cardiometabolic outcomes were examined, the differences between W12 lorcaserin responders and non-responders appeared to be somewhat attenuated. For example, among diabetic patients, W12 lorcaserin responders had a mean decrease of 1.2% in their A1c level by study end, compared to a nearly 1% decrease in W12NRs. For fasting plasma glucose, the improvement at week 52 was pronounced (about 30 mg/dL lower than baseline) and very similar in W12 responders and non-responders.
Among nondiabetics, average blood pressure lowering (SBP and DBP) at week 52 was greater among lorcaserin W12 responders (SBP dropped 4 mm Hg on average, DBP 3 mm Hg) than it was among non-responders (SBP and DBP dropped by about 1 mm Hg). Other than triglycerides, which decreased substantially among W12 responders (whether on placebo or lorcaserin), changes to lipid profile were relatively small for nondiabetics. Among diabetics, however, LDL and HDL both increased on average in all 4 groups (W12 responders/non-responders to placebo/lorcaserin) by week 52.
Common adverse events for lorcaserin-treated patients included headache (15%–17%), upper respiratory infections (9%–14%), nausea (8%–9%), and dizziness (8% among nondiabetics). Among diabetics, hypoglycemia occurred in 29.3% of those treated with lorcaserin (vs. 21% on placebo). Week 12 responders and non-responders appeared to have a similar adverse event profile, and, in general, adverse events were more common among lorcaserin than placebo participants.
Conclusion. The authors of this study concluded that a week-12 weight loss of ≥ 5% on lorcaserin was a strong predictor of achieving at least that same amount of weight loss, as well as improvements in some cardiometabolic parameters, at 1 year.
Commentary
In 2013, the American Medical Association officially recognized obesity as a disease. This shift in terminology, coupled with a movement towards reimbursing primary care providers for obesity-related interventions, has created a growing awareness among providers that better treatment options for this chronic condition are sorely needed. Just as we treat patients with hypertension and type 2 diabetes by titrating medications, discontinuing those that aren’t effective and continuing those that are, so should we approach the management of our patients with obesity. Although behavioral interventions centered around lifestyle changes (diet/exercise) remain first-line therapies for the treatment of obesity [1], many patients will seek additional tools, such as meal replacement, medication, or even bariatric surgery, to help achieve and maintain weight loss.
In the past 2 to 3 years, there has been a flurry of activity by the FDA to approve new medications for weight loss. In keeping with the view of obesity as a chronic condition, some of these medications, including lorcaserin and phentermine-topiramate ER, have even been approved for patient long-term use [2]. While the addition of new options to the weight loss toolkit is exciting, it may also be daunting for clinicians who have witnessed a bevy of weight loss drugs come on, and then off, the market over the years due to serious adverse events experienced by patients. For physicians and patients considering the use of a new weight loss medication, there is therefore a clear need to minimize risk for adverse effects related to the drug, while maximizing the patient’s chances of losing weight.
Growing evidence from trials of behavioral interventions as well as weight loss medications suggests that the individuals who will ultimately achieve weight loss success with a given intervention/medication, tend to indicate that success relatively early on in the course of therapy [3–5]. For clinicians, this fact is extremely useful, because it may allow the physician and patient to more rapidly make a decision to discontinue a likely ineffective option in favor of another that has not yet been tried, thus minimizing risks for adverse events while maximizing chances of weight loss outcomes.
In this paper, Smith and colleagues addressed this very important issue for one of the more recently FDA-approved medications, lorcaserin. This 5-HT2c agonist is a useful addition to the list of weight loss medications, as it has relatively few contraindications, other than that it cannot be used in pregnancy/lactation and should be avoided in those with a history of heart failure. However, lorcaserin is still relatively costly (eg, compared to phentermine) and, if it is going to be used for long-term weight loss/maintenance, the financial outlay faced by patients might be considerable. In addition to answering an important question, this paper also examined not only weight loss outcomes but also cardiometabolic impacts of the medication. Furthermore, the authors separately examined outcomes for diabetic and nondiabetic patients, as the risk/benefit ratio of remaining on this medication could be quite different between the 2 groups.
Importantly, the study represented a group of secondary analyses of data aggregated from several trials—trials that were not originally designed to answer this question. Although the majority of original trial participants did have data at weeks 12 and 52 (requirement for inclusion in this analysis), up to a quarter of patients in some groups were missing one or the other measure. Whether or not those analyzed represented a biased subsample, and therefore do not have generalizable results, cannot be ascertained.
In reviewing the outcomes achieved by early responders and non-responders, it was very interesting to note that so-called “responders” to placebo followed a nearly identical weight loss trajectory as those on lorcaserin. This fact should not be taken to indicate that lorcaserin is no different from placebo, as the overall chances of achieving weight loss were significantly greater among the lorcaserin participants. However, it is interesting that, for those placebo patients who clearly followed the recommended lifestyle changes, they did just as well as patients receiving active study drug. This underscores the need to educate patients and encourage them, first and foremost, to make a real effort to diet and exercise regardless of what other tools are employed to achieve weight loss.
Another issue to consider for this study is that there are clear differences in the racial/ethnic makeup of responders versus non-responders. This finding is not unexpected, as in many prior weight loss trials, particularly for behavioral interventions, African-American women have experienced less weight loss than their non-Hispanic white counterparts [6]. These differences were observed both for lorcaserin and placebo patients, raising a concern that the lifestyle intervention component of the study was not equally successful for minorities compared to the non-Hispanic white participants. More research is needed on behavioral interventions that work well in diverse populations.
One finding of interest is that among diabetic participants (BLOOM-DM), glycemic control parameters improved nearly equally between lorcaserin early responders and non-responders, despite the differences between those groups for year-end weight loss. The reasons for this are not clear but could merit further investigation.
Ultimately however, even among this large group of randomized trial participants, who were likely highly motivated, only about 40% of nondiabetics and 30% of diabetics were classified as week 12 responders to lorcaserin. That means that likely well over half of the real-world patients who initiate the drug may not achieve their desired weight loss goals with it. Given the cost of the medication, this must be considered before prescribing it, and it reinforces the importance of being willing to reassess a patient’s weight loss progress early and often so that the medication can be discontinued in favor of other therapies as needed.
Applications for Clinical Practice
For providers interested in prescribing lorcaserin to their patients, a clear plan should be made to have regular and early follow-up to assess the patient’s response to the medication. Patients should understand that if they are not responding to the medication within 3 months, or perhaps sooner if they are experiencing any negative side effects, their physician may elect to discontinue it. Importantly, they should only be given lorcaserin if they are also willing to undertake the behavioral changes necessary to promote weight loss, and it should be underscored that their chances of successful weight loss with or without the medication will be greatly enhanced by doing so.
—Kristina Lewis, MD, MPH
1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63(25 Pt B):2985–3023.
2. Hurt RT, Jithinraj EV, Ebbert JO. New pharmacological treatments for the management of obesity. Cur Gastroenterol Rep 2014;16.6:1–8.
3. Wadden TA, Foster GD, Wang J, et al. Clinical correlates of short- and long-term weight loss. Am J Clin Nutr 1992;56(Suppl 1):271S–274S.
4. Rissanen A, Lean M, Rossner S, et al. Predictive value of early weight loss in obesity management with orlistat: An evidence-based assessment of prescribing guidelines. Int J Obes Relat Metab Disord 2003;27:103–9.
5. O’Neil P, Foster G, Billes S, et al. Early weight loss with naltrexone SR/bupropion SR combination therapy for obesity predicts long-term weight loss (Abstract). Obesity 2009;17:S109.
6. Kumanyika SK, Whitt-Glover MC, Haire-Joshu D. What works for obesity prevention and treatment in black Americans? Research directions. Obes Rev 2014;15:204–12.
Study Overview
Objective. To examine whether an early response (or non-response) to lorcaserin therapy predicts ≥ 5% weight loss achieved at 1 year.
Study design. Secondary analysis of data collected in 3 placebo-controlled blinded randomized trials.
Setting and participants. This study relied upon data collected as part of 3 separate phase 3 clinical trials of lorcaserin, a weight loss drug and selective serotonin 2c (5-HT2c) agonist. The first study, “Behavioral Modification and Lorcaserin for Overweight and Obesity Management” (BLOOM; n = 3182) enrolled overweight (with at least 1 comorbidity) or obese (no comorbidity needed) adult patients (18–65 yr) without diabetes, to determine the safety and efficacy of lorcaserin. The second trial, “Behavioral Modification and Lorcaserin Second Study of Obesity Management” (BLOSSOM; n = 4008) enrolled a similar population as BLOOM. For both BLOOM and BLOSSOM, patients were randomly assigned to receive either lorcaserin (10 mg po bid) or placebo for a 1-year period, and all patients received advice and instruction in exercise goals (at least 30 min/day) and caloric intake (600 kcal less than recommended for weight maintenance for that individual) necessary to promote weight loss. The third trial, BLOOM-DM (n = 604) focused on overweight or obese diabetic patients, but otherwise was similar in methodology to BLOOM and BLOSSOM. All studies took place in multiple US academic and private medical centers and were funded by Arena Pharmaceuticals. For the current analysis, the investigators used data from these trials and classified participants as either “responders” or “non-responders” based on each participant’s early weight loss response to either lorcaserin or placebo.
Main outcome measures. The investigators used area under the curve for the receiver operating characteristic (AUC for ROC) analysis to determine whether an early weight loss response to lorcaserin or placebo predicted a patient’s longer-term (52-week) weight loss. Several steps were used to conduct these analyses.
First, the investigators needed to determine what amount of weight loss at which of several early time-points would qualify a participant as a “responder” to either drug or placebo. They compared weight lost at weeks 2, 4, 8 and 12, using AUC for ROC analysis to identify the appropriate “responder” or “non-responder” cut-points, and classified all participants with data points in these early weeks as such. Second, all of the early responder and non-responder participants with 52-week weight data were then classified as to whether or not they had achieved at least a 5% weight loss at the end of the study. AUC for ROC analysis was again used to determine whether this early categorization was predictive of final study response. In addition to looking at early response as predictive of final weight loss, the investigators also examined the response/non-response variable’s ability to predict other health outcomes, including changes in lipid levels, blood pressure, and, for type 2 diabetic participants, changes in glycemic control (fasting plasma glucose [FPG] and HgbA1c). Finally, the investigators examined the incidence of adverse events in the different groups as well.
Results. The investigators identified a 4.6% weight loss by week 12 on lorcaserin or placebo as the optimal cut-point for determining whether a participant was a “responder” or “non-responder” (“W12R” or “W12NR”). This cut-point had an AUC (95% CI) of 0.849 (0.828–0.870) for predicting ≥ 5% weight loss at 52 weeks, with a positive predictive value (PPV) of 0.855 and negative predictive value (NPV) of 0.740, thus optimizing specificity and sensitivity of the time/weight cut-point compared to those at weeks 2, 4, or 8. Given the need for practical clinical recommendations, however, the investigators used a cut-point of 5% weight loss by week 12 to determine response/non-response for the health outcome analyses. The breakdown of responders vs. non-responders was as follows: For the pooled BLOOM/BLOSSOM participants, there were 1251 lorcaserin-recipient responders and 1286 lorcaserin-recipient non-responders (about 40% of those randomized to lorcaserin were “responders”). Among placebo recipients, there were 541 early responders and 1852 non-responders (about 17% of those randomized to placebo were “responders”). For the diabetic BLOOM-DM participants, the ratios were similar although slightly less favorable, with only about 30% (n = 78) of lorcaserin patients classified W12 responders (139 non-responders), and 10% (n = 25) of placebo patients as W12 responders (192 non-responders).
The lorcaserin and placebo groups in BLOOM and BLOSSOM were similar to one another, with overall mean (SD) age of 43.8 (11.6) years for lorcaserin and 44.0 (11.4) years for placebo. The vast majority of participants in these 2 trials were female (81.7% in lorcaserin arms, 81.0% in placebo), and the majority were non-Hispanic white (67.6% in lorcaserin and 66.2% in placebo). The mean (SD) baseline body mass index (BMI, kg/m2) was 36.1 (4.3) for lorcaserin and 36.1 (4.2) for placebo. The BLOOM-DM participants were also similar in the lorcaserin and placebo arms, although they were older (mean age, 53.2 years lorcaserin, 52 years placebo), and more likely to be female (53.5% lorcaserin, 54.4% placebo). Otherwise, the BLOOM-DM participants were similar on reported demographic characteristics to those in the other 2 trials.
Importantly, however, for all 3 trials there were differences in demographic characteristics between those participants characterized as responders and those characterized as non-responders. Amongst the nondiabetic participants in the BLOOM and BLOSSOM studies, responders (to both lorcaserin and placebo) were more likely to be non-Hispanic white (as opposed to African American or Hispanic participants, who were more likely to be non-responders), and responders were older than non-responders. Interestingly, for the diabetics in the BLOOM-DM trial, the responder/non-responder differences were less pronounced, although the responders were still slightly more likely to be non-Hispanic white and older, particularly for placebo.
Among BLOOM and BLOSSOM participants who received lorcaserin, mean weight loss at 52 weeks was 10.8% among W12Rs and only 2.7% among W12NRs. A similar pattern was observed in the BLOOM and BLOSSOM placebo participants; W12Rs averaged 9.5% weight loss at 52 weeks, versus just 1.1% in W12NRs. Among diabetics receiving lorcaserin in the BLOOM-DM study, weight loss at 1 year was 9.1% in W12Rs versus 3.1% in W12NRs. Similarly, in placebo-recipients in BLOOM-DM, weight loss at 1 year was 7% for W12Rs and 1.3% for W12NRs. When the weight loss at 1 year was categorized in terms of whether or not participants achieved at least 5% or 10% weight loss, once again early responders to either lorcaserin or placebo had higher rates of achieving both thresholds. Namely, 85.5% of nondiabetic W12Rs had achieved or maintained 5% weight loss at week 52, while only 26% of the W12NRs ultimately did so. Seventy percent of diabetic W12Rs to lorcaserin had ≥ 5% weight loss at week 52 and 25.2% of W12NRs did. The pattern of prediction for achieving 10% weight loss at week 52 was even more pronounced, with, for example, 49.8% of nondiabetic W12Rs having lost at least 10% of their starting weight at 1 year, versus just 4.7% of W12NRs.
When cardiometabolic outcomes were examined, the differences between W12 lorcaserin responders and non-responders appeared to be somewhat attenuated. For example, among diabetic patients, W12 lorcaserin responders had a mean decrease of 1.2% in their A1c level by study end, compared to a nearly 1% decrease in W12NRs. For fasting plasma glucose, the improvement at week 52 was pronounced (about 30 mg/dL lower than baseline) and very similar in W12 responders and non-responders.
Among nondiabetics, average blood pressure lowering (SBP and DBP) at week 52 was greater among lorcaserin W12 responders (SBP dropped 4 mm Hg on average, DBP 3 mm Hg) than it was among non-responders (SBP and DBP dropped by about 1 mm Hg). Other than triglycerides, which decreased substantially among W12 responders (whether on placebo or lorcaserin), changes to lipid profile were relatively small for nondiabetics. Among diabetics, however, LDL and HDL both increased on average in all 4 groups (W12 responders/non-responders to placebo/lorcaserin) by week 52.
Common adverse events for lorcaserin-treated patients included headache (15%–17%), upper respiratory infections (9%–14%), nausea (8%–9%), and dizziness (8% among nondiabetics). Among diabetics, hypoglycemia occurred in 29.3% of those treated with lorcaserin (vs. 21% on placebo). Week 12 responders and non-responders appeared to have a similar adverse event profile, and, in general, adverse events were more common among lorcaserin than placebo participants.
Conclusion. The authors of this study concluded that a week-12 weight loss of ≥ 5% on lorcaserin was a strong predictor of achieving at least that same amount of weight loss, as well as improvements in some cardiometabolic parameters, at 1 year.
Commentary
In 2013, the American Medical Association officially recognized obesity as a disease. This shift in terminology, coupled with a movement towards reimbursing primary care providers for obesity-related interventions, has created a growing awareness among providers that better treatment options for this chronic condition are sorely needed. Just as we treat patients with hypertension and type 2 diabetes by titrating medications, discontinuing those that aren’t effective and continuing those that are, so should we approach the management of our patients with obesity. Although behavioral interventions centered around lifestyle changes (diet/exercise) remain first-line therapies for the treatment of obesity [1], many patients will seek additional tools, such as meal replacement, medication, or even bariatric surgery, to help achieve and maintain weight loss.
In the past 2 to 3 years, there has been a flurry of activity by the FDA to approve new medications for weight loss. In keeping with the view of obesity as a chronic condition, some of these medications, including lorcaserin and phentermine-topiramate ER, have even been approved for patient long-term use [2]. While the addition of new options to the weight loss toolkit is exciting, it may also be daunting for clinicians who have witnessed a bevy of weight loss drugs come on, and then off, the market over the years due to serious adverse events experienced by patients. For physicians and patients considering the use of a new weight loss medication, there is therefore a clear need to minimize risk for adverse effects related to the drug, while maximizing the patient’s chances of losing weight.
Growing evidence from trials of behavioral interventions as well as weight loss medications suggests that the individuals who will ultimately achieve weight loss success with a given intervention/medication, tend to indicate that success relatively early on in the course of therapy [3–5]. For clinicians, this fact is extremely useful, because it may allow the physician and patient to more rapidly make a decision to discontinue a likely ineffective option in favor of another that has not yet been tried, thus minimizing risks for adverse events while maximizing chances of weight loss outcomes.
In this paper, Smith and colleagues addressed this very important issue for one of the more recently FDA-approved medications, lorcaserin. This 5-HT2c agonist is a useful addition to the list of weight loss medications, as it has relatively few contraindications, other than that it cannot be used in pregnancy/lactation and should be avoided in those with a history of heart failure. However, lorcaserin is still relatively costly (eg, compared to phentermine) and, if it is going to be used for long-term weight loss/maintenance, the financial outlay faced by patients might be considerable. In addition to answering an important question, this paper also examined not only weight loss outcomes but also cardiometabolic impacts of the medication. Furthermore, the authors separately examined outcomes for diabetic and nondiabetic patients, as the risk/benefit ratio of remaining on this medication could be quite different between the 2 groups.
Importantly, the study represented a group of secondary analyses of data aggregated from several trials—trials that were not originally designed to answer this question. Although the majority of original trial participants did have data at weeks 12 and 52 (requirement for inclusion in this analysis), up to a quarter of patients in some groups were missing one or the other measure. Whether or not those analyzed represented a biased subsample, and therefore do not have generalizable results, cannot be ascertained.
In reviewing the outcomes achieved by early responders and non-responders, it was very interesting to note that so-called “responders” to placebo followed a nearly identical weight loss trajectory as those on lorcaserin. This fact should not be taken to indicate that lorcaserin is no different from placebo, as the overall chances of achieving weight loss were significantly greater among the lorcaserin participants. However, it is interesting that, for those placebo patients who clearly followed the recommended lifestyle changes, they did just as well as patients receiving active study drug. This underscores the need to educate patients and encourage them, first and foremost, to make a real effort to diet and exercise regardless of what other tools are employed to achieve weight loss.
Another issue to consider for this study is that there are clear differences in the racial/ethnic makeup of responders versus non-responders. This finding is not unexpected, as in many prior weight loss trials, particularly for behavioral interventions, African-American women have experienced less weight loss than their non-Hispanic white counterparts [6]. These differences were observed both for lorcaserin and placebo patients, raising a concern that the lifestyle intervention component of the study was not equally successful for minorities compared to the non-Hispanic white participants. More research is needed on behavioral interventions that work well in diverse populations.
One finding of interest is that among diabetic participants (BLOOM-DM), glycemic control parameters improved nearly equally between lorcaserin early responders and non-responders, despite the differences between those groups for year-end weight loss. The reasons for this are not clear but could merit further investigation.
Ultimately however, even among this large group of randomized trial participants, who were likely highly motivated, only about 40% of nondiabetics and 30% of diabetics were classified as week 12 responders to lorcaserin. That means that likely well over half of the real-world patients who initiate the drug may not achieve their desired weight loss goals with it. Given the cost of the medication, this must be considered before prescribing it, and it reinforces the importance of being willing to reassess a patient’s weight loss progress early and often so that the medication can be discontinued in favor of other therapies as needed.
Applications for Clinical Practice
For providers interested in prescribing lorcaserin to their patients, a clear plan should be made to have regular and early follow-up to assess the patient’s response to the medication. Patients should understand that if they are not responding to the medication within 3 months, or perhaps sooner if they are experiencing any negative side effects, their physician may elect to discontinue it. Importantly, they should only be given lorcaserin if they are also willing to undertake the behavioral changes necessary to promote weight loss, and it should be underscored that their chances of successful weight loss with or without the medication will be greatly enhanced by doing so.
—Kristina Lewis, MD, MPH
Study Overview
Objective. To examine whether an early response (or non-response) to lorcaserin therapy predicts ≥ 5% weight loss achieved at 1 year.
Study design. Secondary analysis of data collected in 3 placebo-controlled blinded randomized trials.
Setting and participants. This study relied upon data collected as part of 3 separate phase 3 clinical trials of lorcaserin, a weight loss drug and selective serotonin 2c (5-HT2c) agonist. The first study, “Behavioral Modification and Lorcaserin for Overweight and Obesity Management” (BLOOM; n = 3182) enrolled overweight (with at least 1 comorbidity) or obese (no comorbidity needed) adult patients (18–65 yr) without diabetes, to determine the safety and efficacy of lorcaserin. The second trial, “Behavioral Modification and Lorcaserin Second Study of Obesity Management” (BLOSSOM; n = 4008) enrolled a similar population as BLOOM. For both BLOOM and BLOSSOM, patients were randomly assigned to receive either lorcaserin (10 mg po bid) or placebo for a 1-year period, and all patients received advice and instruction in exercise goals (at least 30 min/day) and caloric intake (600 kcal less than recommended for weight maintenance for that individual) necessary to promote weight loss. The third trial, BLOOM-DM (n = 604) focused on overweight or obese diabetic patients, but otherwise was similar in methodology to BLOOM and BLOSSOM. All studies took place in multiple US academic and private medical centers and were funded by Arena Pharmaceuticals. For the current analysis, the investigators used data from these trials and classified participants as either “responders” or “non-responders” based on each participant’s early weight loss response to either lorcaserin or placebo.
Main outcome measures. The investigators used area under the curve for the receiver operating characteristic (AUC for ROC) analysis to determine whether an early weight loss response to lorcaserin or placebo predicted a patient’s longer-term (52-week) weight loss. Several steps were used to conduct these analyses.
First, the investigators needed to determine what amount of weight loss at which of several early time-points would qualify a participant as a “responder” to either drug or placebo. They compared weight lost at weeks 2, 4, 8 and 12, using AUC for ROC analysis to identify the appropriate “responder” or “non-responder” cut-points, and classified all participants with data points in these early weeks as such. Second, all of the early responder and non-responder participants with 52-week weight data were then classified as to whether or not they had achieved at least a 5% weight loss at the end of the study. AUC for ROC analysis was again used to determine whether this early categorization was predictive of final study response. In addition to looking at early response as predictive of final weight loss, the investigators also examined the response/non-response variable’s ability to predict other health outcomes, including changes in lipid levels, blood pressure, and, for type 2 diabetic participants, changes in glycemic control (fasting plasma glucose [FPG] and HgbA1c). Finally, the investigators examined the incidence of adverse events in the different groups as well.
Results. The investigators identified a 4.6% weight loss by week 12 on lorcaserin or placebo as the optimal cut-point for determining whether a participant was a “responder” or “non-responder” (“W12R” or “W12NR”). This cut-point had an AUC (95% CI) of 0.849 (0.828–0.870) for predicting ≥ 5% weight loss at 52 weeks, with a positive predictive value (PPV) of 0.855 and negative predictive value (NPV) of 0.740, thus optimizing specificity and sensitivity of the time/weight cut-point compared to those at weeks 2, 4, or 8. Given the need for practical clinical recommendations, however, the investigators used a cut-point of 5% weight loss by week 12 to determine response/non-response for the health outcome analyses. The breakdown of responders vs. non-responders was as follows: For the pooled BLOOM/BLOSSOM participants, there were 1251 lorcaserin-recipient responders and 1286 lorcaserin-recipient non-responders (about 40% of those randomized to lorcaserin were “responders”). Among placebo recipients, there were 541 early responders and 1852 non-responders (about 17% of those randomized to placebo were “responders”). For the diabetic BLOOM-DM participants, the ratios were similar although slightly less favorable, with only about 30% (n = 78) of lorcaserin patients classified W12 responders (139 non-responders), and 10% (n = 25) of placebo patients as W12 responders (192 non-responders).
The lorcaserin and placebo groups in BLOOM and BLOSSOM were similar to one another, with overall mean (SD) age of 43.8 (11.6) years for lorcaserin and 44.0 (11.4) years for placebo. The vast majority of participants in these 2 trials were female (81.7% in lorcaserin arms, 81.0% in placebo), and the majority were non-Hispanic white (67.6% in lorcaserin and 66.2% in placebo). The mean (SD) baseline body mass index (BMI, kg/m2) was 36.1 (4.3) for lorcaserin and 36.1 (4.2) for placebo. The BLOOM-DM participants were also similar in the lorcaserin and placebo arms, although they were older (mean age, 53.2 years lorcaserin, 52 years placebo), and more likely to be female (53.5% lorcaserin, 54.4% placebo). Otherwise, the BLOOM-DM participants were similar on reported demographic characteristics to those in the other 2 trials.
Importantly, however, for all 3 trials there were differences in demographic characteristics between those participants characterized as responders and those characterized as non-responders. Amongst the nondiabetic participants in the BLOOM and BLOSSOM studies, responders (to both lorcaserin and placebo) were more likely to be non-Hispanic white (as opposed to African American or Hispanic participants, who were more likely to be non-responders), and responders were older than non-responders. Interestingly, for the diabetics in the BLOOM-DM trial, the responder/non-responder differences were less pronounced, although the responders were still slightly more likely to be non-Hispanic white and older, particularly for placebo.
Among BLOOM and BLOSSOM participants who received lorcaserin, mean weight loss at 52 weeks was 10.8% among W12Rs and only 2.7% among W12NRs. A similar pattern was observed in the BLOOM and BLOSSOM placebo participants; W12Rs averaged 9.5% weight loss at 52 weeks, versus just 1.1% in W12NRs. Among diabetics receiving lorcaserin in the BLOOM-DM study, weight loss at 1 year was 9.1% in W12Rs versus 3.1% in W12NRs. Similarly, in placebo-recipients in BLOOM-DM, weight loss at 1 year was 7% for W12Rs and 1.3% for W12NRs. When the weight loss at 1 year was categorized in terms of whether or not participants achieved at least 5% or 10% weight loss, once again early responders to either lorcaserin or placebo had higher rates of achieving both thresholds. Namely, 85.5% of nondiabetic W12Rs had achieved or maintained 5% weight loss at week 52, while only 26% of the W12NRs ultimately did so. Seventy percent of diabetic W12Rs to lorcaserin had ≥ 5% weight loss at week 52 and 25.2% of W12NRs did. The pattern of prediction for achieving 10% weight loss at week 52 was even more pronounced, with, for example, 49.8% of nondiabetic W12Rs having lost at least 10% of their starting weight at 1 year, versus just 4.7% of W12NRs.
When cardiometabolic outcomes were examined, the differences between W12 lorcaserin responders and non-responders appeared to be somewhat attenuated. For example, among diabetic patients, W12 lorcaserin responders had a mean decrease of 1.2% in their A1c level by study end, compared to a nearly 1% decrease in W12NRs. For fasting plasma glucose, the improvement at week 52 was pronounced (about 30 mg/dL lower than baseline) and very similar in W12 responders and non-responders.
Among nondiabetics, average blood pressure lowering (SBP and DBP) at week 52 was greater among lorcaserin W12 responders (SBP dropped 4 mm Hg on average, DBP 3 mm Hg) than it was among non-responders (SBP and DBP dropped by about 1 mm Hg). Other than triglycerides, which decreased substantially among W12 responders (whether on placebo or lorcaserin), changes to lipid profile were relatively small for nondiabetics. Among diabetics, however, LDL and HDL both increased on average in all 4 groups (W12 responders/non-responders to placebo/lorcaserin) by week 52.
Common adverse events for lorcaserin-treated patients included headache (15%–17%), upper respiratory infections (9%–14%), nausea (8%–9%), and dizziness (8% among nondiabetics). Among diabetics, hypoglycemia occurred in 29.3% of those treated with lorcaserin (vs. 21% on placebo). Week 12 responders and non-responders appeared to have a similar adverse event profile, and, in general, adverse events were more common among lorcaserin than placebo participants.
Conclusion. The authors of this study concluded that a week-12 weight loss of ≥ 5% on lorcaserin was a strong predictor of achieving at least that same amount of weight loss, as well as improvements in some cardiometabolic parameters, at 1 year.
Commentary
In 2013, the American Medical Association officially recognized obesity as a disease. This shift in terminology, coupled with a movement towards reimbursing primary care providers for obesity-related interventions, has created a growing awareness among providers that better treatment options for this chronic condition are sorely needed. Just as we treat patients with hypertension and type 2 diabetes by titrating medications, discontinuing those that aren’t effective and continuing those that are, so should we approach the management of our patients with obesity. Although behavioral interventions centered around lifestyle changes (diet/exercise) remain first-line therapies for the treatment of obesity [1], many patients will seek additional tools, such as meal replacement, medication, or even bariatric surgery, to help achieve and maintain weight loss.
In the past 2 to 3 years, there has been a flurry of activity by the FDA to approve new medications for weight loss. In keeping with the view of obesity as a chronic condition, some of these medications, including lorcaserin and phentermine-topiramate ER, have even been approved for patient long-term use [2]. While the addition of new options to the weight loss toolkit is exciting, it may also be daunting for clinicians who have witnessed a bevy of weight loss drugs come on, and then off, the market over the years due to serious adverse events experienced by patients. For physicians and patients considering the use of a new weight loss medication, there is therefore a clear need to minimize risk for adverse effects related to the drug, while maximizing the patient’s chances of losing weight.
Growing evidence from trials of behavioral interventions as well as weight loss medications suggests that the individuals who will ultimately achieve weight loss success with a given intervention/medication, tend to indicate that success relatively early on in the course of therapy [3–5]. For clinicians, this fact is extremely useful, because it may allow the physician and patient to more rapidly make a decision to discontinue a likely ineffective option in favor of another that has not yet been tried, thus minimizing risks for adverse events while maximizing chances of weight loss outcomes.
In this paper, Smith and colleagues addressed this very important issue for one of the more recently FDA-approved medications, lorcaserin. This 5-HT2c agonist is a useful addition to the list of weight loss medications, as it has relatively few contraindications, other than that it cannot be used in pregnancy/lactation and should be avoided in those with a history of heart failure. However, lorcaserin is still relatively costly (eg, compared to phentermine) and, if it is going to be used for long-term weight loss/maintenance, the financial outlay faced by patients might be considerable. In addition to answering an important question, this paper also examined not only weight loss outcomes but also cardiometabolic impacts of the medication. Furthermore, the authors separately examined outcomes for diabetic and nondiabetic patients, as the risk/benefit ratio of remaining on this medication could be quite different between the 2 groups.
Importantly, the study represented a group of secondary analyses of data aggregated from several trials—trials that were not originally designed to answer this question. Although the majority of original trial participants did have data at weeks 12 and 52 (requirement for inclusion in this analysis), up to a quarter of patients in some groups were missing one or the other measure. Whether or not those analyzed represented a biased subsample, and therefore do not have generalizable results, cannot be ascertained.
In reviewing the outcomes achieved by early responders and non-responders, it was very interesting to note that so-called “responders” to placebo followed a nearly identical weight loss trajectory as those on lorcaserin. This fact should not be taken to indicate that lorcaserin is no different from placebo, as the overall chances of achieving weight loss were significantly greater among the lorcaserin participants. However, it is interesting that, for those placebo patients who clearly followed the recommended lifestyle changes, they did just as well as patients receiving active study drug. This underscores the need to educate patients and encourage them, first and foremost, to make a real effort to diet and exercise regardless of what other tools are employed to achieve weight loss.
Another issue to consider for this study is that there are clear differences in the racial/ethnic makeup of responders versus non-responders. This finding is not unexpected, as in many prior weight loss trials, particularly for behavioral interventions, African-American women have experienced less weight loss than their non-Hispanic white counterparts [6]. These differences were observed both for lorcaserin and placebo patients, raising a concern that the lifestyle intervention component of the study was not equally successful for minorities compared to the non-Hispanic white participants. More research is needed on behavioral interventions that work well in diverse populations.
One finding of interest is that among diabetic participants (BLOOM-DM), glycemic control parameters improved nearly equally between lorcaserin early responders and non-responders, despite the differences between those groups for year-end weight loss. The reasons for this are not clear but could merit further investigation.
Ultimately however, even among this large group of randomized trial participants, who were likely highly motivated, only about 40% of nondiabetics and 30% of diabetics were classified as week 12 responders to lorcaserin. That means that likely well over half of the real-world patients who initiate the drug may not achieve their desired weight loss goals with it. Given the cost of the medication, this must be considered before prescribing it, and it reinforces the importance of being willing to reassess a patient’s weight loss progress early and often so that the medication can be discontinued in favor of other therapies as needed.
Applications for Clinical Practice
For providers interested in prescribing lorcaserin to their patients, a clear plan should be made to have regular and early follow-up to assess the patient’s response to the medication. Patients should understand that if they are not responding to the medication within 3 months, or perhaps sooner if they are experiencing any negative side effects, their physician may elect to discontinue it. Importantly, they should only be given lorcaserin if they are also willing to undertake the behavioral changes necessary to promote weight loss, and it should be underscored that their chances of successful weight loss with or without the medication will be greatly enhanced by doing so.
—Kristina Lewis, MD, MPH
1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63(25 Pt B):2985–3023.
2. Hurt RT, Jithinraj EV, Ebbert JO. New pharmacological treatments for the management of obesity. Cur Gastroenterol Rep 2014;16.6:1–8.
3. Wadden TA, Foster GD, Wang J, et al. Clinical correlates of short- and long-term weight loss. Am J Clin Nutr 1992;56(Suppl 1):271S–274S.
4. Rissanen A, Lean M, Rossner S, et al. Predictive value of early weight loss in obesity management with orlistat: An evidence-based assessment of prescribing guidelines. Int J Obes Relat Metab Disord 2003;27:103–9.
5. O’Neil P, Foster G, Billes S, et al. Early weight loss with naltrexone SR/bupropion SR combination therapy for obesity predicts long-term weight loss (Abstract). Obesity 2009;17:S109.
6. Kumanyika SK, Whitt-Glover MC, Haire-Joshu D. What works for obesity prevention and treatment in black Americans? Research directions. Obes Rev 2014;15:204–12.
1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63(25 Pt B):2985–3023.
2. Hurt RT, Jithinraj EV, Ebbert JO. New pharmacological treatments for the management of obesity. Cur Gastroenterol Rep 2014;16.6:1–8.
3. Wadden TA, Foster GD, Wang J, et al. Clinical correlates of short- and long-term weight loss. Am J Clin Nutr 1992;56(Suppl 1):271S–274S.
4. Rissanen A, Lean M, Rossner S, et al. Predictive value of early weight loss in obesity management with orlistat: An evidence-based assessment of prescribing guidelines. Int J Obes Relat Metab Disord 2003;27:103–9.
5. O’Neil P, Foster G, Billes S, et al. Early weight loss with naltrexone SR/bupropion SR combination therapy for obesity predicts long-term weight loss (Abstract). Obesity 2009;17:S109.
6. Kumanyika SK, Whitt-Glover MC, Haire-Joshu D. What works for obesity prevention and treatment in black Americans? Research directions. Obes Rev 2014;15:204–12.