A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults.
ABSTRACT: To evaluate safety and efficacy of phentermine 15 mg plus extended-release topiramate 92 mg for treatment of moderate to severe obstructive sleep apnea (OSA) in obese adults.This phase 2, randomized, double-blind, placebo-controlled study included 2-week screening and 28-week treatment periods. Overnight polysomnography was performed at baseline, Week 8, and Week 28.Single-center study conducted from August 2008 to September 2009.Forty-five subjects with moderate to severe OSA not receiving positive airway pressure (PAP) treatment with body mass index of 30-40 kg/m(2).Subjects were randomized to receive placebo (n = 23) or phentermine 15 mg plus extended-release topiramate 92 mg (n = 22). Both groups received lifestyle-modification counseling.Primary endpoint, change in apnea-hypopnea index (AHI), significantly favored phentermine 15 mg plus extended-release topiramate 92 mg (-31.5 events/h, 95% CI: -40.0, -22.9) over placebo (-16.6 events/h, 95% CI: -25.0, -8.2) at Week 28 (P =0.0084). At Week 28, there was a 10.2% (95% CI: -12.7, -7.6; 10.8 kg, 95% CI: -13.5, -8.0) mean decrease in weight in the phentermine 15 mg plus extended-release topiramate 92 mg group compared with 4.3% (95% CI: -6.6, -2.0; 4.7 kg, 95% CI: -7.2, -2.2) in the placebo group (P = 0.0006) and a positive, significant (P = 0.0003) correlation between percent change in weight and change in AHI. Significant improvements in overnight oxygen saturation and reduction in blood pressure compared with placebo were observed. Phentermine 15 mg plus extended-release topiramate 92 mg was well tolerated with low adverse event rates.Phentermine 15 mg plus extended-release topiramate 92 mg induced significant weight reductions and concomitant improvements in OSA and related symptoms vs placebo. This suggests weight loss mediated by phentermine 15 mg plus extended-release topiramate 92 mg may be useful in treatment of moderate to severe OSA in obese subjects unable or unwilling to comply with PAP treatment.
Project description:BACKGROUND:Obesity is a serious chronic disease. Controlled-release phentermine/topiramate (PHEN/TPM CR), as an adjunct to lifestyle modification, has previously shown significant weight loss compared with placebo in a 56-wk study in overweight and obese subjects with ?2 weight-related comorbidities. OBJECTIVE:This study evaluated the long-term efficacy and safety of PHEN/TPM CR in overweight and obese subjects with cardiometabolic disease. DESIGN:This was a placebo-controlled, double-blind, 52-wk extension study; volunteers at selected sites continued with original randomly assigned treatment [placebo, 7.5 mg phentermine/46 mg controlled-release topiramate (7.5/46), or 15 mg phentermine/92 mg controlled-release topiramate (15/92)] to complete a total of 108 wk. All subjects participated in a lifestyle-modification program. RESULTS:Of 866 eligible subjects, 676 (78%) elected to continue in the extension. Overall, 84.0% of subjects completed the study, with similar completion rates between treatment groups. At week 108, PHEN/TPM CR was associated with significant, sustained weight loss (intent-to-treat with last observation carried forward; P < 0.0001 compared with placebo); least-squares mean percentage changes from baseline in body weight were -1.8%, -9.3%, and -10.5% for placebo, 7.5/46, and 15/92, respectively. Significantly more PHEN/TPM CR-treated subjects at each dose achieved ?5%, ?10%, ?15%, and ?20% weight loss compared with placebo (P < 0.001). PHEN/TPM CR improved cardiovascular and metabolic variables and decreased rates of incident diabetes in comparison with placebo. PHEN/TPM CR was well tolerated over 108 wk, with reduced rates of adverse events occurring between weeks 56 and 108 compared with rates between weeks 0 and 56. CONCLUSION:PHEN/TPM CR in conjunction with lifestyle modification may provide a well-tolerated and effective option for the sustained treatment of obesity complicated by cardiometabolic disease. This trial was registered at clinicaltrials.gov as NCT00796367.
Project description:Thirty-six percent of US adults are obese, and many cannot lose sufficient weight to improve health with lifestyle interventions alone.To conduct a systematic review of medications currently approved in the United States for obesity treatment in adults. We also discuss off-label use of medications studied for obesity and provide considerations for obesity medication use in clinical practice.A PubMed search from inception through September 2013 was performed to find meta-analyses, systematic reviews, and randomized, placebo-controlled trials for currently approved obesity medications lasting at least 1 year that had a primary or secondary outcome of body weight change, included at least 50 participants per group, reported at least 50% retention, and reported results on an intention-to-treat basis. Studies of medications approved for other purposes but tested for obesity treatment were also reviewed.Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate-extended release at 1 year. The proportion of patients achieving clinically meaningful (at least 5%) weight loss ranges from 37% to 47% for lorcaserin, 35% to 73% for orlistat, and 67% to 70% for top-dose phentermine plus topiramate-extended release. All 3 medications produce greater improvements in many cardiometabolic risk factors than placebo, but no obesity medication has been shown to reduce cardiovascular morbidity or mortality. Most prescriptions are for noradrenergic medications, despite their approval only for short-term use and limited data for their long-term safety and efficacy.Medications approved for long-term obesity treatment, when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo. By discontinuing medication in patients who do not respond with weight loss of at least 5%, clinicians can decrease their patients' exposure to the risks and costs of drug treatment when there is little prospect of long-term benefit.
Project description:OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m(2)) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.
Project description:Phase 3 clinical trial results reveal that Qsymia is a clinically effective long-term treatment for obesity, but whether this treatment is cost-effective compared to a diet and lifestyle intervention has yet to be explored.To quantify the incremental cost-effectiveness of Qsymia (phentermine and topiramate extended-release) for health-related quality of life improvements.Estimates are based on cost and quality of life outcomes from a 56-week, multicenter, placebo-controlled, phase 3 clinical trial undertaken in 93 health centers in the US. Participants were overweight and obese adults (aged 18-70 years) with a body-mass index of 27-45 kg/m(2) and two or more comorbidities (hypertension, dyslipidemia, diabetes or pre-diabetes or abdominal obesity). The intervention was diet and lifestyle advice plus the recommended dose of Qsymia (phentermine 7.5 mg plus topiramate 46.0 mg) vs. control, which included diet and lifestyle advice plus placebo. The study was from the payer perspective. Costs included the prescription cost, medication cost offsets and physician appointment costs. Effectiveness was measured in terms of quality-adjusted life years gained (QALYs). The main outcome measure was incremental cost per QALY gained of the intervention relative to control.Our base-case model, in which participants take Qsymia for 1 year with benefits linearly decaying over the subsequent 2 years, generates an incremental cost-effectiveness ratio (ICER) of $48,340 per QALY gained. Using the base-case assumptions, probabilistic sensitivity analyses reveal that the ICER is below $50,000 per QALY in 54 % of simulations. However, results are highly dependent on the extent to which benefits are maintained post medication cessation. If benefits persist for only 1 year post cessation, the ICER increases to $74,480.Although base-case results suggest that Qsymia is cost-effective, this result hinges on the time on Qsymia and the extent to which benefits are maintained post medication cessation. This should be an area of future research.
Project description:OBJECTIVE:Our objective was to estimate 4-year healthcare costs associated with the metabolic profile of patients before and after 1 year of treatment with phentermine (15 mg) and topiramate extended-release (92 mg) [phentermine-topiramate ER]. DESIGN AND METHODS:Using a medical records database, we created two patient cohorts reflecting metabolic profiles of subjects before and after phentermine-topiramate ER therapy during the 1-year CONQUER trial. We matched database patients with trial subjects by age, sex, body mass index (BMI), and hypertension, glycemic, and triglyceride status. We collected real-world data on emergency department and outpatient visits, hospitalizations, and drug prescriptions over 4 years, linking them to reimbursements to estimate US private insurance costs for post-trial (n = 2295) versus pre-trial intention-to-treat (ITT) patients (n = 2295). Secondary analysis assessed responders (completers losing ?5 % body weight [n = 1285]). RESULTS:Over 4 years, the mean cost per patient in the post- versus pre-trial ITT-group was $US32,432 versus $US34,725 (mean difference -2292; 95 % confidence interval [CI] -4776 to 209). In responders, corresponding costs were $US30,558 versus $US33,936 (mean difference -3378; 95 % CI -6496 to -464). Costs for post- versus pre-trial responders were lower for outpatient visits, emergency visits, and medications (all P < 0.05). CONCLUSION:Excluding treatment cost and potential side effects, patients matched to profiles of phentermine-topiramate ER responders had lower costs than patients matched to pre-treatment profiles.
Project description:Weight loss can reduce the increased cardiovascular risk associated with obesity. Pharmacotherapy is a recognized weight loss treatment option; however, cardiovascular safety issues with some previous weight loss drugs raise concerns for newly approved pharmacotherapies. Phentermine is approved for short-term obesity treatment in conjunction with lifestyle modifications, but is commonly used chronically. Topiramate, approved for treating epilepsy and preventing migraines, also induces weight loss. A single-dose combination of low-dose phentermine and topiramate extended-release was recently approved by the United States Food and Drug Administration as an adjunct to lifestyle intervention for the chronic treatment of overweight/obese adults. This review summarizes and evaluates the cardiovascular risk/benefit profile associated with phentermine and topiramate, individually and in combination. Cardiovascular data associated with long-term use of phentermine and topiramate extended-release indicate that this combination may be a safe and effective option for reducing weight in overweight/obese patients at low-to-intermediate cardiovascular risk.
Project description:A 56-week randomized controlled trial was conducted to evaluate safety and efficacy of a controlled-release combination of phentermine and topiramate (PHEN/TPM CR) for weight loss (WL) and metabolic improvements. Men and women with class II and III obesity (BMI ? 35 kg/m(2)) were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg, added to a reduced-energy diet. Primary end points were percent WL and proportions of patients achieving 5% WL. Secondary end points included waist circumference (WC), systolic and diastolic blood pressure (BP), fasting glucose, and lipid measures. In the primary analysis (randomized patients with at least one postbaseline weight measurement who took at least one dose of assigned drug or placebo), patients in the placebo, 3.75/23, and 15/92 groups lost 1.6%, 5.1%, and 10.9% of baseline body weight (BW), respectively, at 56 weeks (P < 0.0001). In categorical analysis, 17.3% of placebo patients, 44.9% of 3.75/23 patients, and 66.7% of 15/92 patients, lost at least 5% of baseline BW at 56 weeks (P < 0.0001). The 15/92 group had significantly greater changes relative to placebo for WC, systolic and diastolic BP, fasting glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The most common adverse events were paresthesia, dry mouth, constipation, dysgeusia, and insomnia. Dropout rate from the study was 47.1% for placebo patients, 39.0% for 3.75/23 patients, and 33.6% of 15/92 patients. PHEN/TPM CR demonstrated dose-dependent effects on weight and metabolic variables in the direction expected to be beneficial with no evidence of serious adverse events induced by treatment.
Project description:BACKGROUND:This pilot study evaluated whether adding phentermine to liraglutide would induce further weight loss in participants who had previously lost weight with liraglutide alone. SUBJECTS/METHODS:Participants were 45 adults with obesity (75.6% female, 55.6% white, body mass index?=?34.3?±?4.7?kg/m2) who had lost an average of 12.6?±?6.8% of initial weight during a prior 1-year randomized trial with liraglutide and intensive behavioral treatment. Participants were re-randomized, in a double-blinded fashion, to liraglutide 3.0?mg plus phentermine 15.0?mg (liraglutide-phentermine) or liraglutide plus placebo (liraglutide-placebo). Participants also were provided with four, 15-minute counseling sessions during the 12-week extension study. RESULTS:At week 12, the liraglutide-phentermine and liraglutide-placebo groups lost a mean (±SEM) of 1.6?±?0.6% and 0.1?±?0.5% of re-randomization weight, respectively (p?=?0.073). Two (9.1%) liraglutide-phentermine participants and one (4.3%) liraglutide-placebo participant lost ?5% of re-randomization weight; 19 (86.4%) and 16 (69.9%) participants, respectively, maintained their full weight loss achieved in the prior 1-year trial (p?=?0.125). Liraglutide-phentermine participants generally reported larger reductions in hunger and food preoccupation than liraglutide-placebo participants during the first 8?weeks of the extension study. CONCLUSIONS:The combination of liraglutide and phentermine appeared to be well-tolerated but did not produce additional clinically meaningful weight loss in individuals who had already lost 12.6% of initial weight with liraglutide alone. TRIAL REGISTRATION:ClinicalTrials.gov number, NCT02911818.
Project description:To assess the ability of medication-assisted weight loss to prevent diabetes as a function of the baseline weighted Cardiometabolic Disease Staging (CMDS) score.We pooled data from 3,040 overweight and obese participants in three randomized controlled trials-CONQUER, EQUIP, and SEQUEL-assessing efficacy and safety of phentermine/topiramate extended release (ER) for weight loss. In these double-blind phase III trials, overweight/obese adult patients were treated with a lifestyle intervention and randomly assigned to placebo versus once-daily oral phentermine/topiramate ER. The weighted CMDS score was calculated using baseline quantitative clinical data including waist circumference, blood glucose, blood pressure, and blood lipids. Incident diabetes was defined based on serial measures of fasting glucose, 2-h oral glucose tolerance test glucose, and/or HbA1c.The absolute decrease in 1-year diabetes incidence rates in subjects treated with medication versus placebo was greatest in those with high-risk CMDS scores at baseline (10.43-6.29%), intermediate in those with moderate CMDS risk (4.67-2.37%), and small in the low-risk category (1.51-0.67%). The number of participants needed to treat to prevent one new case of diabetes over a 56-week period was 24, 43, and 120 in those with baseline CMDS scores of ≥60, 30-59, and 0-29, respectively.Numbers needed to treat to prevent one case of type 2 diabetes are markedly lower in patients with high-risk scores. CMDS can be used to quantify risk of diabetes in overweight/obese individuals and predict the effectiveness of weight-loss therapy to prevent diabetes.
Project description:Weight-management options include lifestyle modifications, bariatric surgery and, until recently, limited pharmacotherapy. Phentermine and topiramate extended-release (phentermine/topiramate ER) has recently been approved in the USA for chronic weight management in obese adults and overweight adults with weight-related co-morbidities in conjunction with a reduced-calorie diet and increased physical activity.This review describes the pharmacology and clinical trials data for phentermine/topiramate ER and its role in a complications-centric approach to medical care of the overweight and obese patient.Phentermine/topiramate ER is an effective and safe weight-loss medication that can produce and sustain approximately 10% loss of body weight. This is a landmark development in the pharmacotherapy of obesity. By offering an effective medical option to complement lifestyle and surgical approaches, phentermine/topiramate ER enables a comprehensive medical model for obesity care. The overall approach to the overweight and obese patient should be to identify individuals who will benefit most from therapy based on cardiometabolic or mechanical complications, establish therapeutic targets and goals for ameliorating these complications and selecting the treatment modality and intensity for weight loss to achieve these goals. This complications-centric model emphasizes weight loss as a tool to ameliorate obesity-related complications and optimizes benefit/risk for achieving the best outcomes in overweight/obese patients.