The aim of this analysis was to evaluate changes in cardiovascular risk factors in obese patients with dyslipidemia and/or hypertension receiving phentermine (PHEN) and topiramate extended-release (TPM ER). In the 56-week, randomized, double-blind, placebo-controlled, multicenter CONQUER trial, PHEN/TPM ER demonstrated significant weight loss compared with placebo in overweight or obese participants with ≥2 weight-related co-morbidities. Participants with body mass indexes of 27 to 45 kg/m 2 were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg, or PHEN 15 mg/TPM ER 92 mg; participants also received lifestyle modification counseling. Primary end points were percentage weight loss and the proportion of participants achieving ≥5% weight loss. Additional end points were changes in lipid variables in the dyslipidemia population and blood pressure in the hypertensive population, stratified by treatment and magnitude of weight loss. PHEN/TPM ER produced significantly greater dose-related mean percentage weight loss compared with placebo in the subgroups of participants with dyslipidemia and those with hypertension. Regardless of treatment group assignment, participants with dyslipidemia who lost ≥5% of their baseline weight experienced significantly greater reductions in triglycerides (−14.5% to −39.8%), and in non–high-density lipoprotein cholesterol (−9.4% to −14.8%) than those losing <5% of their weight (p <0.05). Similarly, participants with hypertension at baseline showed reduced systolic blood pressure by −7.5 to −11.8 mm Hg (p <0.001 vs those with <5% weight loss). In conclusion, the dose-related weight loss induced by PHEN/TPM ER treatment was accompanied by significant improvements in cardiovascular disease risk factors in participants who had dyslipidemia or hypertension at baseline, suggesting that facilitating weight loss by augmenting lifestyle changes with pharmacotherapies may decrease the risk for cardiovascular disease in obese and overweight patients with co-morbidities.
Pharmacotherapy with phentermine (PHEN) and topiramate extended-release (TPM ER) has been shown to reduce weight in obese patients and was approved in 2012 as an adjunct to a reduced-calorie diet and increased physical activity for long-term weight management in adult patients with initial body mass indexes ≥30 kg/m 2 (obese) or ≥27 kg/m 2 (overweight) in the presence of ≥1 weight-related co-morbidity. The combination therapy includes PHEN hydrochloride, a centrally acting appetite suppressant, approved by the US Food and Drug Administration for the short-term (a few weeks; up to 37.5 mg/day) treatment of obesity, and TPM, a centrally acting agent approved in immediate-release formulation for the treatment of epilepsy and the prevention of migraine headaches. This combination has been shown to result in weight loss and improvements in lipids, glycemic variables, and blood pressure in obese patients in randomized studies, but it is not approved by the Food and Drug Administration for weight reduction. The 56-week phase 3 CONQUER study demonstrated that the administration of the once-daily, extended-release combination of PHEN/TPM ER as an adjunct to lifestyle intervention had good tolerability and was effective in reducing weight and improving cardiometabolic risk factors in overweight and obese patients with ≥2 weight-related co-morbidities. In the present subanalysis, we evaluated changes in cardiovascular disease risk factors in subgroups of participants with dyslipidemia and/or hypertension at the start of the study.
Methods
The design and main results of the study have been published previously. Briefly, CONQUER was a 56-week, randomized, double-blind, placebo-controlled, multicenter (93 United States sites) study that evaluated weight loss in overweight and obese participants with multiple weight-related co-morbidities who were treated with PHEN/TPM ER as an adjunct to lifestyle modification. The trial was approved by each site’s institutional review board, and all participants provided written informed consent. The study was conducted from November 1, 2007 to June 30, 2009. This trial is registered with ClinicalTrials.gov ( NCT00553787 ).
Participants were eligible to enroll in the study if they had body mass indexes of 27 to 45 kg/m 2 , were 18 to 70 years of age, and had ≥2 weight-related co-morbidities. Hypertension was defined as systolic blood pressure ≥140 and ≤160 mm Hg (or ≥130 and ≤160 mm Hg if diabetic), diastolic blood pressure ≥90 and ≤100 mm Hg (or ≥85 and ≤100 mm Hg if diabetic), or the use of ≥2 antihypertensive medications. Although the study protocol defined dyslipidemia as triglycerides ≥200 and ≤400 mg/dl (or using ≥2 lipid-lowering medications), for the purposes of this subgroup evaluation, analyses were performed using a lower triglyceride threshold (≥150 mg/dl) on the basis of established criteria. Detailed inclusion and exclusion criteria for this study have been described previously.
After a 2-week screening period, eligible participants were randomly assigned in a 2:1:2 ratio to receive blinded, once-daily treatment with placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92). They then underwent a blinded 4-week titration period and were maintained for 52 weeks at the randomized dose. Randomization was stratified by gender and diabetic status. All participants received standardized diet and lifestyle modification counseling at each study visit, including a 500 kcal/day reduction in caloric intake, on the basis of the LEARN (Lifestyle, Exercise, Attitudes, Relationships, Nutrition) program. Co-morbidities were actively managed according to national guidelines, including the careful monitoring and adjustment of concomitant medications.
Predefined end points in the overall population were mean percentage weight loss and the proportion of participants achieving ≥5% weight loss. In this post hoc analysis of subjects with dyslipidemia, mean percentage weight loss, changes in lipid variables, concomitant lipid-lowering medications, and serum inflammatory biomarkers (adiponectin, fibrinogen, and high-sensitivity C-reactive protein) were evaluated. In the post hoc analysis of subjects with hypertension, mean percentage weight loss, changes in blood pressure, achievement of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommended blood pressure goal of <140/90 mm Hg (or <130/80 mm Hg in patients with type 2 diabetes mellitus), and concomitant antihypertensive medication use were assessed. All additional end points were also stratified by degree of weight loss (<5%, ≥5% to <10%, ≥10% to <15%, and ≥15%). Safety assessments included physical examination, incidence of adverse events, changes in laboratory safety parameters, vital signs including heart rate, and electrocardiographic parameters (RR interval, QRS duration, and QT interval). Subjects with clinically significant abnormal electrocardiographic findings at baseline were excluded from the study.
Statistical analyses of the coprimary and other efficacy end points were described previously. Analysis-of-covariance and analysis-of-variance models were used to determine if there were residual effects of drug treatment on lipid parameters and blood pressure after adjusting for weight loss. The percentages of subjects achieving categorical weight loss ≥5%, ≥10%, and ≥15% were compared among treatment groups using the chi-square test.
Results
Of the overall randomized population (N = 2,487), 1,341 participants (53.9%) met criteria for dyslipidemia, 1,305 participants (52.5%) had hypertension, and 393 (15.8%) had type 2 diabetes mellitus at baseline. Of the randomized population, 18.5% (459 of 2,487) had triglycerides <150 mg/dl but had high-density lipoprotein cholesterol <40 to 50 mg/dl and low-density lipoprotein cholesterol >160 mg/dl. These participants were not considered as meeting criteria for dyslipidemia in the present analysis. In total, 647 subjects (26.0%) had dyslipidemia and hypertension at baseline and were included in the 2 subgroup analyses. Some differences in baseline characteristics were seen between the overall sample and the subgroups of participants in the present analyses in blood pressure, lipid profile, gender, and ethnicity ( Table 1 ).
| Variable | Overall Population | Subgroup With Dyslipidemia | Subgroup With Hypertension | |||
|---|---|---|---|---|---|---|
| N | Value | n | Value | n | Value | |
| Age (yrs) | 2,487 | 51.1 ± 10.4 | 1,341 | 50.7 ± 10.5 | 1,305 | 53.0 ± 9.8 |
| Women | 2,487 | 1,737 (69.8%) | 1,341 | 867 (64.7%) | 1,305 | 860 (65.9%) |
| White | 2,487 | 2,140 (86.0%) | 1,341 | 1,240 (92.5%) | 1,305 | 1,087 (83.3%) |
| Black | 2,487 | 292 (11.7%) | 1,341 | 64 (4.8%) | 1,305 | 191 (14.6%) |
| Hispanic or Latino | 2,487 | 328 (13.2%) | 1,341 | 184 (13.7%) | 1,305 | 132 (10.1%) |
| Not Hispanic or Latino | 2,487 | 2,159 (86.8%) | 1,341 | 1,157 (86.3%) | 1,305 | 1,173 (89.9%) |
| Weight (kg) | 2,485 | 103.1 ± 17.9 | 1,341 | 103.7 ± 18.1 | 1,305 | 104.4 ± 18.4 |
| Body mass index (kg/m 2 ) | 2,485 | 36.6 ± 4.5 | 1,341 | 36.5 ± 4.5 | 1,305 | 36.7 ± 4.6 |
| Waist circumference (cm) | 2,485 | 113.2 ± 12.3 | 1,341 | 113.7 ± 12.0 | 1,305 | 114.0 ± 12.6 |
| Blood pressure (mm Hg) | ||||||
| Systolic | 2,485 | 128.4 ± 13.5 | 1,341 | 127.6 ± 13.4 | 1,305 | 134.2 ± 13.0 |
| Diastolic | 2,485 | 80.6 ± 9.1 | 1,341 | 80.4 ± 9.1 | 1,305 | 83.7 ± 9.1 |
| Heart rate (beats/min) | 2,485 | 72.3 ± 10.0 | 1,341 | 72.8 ± 10.3 | 1,305 | 71.6 ± 10.4 |
| Non-HDL cholesterol (mg/dl) | 2,485 | 155.6 ± 39.7 | 1,341 | 166.7 ± 40.7 | 1,305 | 153.8 ± 39.1 |
| LDL cholesterol (mg/dl) | 2,480 | 123.1 ± 35.4 | 1,336 | 124.3 ± 37.7 | 1,303 | 123.0 ± 35.7 |
| HDL cholesterol (mg/dl) | 2,485 | 48.9 ± 13.6 | 1,341 | 44.4 ± 11.4 | 1,305 | 49.6 ± 13.7 |
| Triglycerides (mg/dl) | 2,485 | 162.5 ± 74.1 | 1,341 | 212.5 ± 64.0 | 1,305 | 154.0 ± 68.3 |
| Fasting glucose (mg/dl) | 2,476 | 106.1 ± 22.2 | 1,335 | 107.4 ± 23.4 | 1,301 | 105.6 ± 20.7 |
| Glycosylated hemoglobin (%) | 2,478 | 5.9 ± 0.8 | 1,339 | 5.9 ± 0.8 | 1,302 | 5.9 ± 0.7 |
| Fasting insulin (μIU/ml) | 2,467 | 18.1 ± 15.1 | 1,335 | 19.8 ± 14.8 | 1,295 | 18.4 ± 15.2 |
| High-sensitivity C-reactive protein (mg/L) | 2,473 | 6.6 ± 10.1 | 1,337 | 6.6 ± 11.5 | 1,297 | 6.5 ± 11.4 |
| Adiponectin (μg/mL) | 2,001 | 8.0 ± 4.6 | 1,066 | 7.1 ± 3.9 | 1,058 | 8.1 ± 4.7 |
| Fibrinogen (mg/dl) | 2,479 | 457.4 ± 92.4 | 1,340 | 448.9 ± 90.7 | 1,301 | 458.5 ± 92.0 |
| 10-year Framingham score | 1,887 | 4.8 ± 5.7 | 1,024 | 5.6 ± 6.3 | 1,004 | 5.8 ± 6.1 |
| 10-year Reynolds risk score | 2,051 | 5.9 ± 6.2 | 1,112 | 6.5 ± 6.5 | 1,068 | 7.2 ± 6.9 |
However, other baseline characteristics were similar across treatment groups in each of these populations (data not shown). In total, 147 participants (6.0%) in the overall population had histories of cardiac disorders, including histories of myocardial infarction (37 [1.5%]), coronary artery disease (26 [1.1%]), arrhythmia (10 [0.4%]), angina pectoris (7 [0.3%]), unstable angina (2 [0.1%]), and heart failure (3 [0.1%]).
The most common classes of lipid-controlling medications used at baseline in participants with dyslipidemia were statins (28.9%), fibrates (5.9%), nicotinic acid and its derivatives (3.5%), and bile-acid sequestrants (1.1%). The most common antihypertensive medications used in participants with hypertension at baseline were angiotensin-converting enzyme inhibitors alone (26.9%) or in combination with diuretics (5.8%) or calcium channel blockers (3.5%), β blockers alone (24.1%), and angiotensin II antagonists alone (15.5%) or in combination with diuretics (12.4%) or calcium channel blockers (0.9%). Twenty-nine participants (2.4%) with dyslipidemia at baseline and 38 (3.0%) with hypertension at baseline were taking aspirin at the beginning of the study.
Compared with placebo, PHEN/TPM ER produced significantly greater least squares mean percentage weight loss in the subgroup with dyslipidemia at baseline (−2.1%, −8.5%, and −10.5% for placebo, 7.5/46, and 15/92, respectively, p <0.0001; Figure 1 ) and in those with hypertension at baseline (−1.9%, −8.1%, and −10.1% for placebo, 7.5/46, and 15/92, respectively, p <0.0001; Figure 2 ). In addition, significantly more participants receiving PHEN/TPM ER achieved weight loss of ≥5%, ≥10%, and ≥15% compared with those receiving placebo in the subgroup with dyslipidemia and in the subgroup with hypertension ( Supplemental Table 1 ).
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