Changes in Cardiovascular Risk Associated With Phentermine and Topiramate Extended-Release in Participants With Comorbidities and a Body Mass Index ≥27 kg/m2
2013; Elsevier BV; Volume: 111; Issue: 8 Linguagem: Inglês
10.1016/j.amjcard.2012.12.038
ISSN1879-1913
AutoresMichael H. Davidson, Serena Tonstad, Suzanne Oparil, Michael Schwiers, Wesley Day, Charles H. Bowden,
Tópico(s)Diabetes Treatment and Management
ResumoThe 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/m2 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. 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/m2 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/m2 (obese) or ≥27 kg/m2 (overweight) in the presence of ≥1 weight-related co-morbidity.1Allison D.B. Gadde K.M. Garvey W.T. Peterson C.A. Schwiers M.L. Najarian T. Tam P.Y. Troupin B. Day W.W. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP).Obesity. 2012; 20: 330-342Crossref PubMed Scopus (386) Google Scholar, 2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar, 3Garvey W.T. Ryan D.H. Look M. Gadde K.M. Allison D.B. Peterson C.A. Schwiers M. Day W.W. Bowden C.H. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study.Am J Clin Nutr. 2012; 95: 297-308Crossref PubMed Scopus (399) Google Scholar, 4Colman E. Golden J. Roberts M. Egan A. Weaver J. Rosebraugh C. The FDA's assessment of two drugs for chronic weight management.N Engl J Med. 2012; 367: 1577-1579Crossref PubMed Scopus (137) Google Scholar 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,5Hussain S.S. Bloom S.R. The pharmacological treatment and management of obesity.Postgrad Med. 2011; 123: 34-44Crossref PubMed Scopus (36) Google Scholar, 6Melnikova I. Wages D. Anti-obesity therapies.Nat Rev Drug Discov. 2006; 5: 369-370Crossref PubMed Scopus (86) Google Scholar and TPM, a centrally acting agent approved in immediate-release formulation for the treatment of epilepsy and the prevention of migraine headaches.7Bays H. Phentermine, topiramate and their combination for the treatment of adiposopathy ('sick fat') and metabolic disease.Expert Rev Cardiovasc Ther. 2010; 8: 1777-1801Crossref PubMed Scopus (47) Google Scholar 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.8Bray G.A. Hollander P. Klein S. Kushner R. Levy B. Fitchet M. Perry B.H. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity.Obes Res. 2003; 11: 722-733Crossref PubMed Scopus (323) Google Scholar, 9Tonstad S. Tykarski A. Weissgarten J. Ivleva A. Levy B. Kumar A. Fitchet M. Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension.Am J Cardiol. 2005; 96: 243-251Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 10Wilding J. Van Gaal L. Rissanen A. Vercruysse F. Fitchet M. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects.Int J Obes Relat Metab Disord. 2004; 28: 1399-1410Crossref PubMed Scopus (190) Google Scholar 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.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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. The design and main results of the study have been published previously.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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/m2, were 18 to 70 years of age, and had ≥2 weight-related co-morbidities.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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.11National Cholesterol Education Program. Third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf. Accessed December 7, 2012.Google Scholar Detailed inclusion and exclusion criteria for this study have been described previously.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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.12Brownell K. The LEARN Program for Weight Management. The Life Style Company, Dallas, Texas2000Google Scholar 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),13Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Available at: http://ww.nhlbi.nih.gov/guidelines/hypertension/. Accessed December 7, 2012.Google Scholar 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).2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar 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. 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 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).Table 1Baseline characteristicsVariableOverall PopulationSubgroup With DyslipidemiaSubgroup With HypertensionNValuenValuenValueAge (yrs)2,48751.1 ± 10.41,34150.7 ± 10.51,30553.0 ± 9.8Women2,4871,737 (69.8%)1,341867 (64.7%)1,305860 (65.9%)White2,4872,140 (86.0%)1,3411,240 (92.5%)1,3051,087 (83.3%)Black2,487292 (11.7%)1,34164 (4.8%)1,305191 (14.6%)Hispanic or Latino2,487328 (13.2%)1,341184 (13.7%)1,305132 (10.1%)Not Hispanic or Latino2,4872,159 (86.8%)1,3411,157 (86.3%)1,3051,173 (89.9%)Weight (kg)2,485103.1 ± 17.91,341103.7 ± 18.11,305104.4 ± 18.4Body mass index (kg/m2)2,48536.6 ± 4.51,34136.5 ± 4.51,30536.7 ± 4.6Waist circumference (cm)2,485113.2 ± 12.31,341113.7 ± 12.01,305114.0 ± 12.6Blood pressure (mm Hg) Systolic2,485128.4 ± 13.51,341127.6 ± 13.41,305134.2 ± 13.0 Diastolic2,48580.6 ± 9.11,34180.4 ± 9.11,30583.7 ± 9.1Heart rate (beats/min)2,48572.3 ± 10.01,34172.8 ± 10.31,30571.6 ± 10.4Non-HDL cholesterol (mg/dl)2,485155.6 ± 39.71,341166.7 ± 40.71,305153.8 ± 39.1LDL cholesterol (mg/dl)2,480123.1 ± 35.41,336124.3 ± 37.71,303123.0 ± 35.7HDL cholesterol (mg/dl)2,48548.9 ± 13.61,34144.4 ± 11.41,30549.6 ± 13.7Triglycerides (mg/dl)2,485162.5 ± 74.11,341212.5 ± 64.01,305154.0 ± 68.3Fasting glucose (mg/dl)2,476106.1 ± 22.21,335107.4 ± 23.41,301105.6 ± 20.7Glycosylated hemoglobin (%)2,4785.9 ± 0.81,3395.9 ± 0.81,3025.9 ± 0.7Fasting insulin (μIU/ml)2,46718.1 ± 15.11,33519.8 ± 14.81,29518.4 ± 15.2High-sensitivity C-reactive protein (mg/L)2,4736.6 ± 10.11,3376.6 ± 11.51,2976.5 ± 11.4Adiponectin (μg/mL)2,0018.0 ± 4.61,0667.1 ± 3.91,0588.1 ± 4.7Fibrinogen (mg/dl)2,479457.4 ± 92.41,340448.9 ± 90.71,301458.5 ± 92.010-year Framingham score1,8874.8 ± 5.71,0245.6 ± 6.31,0045.8 ± 6.110-year Reynolds risk score2,0515.9 ± 6.21,1126.5 ± 6.51,0687.2 ± 6.9Data are expressed as mean ± SD or as number (percentage).HDL = high-density lipoprotein; LDL = low-density lipoprotein. Open table in a new tab Data are expressed as mean ± SD or as number (percentage). HDL = high-density lipoprotein; LDL = low-density lipoprotein. 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).Figure 2Effects of PHEN/TPM ER treatment on blood pressure (BP) and antihypertensive medications in the hypertensive subgroup. Least squares (LS) mean percentage changes from baseline to week 56 in (A) weight, (B) systolic BP, and (C) diastolic BP and (D) net change (percentage increase minus percentage decrease) in concomitant antihypertensive medication use. ∗p <0.0001 versus placebo; †p <0.05 versus placebo; §p <0.0001 for between-group comparisons. LOCF = last observation carried forward.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Similar to the overall population,2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar among participants with dyslipidemia, there were significant improvements with PHEN/TPM ER versus placebo in serum high-density lipoprotein cholesterol and triglyceride levels (Figure 1). In this subanalysis, significant improvements were also seen in non–high-density lipoprotein cholesterol (Figure 1). Importantly, improvements in these lipid variables were greater with increasing degrees of weight loss, as were improvements in inflammatory biomarkers (Table 2). No clinically meaningful or statistically significant differences among treatment groups were observed in lipid parameters after adjusting for degree of weight loss (data not shown). A trend toward a net reduction in the percentage of participants using lipid-lowering medications was also seen in the 2 PHEN/TPM ER groups compared with the placebo group (p = 0.1803 for between-group comparisons; Figure 1).Table 2Effects of weight loss on cardiometabolic parameters stratified by magnitude of weight loss for subjects with dyslipidemia at baselineVariablen<5% Weight Lossn≥5% to <10% Weight Lossn≥10% to <15% Weight Lossn≥15% Weight LossNon-HDL cholesterol617−5.8% (−7.2% to −4.4%)267−9.4% (−11.5% to −7.3%)∗p <0.05 versus <5% weight loss.178−10.7% (−13.3% to −8.2%)∗p <0.05 versus <5% weight loss.217−14.8% (−17.1% to −12.5%)†p <0.0001 versus <5% weight loss., ‡p <0.05 versus ≥5% to <10% weight loss.LDL cholesterol609−4.6% (−6.5% to −2.7%)267−4.8% (−7.7% to −1.9%)178−3.2% (−6.8% to 0.3%)217−2.3% (−5.5% to 0.9%)HDL cholesterol6171.7% (0.4% to 3.1%)2674.7% (2.6% to 6.7%)∗p <0.05 versus <5% weight loss.17810.8% (8.3% to 13.4%)†p <0.0001 versus <5% weight loss., ‡p <0.05 versus ≥5% to <10% weight loss.21719.7% (17.4% to 22.0%)†p <0.0001 versus <5% weight loss., §p <0.0001 versus ≥5% to <10% weight loss.Triglycerides617−5.5% (−8.2% to −2.8%)267−14.5% (−18.6% to −10.4%)∗p <0.05 versus <5% weight loss.178−28.7% (−33.7% to −23.7%)†p <0.0001 versus <5% weight loss., §p <0.0001 versus ≥5% to <10% weight loss.217−39.8% (−44.3% to −35.3%)†p <0.0001 versus <5% weight loss., §p <0.0001 versus ≥5% to <10% weight loss.High-sensitivity C-reactive protein (mg/L)464−1.1 (−1.7 to −0.5)228−2.1 (−3.0 to −1.2)164−3.1 (−4.2 to −2.0)∗p <0.05 versus <5% weight loss.206−3.1 (−4.0 to −2.1)∗p <0.05 versus <5% weight loss.Adiponectin (μg/ml)4620.2 (0.0 to 0.4)2271.1 (0.8 to 1.4)†p <0.0001 versus <5% weight loss.1611.8 (1.4 to 2.1)†p <0.0001 versus <5% weight loss., ‡p <0.05 versus ≥5% to <10% weight loss.2093.6 (3.3 to 3.9)†p <0.0001 versus <5% weight loss., §p <0.0001 versus ≥5% to <10% weight loss.Fibrinogen (mg/dl)462−6.6 (−13.7 to 0.5)227−1.2 (−11.2 to 8.9)163−4.6 (−16.5 to 7.4)208−13.6 (−24.2 to −3.1)Values in parentheses are 95% confidence intervals.Abbreviations as in Table 1.∗ p <0.05 versus <5% weight loss.† p <0.0001 versus <5% weight loss.‡ p <0.05 versus ≥5% to <10% weight loss.§ p <0.0001 versus ≥5% to <10% weight loss. Open table in a new tab Values in parentheses are 95% confidence intervals. Abbreviations as in Table 1. In line with the findings from the overall population,2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar there were greater reductions from baseline in systolic blood pressure and diastolic blood pressure in participants with hypertension receiving PHEN/TPM ER compared with placebo (Figure 2). Importantly, greater weight loss resulted in greater improvements in blood pressure, regardless of treatment group assignment (Table 3), with no significant differences between treatment groups in blood pressure reduction after adjusting for degree of weight loss (data not shown). However, no additional improvement was seen when weight loss was ≥15%.Table 3Effects of weight loss on blood pressure stratified by magnitude of weight loss for subjects with hypertension at baselineVariable<5% Weight Loss (n = 657)≥5% to <10% Weight Loss (n = 253)≥10% to <15% Weight Loss (n = 177)≥15% Weight Loss (n = 199)Systolic blood pressure (mm Hg)−4.2 (−5.2 to −3.2)−7.5 (−9.2 to −5.9)∗p = 0.0007 versus <5% weight loss.−10.8 (−12.7 to −8.9)†p <0.0001 versus 5% weight loss., ‡p = 0.0116 versus ≥5% to <10% weight loss.−11.8 (−13.6 to −10.0)†p <0.0001 versus 5% weight loss., §p = 0.0006 versus ≥5% to <10% weight loss.Diastolic blood pressure (mm Hg)−3.1 (−3.7 to −2.4)−5.9 (−7.0 to −4.9)†p <0.0001 versus 5% weight loss.−7.5 (−8.8 to −6.3)†p <0.0001 versus 5% weight loss.−7.4 (−8.6 to −6.2)†p <0.0001 versus 5% weight loss.Data are least squares mean changes (intent to treat, last observation carried forward) with 95% confidence intervals in parentheses.∗ p = 0.0007 versus <5% weight loss.† p <0.0001 versus 5% weight loss.‡ p = 0.0116 versus ≥5% to <10% weight loss.§ p = 0.0006 versus ≥5% to <10% weight loss. Open table in a new tab Data are least squares mean changes (intent to treat, last observation carried forward) with 95% confidence intervals in parentheses. Compared with placebo, a greater percentage of PHEN/TPM ER–treated participants with uncontrolled hypertension at baseline (≥140/90 mm Hg; placebo n = 104, 7.5/46 n = 40, and 15/92 n = 72) achieved the blood pressure goal of <140/90 mm Hg by week 56: 55 (52.9%) in the placebo group, 25 (62.5%) in the 7.5/46 group, and 54 (75.0%) in the 15/92 group (p = 0.2996 for 7.5/46 vs placebo, p = 0.0034 for 15/92 vs placebo). Furthermore, in 11 (10.6%), 4 (10.0%), and 13 (18.1%) participants with uncontrolled hypertension at baseline in the placebo, 7.5/46, and 15/92 groups, respectively, blood pressure was normalized to ≤120/80 mm Hg at 1 year. Use of concomitant antihypertensive drugs in participants with hypertension was reduced in PHEN/TPM ER–treated participants, but there was a net increase in the use of antihypertensive medications in the placebo group (p <0.0001 for between-group comparisons; Figure 2). The overall safety of treatment with PHEN/TPM ER in the entire population of the CONQUER trial was similar to that observed in the subgroups presented here.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar Safety findings for the overall population have been described fully elsewhere.2Gadde K.M. Allison D.B. Ryan D.H. Peterson C.A. Troupin B. Schwiers M.L. Day W.W. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.Lancet. 2011; 377: 1341-1352Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar In the subgroup with dyslipidemia, treatment-emergent adverse events occurred in 75.9%, 86.5%, and 88.3% of the placebo, 7.5/46, and 15/92 groups, respectively. In the subgroup with hypertension, the rates were 77.3%, 85.4%, and 88.8%, respectively. The most common treatment-emergent adverse events in the subgroup with dyslipidemia and the subgroup with hypertension were dry mouth, paresthesia, constipation, upper respiratory tract infection, and nasopharyngitis (Table 4). The rates of serious adverse events were similar among treatment groups (for placebo, 7.5/46, and 15/92, in the subgroup with dyslipidemia, 4.3%, 4.0%, and 3.8%, and in the subgroup with hypertension, 4.2%, 3.4%, and 3.7%, respectively). For the placebo, 7.5/46, and 15/92 groups, respectively, discontinuation because of adverse events occurred in 8.8%, 12.4%, and 18.0% in the subgroup with dyslipidemia and 9.7%, 11.9%, and 19.8% in the subgroup with hypertension. There was 1 death, occurring in the placebo group of the subgroup with dyslipidemia.Table 4Most common treatment-emergent adverse events in the subgroups with dyslipidemia and hypertensionAdverse EventSubgroup With Dyslipidemia (ITT)Subgroup With Hypertension (ITT)Placebo (n = 535)PHEN 7.5 mg/TPM ER 4
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