Results were similar, although less pronounced in the 2-year cohort based on management to standard of care and medication changes; all PHEN/TPM-ER-treated patients showed reductions in SBP and DBP (see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) [87,92]. At 2 years, there was also a significant net reduction in concomitant antihypertensive medication use in patients treated with PHEN/TPM-ER, whereas placebo-treated patients experienced a net increase in antihypertensive medication use (P = 0.0165 for between-group differences; see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) . The slight mean increases in heart rate vs. baseline with PHEN/TPM-ER treatment observed in the 1-year cohort were still evident after 2 years of treatment, but were not significant compared with placebo (see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) .
Increased myocardial oxygen demand is the putative mechanism by which increased heart rate promotes cardiac ischaemia in patients with macrovascular or microvascular coronary disease . The rate pressure product, defined as the product of heart rate and SBP divided by 1000, is related to myocardial oxygen demand, and was decreased in the placebo group and each of the PHEN/TPM-ER groups in the 1-year cohort (with greatest reductions seen in the PHEN/TPM-ER 7.5/46 dose; Fig. 2c)  and the 2-year cohort (see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) . These data suggest that the mild heart rate increase with PHEN/TPM-ER over 2 years may not increase myocardial oxygen demand.
In patients with dyslipidaemia or hypertension at baseline participating in the 56-week CONQUER study, PHEN/TPM-ER induced significantly greater, dose-related mean percentage weight loss vs. placebo (P < 0.0001), with a greater proportion of PHEN/TPM-ER-treated patients achieving at least 5, 10, and 15% weight loss . PHEN/TPM-ER treatment was associated with significant improvements in serum triglyceride, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels vs. placebo (P < 0.05) in patients with dyslipidaemia at week 56, along with a net reduction in lipid-lowering medication use . In patients with hypertension at baseline, PHEN/TPM-ER-treated patients showed significant improvements in BP at week 56 [SBP: −6.9 and −9.1 mmHg for PHEN/TPM-ER 7.5/46 and 15/92, respectively, vs. −4.9 mmHg for placebo (P < 0.05); DBP: −5.2 and −5.8 mmHg for PHEN/TPM-ER 7.5/46 and 15/92, respectively, vs. −3.9 mmHg for placebo (P < 0.05)], as well as a net decrease in antihypertensive medication use (P < 0.0001 for between-group differences) . Similar to the overall CONQUER population, a slight increase in heart rate (0.1 to 1.3 b.p.m.) was observed in the dyslipidaemia and hypertension subgroups [85,86].
In pooled data of hypertensive patients from the two 1-year studies (CONQUER and EQUIP), reductions in SBP and DBP were seen in all PHEN/TPM-ER groups, whereas heart rate was slightly increased in the 7.5/46 and 15/92 dose groups (Table 3) . At endpoint in the 2-year cohort, patients with hypertension at baseline showed reductions in SBP and DBP. Concomitant antihypertensive medication use in PHEN/TPM-ER-treated patients was significantly reduced, compared to a net increase in antihypertensive medication use in the placebo group (P = 0.0012 for between-group differences; see Figure S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) .
Common adverse events in PHEN/TPM-ER clinical trials were paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Adverse events were generally dose-related and mild to moderate in severity, occurring mostly during the titration period [26,84,86–88]. PHEN/TPM-ER contraindications are similar to those of phentermine and topiramate monotherapy (Table 2) [18–20,26,65,66].
Cardiac arrhythmia-related adverse events reported by patients (as defined by mapping to the Medical Dictionary for Regulatory Activities Cardiac Disorders System Organ Class) were palpitations, increased heart rate, and tachycardia, and occurred in between 0.1 and 2.4% of patients (palpitations: 0.8, 0.8, 2.4, and 1.7% for placebo and PHEN/TPM-ER 3.75/23, 7.5/46, and 15/92, respectively; heart rate increased: 0.1, 0.0, 0.4, and 0.8%, respectively; tachycardia: 0.1, 0.4, 0.4, and 0.7%, respectively) . There were low rates of serious adverse events classified as cardiac disorders .
Within the 1-year safety cohort, 752 (19.8%) patients were considered to have low cardiovascular risk, 2498 (65.6%) had moderate cardiovascular risk, and 14.6% were in a high cardiovascular risk category [modified Adult Treatment Panel (ATP) III criteria] . In the 1 and 2-year safety cohorts, the different outcome definitions of major adverse cardiac events (MACEs) each had a hazard ratio (PHEN/TPM-ER vs. placebo) below 1.0, ranging from 0.49 [95% confidence interval (CI) 0.19, 1.25] for US FDA MACE to 0.84 (95% CI 0.26, 2.64) for the traditional MACE composite endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke; Table 4) . The traditional MACE composite endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) was incident in 12 of the 4323 patients (5/1742 in the placebo group and 7/2581 in the PHEN/TPM-ER group; Table 4); the wide CI found in the analysis of the traditional MACE composite endpoint indicates that a larger sample is required to sufficiently address this issue . The hazard ratio for the broadest MACE criteria (cardiovascular/neurovascular serious adverse events), which had a total of 43 events (20/1742 in the placebo group and 23/2581 in the PHEN/TPM-ER group), had a 95% CI with an upper bound of 0.98, representing a statistically significant reduction in cardiovascular risk (Table 4) . At this time, there are too few events from clinical trial data to draw firm conclusions about decreases or increases in MACE in patients treated with PHEN/TPM-ER; however, available data do not indicate any increased cardiovascular risk associated with PHEN/TPM-ER. A cardiovascular outcomes trial is planned by the drug's manufacturer, in accordance with one of the US FDA's post-marketing study requirements . The EMA's CHMP has indicated that a long-term cardiovascular outcomes trial would be necessary to support PHEN/TPM-ER centralized approval in Europe . In addition to the planned long-term cardiovascular outcomes trial, future research might beneficially be directed at exploring the effects of PHEN/TPM-ER on surrogate physiologic measures of cardiovascular health, such as endothelial function, and in obese individuals with resistant hypertension.
There is a current unmet need for an effective weight-loss pharmacotherapy that can be used for long term for the many patients unable to attain or to maintain weight loss through dietary interventions and exercise. Given the increased cardiovascular and metabolic risk in this patient population, obesity pharmacotherapies must present minimal unwanted or adverse cardiovascular risks, which if present, should be outweighed by their other cardiovascular-related benefits. The rationale of combining low doses of PHEN/TPM-ER is to minimize side effects while maintaining weight loss efficacy. However, the treatment is not without side effects. For example, the topiramate extended-release component can induce paraesthesia and taste change, likely through carbonic anhydrase inhibition. Topiramate cannot be used by pregnant women due to teratogenic risks. The phentermine component can produce adrenergic symptoms, such as dry mouth. However, it is clinically reassuring that weight loss induced by PHEN/TPM-ER was associated with improved BP through 1 and 2 years of treatment. Although small, usually transient, increases in heart rate were observed in some patients, there were concurrent reductions in BP and rate pressure product, suggesting that, when used in conjunction with lifestyle modifications, PHEN/TPM-ER may represent a safe and effective therapy for the management of obesity in the patient populations studied (those with low-to-intermediate cardiovascular risk). The influences of PHEN/TPM-ER treatment on cardiovascular outcomes are currently being tested in a large multinational trial.
We would like to acknowledge and thank The Lockwood Group for editorial assistance.
Funding for this manuscript was provided by VIVUS, Inc.
J.J. has participated in advisory boards for Boehringer-Ingelheim, Sanofi-Aventis, and Novartis, has been a consultant for Sanofi-Aventis and Novartis, and has received research support from Novartis, Sanofi-Aventis, CVRx, Inc., and Boehringer-Ingelheim. A.A. has been a consultant for Arena Pharmaceuticals, Basic Research, Gelesis, Inc., Doyen Medical Inc., Novo Nordisk, Orexigen Therapeutics Inc., Rhythm Pharmaceuticals, S-Biotek, Twinlab, and VIVUS, Inc. S.E. has received research support for clinical trials from Novartis. K.N. has participated in advisory boards for Medtronic and Boehringer-Ingelheim, has been a consultant for Medtronic, and has received research support for clinical trials for Abbott and Daiichi Sankyo. K.N. has also received honoraria for speakers/chairmanship at meetings for Abbott, Adamed, Astra Zeneca, Bayer, Berlin-Chemie, Boehringer-Ingelheim, Daiichi-Sankyo, Krka, Menarini, Novartis, Pfizer, Polpharma, Sanofi-Aventis, and Servier. W.W.D. is an employee of VIVUS, Inc. N.F. has been a consultant to VIVUS, Inc., and has participated in advisory board(s) for Novo Nordisk, Abbott, and Sanofi-Aventis, is a stockholder of Counterweight plc, and is an employee of UCLH NHS Trust.
Reviewers’ Summary Evaluations Reviewer 1
This review showed that combining low doses of phentermine and topiramate for the treatment of obesity minimized side effects while maintained weight loss efficacy. The side effects were paraesthesia, taste changes and dry mouth.
Weight loss induced by the combination was associated with improved BP through one and two years of treatment. A small, usually transient increase in heart rate was observed. However, reductions in BP and rate pressure product were seen suggesting that when used in conjunction with lifestyle modifications, the combination may represent a safe and effective therapy for the management of obesity. A large multinational trial concerning cardiovascular outcomes is ongoing.
Combination drug treatment based on phentermine and topiramate has been recently approved by the FDA for the treatment of overweight and obesity. The paper by Jordan et al. provides an updated review on the cardiovascular effects of this new therapeutic approach which, along with its significant and sustained weight loss effects, improves triglycerides and HDL cholesterol and significantly decreases blood pressure values throughout the body weight reduction.
The information available so far on the impact the drug has on cardiovascular events (limited at present at the one year follow-up) confirms the favourable effects the drug has on cardiovascular risk.
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