The previously published CONQUER study reported that treatment of overweight and obese adults with PHEN/TPM CR as an adjunct to lifestyle intervention promoted weight loss and reduced manifestations of cardiometabolic disease over 56 wk when compared with lifestyle intervention plus placebo (17
). This extension study, SEQUEL, maintained the blinded treatment groups for an additional 52 wk and showed that these beneficial therapeutic effects were sustained during a 2-y period.
After 108 wk, the addition of PHEN/TPM CR to a standardized lifestyle modification led to substantial weight loss that coincides with the weight-loss target of 10% recommended by the National Heart, Lung, and Blood Institute for overweight and obese individuals (8
). The percentage changes in body weight from baseline were –1.8%, –9.3%, and –10.5% in subjects treated with placebo, 7.5/46, and 15/92, respectively (ITT-LOCF); and 10% weight loss was achieved by >50% of PHEN/TPM CR–treated subjects, whereas <12% of subjects receiving placebo met this goal. Importantly, both doses of PHEN/TPM CR were significantly more effective than placebo regardless of baseline BMI and were similarly effective at baseline BMI values extending from <30 to <40. In those subjects with class III obesity (BMI ≥40), the 15/92 dose produced an even more pronounced degree of weight loss, exceeding that observed with 7.5/46. These data are indicative of therapeutic efficacy for PHEN/TPM CR over a wide range of initial BMI, although higher doses might be more effective in cases of more severe obesity.
By design, subjects in the SEQUEL study were highly affected by cardiometabolic disease, and many were treated with numerous concomitant medications to control blood pressure, lipid variables, and glycemic variables, which were actively managed throughout the trial. PHEN/TPM CR improved these comorbidities and decreased the need for associated medications in comparison with the placebo group. For example, after 2 y of therapy, diastolic and systolic blood pressure showed equal reductions in the placebo and PHEN/TPM CR groups; however, this was accompanied by a net decrease in concomitant antihypertensive medication use in PHEN/TPM CR treatment groups, whereas antihypertensive medications were increased in the placebo group. Reducing the need for medications used to specifically control these comorbidities not only reduces the medication burden associated with cardiometabolic disease but could also improve subject compliance by decreasing their medication regimen complexity and reducing the overall treatment costs (24
When compared with placebo, PHEN/TPM CR–treated subjects exhibited lower fasting glucose and fasting insulin values compared with subjects receiving placebo, which is indicative of an improvement in insulin sensitivity (23
), and experienced greater reductions in waist circumference, a measure of central adiposity related to increased morbidity and mortality (21
). Because insulin resistance and central adiposity are integral to the development of cardiometabolic disease, it appears that PHEN/TPM CR–induced weight loss is accompanied by favorable effects on pathophysiologic processes that could reduce risk of metabolic syndrome, T2D, and CVD (8
). In support of this, we observed that, among subjects without T2D at baseline, treatment with PHEN/TPM CR reduced progression to T2D by 54% with the 7.5/46 dose and by 76% with the 15/92 dose when compared with the placebo intervention. Previous studies have shown that lifestyle-intervention programs reduce progression to T2D among high-risk individuals with impaired glucose tolerance, and the degree of protection correlated with the amount of weight loss (28
). Along these same lines, incremental improvements in cardiometabolic disease risk factors have also been shown to correlate with an increasing degree of weight loss, together with associated reductions in morbidity and mortality (5
Approximately 20% of subjects had T2D at study entry and had been treated with lifestyle modifications alone, single-agent metformin, or both. In the T2D subgroup, PHEN/TPM CR led to significant reductions in Hb A1c after 2 y compared with placebo. Improvements in fasting glucose, fasting insulin, and Hb A1c were experienced without any net change in concomitant antidiabetic medications in subjects with T2D who were randomly assigned to 15/92 and a modest net increase in medications in those assigned to 7.5/46, whereas the placebo group experienced a substantial net increase in required antidiabetic medications to achieve guideline-dictated goals. Thus, weight loss associated with PHEN/TPM CR had a favorable impact on glycemic control in the subjects with T2D, without a need for added oral hypoglycemic agents.
Discontinuation rates during the extension study were similar between placebo and PHEN/TPM CR–treated subjects. The type of AEs reported during weeks 56–108 in the extension study were similar to those in the first 56 wk of the study; however, the incidence rates were lower in the second year of the study. In some subjects, PHEN/TPM CR treatment was associated with reductions in serum bicarbonate, particularly in the first 3 mo of the study, which is likely a manifestation of the carbonic anhydrase activity of topiramate. However, this effect was not progressive in these subjects, and serum bicarbonate tended to return toward normal during the remaining 2 y of the study without the need for clinical intervention. PHEN/TPM CR increased mean heart rate by 1.3–1.7 bpm over baseline; this increase was not accompanied by any related AE reporting and was accompanied by reductions in systolic and diastolic blood pressure. Rigorous assessments of suicidality were conducted by using the C-SSRS, which showed no increase in suicidal ideation associated with PHEN/TPM CR and no difference from placebo in AE reporting for incident depression. PHEN/TPM CR was associated with a dose-dependent increase in the incidence of anxiety. However, these anxiety-related TEAEs were mostly mild in nature and led to only one discontinuation of study drug. Finally, during the 108-wk trial, there were 2 pregnancies, with one pregnancy carried to term in a subject who was randomly assigned to 15/92, resulting in a healthy infant without any observed congenital malformations.
Limitations of this study were that not all CONQUER subjects were eligible to enroll into the SEQUEL extension because only high-enrolling centers were used. Furthermore, participation in the second-year extension study was optional. These aspects may have resulted in bias toward the inclusion of subjects with positive treatment outcomes, because one would expect that subjects who achieved satisfactory weight loss would be more likely to enroll for a second year. However, the baseline clinical characteristics of the subgroup entering the SEQUEL study were similar to those of the CONQUER cohort, with the exception of a greater percentage of subjects with T2D in SEQUEL. Another point pertains to the higher rate of subjects lost to follow-up in the 15/92 arm than in the placebo or 7.5/46 arms. Because the real reason for study discontinuation in these subjects is not known, this could result in an underestimation of important reasons for patients dropping out, including AEs or lack of efficacy. A third limitation of this study is that hyperglycemia, high blood pressure, and dyslipidemia were actively managed on the basis of national treatment guidelines, resulting in the confounding impact of medication changes on the secondary cardiometabolic variables. Actual treatment effects may have been different if related medications and doses were required to be fixed, thereby better isolating an effect of PHEN/TPM CR.
Medical options to promote sustained weight loss are limited. The lipase inhibitor orlistat is currently the only approved medication for chronic treatment of obesity in the United States (10
). Bariatric surgery is an option for long-term weight loss but is generally limited to selected subjects with complicated or severe obesity because of the inherent risks of invasive surgical procedures and the requirements for long-term medical follow-up (9
). Results of this study suggest that PHEN/TPM CR together with lifestyle measures may be an additional therapeutic option for achieving long-term weight-loss in moderately to severely obese subjects.
In conclusion, PHEN/TPM CR used as an adjunct to lifestyle intervention for the treatment of obesity was well tolerated and produced significant, dose-related weight loss that was maintained during a 108-wk period. PHEN/TPM CR was also associated with sustained improvements in the clinical manifestations of weight-related cardiometabolic disease, including hyperglycemia, dyslipidemia, and elevated blood pressure, despite reduced use of concomitant medications. Importantly, these effects of PHEN/TPM CR led to a reduction in the rate of progression to T2D, with the greatest benefits seen in subjects receiving PHEN/TPM CR 15/92. Thus, PHEN/TPM CR may provide a well-tolerated, effective, and sustainable treatment option for obese subjects with cardiometabolic disease. Furthermore, the unmet clinical need for effective weight-loss medications, together with the favorable risk-benefit profile in the current study, suggests that PHEN/TPM CR in conjunction with a lifestyle-intervention program could be a valuable therapeutic approach to counteract increasing rates of obesity and its related complications.