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

Abstract

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.

FIGURE 1.

Trial profile. Standardized lifestyle intervention was used across all treatment groups. Of the 27 subjects who discontinued the study drug because of adverse events during the SEQUEL study, the event began during the CONQUER study for 3 subjects (one in each treatment group). For the remaining 24 subjects, the adverse event leading to discontinuation of the study drug began during the SEQUEL study. *One subject in the 7.5/46 group enrolled in the study but discontinued before receiving the study drug. 7.5/46, 7.5 mg phentermine/46 mg controlled-release topiramate; 15/92, 15 mg phentermine/92 mg controlled-release topiramate.

FIGURE 2.

Mean (95% CI) percentage weight loss from baseline to week 108. LS mean change in the overall study completer sample. Standardized lifestyle intervention was used across all treatment groups. P < 0.0001 compared with placebo at all time points assessed. LOCF, last observation carried forward; LS, least-squares; PHEN/TPM CR 7.5/46, 7.5 mg phentermine/46 mg controlled-release topiramate; PHEN/TPM CR 15/92, 15 mg phentermine/92 mg controlled-release topiramate.

FIGURE 3.

Percentages (and 95% CIs) of subjects achieving ≥5%, ≥10%, ≥15%, or ≥20% weight loss from baseline to week 108 (ITT-LOCF). Standardized lifestyle intervention was used across all treatment groups. *P < 0.0001 compared with placebo; ^†P = 0.0072 compared with placebo. ITT, intent-to-treat; LOCF, last observation carried forward; PHEN/TPM CR 7.5/46, 7.5 mg phentermine/46 mg controlled-release topiramate; PHEN/TPM CR 15/92, 15 mg phentermine/92 mg controlled-release topiramate.

FIGURE 4.

Effects of PHEN/TPM CR on cardiometabolic variables. LS mean changes (95% CI) in (A) blood pressure, (B) antihypertensive medications, (C) lipid variables, (D) lipid-lowering medications, (E) Hb A_1c, and (F) antidiabetic medications from baseline (week 0) to week 108 (ITT-LOCF). Changes in Hb A_1c represent the T2D subgroup. Changes in concomitant medications represent the safety study. Standardized lifestyle intervention was used across all treatment groups. *Percentage increase minus percentage decrease; P < 0.05 for between-group differences. ^†P < 0.01 compared with placebo; ^‡P < 0.0001 compared with placebo. Hb A_1c, glycated hemoglobin; HDL-C, HDL cholesterol; ITT, intent-to-treat; LDL-C, LDL cholesterol; LOCF, last observation carried forward; LS, least-squares; PHEN/TPM CR 7.5/46, 7.5 mg phentermine/46 mg controlled-release topiramate; PHEN/TPM CR 15/92, 15 mg phentermine/92 mg controlled-release topiramate; T2D, type 2 diabetes.

FIGURE 5.

Annualized incidence rate for progression to T2D. Data represent subjects without T2D at baseline. Standardized lifestyle intervention was used across all treatment groups. *P = 0.1514 compared with placebo; ^†P = 0.0078 compared with placebo. PHEN/TPM CR 7.5/46, 7.5 mg phentermine/46 mg controlled-release topiramate; PHEN/TPM CR 15/92, 15 mg phentermine/92 mg controlled-release topiramate; T2D, type 2 diabetes.