SEQUEL: Longer-Term Safety, Efficacy of Phentermine + Topiramate for Weight Reduction Among Overweight or Obese Individuals with Cardiometabolic Disease

Garvey WT, Ryan DH, Look M, et al. 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;95:297-308. 

The SEQUEL study, an extension of the CONQUER study,1 was a double-blind, placebo-controlled study that evaluated the longer-term efficacy and safety of once-daily, controlled-release phentermine plus topiramate, as an adjunct to lifestyle modification, among overweight and obese subjects with cardiometabolic disease.  

Subjects were aged 18-70 years (females of childbearing potential required to continue contraception if continuing to SEQUEL), had BMI 27-45 kg/m2 (no lower BMI limit set for subjects with diabetes at baseline), and ≥2 of the following comorbidities  

  • Systolic BP 140-160 mm Hg (130-160 mm Hg in those with diabetes), diastolic BP 90-100 mm Hg (85-100 mm Hg in those with diabetes), or taking ≥2 antihypertensive agents  
  • TG 47.2-81.4 mg/dL or using ≥2 lipid-lowering agents  
  • FBG >100 mg/dL, blood glucose >140 mg/dL at 2 h after oral glucose load during OGTT, or frank type 2 diabetes managed with lifestyle changes or metformin monotherapy  
  • Waist circumference ≥40 in men; ≥35 in women  

Subjects continued with their original treatment assignment from CONQUER for 52 weeks (total treatment duration for CONQUER and SEQUEL=108 weeks); all subjects received standardized counseling for diet and lifestyle modification. 

  • Once-daily, controlled-release phentermine 7.5 mg plus topiramate 46.0 mg (n=153)  
  • Once-daily, controlled-release phentermine 15.0 mg plus topiramate 92.0 mg (n=295)  
  • Placebo (n=227)  

Participants were also stratified based on sex and diabetic status (diabetes only; not prediabetes). Study visits took place at 4-week intervals after the final CONQUER visit.  

The co-primary outcomes in SEQUEL were carried over from CONQUER: mean percentage change in body weight and proportion of subjects achieving ≥5% weight loss from baseline (Week 0 of CONQUER) to Week 108. Secondary outcomes included weight loss, proportion of subjects achieving ≥10%, ≥15%, or ≥20% weight loss, and change in waist circumference from baseline to Week 108.  

Results: Primary outcomes (intention-to-treat population with last observation carried forward):  

First co-primary outcome: mean change in body weight  

  • Once-daily, controlled-release phentermine 7.5 mg plus topiramate 46.0 mg (n=153): -9.3% change from baseline; P<0.0001  
  • Once-daily, controlled-release phentermine 15.0 mg plus topiramate 92.0 mg (n=295): -10.5% change from baseline; P<0.0001  
  • Placebo (n=227): -1.8% change from baseline  

Second co-primary endpoint: proportion of subjects achieving ≥5% weight loss  

  • Once-daily, controlled-release phentermine 7.5 mg plus topiramate 46.0 mg (n=153): 75.2%; P<0.0001  
  • Once-daily, controlled-release phentermine 15.0 mg plus topiramate 92.0 mg (n=295): 79.3%; P<0.0001  
  • Placebo (n=227): 30.0%  

Analysis of secondary outcomes showed that when compared with the placebo group, use of phentermine + topiramate resulted in:  

  • Greater mean weight loss  
  • Greater proportions of subjects with ≥10%, ≥15%, ≥20% weight loss  
  • Significant reductions in waist circumference  

The most common adverse events were upper respiratory tract infection, constipation, paraesthesia, sinusitis, and dry mouth. The incidence of adverse events was markedly lower in the second year of treatment vs the first year. Depression- and anxiety-related adverse events, respectively, were seen as follows (incidence of anxiety-related AEs correlated with increasing dose):  

  • Phentermine 7.5 mg plus topiramate 46.0 mg: 8.1%; 6.5%  
  • Phentermine 15.0 mg plus topiramate 92.0 mg: 3.9%; 9.5%  
  • Placebo: 7.9%; 3.1%  

The incidence of serious adverse events was as follows:  

  • Phentermine 7.5 mg plus topiramate 46.0 mg: 5.9%  
  • Phentermine 15.0 mg plus topiramate 92.0 mg: 8.1%  
  • Placebo: 6.2%  

1. Gadde KM, Allison DB, Ryan DH, et al. 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;377:1341-1352.  

 

August 2012  

 This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest. 

Related content: 

Overview: CONQUER: Safety, Efficacy of Phentermine + Topiramate for Weight Reduction Among Overweight or Obese Individuals with Weight-Related Comorbidities  

SEQUEL: Design Extension of CONQUER Study  

SEQUEL: Primary and Secondary Outcomes  

SEQUEL Co-Primary Outcome: Change in Body Weight*  

SEQUEL Co-Primary Outcome: Proportion of Subjects Achieving ≥5% Weight Loss*  

SEQUEL: Secondary Outcomes and Adverse Events  

CONQUER: Design  

CONQUER: Randomization and Endpoints  

CONQUER: Subject Profile  

CONQUER Co-Primary Outcome: Change in Body Weight*  

CONQUER Co-Primary Outcome: Proportion of Subjects Achieving ≥5% Weight Loss*  

CONQUER: Secondary Outcomes and Adverse Events  

Last Modified: 3/23/2015