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Review of the data for combination phentermine and controlled-release topiramate in obesity

Review of the data for combination phentermine and controlled-release topiramate in obesity

An FDA advisory committee recommended approval of the first diet drug since 1999 (We all know how that turned out), combination phentermine and controlled-release topiramate (Qnexa or PHEN/TPM CR). I decided to write a review of the data available to demonstrate the effectiveness of in obesity. This is quite interesting for a HeartMeds audience.

The first study is the CONQUER (Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults) trial. This 56 week trial of 2487 overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m(2) and two or more comorbidities (hypertension, dyslipidemia, diabetes or prediabetes, or abdominal obesity). There were 994 assigned to placebo, 498 to phentermine 7.5 mg plus topiramate 46 mg, and 995 to phentermine 15 mg plus topiramate 92 mg. At 56 weeks, there was a significant reduction in body weight with the new medication combination (PBO -1.4 kg; P7.5/T46 -8.1 kg, p<0.0001 compared to PBO; P15/T92 -10.2 kg, p<0.0001 compared to PBO). Significantly more patients in the active groups lost at least 5% and greater than 10% of their weight compare to placebo. The most common adverse events were dry mouth (2%, 13%, and 21%, respectively), paraesthesia (2%, 14%, 21%, respectively), constipation (6%, 15%, and 17%, respectively), insomnia (5%, 6%, 10%, respectively), dizziness (3%, 7%, 10%, respectively), and dysgeusia (1%, 7%, 10%, respectively).

The SEQUEL study (Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults) was an extension of the CONQUER trial. This was a 52 week placebo controlled study (after the SEQUEL 56 weeks) with 866 patientswith the groups placebo, 7.5 mg phentermine/46 mg controlled-release topiramate (7.5/46), or 15 mg phentermine/92 mg controlled-release topiramate (15/92). At week 108, PHEN/TPM CR was associated with significant, sustained weight loss from baseline in body weight were -1.8%, -9.3%, and -10.5% for placebo, 7.5/46, and 15/92, respectively (p<0.001 for both groups compared to PBO). Significantly more active treated patients 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 (lower Trig, higher HDL, no effect on LDL, lower A1c) and decreased rates of incident diabetes in comparison with placebo. PHEN/TPM CR was well tolerated over 108 wk, with lower rates of adverse events occurring between weeks 56 and 108 compared with between weeks 0 and 56.

Another trial is the EQUIP (Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial) trial. This was a 56 week randomized trial comparing placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg. There were similar weight loss results seen in the previous trial, but this was the first study to look at the drugs effect on blood pressure. Comparing baseline to follow-up SBP increased in the placebo group over time (0.9 mmHg, 95% CI -0.2 to 2.1). Compared to placebo, PHEN/TPM CR 3.75/23 mg significantly lowered SBP (-1.6 mmHg, 95% CI -3.7 to 0.5, p=0.0019). Compared to placebo, PHEN/TPM CR 15/92 mg significantly lowered SBP (-3.6 mmHg, 95% CI -5.1 to -2.1, p<0.0001). All other metabolic effects were similar to the SEQUEL study.

When I originally heard about this combination product, I thought it was just another catecholamine product that would worsen CV events. On the contrary, all the surrogate CV endpoints are moving in the positive way. The CV events seem to be going in the right direction as well. The figure from the FDA documents that demonstrates the effects on CV events looks good (and NOT negative).

In the FDA documents, the company does demonstrates an increase in HR with active treatment.

Evaluation of the incidence of TEAEs in the cardiac arrhythmia subclass demonstrated a higher frequency of events in the QNEXA Top dose group (4.7%) and Mid dose group (4.2%) than in the placebo group (1.8%). This observed dose response, however, was accounted for almost entirely by increases in events that are not true arrhythmias. Palpitations, increased heart rate, and tachycardia represented the majority of cardiac arrhythmia TEAEs in the 1-Year Cohort. Palpitations and increased heart rate are expected and dose-related side effects of phentermine. The cardiac arrhythmia TEAEs were primarily mild or moderate in severity and were serious for 4 (0.3%) subjects in the placebo group,
2 (0.4%) subjects in the Mid dose group, and 2 (0.1%) subjects in the Top dose group. Importantly, an examination of clinically meaningful arrhythmias showed no difference between treatment groups.

Overall, I am shocked! I don’t know what to think. Everything looks good, but I am just waiting for something bad to come out. What do you think?

References:
1. 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.
Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW.
Lancet. 2011 Apr 16;377(9774):1341-52.

2. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, Bowden CH. 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 Feb;95(2):297-308.
3. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, Tam PY, Troupin B, Day WW. Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP). Obesity. 2012 Feb;20(2):330-42.
4. FDA Documents (Excellent review!!)

Image: Michelle Meiklejohn / FreeDigitalPhotos.net


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