Phentermine/Topiramate Combo for Obesity

Molecular Model of Topiramate

Previous Brain Posts summarized some of the pharmacologic agents in the pipeline for weight loss as well as some drug combinations.  A recent research study published in Lancet provides additional data on one of the drug combinations being studied: phentermine and topiramate.

This new study is important because it looked at 56 weeks of treatment and target obese individuals with at least two obesity-related medical complications.  Subjects were required to have significant obesity (BMI 27-45 kg/m2) and at least two of the following:  hypertension, dyslipidemia, diabetes or prediabetes, abdominal obesity).  Each of these factors increases the risk of mortality associated with being overweight.

The key findings from the study--number of pounds lost at 56 weeks:

• placebo-- 3.1 pounds (1.4 kg)
• phentermine 7.5mg/topiramate 46 mg-- 17.8 pounds (8.1 kg)
• phentermine 15.0mg/topiramate 92 mg-- 22.4 pounds (10.2 kg)

The weight loss outcome in the highest dose group was approximately 10% of body weight--a significantly positive result in light of previous single agent trials.

One area of outcome caught my eye, the change in physiological and metabolic parameters over the course of the study.  Waist circumference decreased about an inch (2.4 cm) in the control group but three (7.6 cm) to three and one half inches (9.2 cm) in the low dose and high dose treatment group.  Blood lipid changes were also pretty impressive with LDL and triglycerides falling more in the treatment groups while good cholesterol values (HDL) increased more with the active drug combination.  Fasting insulin levels dropped significantly more in the active groups also.

Given historical problems with use of weight loss drugs, safety issues are important to monitor closely.  The most common adverse events in the active agent groups with rates higher than placebo were dry mouth (21%), paresthesias (numbness and tingling) (21%),  constipation (17%), dysguesia (10%), insomnia (10%), dizziness (10%), anxiety (4%) and irritability (3%).  Although infrequent (1%) depression was noted in the high dose group more than placebo.  One potential red flag with this combination was report of 11 cases of renolithiasis (kidney stones) in the high dose active agent group.

Topiramate inhibits the action of carbonic anhydrase.  This effect can cause decreases in serum bicarbonate and potassium as well as increasing risk of renolithiasis.  The rate of renolithiasis was lower in the low dose group suggesting a dose-related effect.  Additional, inhibitors of carbonic anhydrase have been noted to cause alterations in sensation (paresthesias) and in taste (dysguesia).

The authors note several relevant areas of caution.  Subjects with clinically relevant depression were excluded from the study due to concern about drug-induced depression.  Also some subjects noted cognitive adverse events, attention or memory problems, and this needs to be monitored in those more prone to such effects.  Additionally, the first application to approve this combination of phentermine and topiramate was turned down for lack of long-term cardiac safety data and data on risk of use during pregnancy.  This additional data is likely being collected for analysis and possible re-application given the impressive level of weight loss associated with this combination.

Molecular model of topiramate from Wikipedia Creative Commons, Author fvasconcellos.

Kishore M Gadde, David B Allison, Donna H Ryan, Craig A Peterson, Barbara Troupin, Michael L Schwiers, Wesley W Day (2011). Eff ects 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 : 10.1016/S0140- 6736(11)60205-5