Updated– The experimental diet drug combination of phentermine and topiramate demonstrated “robust efficacy” in CONQUER, a large new trial published online in the Lancet. The results of the trial follow a year in which the FDA turned down 3 new investigational diet drugs (including Qnexa, the phentermine and topiramate combination used here) and removed the diet drug sibutramine from the market, leaving only one diet drug, Orlistat, still on the market.
Kishore Gadde and colleagues randomized 2,487 overweight or obese patients who had at least two comorbidities to placebo or a high- or low-dose combination of phentermine and topiramate for 56 weeks.
At 56 weeks, weight loss was
- 1·4 kg in the placebo group,
- 8·1 kg in the low-dose combination group (p<0.0001), and
- 10·2 kg in the high-dose combination group (p<0.0001).
At least 5% weight loss was reached by:
- 21% of patients in the placebo group
- 62% of patients in the low-dose group (p<0·0001), and
- 70% of patients in the high-dose group (p<0·0001).
The investigators also reported improvements in blood pressure, lipids, glucose control, and inflammatory markers.
The most common side effect associated with the experimental combination was dry mouth. The investigators concluded that the side effects either were tolerable, including paraesthesias and taste disturbance, or could be managed by discontinuing the drug (nephrolithiasis, metabolic acidosis, and cognitive and psychiatric adverse events).
The authors concluded that the drug combination “could be a valuable addition to the small arsenal of effective obesity treatments that are available to family doctors.”
Update: I just want to point out an important caveat to this news story (which I probably should have realized when I wrote it!):
The data in this study are not entirely new. Although unpublished until now, the data from this trial WAS considered by the FDA advisory committee last year. Click here to read an excellent news report from the LA Times that puts the study in context.
When FDA staff looked at the data from this trial along with a second trial, they concluded that the difference between Qnexa and placebo was “of nominal statistical significance.”
So the message is to beware the hype. The Lancet press release and numerous news stories have already touted this study as a potential turnaround for the drug. Let’s see what happens.
Here is the press release from the Lancet:
NEW TWO DRUG COMBINATION FOR OBESITY COMPARES FAVOURABLY WITH CURRENTLY APPROVED AND EMERGING WEIGHT-LOSS DRUGS (The Lancet)
A new two drug combination (phentermine and topiramate) achieves more than double the weight loss of orlistat, the only drug approved for the long-term treatment of obesity, and compares favourably with drugs in clinical development reported in phase 3 trials*. The findings published Online First in The Lancet also suggest that this promising new treatment has additional metabolic benefits—improving blood pressure, lipids, glycaemia, and inflammatory markers.
Obesity is associated with reduced life expectancy and increased mortality from diabetes, heart disease, cancer, and other causes. Phentermine is the most widely prescribed weight loss drug in the USA, but no long-term randomised trials have been done to assess its efficacy and safety. Topiramate is an anticonvulsant medication approved for the treatment of seizure disorders and migraine prevention. It showed significant success for weight loss in obese patients with type 2 diabetes and hypertension, but a high frequency of cognitive and psychiatric side effects stopped further development. It has been suggested that drug combinations using lower doses and controlled-release formulations might improve tolerability.
The CONQUER phase 3 trial was designed to assess the efficacy and safety of the controlled-release combination of phentermine and topiramate in addition to diet and lifestyle changes to promote weight loss in overweight and obese adults with two or more weight related-comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity).
Between November 2007 and June 2009, 2487 overweight or obese adults from 93 centres across the USA were prescribed standardised counselling for diet and lifestyle changes and randomly assigned to a once-daily treatment with placebo (994 patients), once-daily controlled-release phentermine 7.5 mg and topiramate 46 mg (498 patients), or once-daily controlled-release phentermine 15 mg and topiramate 92 mg (995 patients) for 56 weeks.
At 56 weeks, change in bodyweight was significantly greater in the groups prescribed both doses of the phentermine and topiramate combination. The mean weight change recorded for placebo was -1.4 kg (3 lb), for low dose phentermine and topiramate -8.1 kg (18 lb), and for high dose phentermine and topiramate -10.2 kg (22 lb).
Overall, 21% of patients achieved 5% weight loss with placebo, compared with 62% in the lower dose phentermine and topiramate group and 70% in the higher dose group.
Phentermine and topiramate treatment was generally well tolerated with dry mouth, constipation, and paraesthesia (a feeling of pins and needles) the most commonly reported side effects. However, a dose related increase in the incidence of psychiatric and cognitive adverse events was noted. Discontinuation rates due to adverse events roughly doubled with the higher dose versus placebo, with a smaller increase at the lower dose.
The authors say: “Most importantly, weight loss achieved with phentermine and topiramate was sustained during 56 weeks with improvements in blood pressure, lipids, glycaemia, and inflammatory markers. Reduction in concomitant use of drugs with phentermine and topiramate suggests that an effective weight loss treatment could reduce the need for treatment of each disease by addressing the underlying pathophysiological changes and obesity-related disease.”
They conclude: “The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors.”
Notes to Editors:
* After subtraction of the weight loss with placebo, 1-year weight loss with phentermine plus topiramate (–6.6% to –8.6%, some diabetic patients) compared favourably with orlistat (–2.9% after 1–4 years, some diabetic patients), the only drug approved for long-term treatment of obesity, and emerging drugs with reported phase 3 trial data—lorcaserin (–3.3% for non-diabetic patients), and naltrexone plus bupropion (–4.2% with some diabetic patients, –4.5% for non-diabetic patients).