New 2 drug combination for obesity compares favorably with currently approved and emerging weight-loss drugs

April 10, 2011

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."
Dr Kishore Gadde, Duke University Medical Centre, Durham, USA. T) +1 919 668 0208 E) Please note: the best method of contacting Dr Gadde over the weekend (9/10 April) is by email.

Also via Debbe Geiger Senior Media Relations Officer, Duke Medicine News and Communications T) +1 919-660-9461 / + 1 919-724-8023 E)

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).



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