On average, slimmers taking the twice-daily pills lost 4kg - around a dress size for the average woman - while those who stuck to traditional diet tips shed just 1.3kg.
And more than three years after the trial began, they had kept the weight off, the study found.
Scientists said the drug was an "important milestone" after decades of failed attempts to to develop effective diet medication, in a bid to combat the growing global obesity epidemic.
Until now, drugs which showed early promise have had little success - or been dogged by safety concerns, in particular about potential dangers to the heart.
Harvard researchers said their results, presented at the world's largest cardiac conference, show for the first time that a weight loss drug can cause consistent and sustained weight loss with no such increased risk.
Scientists said the breakthrough was particularly significant, because the drug targets signals in the brain which have been linked to weight gain in middle age.
How the medication works
- The drug, called lorcaserin, works by activating the neurons in the brain that control "satiety" – and signal fullness.
- These become less efficient with age, which is believed to be a key cause of middle-age spread.
- Experts said the new drug - which is currently licensed in the United States, and costs around NZ$422 a month - works by reinvigorating the cells, helping people control their appetite better.
Drug manufacturers Eisai said they were now evaluating the findings, ahead of any application for a European licence.
The findings, presented at the European Society of Cardiology conference, in Munich, and published in the New England Journal of Medicine today, sparked excitement among obesity and cardiac experts.
Tam Fry, from the National Obesity said the new approach was the "Holy Grail" of anti-obesity medication.
The only weight-loss drug currently available on the NHS is orlistat – which stops fat being absorbed into the body.
For years, scientists have been trying to develop pills that stop people eating so much in the first place.
But attempts to develop "centrally acting" appetite suppressors – which make people feel they are full more quickly – have been beset with difficulties because until now they have also caused heart problems.
The findings suggest the new approach is around twice as effective as that orlistat, which can have unpleasant side effects.
While 21 per cent of those taking orlistat lost at least 5 per cent of their total body weight after one year, the new trial found 37 per cent of dieters lost this much weight, after 12 months on lorcaserin.
And those on the new drug also saw the risk of developing diabetes fall by 19 per cent, compared to those given a placebo.
Lead author Erin Bohula, a cardiovascular medicine and critical care specialist at Harvard's Brigham and Women's Hospital, said the findings were an "important milestone" after decades of failed attempts to develop a safe drug, while global obesity rates have tripled.
