Despite the fact that Obesity is one of the biggest preventable causes of death, investors may find that fat-fighting drugs are a far riskier business than they seem.

Take today’s announcement from Arena Pharmaceuticals, a biotech with a market capitalization of a mere $230 million. Arena’s shares jumped 20% on news that its experimental pill, APD356, helped patients shed an average of 2.9 pounds in only 28 days. But the short duration of the study means it may not be able to answer some important safety questions.

“It’s promising and also a bit scary,” says Steven Nissen, a cardiologist at the Cleveland Clinic who is working on another obesity drug, the much anticipated Acomplia from Sanofi-Aventis.

Arena’s pill was born from one of the drug industry’s biggest disasters: the diet combo fen-phen. That combo of two medicines, fenfluramine and phentermine, damaged the heart valves of some of the people who took it. Fenfluramine was withdrawn from the market, resulting in massive legal costs for drugmaker Wyeth, which has set aside some $21 billion to pay for legal settlements related to the drug. Some analysts expect that number could grow even more.

Fenfluramine worked by increasing the amount of serotonin in the brain in a way that reduced appetite. But Arena argues that fen-phen hit more brain receptors than was necessary. Its APD356 is far more specific, and so far the heart valve damage that led to fen-phen’s withdrawal has not reared its head. Jack Lief, Arena’s chief executive, points out that the heart valve side effects were rare, and that a big clinical trial could settle the issue. The current trial is too small to lead to definite conclusions. To finish developing the drug, Arena may need to enlist a big pharmaceutical partner. “I’m looking for an over-the-top kind of deal,” says Lief.

But the field of anti-obesity medicines is littered with disappointments. Fen-phen was effective but proved deadly, and many doctors say it was overused on patients whose obesity was cosmetic and not a health risk. Meridia ®, from Abbott Laboratories, and Xenical, from Roche, have both failed to ignite, partly because of side effects.

Sanofi’s new entrant, Acomplia, which is expected to be submitted to the FDA this year, is the exception that proves the rule. The drug is, in a sense, the anti-marijuana. It blocks the same receptors that give pot smokers the munchies, and, in doing so, helps overweight patients lose weight. It also makes it easier for tobacco smokers to quit smoking.

Some analysts predict annual sales of $5 billion or more for Acomplia. But the reason for the optimism is that the same cannabinoid (from cannabis or marijuana) receptors that reduce cravings are also present in fat cells.

Along with helping heavy patients lose weight (it doesn’t seem to work as well on thinner patients), Acomplia also raises good cholesterol, cuts bad cholesterol, reduces triglicerides and generally seems as if it should reduce the risk of heart disease and other obesity-related killers. The trial in which Nissen is involved aims at proving that the drug will reduce the amount of plaque that builds up in arteries. Acomplia’s potential is to be a chronic medicine on a par with Pfizer’s cholesterol-lowering medicine Lipitor, the world’s top seller with annual sales of $11 billion.

Bristol-Myers Squibb recently licensed its own Acomplia-like drug, which is in early safety trials.

An appetite-reducing drug that works in the brain probably doesn’t have that kind of potential. Even if Arena’s pill clears all safety hurdles, investors might want to be careful about expecting huge potential from it. But this little company does have some other irons in the fire, including a couple other experimental drugs, including a sleeping pill. Arena also recently signed a deal that could be worth $317 million with Johnson & Johnson to develop Diabetes medicines. Lief says it is the biggest such deal ever in biotech.