Older & other weight-loss drugs

Placebo-subtracted weight loss, roughly: phentermine ~3–5% (a stimulant, labelled short-term, raises heart rate/BP); phentermine/topiramate (Qsymia) ~9–10% (best of the older orals, but carries an oral-cleft pregnancy risk and a restricted program); naltrexone/bupropion (Contrave) ~5% (boxed suicidality warning from the bupropion); orlistat ~3% (blocks fat absorption — hence the GI effects — OTC, and cut diabetes progression 37% over four years). Evidence ●●●●○

Metformin gives a modest but durable ~2–2.5%, best in insulin resistance, PCOS or antipsychotic-related gain. SGLT2 inhibitors lose ~2–3% (a urinary-calorie leak that plateaus as appetite compensates). Setmelanotide is dramatic but only for confirmed rare genetic obesity, at ~$400,000/year. None approaches the incretins for magnitude.

Weight-loss drugs have a long graveyard: fen-phen (heart-valve damage, pulled 1997), sibutramine (raised heart attack and stroke, 2010), lorcaserin (a cancer signal, 2020), and rimonabant (depression and suicidality, never approved in the US). The pattern isn’t that these drugs are inherently dangerous — it’s that appetite is wired into receptors that also govern heart valves, blood vessels and mood. Each failure is why modern drugs now face cardiovascular, cancer and psychiatric surveillance as routine.