Why do people with type 2 diabetes lose less weight on GLP-1s? @KevinH_PhD (the energy balance modeling 🐐) just put out a preprint with a clean mechanistic answer. The gap is big. In STEP UP, people with obesity but no T2D lost ~18% (2.4 mg) and ~21% (7.2 mg) at 72 weeks. In STEP UP T2D, the same doses got ~11% and ~14%. Roughly 7 points less. His model says a good chunk of that gap comes from two "energy leaks" that only exist in diabetes. The twist is that GLP-1s help close them and this what actually eats into the weight loss. 1. Leak #1: Sugar in the urine. Your kidneys pull sugar out of your urine and return it to your blood, but only up to a point, roughly a blood sugar of 180 mg/dl. Below that line, no sugar leaves the body. People without diabetes rarely get near it. Someone with poorly controlled diabetes spends part of every day above it, so a bit of sugar (~20 g, about 80 calories) ends up in the toilet. SGLT2 inhibitors work by deliberately lowering that line to ~110 mg/dl (estimate), which is why far more sugar leaks out on them (~125 g, about 500 calories a day). Here's the catch: semaglutide brings blood sugar down. Lower blood sugar means less time above the line, so the leak shrinks, to zero for the first person and to ~40 g for the second. Calories that used to leave the body for free now stay in it so there is less of a deficit. (chart attached) Leak #2: a revved-up metabolism. Running high blood sugar is expensive, mostly because the liver is working overtime making glucose. As blood sugar comes back to normal on semaglutide, the body burns roughly 175 fewer calories a day in the model. So picture two people cutting the same calories. The person without diabetes is a car with a sealed gas tank and a normal engine. Every gallon they stop putting in is a gallon that has to come out of their reserves. The full cut shows up as weight loss. The person with diabetes is a car with a small hole in the tank and an engine idling too hard. Both waste fuel. Semaglutide patches the hole and calms the engine down, which is great for their health, but it also means they now waste less fuel. Part of the calorie cut just replaces fuel they were losing anyway, so less has to come out of their reserves. Same cut, smaller deficit. (chart attached) The counterintuitive part: SGLT2 inhibitors cause weight loss on their own precisely by opening the leak. But if you're already stable on one and then add a GLP-1, the better glycemia partially closes it, so you get less from the new drug than someone starting fresh. Starting both together is predicted to beat either alone. A few call outs: this is a mathematical model fit to trial averages, not measured urine or metabolic chambers. It's a preprint, and the author works for AstraZeneca. For T2D patients not on SGLT2i, the model only partially explains the gap. And STEP UP was 74% female vs 52% in STEP UP T2D, and women tend to lose more on GLP-1s. Hold it loosely. But it reframes the question. "Diabetics respond worse" becomes "diabetics were running a hidden calorie deficit that the drug fixed." Can we confirm it with CGM plus urine collection? Does the gap close in people who normalize glycemia early? Should we sequence these drugs differently? Better answers here mean better expectations for a lot of patients, and probably more remissions.