Ozempic Metabolism and Energy Expenditure: What the Clinical Evidence Shows

What the label says about how Ozempic works

Semaglutide is a GLP-1 receptor agonist. The label says it selectively binds and activates the GLP-1 receptor, including receptors in brain areas that regulate appetite and calorie intake, and that it delays gastric emptying [3]. The label adds that the exact mechanism by which semaglutide reduces cardiovascular risk is not established [3].

Does weight change track dose?

In SUSTAIN FORTE, 961 adults with type 2 diabetes on metformin received 2 mg or 1 mg weekly for 40 weeks [1]. HbA1c fell 2.2 points on 2 mg versus 1.9 points on 1 mg, and weight fell 6.9 kg versus 6.0 kg [1].

In SUSTAIN 7, 1,201 adults on metformin received semaglutide 0.5 mg or 1 mg, or dulaglutide 0.75 mg or 1.5 mg, for 40 weeks [2]. Weight fell 4.6 kg with semaglutide 0.5 mg versus 2.3 kg with dulaglutide 0.75 mg, and 6.5 kg with semaglutide 1 mg versus 3.0 kg with dulaglutide 1.5 mg. HbA1c fell 1.5 versus 1.1 points at the lower doses and 1.8 versus 1.4 points at the higher doses [2].

What the energy-expenditure studies measured

Native GLP-1 infusion. Twenty healthy men of normal weight received GLP-1 (50 pmol/kg per hour) or saline with a fixed breakfast in a randomized, blinded crossover. Diet-induced thermogenesis was 47% lower during GLP-1 (P<0.0001), driven by lower carbohydrate oxidation; fat oxidation did not differ [6].

Liraglutide. Forty-nine adults with obesity and no diabetes were randomized to two of three treatments (liraglutide 1.8 mg, 3.0 mg or placebo) for 5 weeks in a double-blind crossover. In a respiratory chamber, the fall in 24-hour energy expenditure was partly explained by the decrease in body weight, and there was a relative shift toward fat and away from carbohydrate oxidation; ad libitum energy intake fell about 16% [5].

Liraglutide in mice, plus a 1-year observation. In mice, liraglutide given directly into the brain stimulated brown-fat heat production independently of food intake. Activating AMPK in the hypothalamic ventromedial nucleus blunted that effect [4]. The same paper reports a 1-year longitudinal study in adults with obesity and type 2 diabetes in which exenatide and liraglutide increased energy expenditure [4].

What the Ozempic label lists

In pooled placebo-controlled trials, 262 people received placebo, 260 received 0.5 mg and 261 received 1 mg (mean 32.9 weeks) [3]. Nausea occurred in 6.1%, 15.8% and 20.3%; vomiting in 2.3%, 5% and 9.2%; diarrhea in 1.9%, 8.5% and 8.8%; and constipation in 1.5%, 5% and 3.1% [3]. The label says Ozempic is not recommended in patients with severe gastroparesis, and it warns about acute kidney injury from volume depletion, acute pancreatitis and gallbladder disease [3]. The boxed warning covers thyroid C-cell tumors seen in rodents at clinically relevant exposures, with human relevance unknown, and the drug is contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2 [3].

Ozempic is approved for type 2 diabetes, cardiovascular risk reduction in adults with type 2 diabetes and established cardiovascular disease, and kidney outcomes in adults with type 2 diabetes and chronic kidney disease. It has no weight-loss indication [3].