What are the head‑to‑head A1C and weight results for semaglutide versus other GLP‑1RAs and SGLT2 inhibitors?
Executive summary
Randomized trials and pooled analyses show semaglutide delivers larger average reductions in HbA1c and body weight than many other GLP‑1 receptor agonists (GLP‑1RAs), with head‑to‑head meta‑analysis finding about −0.44% greater A1C lowering and −2.53 kg greater weight loss versus other GLP‑1RAs [1]. Real‑world and network meta‑analyses also place semaglutide among the most potent agents for weight loss and glycaemic control [2] [3], but GLP‑1RAs carry a higher risk of adverse events compared with SGLT2 inhibitors, and there are few randomized, direct comparisons between GLP‑1RAs and SGLT2 inhibitors [2] [4].
1. Semaglutide versus other GLP‑1RAs — pooled randomized evidence
Meta‑analytic pooling of phase 3 head‑to‑head trials found semaglutide reduced HbA1c by a mean 0.44% more than other GLP‑1RAs and produced an average additional body‑weight reduction of 2.53 kg (0.91 kg/m2 BMI) across five trials and 3,760 participants, a statistically significant advantage in glycaemic and weight endpoints [1]. Individual trial syntheses and reviews reinforce that long‑acting GLP‑1RAs such as semaglutide generally outperform shorter‑acting agents for fasting glucose, A1C and weight, and several trials reported superior A1C and weight reductions with once‑weekly semaglutide 1.0 mg against liraglutide 1.2 mg daily, exenatide ER and dulaglutide 1.5 mg [5] [6].
2. Dose matters — semaglutide 1.0 mg vs 2.4 mg and context of obesity trials
Network meta‑analysis that included obese and overweight populations highlighted semaglutide 2.4 mg as among the most effective interventions for weight loss (mean difference −11.51 kg) and for lowering HbA1c (approx. −1.49%), indicating substantially larger effects at higher anti‑obesity dosing regimens used in Wegovy trials relative to diabetes‑dose regimens [2]. These larger estimates derive from trials in overweight/obese cohorts and should be read separately from diabetes‑specific head‑to‑head trials of lower semaglutide doses [2].
3. How semaglutide compares with SGLT2 inhibitors — scarcity of RCT head‑to‑head data
No large randomized cardiovascular or kidney outcome trials directly compared GLP‑1RAs such as semaglutide head‑to‑head with SGLT2 inhibitors; observational and real‑world comparative studies provide the available cross‑class comparisons [4]. A real‑world cohort study reported that adults with type 2 diabetes starting once‑weekly semaglutide experienced greater reductions in weight, BMI and HbA1c after one year than those starting SGLT2 inhibitors [3], but these observational findings are subject to confounding and cannot fully substitute for randomized head‑to‑head trials [3] [4].
4. The class landscape — tirzepatide, relative potency and clinical nuance
Network meta‑analysis across GLP‑1‑related agents ranked tirzepatide (a GIP/GLP‑1 dual agonist) as producing the largest HbA1c and fasting glucose reductions and among the greatest weight losses, placing semaglutide highly but not necessarily first when novel dual agonists are included [7]. This nuance matters clinically: semaglutide outperforms many established GLP‑1RAs, but newer multi‑agonists like tirzepatide may surpass semaglutide on average in trials conducted to date [7].
5. Safety, variability and limits of the evidence
GLP‑1RAs overall are associated with higher rates of gastrointestinal and other adverse events compared with SGLT2 inhibitors, and semaglutide’s superior efficacy comes with higher adverse‑event signals in some analyses [2]. Weight and glycaemic responses vary widely between individuals, trial doses and populations, and many cross‑class comparisons rely on indirect network analyses or observational data rather than randomized head‑to‑head trials — a limitation repeatedly noted in reviews and expert commentaries [2] [4].
6. Bottom line for clinicians and policy — magnitude and tradeoffs
Quantitatively, semaglutide has been shown in pooled head‑to‑head randomized data to lower A1C by ~0.44% more and body weight by ~2.5 kg more than other GLP‑1RAs [1], and higher‑dose semaglutide formulations produce much larger weight and A1C effects in overweight/obese trial populations [2]; compared with SGLT2 inhibitors, available real‑world evidence suggests greater glycaemic and weight benefits with semaglutide but randomized head‑to‑head confirmation is lacking and safety profiles differ between classes [3] [4].