Incretin drugs for T2D: 2026 NMA results

A network meta-analysis published in Frontiers in Pharmacology in June 2026 pooled 102 randomised controlled trials involving 98,693 adults with type 2 diabetes (T2D) to rank 15 incretin-based therapies (IBTs) against each other on glycaemic control, weight loss, and safety^[1]. It is the largest such head-to-head comparison of this drug class in a single analysis.

The analysis covered single-agent GLP-1 receptor agonists such as semaglutide and liraglutide, the dual GIP/GLP-1 agent tirzepatide, the oral GLP-1 agent orforglipron, and the triple GIP/GLP-1/glucagon receptor agonist retatrutide. The primary ranking metric was the surface under the cumulative ranking curve (SUCRA): a score from 0 to 100 where a higher value means a treatment is more likely to be the best option in the comparison.

Blood sugar control: tirzepatide leads, orforglipron close behind

On HbA1c reduction versus placebo, tirzepatide produced the largest mean drop in the analysis: 2.30 percentage points (95% credible interval 1.80 to 2.70), SUCRA 99.72%^[1]. Orforglipron, an oral daily non-peptide GLP-1 receptor agonist that does not require injection, ranked second at 1.80 percentage points (95% CrI 0.96 to 2.70), SUCRA 91.71%.

The tirzepatide result aligns with the Phase 3 SURPASS programme, where the 15 mg dose reduced HbA1c by 2.3 percentage points versus placebo in people with T2D. The network analysis aggregates results across multiple doses and trial populations. Tirzepatide is approved for T2D in all major markets under the Mounjaro brand.

Weight loss: retatrutide stands apart from the field

For body-weight reduction versus placebo, retatrutide ranked first by a clear margin: a mean 17.00 kg reduction (95% CrI 14.00 to 20.00 kg), SUCRA 99.81%^[1]. That figure draws primarily on the Phase 2 T2D trial, in which the 12 mg dose produced 16.9% body-weight reduction at 36 weeks versus 3.0% on placebo in 281 participants^[2].

The weight-loss gap between retatrutide and the rest of the class reflects its triple mechanism. Activating GIP, GLP-1, and glucagon receptors simultaneously drives energy expenditure effects that single GLP-1 agents do not match. Tirzepatide (dual GIP/GLP-1) outperforms semaglutide on weight in direct trial data, but the network analysis places retatrutide further ahead on weight while tirzepatide leads on glycaemic ranking. The full picture from a direct comparator trial (TRIUMPH-5, retatrutide versus tirzepatide) has not yet read out as of July 2026.

Safety: gastrointestinal effects track with dose

The analysis confirmed the class pattern: gastrointestinal adverse events (nausea, vomiting, diarrhoea) are dose-dependent and present across all active IBTs^[1]. The highest nausea odds ratios in the network belonged to ITCA 650 (OR 6.70, a continuous-delivery osmotic mini-pump formulation) and visepegenatide (OR 5.30). Liraglutide carried OR 3.60. Newer agents ranked lower on this measure.

Among the newer agents, 45 mg orforglipron offered a favourable efficacy-to-tolerability ratio: glycaemic benefit near the top of the oral-agent range without the nausea rates seen at higher doses. Orforglipron is a daily tablet rather than an injection, which matters for patients who cannot or prefer not to self-inject.

Hypoglycaemia risk across the IBT class remains low outside of combinations with sulfonylureas or insulin. The Phase 2 retatrutide T2D trial reported no severe hypoglycaemia and no deaths across all dose groups over 36 weeks^[2]. Higher doses improved metabolic outcomes but also increased the proportion of participants stopping treatment for adverse events.

Limits of the analysis and what is still missing

Network meta-analyses rank agents across pooled trial data using statistical modelling. They cannot replicate the precision of a direct randomised comparison. The retatrutide weight figure, for example, comes from Phase 2 data with shorter follow-up than the SURMOUNT or SURPASS programmes used for tirzepatide and semaglutide. Results from direct comparator trials carry more weight for specific pairs.

The analysis does not cover cardiovascular outcomes. The SELECT trial demonstrated a 20% reduction in major cardiovascular events with semaglutide 2.4 mg in adults with cardiovascular disease and obesity but without T2D. Retatrutide's cardiovascular outcomes trial (TRIUMPH-Outcomes, NCT06383390) is running to a 2029 primary completion. No equivalent outcomes data exists yet for retatrutide or orforglipron.

Regulatory status of the ranked agents

Tirzepatide is approved by the FDA (Mounjaro for T2D, Zepbound for obesity) and the EMA (Mounjaro for both). Semaglutide is approved in all major markets. Orforglipron is in Phase 3 trials and not approved anywhere as of writing. Retatrutide is investigational: the FDA and EMA have not approved it. The EMA agreed a paediatric investigation plan in September 2024, but that is not an approval.

This article is for informational purposes only. It does not constitute medical advice. Consult a qualified healthcare provider before making any treatment decision.