Type 2 diabetes

Research context

Type 2 diabetes is the dominant condition shaping incretin medicine development. In the UK, around 4.4 million people live with a diabetes diagnosis (approximately 90% type 2), with an estimated further 1.3 million cases undiagnosed. The evidence base for metabolic peptides in T2D spans four overlapping randomised programmes: the LEAD programme for liraglutide (LEAD-1 to LEAD-6, over 4,400 participants), the SUSTAIN programme for subcutaneous semaglutide (SUSTAIN-1 to SUSTAIN-7), the PIONEER programme for oral semaglutide, and the SURPASS programme for tirzepatide (SURPASS-1 to SURPASS-5, over 6,000 participants). Across these, incretin therapies achieve HbA1c reductions of roughly 1.5–2.5 percentage points while reducing body weight and, in dedicated outcome trials, cardiovascular event rates. LEADER (liraglutide) and SUSTAIN-6 (semaglutide) provided the first cardiovascular outcome data for the class; SURPASS-CVOT (tirzepatide vs dulaglutide) is the ongoing cardiovascular outcomes trial.

Why this matters metabolically

The incretin system provides the mechanistic rationale. After a meal, intestinal L-cells release GLP-1, which stimulates glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying and promotes satiety. In T2D this incretin response is blunted, making exogenous receptor agonism therapeutically advantageous; because the insulinotropic effect is glucose-dependent, it self-limits at euglycaemia, giving a favourable hypoglycaemia profile relative to sulfonylureas. Tirzepatide extends this by co-activating the GIP receptor — GIP is the dominant physiological incretin but its action is specifically impaired in T2D, and dual agonism appears to partially restore that lost sensitivity. T2D also sits at the centre of the cardiometabolic cluster (obesity, hypertension, dyslipidaemia, MASLD/MASH, CKD, ASCVD), so glycaemic management is both an outcome and a gateway to benefits that extend across the cluster (SELECT, FLOW, SUMMIT, SURPASS-CVOT).

FAQs

Which incretin medicines are MHRA-licensed for type 2 diabetes in the UK?

Semaglutide (Ozempic, Rybelsus), liraglutide (Victoza), dulaglutide (Trulicity) and tirzepatide (Mounjaro) are all MHRA-licensed prescription-only medicines for type 2 diabetes glycaemic control in eligible adults.

What HbA1c reduction does tirzepatide achieve in type 2 diabetes trials?

In the SURPASS programme, tirzepatide at the 15 mg maintenance dose reduced HbA1c by approximately 2.0–2.5 percentage points from baseline, with a substantial proportion of participants achieving target HbA1c below 7.0% and below 5.7%. SURPASS-2 showed tirzepatide achieved greater HbA1c reductions than semaglutide 1 mg across all doses tested.

How does semaglutide compare to liraglutide for glycaemic control in T2DM?

Head-to-head trial SUSTAIN-7 compared weekly semaglutide 0.5 mg and 1.0 mg against daily liraglutide 1.2 mg and 1.8 mg respectively, demonstrating superior HbA1c reductions with both semaglutide doses (mean differences of approximately 0.3–0.4 percentage points) alongside greater weight reduction. Both compounds are GLP-1 receptor agonists but semaglutide's structural modifications confer higher receptor binding affinity and a longer half-life.

Which trials demonstrated cardiovascular outcome benefits in T2DM?

SUSTAIN-6 (2016) was the first GLP-1 agonist trial to show MACE reduction — a 26% relative risk reduction — with semaglutide 0.5 mg and 1.0 mg. LEADER (2016) established liraglutide's cardiovascular credentials with a 13% MACE reduction. SURPASS-CVOT for tirzepatide is the cardiovascular outcomes trial in T2DM populations.

What is the current NICE position on tirzepatide for T2DM in the UK?

NICE technology appraisal TA924 (2024) recommended tirzepatide (Mounjaro) as an option for managing blood glucose in adults with T2DM when used in combination with diet and exercise, with or without other glucose-lowering medicines, meeting specified HbA1c and BMI criteria. The MHRA granted UK marketing authorisation for tirzepatide in T2DM in November 2023.

Does oral semaglutide have comparable efficacy to injectable formulations?

PIONEER trials compared oral semaglutide 14 mg against placebo and active comparators in T2DM. PIONEER-3 and PIONEER-4 showed oral semaglutide achieved clinically meaningful HbA1c reductions, though the absolute magnitude of effect was modestly lower than subcutaneous semaglutide 1 mg in matched comparisons, partly owing to variable oral bioavailability (approximately 1%). PIONEER-6 provided cardiovascular safety data supporting the oral formulation's risk profile.