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Page 12 of 19 Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26

Higher dose GLP-1s in T2DM
With the establishment of the GLP-1 class as good glycaemic and weight-lowering medications, the use of
higher doses has also been looked at to see if there was a further benefit in their effects with a balance to the
side effect profile - a key limiting factor in medication tolerability.

The Sustain Forte trial looked at semaglutide 2 mg compared to 1 mg once weekly in those with T2DM on
metformin and/or sulphonylurea. Semaglutide 2 mg had a -0.23% Hba1c and -0.93 kg estimated treatment
difference (as per treatment policy estimand) with a similar adverse event profile (34% vs. 31% reported
[67]
gastrointestinal disturbances) . Similarly, Dulaglutide 3 mg and 4.5 mg, which is already licensed in the
UK for T2DM, showed a -0.24% Hba1c and -1.6 kg weight reduction with 4.5 mg compared to 1.5 mg
[68]
dose . Both these higher strength doses show benefits in terms of Hba1c and weight loss compared to the
conventional dosing with a relatively similar side effect profile, though one could argue the Hba1c reduction
was relatively minimal compared to the weight loss. However, the role of these higher-dose medications
may be limited in the near future due to the potential favouring of newer dual incretin molecules and other
higher-dose GLP-1 therapies in obesity, which are more efficacious in weight reduction.

Semaglutide 2.4 mg is currently licensed in UK and USA for the treatment of obesity based on the findings
from the STEP trials. Though these trials were specifically in participants with obesity, the STEP 2 trial
looked at those with type 2 DM and obesity or overweight with semaglutide 2.4 mg compared to 1mg and
placebo. Semaglutide 2.4 mg resulted in a -1.2% Hba1c reduction and a -6.2% weight reduction compared to
placebo, with 69% of participants achieving weight loss of at least 5% compared to 29% in the placebo arm.
Side effect profile was notably higher in those on semaglutide 2.4mg compared to placebo group, with mild
to moderate gastrointestinal side effects noted in 63.5% to 34.3%, but less notable in those on semaglutide 1
[69]
mg (57.5%), suggesting reasonable tolerability . This poses an interesting consideration for patients with
T2DM who are on semaglutide, with potentially three treatment options of 1 mg, 2 mg or 2.4 mg once
weekly with escalation, perhaps more based on the requirement for weight loss over Hba1c lowering for
dose escalation.

Dual Agonists
Imminently due on the treatment landscape is Tirzepatide, a dual GLP-1/GIP agonist, which is FDA-
approved and available in the USA with a license and NICE guidance in the UK due in the near future.
Building on the efficacy of the GLP-1 molecules, the addition of a second incretin - GIP (Glucose-
dependent insulinotropic polypeptide) further enhances glycaemic and weight lowering, thereby providing
a potentially powerful agent in the management of type 2 diabetes and obesity.

The evidence for this molecule comes from the SURPASS phase III trials which assessed the effects of
Tirzepatide against various comparators.

The SURPASS 1 trial was a placebo-controlled trial assessing 5 mg, 10 mg and 15 mg Tirzepatide with an
estimated treatment difference of -21-23 mmol/mol reduction in Hba1c across the doses compared to
placebo (+ 0.4 mmol/mol) and a 7-9.5 kg reduction in weight loss. Tolerability was similar across the doses
and not far different from previous GLP-1-only studies, with 12%-18% on Tirzepatide developing nausea or
diarrhoea, 2%-6% vomiting, and 14% discontinuing the medication. Impressively, a high proportion of
participants on Tirzepatide achieved Hba1c targets of < 53 mmol/mol (87%-92%) and < 48 mmol/mol (81%-
[70]
86%), showing the efficacy of the glucose-lowering agent Tirzepatide .