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Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26 Page 13 of 19

Directly providing a comparison to GLP-1 therapy, the SURPASS 2 trial compared Tirzepatide (5 mg, 10
mg, 15 mg) to Semaglutide 1mg dose and showed greater reductions (estimated treatment differences) in
Hba1c (-0.15, -0.39 and -0.45 percentage points respectively) and weight (-1.9 kg, -3.6 kg and -4.5 kg
respectively). Although this may show the benefits of Tirzepatide over the current GLP-1 therapy, there is
still debate about whether it is the GLP-1 or the GIP that provides this added benefit, with mechanistic
[71]
studies and clarity still awaited .
The SURPASS 3 trial similarly showed reductions in Hba1c and weight with Tirzepatide compared to
insulin degludec though perhaps the more interesting aspects of this trial were the added trial elements of
continuous glucose monitoring and measurement of liver fat. A sub-study of the trial (SURPASS-3 CGM)
looked at 243 participants of the SURPASS-3 trial and assessed CGM metrics in this group at 3 points across
the trial (baseline, 24 weeks and 52 weeks). Pooled analysis of the Tirzepatide 10 mg and 15mg doses
revealed a greater proportion achieving time in range (71-140 mg/dL or 3.9 -10 mmol/L), with a 25%
estimated treatment difference. Given the increasing use of technology in diabetes care, this data provides
further interesting information and reassurance beyond the limitations of Hba1c targets, such as time in
hypoglycaemia or hyperglycaemia [72,73] . The SURPASS 3 trial had another substudy, the SURPASS-3 MRI,
which assessed MRI changes in liver fat content in a subset of participants in the trial with a fatty liver index
of at least 60 (by MRI-proton density fat fraction MRI-PDFF). Again utilising pooled data from the
Tirzepatide 10 and 15mg groups, liver fat content was reduced compared to placebo (-8.09% vs. -3.38% in
the degludec group) with reductions seen in the volume of visceral and abdominal subcutaneous adipose
[74].
tissue (VAT and ASAT) This adds interest in the effects of Tirzepatide on liver fat, potentially suggesting
a future therapeutic option in NAFLD - something that is being assessed in the ongoing SYNERGY-NASH
[75]
trial, which will also assess histological changes in addition to MRI-PDFF .

Tirzepatide is the most advanced of the dual incretin agonists currently in development though another,
Codatutide, has undergone phase 2 trials and is in development, thereby adding further molecules to this
class of agents .
[76]

One obvious important area is the lack of hard cardiovascular outcomes for this molecule. The SURPASS 4
trial assessed the effects, specifically cardiovascular safety, of Tirzepatide compared to insulin glargine in a
population at high cardiovascular risk, assessing for a MACE-4 composite of cardiovascular mortality,
[77]
myocardial infarction, stroke and hospitalization for unstable angina . Tirzepatide was not associated with
an increased cardiovascular risk in this study and an additional pre-specified metanalysis confirmed this .
[78]
However, though reassuring, such data still requires results from the dedicated cardiovascular outcome trial
SURPASS-CVOT, assessing the cardiovascular effects of Tirzepatide against dulaglutide, a first for CVOTs -
comparison against a medication already proven to have cardiovascular benefit, with completion due in
2024 .
[79]

While the data from the SURPASS trials make clinical interest in the utilisation of this medication in those
with type 2 diabetes, there are a few clinical considerations and real-world data will be beneficial once
widely available. The key is the positioning in the management of type 2 diabetes: could it be reasonable to
start this medication as first choice incretin in order to initiate the treatment most likely to achieve required
targets, or would it be considered only after ‘failure’ of current single incretin GLP-1 therapy. Additionally,
the dose steps involved -2.5 mg increments at 6 weekly intervals could mean that it takes 6 months to reach
the maximum 20 mg dose (if required), thereby posing adherence and treatment persistence considerations.
Nevertheless, the addition of this new class of dual incretins provides an exciting opportunity to enhance
the management of those with type 2 diabetes and/or obesity.

GLP-1s and other considerations