Aims/hypothesis: A precision medicine approach in type 2 diabetes could enhance targeting specific
glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the
recently developed Bayesian causal forest (BCF) method to develop and validate an individualised
treatment selection algorithm for two ...
Aims/hypothesis: A precision medicine approach in type 2 diabetes could enhance targeting specific
glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the
recently developed Bayesian causal forest (BCF) method to develop and validate an individualised
treatment selection algorithm for two major type 2 diabetes drug classes, SGLT2-inhibitors (SGLT2i)
and GLP1-receptor agonists (GLP1-RA).
Methods: We designed a predictive algorithm using BCF to estimate individual-level conditional
average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA,
based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England
(Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation),
with additional external validation in 2,252 people with type 2 diabetes from Scotland (SCI-Diabetes
[Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were
replicated in clinical trial data (HARMONY programme: Liraglutide [n=389] and Albiglutide
[n=1,682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on
glycaemic response on weight change, tolerability, and longer-term risk of new-onset microvascular
complications, macrovascular complications, and adverse kidney events.
Results: Model development identified marked heterogeneity in glycaemic response, with 4,787
(17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>2.4%) with
SGLT2i over GLP1-RA and 5,551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-
RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an
independent Scottish dataset identified clear differences in glycaemic outcomes between those
predicted to benefit from each therapy. Sex, with females markedly more responsive to GLP1-RA,
was identified as a major treatment effect modifier in both the UK observational datasets and in
clinical trial data: HARMONY-7 Liraglutide (GLP1-RA): 4.4 (95%CI 2.2;6.3) mmol/mol greater response
in females than males. Targeting the two therapies based on predicted glycaemic response was also
associated with improvements in short-term tolerability and long-term risk of new-onset
microvascular complications.
Conclusions/interpretation: Precision medicine approaches can facilitate effective individualised
treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical
features for treatment selection could support low-cost deployment in many countries.