Treating Type 2 Diabetes With Early, Intensive, Multimodal Pharmacotherapy: Real-World Evidence From an International Collaborative Database

Aims: We compared the glycaemic and cardiorenal effects of combination therapy involving metformin, pioglitazone, sodium-glucose-linked-cotransporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) versus a more conventional glucocentric treatment approach combining sulphonylureas (SU) and insulin from the point of type 2 diabetes (T2D) diagnosis.Methods: We performed a retrospective cohort study using the Global Collaborative Network in TriNetX. We included individuals prescribed metformin, pioglitazone, an SGLT2i, and a GLP-1 RA for at least 1-year duration, within 3 years of a T2D diagnosis, and compared with individuals prescribed insulin and a SU within the same temporal pattern. Individuals were followed up for 3 years.Results: We propensity score-matched (PSM) for 26 variables. A total of 1762 individuals were included in the final analysis ( <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"><a:mi>n</a:mi><a:mo>=</a:mo><a:mn>881</a:mn></a:math> per cohort). At 3-years, compared to the insulin/SU group, the metformin/pioglitazone/SGLT2i/GLP-1 RA group had a lower risk of heart failure (HR 0.34, 95% CI 0.13–0.87, <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"><c:mi>p</c:mi><c:mo>=</c:mo><c:mn>0.018</c:mn></c:math> ), acute coronary syndrome (HR 0.29, 95% CI 0.12–0.67, <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"><e:mi>p</e:mi><e:mo>=</e:mo><e:mn>0.002</e:mn></e:math> ), stroke (HR 0.17, 95% CI 0.06–0.49, <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"><g:mi>p</g:mi><g:mo><</g:mo><g:mn>0.001</g:mn></g:math> ), chronic kidney disease (HR 0.50, 95% CI 0.25–0.99, <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" id="M5"><i:mi>p</i:mi><i:mo>=</i:mo><i:mn>0.042</i:mn></i:math> ), and hospitalisation (HR 0.59, 95% CI 0.46–0.77, <k:math xmlns:k="http://www.w3.org/1998/Math/MathML" id="M6"><k:mi>p</k:mi><k:mo><</k:mo><k:mn>0.001</k:mn></k:math> ).Conclusions: In this real-world study, early, intensive polytherapy, targeting the distinct pathophysiological defects in T2D, is associated with significantly more favourable cardiorenal outcomes, compared to insulin and SU therapy.