Early introduction of SGLT2 Inhibitors attenuates association between dysglycaemia and CVD risk: Lancet

A recent study published in Lancet Regional Health – Europe has revealed that this association between haemoglobin (Hb) A1c >7% and >8% and later CVD development may be attenuated when sodium-glucose transport protein 2 inhibitors (SGLT2is) are introduced within two years of a diabetes diagnosis.

The findings suggest that SGLT2 inhibitors attenuate the phenomenon of the legacy effect. "Early treatment with these drugs might thus promote a long-lasting benefit in patients not attaining proper glycemic control after the diagnosis of type 2 diabetes, the authors wrote.

Previous studies have shown that a delay in reaching HbA1c targets among newly diagnosed T2D patients is associated with an increased long-term risk of CVD development, a phenomenon referred to as the legacy effect. However, it is unknown if an early introduction of glucose-lowering drugs with proven benefits for CVD can attenuate this phenomenon. To find out the same, Antonio Ceriello, RCCS MultiMedica, Milan, Italy, and colleagues tested the hypothesis that an early introduction of SGLT-2 inhibitors promotes a long-term beneficial effect on the vasculature independently of the attained HbA1c targets.

For this purpose, the researchers identified 251,339 subjects with newly-diagnosed T2D and without CVD at baseline, using data derived from an extensive Italian clinical registry. They examined the association between having a mean HbA1c between 7.1 and 8% or >8%, compared with ≤7%, for several periods of early exposure (0–1, 0–2, 0–3 years) and later CVD development (mean subsequent follow-up 4.6 ± 2.9 years). The risk of later CVD development was evaluated as a composite of stroke, myocardial infarction, coronary or peripheral bypass, and coronary or peripheral revascularization.

This analysis was performed in the overall cohort. Then the population was split into two groups: those that introduced SGLT2 inhibitors during exposure and those not treated with these drugs.

The study revealed the following findings:

· Considering the whole cohort, subjects with both a mean HbA1c between 7.1 and 8% and >8%, compared with patients attaining a mean HbA1c ≤ 7%, showed an increased risk of developing the outcome in all the three early exposure periods assessed, with the highest risk observed in patients with mean HbA1c > 8% in the three years exposure period (hazard ratio [HR]1.33).

· Compared with HbA1c ≤ 7%, patients with mean HbA1c >7% and <8% had hazard ratios (HRs) 1.14, 1.17, and 1.20 for exposure periods 0-1, 0-2, and 0-3 years, respectively.

· For those with mean HbA1c >8%: HR, 1.19, 1.26, and 1.33 for 0-1, 0-2, and 0-3 years, respectively.

· The introduction of SGLT-2i during the exposure periods of 0–1 and 0–2 years eliminated the association between poor glycemic control and the outcome.

· HR was 0.98 vs 1.15 in users vs nonusers for 7% < HbA1c mean ≤8% strata and 0.86 vs 1.22 for users vs nonusers for mean HbA1c >8% in the 1-year exposure period. HR was 0.92 and 1.19 for users vs nonusers for the 7% < HbA1c mean ≤8% strata and 0.78 users vs 1.29 nonusers for the mean HbA1c >8% strata in the 0-2 years exposure period.

· phenomenon was not seen when SGLT2is were introduced in the 0-3 years exposure phase.

"These results indicate that the legacy effect phenomenon is still observable in contemporary cohorts. An early introduction of SGLT-2 inhibitors might ameliorate or even suppress the harmful long-term consequence of early, poor glycemic control on the vasculature," the researchers wrote.

"If confirmed in prospective studies with fully-matched populations, these findings might suggest that SGLT-2i act as disease-modifying drugs, thus advocating a wider and earlier usage for them," they concluded.

Reference:

Ceriello, A., Lucisano, G., Prattichizzo, F., La Grotta, R., Frigé, C., De Cosmo, S., Di Bartolo, P., Di Cianni, G., Fioretto, P., Giorda, C. B., Pontremoli, R., Russo, G., Viazzi, F., & Nicolucci, A. (2023). The legacy effect of hyperglycemia and early use of SGLT-2 inhibitors: A cohort study with newly-diagnosed people with type 2 diabetes. The Lancet Regional Health - Europe, 31, 100666. https://doi.org/10.1016/j.lanepe.2023.100666