The legacy effect of hyperglycemia and early use of SGLT-2 inhibitors: a cohort study with newly-diagnosed people with type 2 diabetes

Abstract

Background: A delay in reaching HbA1c targets in patients with newly-diagnosed type 2 diabetes (T2D) is associated with an increased long-term risk of developing cardiovascular diseases (CVD), a phenomenon referred to as legacy effect. Whether an early introduction of glucose-lowering drugs with proven benefit on CVD can attenuate this phenomenon is unknown.

Methods: Using data derived from a large Italian clinical registry, i.e. the AMD Annals, we identified 251,339 subjects with newly-diagnosed T2D and without CVD at baseline. Through Cox regressions adjusted for multiple risk factors, we examined the association between having a mean HbA1c between 7.1 and 8% or >8%, compared with ≤7%, for various periods of early exposure (0-1, 0-2, 0-3 years) and the development of later (mean subsequent follow-up 4.6 ± 2.9 years) CVD, evaluated as a composite of myocardial infarction, stroke, coronary or peripheral revascularization, and coronary or peripheral bypass. We performed this analysis in the overall cohort and then splitting the population in two groups of patients: those that introduced sodium-glucose transport protein 2 inhibitors (SGLT-2i) during the exposure phase and those not treated with these drugs.

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 3 years exposure period (hazard ratio [HR]1.33; 95% confidence interval [CI] 1.063-1.365). 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 (p for interaction 0.006 and 0.003, respectively, vs. patients with the same degree of glycemic control but not treated with these drugs).

Interpretation: Among patients with newly diagnosed T2D and free of CVD at baseline, a poor glycemic control in the first three years after diagnosis is associated with an increased subsequent risk of CVD. This association is no longer evident when SGLT-2i are introduced in the first two years, suggesting that these drugs attenuate the phenomenon of legacy effect. An early treatment with these drugs might thus promote a long-lasting benefit in patients not attaining proper glycemic control after T2D diagnosis.

Funding: This work was supported, in part, by the Italian Ministry of Health (Ricerca Corrente) to IRCCS MultiMedica.

Keywords: AMD Annals initiative; Cardiovascular diseases; Legacy effect; Metabolic memory; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes.

Fig. 1

Schematic representation of the experimental design.

Fig. 2

Flow-diagram showing included and excluded patients.

Fig. 3

Poor, early glycemic control and the subsequent risk of cardiovascular diseases. Pseudo-forest plot showing the adjusted hazard ratios (HR) with the relative 95% confidence interval (CI) and the p value, derived from the Cox regression analyses exploring the associations between glycemic control and the risk of the CVD at follow-up in the whole cohort according to the degree of glycemic control in the three exposure periods assessed. HbA1c ≤ 7% is the reference.

Fig. 4

Early introduction of SGLT-2i attenuate metabolic memory. Pseudo-forest plot showing the adjusted hazard ratios (HR) with the relative 95% confidence interval (CI) and the p value, derived from the Cox regression analyses exploring the associations between glycemic control and the risk of the CVD at follow-up in patients stratified according to use of SGLT-2i during the exposure phase or not users, in the three exposure periods assessed. HbA1c ≤ 7% is the reference.