Commentary

Why not adding a glucose-lowering agent with proven cardioprotection in high-risk patients with type 2 diabetes at HbA1c target on metformin?

L’European Society of Cardiology (ESC) a publié récemment de nouvelles recommandations pour la prise en charge du patient diabétique de type 2 (DT2) à risque cardiovasculaire, en donnant une place privilégiée aux agonistes des récepteurs du glucagon-like peptide-1 (GLP-1) et aux inhibiteurs des co-transporteurs sodium-glucose de type 2 (gliflozines). Selon ces recommandations, tout patient à haut risque (défini très largement) et, a fortiori, à très haut risque, devrait bénéficier de ces médicaments, quel que soit le niveau du contrôle glycémique et ce, même avant la metformine. Si on respectait ces recommandations à la lettre, quasiment tous les patients avec un DT2 de plus de 10 années d’ancienneté devraient être traités par l’un ou l’autre de ces médicaments (voire les deux). Ceci représente une population cible bien plus large que celle préconisée en prévention cardiovasculaire primaire dans le dernier consensus de l’American Diabetes Association et de l’European Association for the Study of Diabetes (ADA-EASD). Celui-ci, par ailleurs, continue à donner la préséance à la metformine. Cet article analyse de façon critique les points de convergence et de divergence entre ces deux recommandations officielles et donne des arguments en faveur de la position de l’ADA-EASD.

The European Society of Cardiology (ESC) recently published new guidelines for the management of patients with type 2 diabetes (T2D) at cardiovascular risk, and gave a preferential place to glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins). According to these guidelines, any patient at high (with a very large definition), and a fortiori at very high, cardiovascular risk should benefit of these medications, whatever the level of glucose control and even before metformin. Thereby, almost all patients with T2D of more than 10 years should be treated by one of these medications (and possibly both). This represents a much larger population than that recommended in primary cardiovascular prevention by the most recent consensus report by the American Diabetes Association and the European Association for the Study of Diabetes (ADA-EASD), which also kept metformin as first-choice drug. This article provides a critical analysis of the convergent and divergent points between these two official recommendations and gives some arguments in favour of the ADA-EASD consensus.

This study compared the reduction of glycated haemoglobin (HbA1c) with sodium-glucose cotransporter type-2 inhibitors (SGLT2is) vs. dipeptidyl peptidase-4 inhibitors (DPP-4is) as add-ons to metformin in patients with type 2 diabetes mellitus (T2DM), with a specific focus on HbA1c changes according to baseline HbA1c.

Electronic databases were scrutinized for randomized controlled trials (RCTs) evaluating the reduction of HbA1c from baseline (Δ HbA1c) with an SGLT2i or DPP-4i in patients with T2DM not well controlled by metformin monotherapy. The endpoint was Δ HbA1c using both indirect and direct comparisons.

Overall, Δ HbA1c was slightly greater with SGLT2is (−0.80 ± 0.20% from 8.03 ± 0.35%; 44 analyses, 29 RCTs, 15 with two doses, n = 9321) than with DPP-4is (−0.71 ± 0.23% from 8.05 ± 0.43%; 61 analyses, 59 RCTs, n = 17,914; P = 0.0354). When the mean baseline HbA1c was < 8% ([64 mmol/mol] 7.79 ± 0.15% vs. 7.71 ± 0.23%), Δ HbA1c averaged −0.735 ± 0.17% vs. −0.62 ± 0.16% (P = 0.0117) with SGLT2is vs. DPP-4is, respectively. However, this difference vanished when the mean baseline HbA1c was ≥ 8% (−0.87 ± 0.22% from 8.27 ± 0.32% with SGLT2is vs. −0.80 ± 0.24% from 8.35 ± 0.33% with DPP-4is; P = 0.2756). The relationship between Δ HbA1c and baseline HbA1c was only slightly stronger with SGLT2is (slope: −0.39, r² = −0.43; P < 0.0001) than with DPP-4is (slope: −0.26, r² = −0.25; P < 0.0001).

Because of the small difference in Δ HbA1c whatever the baseline HbA1c level with SGLT2is vs. DPP-4is as add-ons to metformin, choosing between these glucose-lowering agents in clinical practice should be based on other efficacy criteria (such as weight and blood pressure changes, cardiovascular and renal protection) or on safety profiles rather than on HbA1c levels.

The management of type 2 diabetes mellitus (T2DM) essentially consists in controlling hyperglycaemia, together with other vascular risk factors, in order to reduce the incidence and severity of diabetic complications. Whereas glucose control using classical glucose-lowering agents (except perhaps metformin) largely fails to reduce cardiovascular disease (CVD), two new pharmacological classes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type 2 inhibitors (SGLT2is), have proven their ability to reduce major cardiovascular events in patients with established CVD. Furthermore, SGLT2is reduced the risk of hospitalisation for heart failure and the progression of renal disease. According to the 2018 ADA-EASD consensus report, the choice of a second agent to be added to metformin should now be driven by the presence or not of atherosclerotic CVD, heart failure or renal disease, all conditions that should promote the use of a SGLT2i or a GLP-1 RA with proven efficacy. Thus endocrinologists have to face a new paradigm in the management of T2DM, with a shift from a primary objective of glucose control without inducing hypoglycaemia and weight gain to a goal of cardiovascular and renal protection, largely independent of glucose control. Of note, however, the latter remains crucial to reduce the risk of microangiopathy.