Class effect for SGLT-2 inhibitors: a tale of 9 drugs - PubMed (original) (raw)

Class effect for SGLT-2 inhibitors: a tale of 9 drugs

Dario Giugliano et al. Cardiovasc Diabetol. 2019.

Abstract

The definition of class effect for SGLT-2 inhibitors may be based on three concepts: a similar chemical structure, a similar mechanism of action and similar pharmacological effects. We have also assumed that a class effect does exist when an effect on a particular outcome is present and is significant for each drug within the class of SGLT-2 inhibitors. For major cardiovascular events (MACE), there is no class effect for SGLT-2 inhibitors, as the 7% reduction of MACE risk observed with dapagliflozin in the DECLARE trial was not significant; on the other hand, a class effect is evident for both heart failure and diabetic kidney disease, as in all four trials so far completed (EMPAREG-OUTCOME, CANVAS, DECLARE, CREDENCE) the risk of hospitalization for heart failure and progression of diabetic kidney disease was significantly reduced by all SGLT-2 inhibitors.

Keywords: Class effect; Diabetic kidney disease; Heart failure; MACE; SGLT-2 inhibitors.

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Conflict of interest statement

D.G. received honoraria for speaking at meetings from Novartis, Sanofi, Lilly, AstraZeneca, and Novo Nordisk. K.E. received honoraria for speaking at meetings from Novartis, Sanofi, Lilly, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Figures

Fig. 1

Fig. 1

The class of SGLT-2 inhibitors with its founder phlorizin. Phlorizin-based analogs can be divided into _O_-glucoside analogs (the sugar group is bonded to another group via a glycoside bond, such the founder phlorizin and remogliflozin) or _C_-glucoside analogs (such as dapagliflozin and the many others); the latter have greater pharmacokinetic stability and selectivity for SGLT2. Inhibitor affinity is the result of a synergistic relationship between binding sites for sugar and the aglycone, with alterations in the sugar resulting in surprising differences in selectivity. All the nine SGLT-2 inhibitors showed in the figure are available in different parts of the world

Fig. 2

Fig. 2

The three concepts that must be fulfilled for the definition of a class effect. Similar chemical structure, similar mechanism of action, similar pharmacological effects at the level of target organs; to all that, it must be added the statistical significance of the effect in each trial

Fig. 3

Fig. 3

Class effects for the cardiorenal outcomes of SGLT-2 inhibitors. A class effect is not evident for MACE (only three trials demonstrated a significant reduction of the MACE risk), but is evident for heart failure (reduced risk of hospitalization for heart failure) and DKD progression (reduced decline of eGFR, renal death, or requirement for renal replacement therapy). MACE, major cardiovascular events; DKD, diabetic kidney disease; EMP, EMPAREG-OUTCOME; CAN, CANVAS; DEC, DECLARE; CRE, CREDENCE

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