There are at least nine different SGLT-2 inhibitors available to treat diabetic hyperglycemia in different parts of the world. However, cardiovascular outcomes trials (CVOTs), a prerequisite for FDA approval of any new antidiabetic drug in order to exclude inacceptable cardiovascular burden for T2D patients [9], have been completed so far for some of them only, namely empagliflozin [10], dapagliflozin [11] and canagliflozin [12, 13]. Even limiting the focus upon these few trials (EMPAREG-OUTCOME, CANVAS, DECLARE, and for some instance CREDENCE), extrapolation of knowledge from one class member to another has become increasingly common [14], although the definition of the term “class effect” is not an easy one. Most pharmacological texts are silent on the matter, and there is no established regulatory definition of the term. It is possible that the term “class effect” represents a term of convenience, an heuristic device, rather than a necessary description of reality.
The definition of drug class effect may be based on three concepts: a similar chemical structure, a similar mechanism of action and similar pharmacological effects [15]. A class effect is, therefore, an effect produced by all components of a chemically related group of drugs and not only by a single drug from that class [16]. Figure 2 shows the three concepts applied to SGLT-2 inhibitors: (a) they have a similar chemical structure derived by the founder phlorizin; (b) they have a similar mechanism of action based on the inhibition of the sodium-glucose transporter 2 predominantly expressed in the brush border membrane of the epithelial cells of the renal proximal tubule; and (c) they have similar pharmacological effects, at the level of the kidney (increase glycosuria and natriuresis, decrease glomerular pressure and albuminuria) and heart (decrease preload and afterload, increase ejection fraction). In order to make these concepts more stringent, we have 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 [16].
Figure 3 shows the class effects of the three SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) according to the more stringent definition, as detailed above. The outcomes considered include MACE (major cardiovascular events), which was the primary outcome in EMPAREG-OUTCOME [10], CANVAS [12] and DECLARE [11], hospitalization for heart failure, which was a secondary outcome in all four trials, and progression of DKD, which was a secondary outcome in EMPAREG-OUTCOME [10], CANVAS [12] and DECLARE [11], and a primary outcome in CREDENCE [13]. The fraction indicates the number of trials that revealed a significant effect. For MACE, there is no class effect, as the 7% reduction of MACE risk observed in DECLARE [11] was not significant (HR = 0.93, 95% confidence interval, 0.84–1.03, P = 0.17); on the other hand, a class effect is evident for both hospitalization for heart failure and progression of DKD, as in all four trials the risk of HF and DKD progression was significantly reduced by all SGLT-2 inhibitors. Besides CVOTs, SGLT-2i use reduced hospitalization for heart failure by 36% compared with DPP-4i use in a real-world nationwide population-based cohort study [17]. Moreover, a beneficial effect of dapagliflozin on left ventricular diastolic functional parameters has been described in patients with heart failure after 6 months of treatment [18] and similar results have been found with canagliflozin after 3 months [19]; in addition, empagliflozin may improve arterial stiffness in patients with type 1 diabetes [20].
Although comparison between trials should always be done with caution, the four trials are consistent with each other, showing reliable cardiorenal benefit and comparable expected adverse effects. The proposed pharmacologic class effect is limited to the three SGLT-2 inhibitors reviewed in this paper (empagliflozin, canagliflozin, and dapagliflozin): it remains to be seen if it will extend to ertugliflozin, sotagliflozin (in Europe and USA for now) and other similar agents (luseogliflozin, ipragliflozin, tofogliflozin, remogliflozin) in other world regions.