There is no absolute right answer here. However if we are to follow how clinical trials were designed in the chronic kidney disease space, I think it would make the most sense to start an ACEi or ARB first, followed by an SGLT2 inhibitor or a mineralocorticoid receptor antagonist. In the pivotal trials with SGLT2i, over 90% of patients were on an ACEi or ARB (RASi) prior to randomization. I don't believe it is an absolute however; In other words, I don't believe that the benefit of an SGLT2 inhibitor depends on the use of RASi.
Another unresolved issue is what to do in CKD patients already taking RASi and an SGLT2i in whom you contemplate starting an MRA. We don't really have trials to answer this question and in the pivotal studies with MRAs like Finerenone, a very small percentage of patients were taking SGLT2i at the time of enrolment. Once again, I don't believe there is a mechanistic reason to doubt the efficacy of an MRA in the context of SGLT2i. In terms of using MRAs for CKD, I generally reserve use of these drugs for diabetics where the data is most plentiful. In this population, I prefer finerenone over spironolactone. Spironolactone might be a good option in the same patients if blood pressure is a priority since finerenone has no real impact on blood pressure, however we do not have any significant CKD outcome data using spironolactone.
In general, I think all therapies will probably perform better in patients with significant albuminuria (at least microalbuminuria) in the sense that those patients have a higher event than those without albuminuria and therefore the impact of an intervention is likely greater over a shorter period of time. I do use SGLT2 inhibitors in patients without albuminuria but generally reserve doing so in younger patients with CKD who have a longer life expectancy and the same goes for MRA in my opinion. I don't prioritize the use of RASi in patients without proteinuria unless they have another indication such as hypertension, heart failure or previous MI. The evidence for SGLT2 inhibitor is more plentiful in this population but still not as robust as in those patients with significant proteinuria.
Regarding the issue of low blood pressure, I would be cautious using an RASi in such patients with CKD. I would be more eager to start this therapy in patients with significant proteinuria and in those individuals I might remove any other agents that do not have specific renal or cardiac benefits that may be lowering the blood pressure as well (such as calcium channel blockers or diuretics) - in this way we "make room" RASi.
- In CKD patients who have at least microalbuminuria I prioritize use of RASi. If blood pressure is low i these individuals, I add RASi cautiously and reduce or remove other drugs that do not have renal/vardiac protection but which do lower blood pressure (diuretics, CCBs)
- In CKD patients without at least microalbuminuria, I do not prioritize the use of RASi unless they have another indication such as hypertension, heart failure or previous MI
- In all patients with CKD especially those with at least microalbuminuria, I strongly consider using SGLT2i
- In CKD patients without at least microalbuminuria, I reserve use of SGLT2i for younger patients with chronic kidney disease (<80 years old)
- I generally add finerenone (or spironolactone) last in patients with diabetic chronic kidney disease (after SGLT2 and RASi). I reserve use of MRAs for those patients with a GFR of at least 25 cc/min and I have at least microalbuminuria.