Polypharmacy in CKD: a reason to review, not withhold, cardiorenal protection

We are fortunate to have a rapidly expanding range of treatments for cardio-kidney-metabolic (CKM) disease, however it can be challenging to know whether adding more drugs will always result in benefit. People with type 2 diabetes (T2D) and chronic kidney disease (CKD) often also have hypertension, heart failure or atherosclerotic cardiovascular disease, each bringing its own treatment recommendations. The result can be a long medication list and a familiar dilemma: how do we balance the benefits of proactive treatment against the burden of taking more medicines? 

Yeung and colleagues explore this question in a post-hoc analysis of the CREDENCE trial, published in Nephrology Dialysis Transplantation this September (Efficacy and safety of canagliflozin are consistent across polypharmacy burden in CKD: the CREDENCE trial). Among 4,401 participants with T2D and albuminuric CKD, they examined whether the efficacy and safety of canagliflozin differed according to medication burden (0–4, 5–9 or ≥10 medications). 

Polypharmacy was common, with participants taking a mean of 8.3 medications. Higher medication burden was associated with more all-cause and heart failure hospitalisations, although not with higher rates of CKD progression or cardiovascular death. Discontinuation was also more common with increasing medication burden, but interestingly this was higher in the placebo group than amongst those randomised to canagliflozin use. 

Crucially, the relative kidney and cardiovascular benefits of canagliflozin were consistent across all three groups, with no clear signal that polypharmacy compromised its safety. Furthermore, the authors estimated greater absolute reductions in all-cause and heart failure hospitalisations (but not rate of CKD progression) among those taking more medications at baseline.  

Why does this matter? Relative benefit tells us how much a treatment reduces risk compared with placebo; absolute benefit tells us how many events are actually prevented. If someone starts at higher risk, the same relative reduction can translate into more events prevented. In this analysis, people taking more medications experienced more hospitalisations, so the potential absolute benefit of canagliflozin was greater for some outcomes. A long medication list, then, may signal an opportunity for meaningful benefit, rather than a reason to hold back. 

That does not mean we should keep adding medicines indiscriminately. Medication count is an imperfect marker of underlying illness and risk, and this post-hoc analysis cannot establish the best prescribing strategy for people with polypharmacy. Nor does it capture regimen complexity, adherence, drug interactions or patient preference. 

The challenge, then, is not simply to reduce the number of medicines, but to make every medicine earn its place. Polypharmacy can reflect the treatment burden of living with several long-term conditions, but it can also reflect the opportunity to prevent serious complications across the CKM spectrum. Regular medication reviews should help us distinguish between treatments that add value and those that no longer do, while making space for therapies with proven benefits. 

Yeung and colleagues’ analysis offers a reassuring message for clinicians wary of adding yet another tablet: among eligible patients with T2D and CKD, a long medication list should not, in itself, be a reason to withhold canagliflozin. The aim is not fewer medicines at any cost, nor more medicines by default, but the right treatment for the right patient — with benefits that matter to them. 

A summary of the study can be read here.