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LOKELMA® (sodium zirconium cyclosilicate) is indicated for the treatment of hyperkalaemia in adult patients.
Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are typically oral prescription medications that belong to a class of therapies known as renin-angiotensin-aldosterone system inhibitors (RAASi).1-4
RAASi therapies provide key cardiorenal protective benefits, however they are also commonly associated with the adverse effect of hyperkalaemia.5 In some cases, this results in the down-titration or discontinuation of RAASi therapies, which can double the mortality risk in cardiorenal patients compared to those maintained on maximum doses.6
Kidney Disease: Improving Global Outcomes (KDIGO) and European Society of Cardiology (ESC) guidelines state that down-titration or discontinuation of RAASi therapy should be a last resort, or alternative measures should be taken, to managing hyperkalaemia in cardiorenal patients,7-9 as this can compromise long-term cardiorenal outcomes. Instead, alternative management strategies should be implemented to maintain normokalaemia during use.7-9
Explore our interactive case study here to see how you can help to deliver optimal cardiorenal protection through improved management of hyperkalaemia.
RAASi therapies – such as ACEi and ARBs – are core pillars of treatment in managing cardiorenal diseases, such as chronic kidney disease (CKD) and heart failure (HF).2-4
To optimise outcomes, international and national clinical guidelines recommend using RAASi therapies – including ACEi and ARBs – at the licensed and highest tolerated dose.7-9 These guidelines have been informed by over 30 years of landmark clinical trials focusing on the importance of maximum dosing in RAASi therapy.
Hyperkalemia is a condition where elevated potassium levels in the blood can disrupt heart rhythm and muscle function, potentially leading to cardiorenal complications.5 Hyperkalemia can be classified as mild (>5.0 to 6.0 mmol/L), moderate (5.5 to 6.0 mmol/L), or severe (>6.0 mmol/L).8
ACEi and ARBs cause hyperkalaemia primarily through their inhibition of the renin-angiotensin-aldosterone system (RAAS), which regulates salt and water homeostasis, enabling the body to maintain fluid balance and control blood pressure.12,13
Under normal conditions, angiotensin II stimulates the adrenal glands to release aldosterone – a hormone that promotes sodium reabsorption – and potassium excretion by the kidneys. Inhibiting RAAS lowers this aldosterone secretion and reduces potassium excretion by the kidneys, increasing the risk of hyperkalaemia. 12,13
While hyperkalaemia can arise directly from ACEi or ARB use, several clinical and physiological factors can significantly increase a patient’s risk.13,14 When addressing hyperkalaemia, you should also consider other factors such as: 13
Over 30 years of landmark clinical trials have consistently demonstrated that RAASi therapy improves renal outcomes in patients with CKD and HF.15-24 These findings form the foundation of current treatment guidelines and highlight the importance of prescribing RAASi therapy at the highest tolerated and licensed dose.
Cardiorenal disease | Study | Publication year | Key inclusion criteria | Follow-up (years) | Treatment arms | Key findings | |
|---|---|---|---|---|---|---|---|
| ARB | CKD | IRMA-21(N=590)15 | 2007 | Hypertension, T2DM, and microalbuminuria | 2 (mean) | Irbesartan vs. placebo | Irbesartan showed a dose-dependent reduction in the rate of progression to clinical albuminuria independent of its blood-pressure-lowering effect |
| CKD | INNOVATION2(N=527)16 | 2007 | T2DM and microalbuminuria | 1.3 (mean) | Telmisartan vs. placebo | Telmisartan achieved superior dose-dependent renoprotection independent of its blood-pressure lowering effect, demonstrated by lower transition rates from incipient to overt nephropathy | |
| CKD | IDNT3(N=1715)17 | 2001 | Hypertension, T2DM, and nephropathy | 2.6 (mean) | Irbesartan vs. amlodipine vs. placebo | Irbesartan was more effective than amlodipine and placebo in preventing the composite of DSCR, ESRD, or death from any cause which was independent of its blood pressure-lowering effect | |
| CKD | RENAAL4(N=1513)18 | 2001 | T2DM and nephropathy | 3.4 (mean) | Losartan vs. placebo | Losartan reduced the composite of DSCR and ESRD independent of its blood pressure-lowering effect | |
| ACEi | CKD | REIN5(N=186)19 | 1997 | Nephropathy with persistent proteinuria (≥1 g to <3g/24h) | 2.6 (median) | Ramipril vs. placebo | Ramipril was not significantly different from placebo in the monthly decline in GFR but significantly reduced the risk of progression to ESRD |
| CKD | GISEN/ REIN Stratum-26 (N=166)20 | 1997 | Nephropathy with persistent proteinuria (≥3 g/24 h) | 1.3 (mean) | Ramipril vs. placebo | Ramipril reduced proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood pressure-lowering | |
| CKD | AIPRI7(N=583)21 | 1996 | Chronic renal insufficiency caused by various disorders | 3 | Benazepril vs. placebo | Benazepril reduced the risk of the composite of DSCR or the need for dialysis | |
| HF | CONSENSUS (N=253)22 | 1987 | NYHA class IV | 0.5 (mean) | Enalapril vs. placebo | Enalapril reduced mortality by 40% at 6 months and 31% at 12 months | |
| HF | SOLVD(N=2569)23 | 1991 | NYHA class I–IVb, LVEF ≤35% | 3.45 (mean) | Enalapril vs. placebo | Enalapril reduced mortality by 16% and the combination of mortality or hospitalisation for worsening HF by 26% | |
| HF | ATLAS(N=3164)24 | 1999 | NYHA class II–IV; LVEF ≤30% | 3.8 (median) | Lisinopril low-dose (2.5–5 mg QD) vs. high-dose (32.5–35 mg QD) | High-dose lisinopril group had a non-significant reduction in mortality and CV mortality (8% and 10% reductions, respectively) and a significant reduction in the combination of mortality or hospitalisation for any reason by 12% compared with low-dose group |
Outcomes presented for illustrative purposes only. Cross-trial comparisons should not be made.
Additional research has shown that patients with stage 3-4 CKD or HF who down-titrate or discontinue RAASi therapy due to hyperkalaemia face double the mortality risk compared to those maintained on maximum tolerated doses.6
Data also showed that down-titration carries a risk nearly comparable to discontinuation, emphasising that any dose reduction or stopping RAASi therapy substantially raises mortality risk.6
Despite strong evidence from landmark trials, concerns about hyperkalaemia have led to underuse of ACEi and ARBs in patients with CKD and HF – often those who stand to benefit the most.25 However, guidelines provide clear recommendations:
Reducing or discontinuing ACEi/ARBs should be a last resort in managing hyperkalaemia in patients with CKD and HF, as these therapies offer significant cardiorenal protection
Instead, guidelines recommend treatment and monitoring strategies that enable control of potassium levels while preserving the proven cardiorenal protective benefits of RAASi therapies, such as ACEi and ARBs.7-9 Strategies – such as dietary management, careful medication review and use of potassium binders – should be considered first. 7-9
This is why potassium binders such as LOKELMA (sodium zirconium cyclosilicate),26 which can be co-administered alongside other medications, are key in enabling continued use of ACEi and ARBs at the licensed and highest tolerated dose by helping control serum potassium levels, managing the risk of hyperkalaemia.
Patients on LOKELMA had 2x the odds of maintaining RAASi therapy vs patients not on a potassium binder following a hyperkalaemic episode. 27
With these treatment and monitoring strategies, clinicians can confidently optimise RAASi therapy without letting hyperkalaemia hold patients back.
If you have any questions about LOKELMA or would like to speak to an
AstraZeneca representative, please contact us
GB-71147 | DOP: February 2026
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