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Hyperkalemia in the Context of SGLT2i and ARNI Use
The first analysis examined patients with heart failure treated with newer cardiometabolic therapies, including SGLT2 inhibitors and angiotensin receptor–neprilysin inhibitors. Despite reduced exposure to ACE inhibitors and ARBs, 32.2% of patients (n=334) experienced at least 1 documented hyperkalemic event during follow-up, and 7.5% had 2 or more events.1
Investigators noted serum potassium levels at the time of the first hyperkalemic event were between 5.1 and 5.5 mEq/L in 71% of cases, 5.6 to 6.0 mEq/L in 22%, and greater than 6.0 mEq/L in 7%. Results also pointed to incidence rates per 100 patient-years of 38.4 for hyperkalemic events, 6.0 for all-cause mortality, and 54.7 for all-cause hospitalization.1
Outcomes for Heart Failure at High Risk of Hyperkalemia according to Optimization of RAASi
A second analysis from the CARE-HK in HF registry compared outcomes in patients who reached at least half the target dose of renin–angiotensin system inhibitors and mineralocorticoid receptor antagonists with those on lower dosing. Hyperkalemia occurred in 31.6% of patients receiving optimal GDMT (≥50% target dosing) compared with 27.8% receiving suboptimal therapy (P = .053), and dose adjustments in response to hyperkalemia were less frequent in the optimal-dose cohort (9.9% vs 16.2%).2
All-cause mortality was 3.8% in the optimal-dose group and 10.7%in the suboptimal-dose group. The unadjusted hazard ratio for mortality with optimal versus suboptimal dosing was 0.43 (95% CI, 0.30 to 0.61; P <.0001). After adjustment for age and sex, the hazard ratio was 0.49 (95% CI, 0.33 to 0.69; P <.001), and after full adjustment it was 0.70 (95% CI, 0.46–1.06; p=.09). Fewer than 1 in 3 patients at risk for hyperkalemia received optimal dosing. Despite a slightly higher rate of hyperkalemia in the optimally treated group, mortality was lower, and most hyperkalemic events did not result in discontinuation or down-titration of therapy.2
For more on these studies and how they help inform management of patients with heart failure, check out our Q&A with study presenter Stephen Greene, MD, advanced heart failure specialist at Duke University Medical Center and co-host of HCPLive’s Don’t Miss a Beat podcast.
Q&A with Stephen Greene, MD, at HFSA 2025
HCPLive: Can you shed some light on the results of your study into RAASi optimization?
Greene: We saw that being on optimal doses of RAAS inhibitors and MRAs was associated with a marginally higher risk of hyperkalemic events. It was high in both groups—the suboptimal group and the optimal RAAS group—but it was marginally higher with optimized RAASi. So, that was the trade-off.
Now, looking at the associated benefit of optimal doses of RAASi and MRA: in unadjusted analyses, there was more than a 60% relative risk reduction in all-cause death. When we adjusted for age and sex, it was consistent. When we adjusted for the full multivariate model, it was attenuated to a hazard ratio of 0.70—a 30% reduction—but it wasn’t quite statistically significant anymore. That was likely a power issue, but it clearly pointed in the direction of a favorable mortality association with optimal dosing of RAASi.
Putting this all together, I think about this patient population that gives us a lot of concern because of their high risk of hyperkalemia. Is it worth trying to prioritize optimizing the RAASi dose? These data show that, yes, there is a marginal price to pay with hyperkalemia, but there’s also an associated mortality benefit. It goes to show that we should still be targeting optimal doses of RAASi—even in this patient population—but with proactive potassium monitoring and treatment strategies to extract as much benefit as possible.
HCPLive: Can you take us through the findings of your study on residual risk of hyperkalemia in users of SGLT2 inhibitors and ARNI?
Greene: The second presentation from CARE-HK focuses on the residual risk of hyperkalemia despite treatment with an SGLT2 inhibitor and ARNI instead of an ACE inhibitor. For context, we know from randomized clinical trials that SGLT2 inhibitors—aside from their other clinical benefits—decrease the risk of hyperkalemia. That’s been seen in heart failure trials and in other CKM populations. Likewise, in the ARNI trials, ARNI compared to ACE inhibitors decreased the risk of hyperkalemia among people on an MRA.
So yes, we should be using SGLT2 inhibitors and ARNI as tolerated for all our heart failure patients. Beyond their morbidity and mortality benefits, these drugs are also essentially first-line treatments for preventing hyperkalemia, and that’s underappreciated.
That being said, we wanted to ask: if you do everything right from a hyperkalemia prevention standpoint—getting your patient on an SGLT2 inhibitor and using an ARNI instead of an ACE inhibitor—what residual risk of hyperkalemia remains downstream?
To assess that, we looked again at the CARE-HK registry, where everyone by definition had a high risk of hyperkalemia. We evaluated more than 1,000 patients who were enrolled on an SGLT2 inhibitor and ARNI at baseline.
We saw that despite using an SGLT2 inhibitor and ARNI instead of an ACE inhibitor or ARB, patients still had a very high risk of hyperkalemic events—about 38 events per 100 patient-years. There was also a very high risk of all-cause mortality—around six events per 100 patient-years—and over 50 events per 100 patient-years for all-cause hospitalization.
So, the way I sum it up is: despite guideline-recommended use of an SGLT2 inhibitor and ARNI, we still saw an enormous residual risk of both hyperkalemic events and broader morbidity and mortality. From a hyperkalemia standpoint, it shows that we are not out of the woods with these high-risk patients, even with SGLT2 inhibitors and ARNI on board.
HCPLive: What might these findings reveal about the broader concept of residual risk in heart failure management, even beyond hyperkalemia?
Greene: We’re appreciating that the phrase “residual risk” is being used more and more in heart failure and other areas of cardiology. In heart failure specifically, we’re really dealing with an extreme-risk condition. Calling it just “high risk” doesn’t do it justice. When you look at the absolute event rates, the prognosis is comparable to cancer.
We’re talking more about residual risk despite quad therapy, for example—residual mortality and hospitalization risk. There are other therapies being tested in randomized trials, including some recently presented at ESC. But we can also think about residual risk from a hyperkalemia perspective.
Again, SGLT2 inhibitors and ARNI should already be used for their benefits on morbidity and mortality, and they additionally reduce the risk of hyperkalemia. But just like we know we’re not out of the woods for morbidity and mortality with quad therapy alone, we also know that patients with a history of hyperkalemia—or active hyperkalemia—are not suddenly low risk just because we get them under control and put them on an SGLT2 inhibitor or ARNI.
The key takeaway is that there will still be a role for further potassium management strategies, including novel potassium binders.
Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools