Influence of SGLT2i and RAASi and Their Combination on Risk of Hyperkalemia in DKD

Abstract

Background This network meta-analysis investigated the effect of various combined regimens of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and renin-angiotensin-aldosterone system inhibitors (RAASis) on the occurrence of hyperkalemia in diabetic kidney disease. Methods The risk of hyperkalemia was compared using the random-effects model of network meta-analysis, with results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The comparative effects of all medications and their combinations with placebo were ranked using the surface under the cumulative ranking probabilities. Results In total, 27 eligible studies involving 43,589 participants with diabetic kidney disease were included. Major findings showed that the use of mineralocorticoid receptor antagonists (MRAs) on top of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) prominently increased hyperkalemia incidence when compared with placebo (OR, 6.08; 95% CI, 2.30 to 16.08), ACEI (OR, 3.07; 95% CI, 1.14 to 8.31), ARB (OR, 2.57; 95% CI, 1.10 to 6.02), SGLT2i (OR, 9.22; 95% CI, 2.99 to 28.46), renin inhibitors+ACEI/ARB (OR, 2.23; 95% CI, 1.14 to 4.36), or SGLT2i+ACEI/ARB (OR, 4.10; 95% CI, 2.32 to 7.26). Subgroup analysis among different generations of MRA found that spironolactone had the strongest effect in combination with ACEI/ARB, even higher than the combined use of ACEI and ARB (OR, 2.89; 95% CI, 1.26 to 6.63). In addition, SGLT2i had a significantly lower incidence of hyperkalemia compared with ACEI (OR, 0.33; 95% CI, 0.12 to 0.91), ARB (OR, 0.28; 95% CI, 0.13 to 0.61), dual RAASi (ACEI combined with ARB; OR, 0.17; 95% CI, 0.06 to 0.47), or MRA or renin inhibitors combined with ACEI/ARB (OR, 0.11; 95% CI, 0.04 to 0.33; OR, 0.24; 95% CI, 0.08 to 0.76, respectively.). Moreover, adding SGLT2i to the combination of MRA and ACEI/ARB, as well as the combinations of different RAASis, markedly reduced the occurrence of hyperkalemia. Conclusions Among the therapeutic drugs with the potential risk of increasing serum potassium in patients with diabetic kidney disease, MRA added an extra risk of hyperkalemia while SGLT2i had the opposite effect and could even reverse the elevation of serum potassium caused by the combined regimen, including MRAs.

Solution is not simple; sodium-glucose cotransporter-2 inhibitor use in Conn syndrome

“…No study has shown that SGLT2-is has aldosterone receptor antagonism. In fact, it has been shown that potassium levels decrease when used together with MRA [12]. Does the increased PRA with SGLT2-i use that we found in our study reflect enhanced aldosterone receptor antagonism or prolonged interference?…”

Efficacy and Safety of the Use of SGLT2 Inhibitors in Patients on Incremental Hemodialysis: Maximizing Residual Renal Function, Is There a Role for SGLT2 Inhibitors?

“…In our series, we observed a significant drop in the levels of potassium at the end of the follow-up. Although the exact mechanism is not clear, there is a hypothesis from a recent meta-analysis that SGLT2i may increase distal sodium and water delivery, enhancing the electronegative charge in the tubular lumen that regulates potassium excretion in the distal nephron caused on some occasions by the combined regimen including ACEi or MRA [29].…”

Recommendations for the management of hyperkalemia in patients receiving renin–angiotensin–aldosterone system inhibitors

“…Depending on the definition, the estimated prevalence of hyperkalemia is 2–3% in the general population and 1–10% in hospitalized patients [ 14 ]. Hyperkalemia prevalence increases with age [ 15 , 16 ], worsening renal function [ 15 – 18 ], the presence of diabetes or HF [ 15 , 16 ], a history of myocardial infarction [ 15 ], the use of RAASis [ 15 , 17 ], or resistant hypertension treated with mineralocorticoid receptor antagonists (MRAs) [ 19 – 21 ]. Therefore, the prevalence of hyperkalemia can be as high as 40–50% in these high-risk groups [ 18 , 22 ].…”

“…Therefore, the prevalence of hyperkalemia can be as high as 40–50% in these high-risk groups [ 18 , 22 ]. Conversely, use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) decreases the risk of hyperkalemia in RAASi-treated patients with CKD, likely because of the kaliuresis induced by osmotic diuresis, the increased distal sodium delivery and the preservation of renal function [ 21 , 23 ].…”