SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: population based cohort study

Abstract

Objectives: To evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in routine clinical practice.

Design: Population based cohort study with active-comparator, new user design.

Setting: Claims data from Medicare and two large commercial insurance databases in the United States from April 2013 to April 2022.

Participants: 1:1 propensity score matched adults with type 2 diabetes newly starting SGLT-2 inhibitors versus DPP-4 inhibitors (n=778 908), GLP-1 receptor agonists versus DPP-4 inhibitors (n=729 820), and SGLT-2 inhibitors versus GLP-1 receptor agonists (n=873 460).

Main outcome measures: Hyperkalemia diagnosis in the inpatient or outpatient setting. Secondary outcomes were hyperkalemia defined as serum potassium levels ≥5.5 mmol/L and hyperkalemia diagnosis in the inpatient or emergency department setting.

Results: Starting SGLT-2 inhibitor treatment was associated with a lower rate of hyperkalemia than DPP-4 inhibitor treatment (hazard ratio 0.75, 95% confidence interval (CI) 0.73 to 0.78) and a slight reduction in rate compared with GLP-1 receptor agonists (0.92, 0.89 to 0.95). Use of GLP-1 receptor agonists was associated with a lower rate of hyperkalemia than DPP-4 inhibitors (0.79, 0.77 to 0.82). The three year absolute risk was 2.4% (95% CI 2.1% to 2.7%) lower for SGLT-2 inhibitors than DPP-4 inhibitors (4.6% v 7.0%), 1.8% (1.4% to 2.1%) lower for GLP-1 receptor agonists than DPP-4 inhibitors (5.7% v 7.5%), and 1.2% (0.9% to 1.5%) lower for SGLT-2 inhibitors than GLP-1 receptor agonists (4.7% v 6.0%). Findings were consistent for the secondary outcomes and among subgroups defined by age, sex, race, medical conditions, other drug use, and hemoglobin A1c levels on the relative scale. Benefits for SGLT-2 inhibitors and GLP-1 receptor agonists on the absolute scale were largest for those with heart failure, chronic kidney disease, or those using mineralocorticoid receptor antagonists. Compared with DPP-4 inhibitors, the lower rate of hyperkalemia was consistently observed across individual agents in the SGLT-2 inhibitor (canagliflozin, dapagliflozin, empagliflozin) and GLP-1 receptor agonist (dulaglutide, exenatide, liraglutide, semaglutide) classes.

Conclusions: In people with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of hyperkalemia than DPP-4 inhibitors in the overall population and across relevant subgroups. The consistency of associations among individual agents in the SGLT-2 inhibitor and GLP-1 receptor agonist classes suggests a class effect. These ancillary benefits of SGLT-2 inhibitors and GLP-1 receptor agonists further support their use in people with type 2 diabetes, especially in those at risk of hyperkalemia.

Fig 1

Patient flowchart. *<65 years for Medicare. DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; SGLT-2=sodium-glucose cotransporter-2

Fig 2

Cumulative incidence curves for SGLT-2 inhibitors versus DPP-4 inhibitors (upper panel), GLP-1 receptor agonists versus DPP-4 inhibitors (middle panel), and SGLT-2 inhibitors versus GLP-1 receptor agonists (lower panel) for primary outcome of risk of hyperkalemia diagnosis in inpatient or outpatient setting after 1:1 propensity score matching. DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; SGLT-2=sodium-glucose cotransporter-2

Fig 3

Comparative effectiveness of SGLT-2 inhibitors versus DPP-4 inhibitors for primary outcome of risk of hyperkalemia diagnosis in inpatient or outpatient setting among subgroups after 1:1 propensity score matching. Number of propensity score matched patients in subgroups do not exactly add up to overall number of propensity score matched patients in main analysis because propensity score matching was performed within each subgroup; therefore, it is possible that more patients are matched within subgroups. ACE=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blocker; ARNI=angiotensin receptor/neprilysin inhibitor; CI=confidence interval; CVD=cardiovascular disease; CKD=chronic kidney disease; DPP-4=dipeptidyl peptidase-4; IR=incidence rate; MRA=mineralocorticoid receptor antagonist; PY=person years; SGLT-2=sodium-glucose cotransporter-2. *Only data from Medicare; †only data from Optum’s deidentified Clinformatics Data Mart Database

Fig 4

Comparative effectiveness of GLP-1 receptor agonists versus DPP-4 inhibitors for primary outcome of risk of hyperkalemia diagnosis in inpatient or outpatient setting among subgroups after 1:1 propensity score matching. Number of propensity score matched patients in subgroups do not exactly add up to overall number of propensity score matched patients in main analysis because propensity score matching was performed within each subgroup; therefore, it is possible that more patients are matched within subgroups. ACE=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blocker; ARNI=angiotensin receptor/neprilysin inhibitor; CI=confidence interval; CVD=cardiovascular disease; CKD=chronic kidney disease; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; IR=incidence rate; MRA=mineralocorticoid receptor antagonist; PY=person years. *Only data from Medicare; †only data from Optum’s deidentified Clinformatics Data Mart Database

Fig 5

Comparative effectiveness of SGLT-2 inhibitors versus GLP-1 receptor agonists for primary outcome of risk of hyperkalemia diagnosis in inpatient or outpatient setting among subgroups after 1:1 propensity score matching. Number of propensity score matched patients in subgroups do not exactly add up to overall number of propensity score matched patients in main analysis because propensity score matching was performed within each subgroup; therefore, it is possible that more patients are matched within subgroups. ACE=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blocker; ARNI=angiotensin receptor/neprilysin inhibitor; CI=confidence interval; CVD=cardiovascular disease; CKD=chronic kidney disease; GLP-1=glucagon-like peptide-1; IR=incidence rate; MRA=mineralocorticoid receptor antagonist; PY=person years; SGLT-2=sodium-glucose cotransporter-2. *Only data from Medicare; †only data from Optum’s deidentified Clinformatics Data Mart Database