Adverse Events of Sodium–Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease: A Retrospective Chart Review



 

Hanul Choi, PharmD1; Leigh-Anh Nguyen, PharmD2; Jenny Wan, PharmD, BCPS2; Hooman Milani, PharmD, MBA1; Kristine McGill, PharmD, BCPS1; Jong Park, MD2

Perm J 2021;25:20.242

https://doi.org/10.7812/TPP/20.242
E-pub: 03/17/2021

ABSTRACT

Background: The renal benefits of sodium–glucose cotransporter-2 inhibitors (SGLT2) are now well established, and these agents are recommended by the American Diabetes Association and Kidney Disease: Improving Global Outcomes guidelines for patients with type 2 diabetes and chronic kidney disease. However, the safety profile of SGLT2 inhibitors in chronic kidney disease is not as clear. We describe the adverse event rates of SGLT2 inhibitors, primarily empagliflozin, in Kaiser Permanente Southern California members with diabetic kidney disease.

Methods: This study was a multicenter retrospective descriptive analysis evaluating Kaiser Permanente Southern California members with type 2 diabetes and chronic kidney disease 1, 2, or 3 who first filled an SGLT2 inhibitor prescription in 2018, with follow-up through 2019. Primary outcomes were event rates of diabetic ketoacidosis, bone fracture, amputation, urinary tract infection, genital mycotic infection, hyperkalemia, and acute kidney injury. Secondary outcomes were mean changes in estimated glomerular filtration rates, serum creatine levels, urine albumin-to-creatinine ratios, and hemoglobin A1c percentages during the follow-up period.

Results: Of 213 patients, 39 experienced at least 1 adverse event, for a total of 50 adverse events. Urinary tract infection had the highest incidence (62.1 events/1000 person-years), followed by genital mycotic infection (58.0 events/1000 person-years). Favorable changes were observed during the follow-up period for urine albumin-to-creatinine ratios and hemoglobin A1c percentages, with mean decreases of 81.8 mg/g and 0.7%, respectively. SGLT2 inhibitors were discontinued in 47.4% of patients, with the top reasons including increase in serum creatinine (8%) and urinary or genital side effects (5.6%).

Conclusion: Although most patients did not experience adverse events, urinary tract infections and genital mycotic infections were more common. Our detection of rates and types of adverse effects replicated most results reported in clinical trials. Discontinuations were largely attributed to reasons other than adverse events.

INTRODUCTION

Diabetes is one of the major risk factors of chronic kidney disease (CKD).1 For the past 2 decades, angiotensin converting enzyme inhibitors and angiotensinogen II receptor blockers have been the standard treatment options to minimize the renal complications of diabetes without a main alternative.2,3

However in 2019, the US Food and Drug Administration approved a new indication for canagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor, to slow the progression of diabetic kidney disease.4 This indication was based on the Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) trial, which studied canagliflozin use in patients with type 2 diabetes and proteinuric kidney disease. The trial was discontinued early after finding significant renal and cardiovascular benefits in patients on canagliflozin.5 Other studies such as the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Canagliflozin Cardiovascular Assessment Study (CANVAS) Program have also demonstrated significant cardiovascular and renal benefits with SGLT2 inhibitor use.6,7 In addition to literature that shows renoprotective effects, these effects are likely a class benefit based on the SGLT2 inhibitor mechanism of action. This justifies our inclusion of various SGLT2 agents in our study.

The renal benefits of SGLT2 inhibitors are now well established, and these agents are recommended by the American Diabetes Association and Kidney Disease: Improving Global Outcomes for patients with type 2 diabetes and CKD.3,8 However, the adverse effect profile of these agents in the context of CKD is not as clear. Some drawbacks of SGLT2 inhibitors include multiple adverse effects, warnings for Fournier’s gangrene and lower limb amputation, as well as the financial cost.6,9

The CREDENCE trial found that adverse event rates were similar in both canagliflozin treatment and placebo groups.5 With findings from CREDENCE and other trials as a starting point, this study aimed to assess the safety profile of SGLT2 inhibitors, primarily empagliflozin, in the context of CKD. Our study describes the adverse event rates in clinical practice at Kaiser Permanente Southern California (KP SCAL), an integrated health system, with the secondary purpose of determining whether the adverse event rates in practice differ significantly from those reported in clinical trials.5-7

METHODS

Study Design

This is a multicenter retrospective analysis that evaluated the safety profiles of KP SCAL members with diagnoses of type 2 diabetes and CKD 1 [glomerular filtration rate (GFR), > 90 mL/min], CKD 2 (GFR, 60–89 mL/min), or CKD 3 (GFR, 30–59 mL/min) who first filled an SGLT2 inhibitor prescription between January 1, 2018, and December 31, 2018. These patients were followed for at least 12 months through December 31, 2019. Patients who were pregnant, younger than 18 years, or had a history of kidney transplant were excluded from the study (Figure 1).

tpj20242f1 copy

Figure 1. Flow diagram for study population formation. CKD, chronic kidney disease; KP SCAL, Kaiser Permanente Southern California; SGLT2, sodium–glucose cotransporter-2.

Data Collection and Statistical Analysis

The SGLT2 inhibitor prescription fill data for this study was retrieved from the KP SCAL CKD Registry. The data included the drug name, first SGLT2 inhibitor prescription fill date, patient demographics, and CKD stage at first prescription fill. Chart reviews were conducted by research investigators for each unique patient to collect data on adverse events and laboratory values for the follow-up period. The first laboratory values were extracted from the latest blood tests before or on the date of the first prescription fill. If the prescription was discontinued or inactivated during the follow-up period, the last laboratory value was from the latest blood test before or on the date of the last fill. If the prescription was still active, we used the most recent blood test within the follow-up period.

The main statistical method used for this study was descriptive. Adverse event rates were measured by the events per 1000 person-years to account for the duration of treatment. Event rate per 1000 person-year was determined by multiplying the number of adverse events by 1000, then dividing by the sum of the time each patient was actively on the treatment. In addition, χ2 tests were used to compare selected data with statistical significance set at P = 0.05.

Statistical methods used in landmark trials differed from those in our study.5-7 We refrained from comparing our results directly with the literature, given the limitations of our study and differences in study design.

Study Outcomes

The objective of this study was to describe the adverse event rates in KP SCAL members with type 2 diabetes and CKD stage 1, 2, or 3 on SGLT2 inhibitors. The primary outcomes of this study were the event rates of diabetic ketoacidosis, bone fracture, amputation, urinary tract infection (UTI), genital mycotic infection, hyperkalemia, and acute kidney injury. The secondary outcomes of this study were the mean changes in estimated GFRs, serum creatinine (SCr) levels, urine albumin-to-creatinine ratios (UACR), and hemoglobin A1c (HbA1c) percentages during the follow-up period. Reasons for discontinuation and their rates were also collected.

RESULTS

Patient Characteristics

After excluding 2 patients with a history of kidney transplant, the final study cohort included a total of 213 patients. Table 1 shows the baseline characteristics of the study population.

Table 1. Patient characteristics of Kaiser Permanente Southern California sodium–glucose cotransporter-2 inhibitor study population

Variable Value, N = 213
Age, y 58.9 ± 11.6
Sex, n (%)
 Male 142 (66.7)
Race, n (%)
 White 66 (31.0)
 Hispanic/Latino 64 (30.0)
 Asian 50 (23.5)
 Black or African descent 22 (10.3)
 Other/unknown 11 (5.2)
HbA1c, %, mean ± SD 8.9 ± 1.6
SCr, mg/dL, mean ± SD 1.1 ± 0.3
eGFR, mL/min/1.73 m2, mean ± SD 75.4 ± 20.9
UACR, mg/g (range)a 257.3 (0-5, 262.2)
Concomitant ACE-I or ARB, n (%) 186 (86.9)
SGLT2 inhibitor, n (%)
 Empagliflozin 209 (86.9)
 Empagliflozin–linagliptin 2 (0.9)
 Canagliflozin 1 (0.5)
 Dapagliflozin 1 (0.5)

aValue is the median albumin-to-creatinine ratio, calculated with albumin measured in milligrams and creatinine measured in grams.

ACE-I = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; SCr = serum creatinine; SD = standard deviation; SGLT2 = sodium–glucose cotransporter-2; UACR = urine albumin-to-creatinine ratio.

The mean patient age was 58, 67% of patients were male, and 31% were white. The mean HbA1c percentage was 8.9% and the mean GFR was 75 mL/min/1.73 m2. The median UACR was 257 mg/g. A total of 86.9% of patients were on angiotensin converting enzyme inhibitors or angiotensinogen II receptor blockers, and 98.1% were on empagliflozin, which is on the Kaiser Permanente formulary. Other SGLT2 inhibitor prescriptions filled included 2 patients on empagliflozin–linagliptin, 1 patient on canagliflozin, and 1 patient on dapagliflozin.

Safety Outcomes

Of the 213 patients in the study, 39 patients experienced an adverse event for a total of 50 adverse events (Figure 2). There was no trend of adverse event rate based on CKD stage (P = 0.79) (Figure 3).

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Figure 2. Number of patients who experienced 0, 1, 2, 3, and 4 adverse events (AEs) during the period of sodium–glucose cotransporter-2 (SGLT-2) inhibitor use.

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Figure 3. Overall adverse event (AE) rate during sodium–glucose cotransporter-2 inhibitor use according to chronic kidney disease (CKD) stage.

Figure 4 shows the primary outcome or individual adverse event rates in this population stratified by CKD stage. There was no observable correlation of any individual adverse event according to CKD stage (P > 0.05). The adverse event with the highest incidence was UTI (62.1 events/1000 person-years), followed by genital mycotic infection (58.0 events/1000 person-years). There was no incidence of diabetic ketoacidosis.

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Figure 4. Individual adverse event rates stratified by chronic kidney disease (CKD) stage. AKI, acute kidney injury; UTI, urinary tract infection.

During the study period, patients were on SGLT2 inhibitors for a median of 14.8 months (range, 0–24.2 months). Table 2 shows the median time to each individual adverse event. The adverse event with the longest median time to event was bone fracture (19.1 months), whereas the event with shortest median time to event was genital mycotic infection (3.9 months).

Table 2. Median time to adverse event from first fill of sodium–glucose cotransporter-2 inhibitor

Adverse event Mean time to event, mo (range), N = 213
Bone fracture 19.1 (5.4–22.2)
Acute kidney injury 10.8 (3.4–25.0)
Amputation 10.7 (3.6–14.1)
Urinary tract infection 7.3 (0.3–22.2)
Hyperkalemia 5.5 (0–14.3)
Genital mycotic infection 3.9 (0.2–11.5)

Effectiveness Outcomes

Table 3 shows the secondary outcomes or mean changes in estimated GFRs, SCr levels, UACRs, and HbA1c percentages during the follow-up period from first fill of the medication to the last fill. Favorable changes were observed in UACRs and HbA1c percentages, with mean decreases of 81.8 mg/g and 0.7%, respectively. However, direct improvements in estimated GFRs or SCr levels were not observed.

Table 3. Mean changes in estimated glomerular filtration rate, serum creatinine level, urine albumin-to-creatinine ratio, and hemoglobin A1c percentage

Parameter Change (mean ± standard deviation), N = 213
Estimated glomerular filtration rate (mL/min/1.73 m2) –5.3 ± 1.1
Serum creatinine (mg/dL) +0.1 ± 0.1
Urine albumin-to-creatinine ratio (mg/g) –81.8 ± 23.9
HbA1c (%) –0.7 ± 0.1

SGLT2 inhibitors were discontinued based on patient or provider preference in nearly half the study population (47.4%), with the top reasons including increase in SCr (8%), urinary or genital side effects (5.6%), other side effects/intolerances (6.6%), and unknown (6.1%) (Table 4).

Table 4. Discontinuation rate and time to discontinuation of sodium–glucose cotransporter-2 inhibitor

Reason for discontinuation n (%) Median time to discontinuation, mo (range)
Increase in creatinine 17 (8.0) 8.3 (0–17.2)
Other side effect/intolerance 14 (6.6) 8.5 (0.2–15.6)
Unknown 13 (6.1) 8.5 (0.9–16.8)
Urinary or genital side effects 12 (5.6) 8.5 (0.2–15.6)
Drug coverage/cost 10 (4.7) 8.4 (1.3–18.5)
Ineffective therapy 9 (4.2) 8.1 (0.7–16.7)
Patient request 9 (4.2) 8.3 (0.5–16.6)
Other reason 9 (4.2) 8.4 (3.4–19.7)
Nonadherence 7 (3.3) 8.6 (6.1–21.0)
Allergic reaction 1 (0.5) 2.3 (n/a)
Total 101 (47.4)  

DISCUSSION

As KP SCAL is a large, integrated health system, chart reviews of the patient health data allowed a comprehensive assessment of patients’ experiences after initiation of SGLT2 inhibitors. This study found that most patients with diabetic kidney disease on SGLT2 inhibitors did not experience adverse events, with 50 adverse events experienced by 39 patients, or 18.3% of the total study population. This rate may have been affected by multiple contributing factors, some of which were not accounted for in this observational review of clinical practice.

In addition, when the adverse event rates were stratified by CKD stage, they did not differ between stages 1, 2, and 3. This points to an SGLT2 inhibitor adverse event profile in CKD patients that is potentially similar to the rates in published studies that include patients without CKD. Although further studies are needed to establish this similarity, the adverse event profile of patients without CKD may possibly be extrapolated with more confidence to those with CKD given the observations in our study.

The highest incidence of adverse events was observed with UTIs, followed by genital mycotic infections. Type 2 diabetes increases the risk of UTIs and genital infections as a result of elevated levels of urinary glucose. In addition, the current evidence from randomized controlled trials shows that SGLT2 inhibitors increase the risk of genital infections.10 Despite the absence of a placebo group in this study, landmark trials show that UTIs and genital mycotic infections had high incidences overall in both placebo and treatment groups, although rates in treatment groups were greater. Further investigation is necessary to determine the significance of the difference between the reports of adverse events in this study population compared to placebo.

The median time to the occurrence of each adverse event was also analyzed. Adverse events experienced earlier include genital mycotic infection (3.9 months) and hyperkalemia (5.5 months), whereas those experienced later include acute kidney injury (10.8 months) and bone fracture (19.1 months) (Table 2). Most of the bone fractures occurred secondary to falls, and not all cases were in patients at high risk for fracture. One patient experienced hyperkalemia on the day of first SGLT2 inhibitor prescription fill, although medical documentation did not attribute the hyperkalemic event to the SGLT2 inhibitor.

In addition, correlation was observed between SGLT2 inhibitor use and improvement in UACRs and HbA1c percentages (Table 2). Despite no apparent improvement in GFRs or SCr levels, it would be valuable to assess whether there was a slower rate of decline in renal function compared to a placebo group or data from literature, as this was the case in the CREDENCE trial.5

Nearly half (47.4%) of the study’s patients discontinued SGLT2 inhibitors, with 20.2% of these discontinuations attributed to an adverse event (Table 4). Several of these adverse events included self-reported symptoms that were documented by providers and may not have correlated with laboratory results or physical exams. In addition, SGLT2 inhibitors were often discontinued independently by the patient because of other reasons, such as reported adverse reactions, fear of adverse events, and the financial cost of higher copays compared to other diabetic agents. Although most reported side effects were expected of SGLT2 inhibitors, others included numbness/tingling, severe muscle cramps, swelling, and headache.

Table 5 shows our study’s results alongside the adverse event data in EMPA-REG OUTCOME CREDENCE, and CANVAS Program.5-7 Our study population’s renal function and use of empagliflozin were most similar to that of EMPA-REG. Therefore, our study’s adverse event rates were plotted alongside those of EMPA-REG’s treatment and placebo groups (Figure 5). The P values reflect the significance in difference between this study and the EMPA-REG treatment group. Comparing the 2 groups shows a significantly higher rate of UTIs (P < 0.001) and a lower rate of acute kidney injury (P = 0.001) in EMPA-REG’s treatment group than our clinical practice group. The discontinuation rate in this study was also higher than the rates in landmark trials. However, limitations in this direct comparison include different study designs, baseline characteristics, study duration, and nuances in the way the adverse events were defined by the study protocols.

Table 5. Comparison of Kaiser Permanente Southern California adverse event rates with landmark trials

Patient Characteristics and Adverse Events KP SCAL EMPA-REG Outcome CREDENCE Trial CANVAS Program  
Drug Empagliflozin Empagliflozin Canagliflozin Canagliflozin  
Renal function of study population CKD 1–3 eGFR ≥ 30 mL/min CKD 2–3 eGFR ≥ 30 mL/min  
UACR > 300 mg/g  
Urinary tract infectiona 62.1 19.7% 48.3 40.0  
7.0% 6.9%  
Genital mycotic infectiona 58.0 6.4% 8.4–12.6 68.8 (female)  
6.6% 1.9%–2.9%  
Hyperkalemiaa 29.0 N/A 29.7 6.9  
6.9%  
3.3%  
Acute kidney injurya 29.0 1.0% 16.9 3.0  
3.3% 3.9%  
Amputationa 16.6 N/A 12.3 6.3  
1.9% 3.2%  
Bone fracturea 12.4 3.8% 11.8 15.4  
1.4% 3.0%  
Diabetic ketoacidosisa 0 0.1% 2.2 0.6  
0.5%  
0%  

a.Row 1 expresses adverse event rate as event rate per 1000 person-years; row 2 expresses adverse event rate as a percentage.

CANVAS = Canagliflozin Cardiovascular Assessment Study; CKD = chronic kidney disease; CREDENCE = Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; eGFR = estimated glomerular filtration rate; EMPA-REG Outcome = Empagliflozin Cardiovascular Outcome Event Trial; KP SCAL = Kaiser Permanente Southern California; N/A = not applicable; UACR = urine albumin-to-creatinine ratio.

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Figure 5. Comparison of adverse event rates with those in the Empagliflozin Cardiovascular Outcome Event Trial (EMPA-REG OUTCOME), with P values reflecting the significance of the difference between adverse event rates of the Kaiser Permanente Southern California (KP SCAL) and EMPA-REG OUTCOME treatment groups. AKI, acute kidney injury; DKA, diabetic ketoacidosis; PBO, placebo; UTI, urinary tract infection.

Limitations

The findings of this study should be viewed in the context of several limitations. First, the study design did not include a comparator group, and the results were mostly reflective of empagliflozin, which is the preferred SGLT2 agent on the Kaiser Permanente formulary because of cost relative to other drugs. In addition, although rough comparisons to placebo can be drawn from landmark trials such as the EMPA-REG Outcome trial, there are limitations in this type of direct comparison resulting from differences in study design, baseline characteristics, study duration, and nuances in the way the adverse events were defined by the study protocols. There were also inconsistencies among patients in the timing of laboratory results relative to the first or last fill, and up to 25% of our patients had no repeat labs after their first prescription fill. Because of limited access to data, certain time periods and duration of exposures could not be extracted in select cases. Last, confounding variables include other comorbidities or patient factors, as well as concomitant antidiabetic agents; these factors were not accounted for in this study.

Future Implications

With this SGLT2 inhibitor safety profile data drawn directly from clinical practice, health-care providers now have the ability to expand confidently on the prescription of SGLT2 inhibitors, inform on the benefits of SGLT2 inhibitors in diabetic kidney disease, educate accurately on the risk of adverse events, provide counseling points, and recommend continued use of these agents for renal benefits. For instance, patients and providers can expect and monitor for genital infections and UTIs as earlier and more common adverse events. In doing so, health-care systems can shift prescribing patterns to target patients with diabetic kidney disease who would likely benefit from SGLT2 inhibitor therapy, ultimately improving patient outcomes.

CONCLUSION

In conclusion, most of the patients in this study did not experience adverse events, and the patients who did were more likely to have experienced UTIs or genital mycotic infections. In addition, compared to landmark clinical trials, our data in a real-world setting showed similar rates and types of adverse events. Accordingly, the notable discontinuation rate was attributed largely to reasons outside of adverse events. The discontinuation rate in this study was greater than those reported in landmark trials, but we must exercise caution in drawing conclusions around this comparison, given the varying study designs, durations, and documentation methods. Based on our data, SGLT2 inhibitors should be considered for more widespread use in patients with type 2 diabetes and CKD.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

Author Affiliations

1Pharmacy Administration, Kaiser Permanente West Los Angeles Medical Center, Los Angeles, CA

2Department of Nephrology, Kaiser Permanente West Los Angeles Medical Center, Los Angeles, CA

Corresponding Author

Hanul Choi, PharmD ()

Author Contributions

Hanul Choi, PharmD, led the study design, acquisition and analysis of data, drafting, critical review, and submission of the final manuscript. Leigh Anh Nguyen, PharmD, and Jong C Park, MD, participated in the study design, acquisition and analysis of data, and critical review of the manuscript. Jenny Wan, PharmD, BCPS, Hooman Milani, PharmD, and Kristine McGill, PharmD, BCPS, participated in the study design, analysis of data, and critical review of the manuscript. All authors participated in final approval of the version to be published.

Funding

No funding was acquired for this study.

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10. Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: A systematic review and meta-analysis. Sci Rep 2017 Jun;7(1):2824. DOI: https://doi.org/10.1038/s41598-017-02733-w, PMID:28588220.

Keywords: adverse events, CKD, diabetes, renal, SGLT2 inhibitors

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