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Cardiovascular and Kidney Outcomes when Discontinuing SGLT-2 Inhibitor

Jul 3, 2021
 
Editor: Steve Freed, R.PH., CDE

Author: Alan Martinez, PharmD Candidate, University of South Florida Taneja College of Pharmacy

Is discontinuing SGLT-2 inhibitor therapy necessary if there is an immediate decline in estimated Glomerular Filtration Rate (eGFR) in patients? 

SGLT-2i have beneficial cardiovascular and kidney effects in patients with type 2 diabetes, but they also have been known to cause a dip in eGFR after patients begin therapy. The eGFR dip typically occurs within six months from initiation of treatment and eventually returns to baseline eGFR. The purpose of this study is to evaluate if there is a risk reduction, specifically with cardiovascular and kidney outcomes, in patients that continue to use SGLT-2i versus those who discontinue the therapy after observing the eGFR dip.  

 

The cohort design of this study involved retrieving patient data from the Veterans Affairs Health Care System between October 1, 2015, and July 31, 2019. The data were further categorized into two groups. The first group had patients who received an SGLT-2i prescription (n=36,638). The second group (n=209,025) consisted of two subgroups, patients who did not receive an SGLT-2i drug and patients who already had non-SGLT-2i antihyperglycemic medication that either added on or switched to another non-SGLT-2i antihyperglycemic prescription. The study population mainly consisted of white males with an average age of 65 years. The significant outcomes of interest included the number of SGLT-2i users with an eGFR dip, and if discontinuation of the SGLT-2i occurred. Also, how that affected cardiovascular outcomes (non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure or all-cause mortality), and kidney outcomes (eGFR decline > 50% from treatment initiation, end-stage kidney disease, or all-cause mortality).   

After the data was analyzed, results showed that less than half of the patients with an SGLT-2i did experience an eGFR dip within six months of starting therapy, with only 6.35% of those experiencing a dip > 30%. On that note, a dip >30% had the highest SGLT-2i discontinuation rate of 29.58 per 100 patients [95% Confidence Interval (CI): 27.72-31.43]. For adjusted rates, the excess rate of eGFR dip >10% was 9.86 per 100 users, while for an eGFR dip >30% was 1.15 per 100 users. The effects of eGFR dips on both cardiovascular and kidney outcomes resulted in a total effect size of 0.92 and 0.78. Additionally, the extent that the protective benefits negated by the eGFR dip >10% were below 5% and 2% for an eGFR dip >30% for both outcomes. This suggested that the protective benefits of SGLT-2i were minimally affected despite the eGFR dips.  

Prevalence of SGLT-2 Inhibitor Users Based on Dip Category  

  • No eGFR Dip – 20,458 (55.84%) 
  • eGFR Dip 10% to 30% – 13,850 (37.81%)  
  • eGFR Dip > 30% – 2326 (6.35%) 

Adjusted Rates of eGFR Dip >10% in the first six months 

  • Excess Rate per 100 Patients Associated with SGLT-2i (95% CI) 
    • 9.86 (8.83 – 11.00) 

Adjusted Rates of eGFR Dip >30% in the first six months 

  • Excess Rate per 100 Patients Associated with SGLT-2i (95% CI) 
    • 1.15 (0.70 – 1.62) 

Hazard Ratio of Total Effect Accounted for eGFR Dip (95% CI) 

  • Composite Cardiovascular Outcome 
    • 0.92 (0.84 – 0.99) 
  • Composite Kidney Outcome 
    • 0.78 (0.71 – 0.87) 

Magnitude of Effect Abrogated by eGFR Dip 

  • Composite Cardiovascular Outcome 
    • eGFR Dip >10% – 3.78% (2.22% – 5.44%) 
    • eGFR Dip >30% – 1.18% (0.62% – 2.22%) 
  • Composite Kidney Outcome 
    • eGFR Dip >10% – 4.76% (3.17% – 6.85%) 
    • eGFR Dip >30% – 1.66% (0.87% – 3.01%) 

 The study demonstrated that eGFR dips within six months of starting SGLT-2i therapy did not heavily reduce the beneficial cardiovascular and kidney outcomes of SGLT-2i. Thus, the continuation of treatment is suggested over discontinuing the SGLT-2i treatment regardless of any dip. The study did show that in patients that had an eGFR dip >30%, there was an increased likelihood that discontinuation of SGLT-2i was done. A limitation of the study includes possible limited generalizability due to the study population mainly consisting of elderly white males. Another limitation is that empagliflozin is the SGLT-2i of choice at the VA, constituting over 97% SGLT-2i use. The clinical implication this study can have within patient care is a more significant reduction of cardiovascular and kidney complications when continuing SGLT-2i, even if an eGFR dip occurs.     

Practice Pearls: 

  • For patients that used SGLT-2 inhibitors, 44.16% experienced an eGFR dip >10%. 
  • Dips >30% were associated with the discontinuation of SGLT-2 inhibitors.  
  • Continuation of SGLT-2 inhibitors despite an eGFR dip within six months of therapy reduced the risk of cardiovascular and kidney outcomes. 

 

Xie, Yan et al. “Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium-Glucose Cotransporter-2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes.” Journal of the American Heart Association vol. 10,11 (2021):  

 

Alan Martinez, PharmD Candidate, University of South Florida Taneja College of Pharmacy 

 

 

 

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