The Effect of Dapagliflozin on Renal Disease Progression

There is a potential role in using dapagliflozin in patients with CKD. 

Chronic kidney disease (CKD) affects around 700million people worldwide and is linked to a decreased quality of life and increased mortality rates. To date, only angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are proven to have renal protective outcomes in patients with type 2 diabetes mellitus (T2DM). Favorable effects were also reported with sodium-glucose cotransporter 2 (SGLT2) inhibitors in cardiovascular and renal outcomes. In the CREDENCE trial, the results showed that long term use of canagliflozin provides cardiovascular and renal protection in patients with T2DM. The exact mechanism is not well known, but it is suggested that the overall effect of SGLT2-inhibitors on sodium and glucose excretion may reduce intraglomerular pressure, leading to renal preservation in patients with CKD.  

This study aimed to assess the long-term effect of dapagliflozin in patients with CKD, regardless of whether they have T2DM or not. The study was a randomized, double-blind, placebo-controlled trial. It was carried out in multiple centers in 21 countries from Feb 2017 to June 2020. It included adults with an eGFR of 25-75ml/min/1.73m2 and albumin(mg)-to-creatinine(g) ratio of 200-5000. Patients must also be on a stable dose of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) 4 weeks before enrollment. Patients with a history of intolerance to ACE-I or ARBs were included in the study. Patients excluded were those with T1DM, lupus nephritis, an antineutrophil cytoplasmic antibody-associated vasculitis, polycystic kidney disease, or use of immunotherapy six months before enrolment. Patients were enrolled to receive dapagliflozin 10mg daily or placebo at a 1:1 ratio. 

The primary outcome was set to be the time for the first event. The events are defined as a 50% reduction in eGFR, development of an end-stage renal disease, renal transplant, or mortality due to cardiovascular or renal disease. Secondary outcomes were defined as a sustained reduction of renal function in addition to the safety outcomes.  

Around 4,304 patients were randomized. Participants had similar baseline characteristics between the study groups. The average eGFR was 43.1ml/minute/1.73 m2, with an average albumin-to-creatinine ratio of 949. Around 67.5% of patients had T2DM. The average follow-up period was 2.4 years. 

In terms of the efficacy outcomes, around 9.2% had one of the pre-defined events in the dapagliflozin group, while 14.5% had those events in the placebo group (HR ratio, 0.61; 95% CI, 0.51-0.72; P<0.001). Most of the events were less reported with dapagliflozin compared to the placebo. Similar outcomes were reported between patients with T2DM and those without it (HR=0.64, 95% CI, 0.52-0.79) and (HR=0.50, 95% CI, 0.35-0.72).  

Secondary outcomes in the dapagliflozin group were significantly lower than the placebo (HR=0.56, 95% CI, 0.45-0.68; P<0.001). Also, cardiovascular and renal related mortality and hospital admissions were significantly less than placebo (P=0.009).  

The reduction in eGFR from the beginning of the study was initially faster in the dapagliflozin group than a placebo within two weeks of treatment. It showed around a -3.97ml/minute/1.73m2 in the dapagliflozin group and -0.82ml/minute/1.73m2 in the placebo group. However, over 30 months of follow-up showed that, overall, dapagliflozin had a lower reduction in eGFR (-2.86 ml/minute/1.73m2/year) than placebo (-3.79 ml/minute/1.73m2/year). It was considered a statistically significant difference between the groups (95% CI, 0.61-1.25).  

Regarding the safety outcomes, the rates of side effects were not significantly different between the groups. Only two patients experienced diabetic ketoacidosis (DKA), and those were in the placebo group. Among the placebo group, DKA was reported only in patients with T2DM. No severe hypoglycemia was reported. One patient experienced Fournier‘s gangrene in the placebo group.  

Similar findings were reported in the CREDENCE trial. Both trials have shown that SGLT2 inhibitors provide cardiovascular and renal protective outcomes when compared to placebo. Although different drugs were used in those trials with varying cut-offs for eGFR, the results showed that SGLT2 inhibitors as a class help maintain renal function from declining further and reduce mortality rates regardless of a diabetes diagnosis.  

One limitation of the trial is the lack of eGFR monitoring after stopping dapagliflozin. It would have been necessary to address to assess whether the initial reduction of eGFR in the dapagliflozin group was reversible or not.  

Practice Pearls: 

• Dapagliflozin has renal protective effects evident by the reduced rate of eGFR decline. 
• The renal protective outcomes were not linked to T2DM diagnosis. 
• Overall, dapagliflozin is well tolerated by patients. 

Heerspink, Hiddo J.L. et al. “Dapagliflozin In Patients With Chronic Kidney Disease.” New England Journal Of Medicine, vol 383, no. 15, 2020, pp. 1436-1446.  

Perkovic, Vlado et al. “Canagliflozin And Renal Outcomes In Type 2 Diabetes And Nephropathy”. New England Journal Of Medicine, vol 380, no. 24, 2019, pp. 2295-2306.  

Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences 

See more about how dapagliflozin and other SGLT2 inhibitors affect CKD and other conditions in our therapy center.