SGLT2 Inhibitors: What Role in Nephroprotection?

Since sodium glucose cotransporter 2 (SGLT2) inhibitors rely on the glomerulus to filter urine, their ability to lower blood glucose is limited in patients with type 2 diabetes who have chronic kidney disease (CKD). On the other hand, there is some research to suggest that use of SGLT2 inhibitors may confer some degree of nephroprotection.

Which raises a question:  what role do SGLT2 inhibitors play in the treatment of patients with diabetic nephropathy?

The nephroprotective potential of SGLT2 inhibitors was the topic of a recent review article in the American Journal of Kidney Disease.¹ SGLT2 inhibitors could slow the progression of diabetic nephropathy, the review suggested, by decreasing glomerular hyperfiltration, hyperglycemia-related tubular growth, kidney hypertrophy, and inflammation and fibrosis implicated in the development of diabetic nephropathy. 

Currently most evidence on the nephroprotective potential of SGLT2 inhibitors comes from animal studies suggesting that SGLT2 inhibitors suppress renal hyperfiltration independent of their effect on blood glucose levels. Conversely, the ability of SGLT2 inhibitors to reduce kidney growth and injury seems to depend on their glycemia-lowering effects. Inflammatory and fibrotic responses resulting from high glucose levels could also be decreased by SGLT2 inhibition, likely by blocking glucose entry into the cell.

While evidence from clinical trials has been hindered by short-term follow-up, some studies have found lower albumin excretion and beneficial effects on eGFR with SGLT2 inhibitor therapy, and seem to support their potential role in nephroprotection. Most recently, results from a phase 2/3 clinical trial looking at longer-term efficacy of dapagliflozin in patients with moderate renal impairment suggested that the treatment group fared better than controls on certain measures of renal function over 104 weeks of treatment.²

The randomized, double-blind, placebo-controlled trial took place at 111 sites in 13 countries in Europe, the Americas and Asia, where patients were enrolled between June 2008 and May 2009.

The Study, in Brief

   -252 patients with T2DM, baseline A1c 8.2-8.5; moderate renal impairment (eGFR, 30 to 59 ml/min)

   -Treatment: dapagliflozin 5- or 10-mg daily, vs placebo

   -24 weeks of initial short-term treatment

   -Those completing 24 weeks were eligible to continue for an additional 28 weeks

   -Those completing 52 weeks could continue for an additional 52 weeks (104 weeks total)

   -Rescue medication was available if fasting plasma glucose (short-term phase) or A1c (longer-term phases) rose above predetermined limits

Key Results at 104 Weeks

139 participants completed all 104 weeks

A1c change from baseline: Not statistically significant, compared to placebo (-0.41% and -0.44% for 5- and 10-mg doses, respectively, vs. -0.32% for placebo.)

Mean weight change: -1.54 and -1.89 kg for 5- and 10- mg doses, respectively, vs +0.21kg for placebo

Blood pressure change: Mean diastolic and systolic blood pressure decreased mildly compared to placebo

eGFR: After 1 week of treatment mean eGFR fell, but thereafter remained roughly unchanged or increased slightly up to 104 weeks; eGFR slowly declined in the placebo group througout this time period.

Microalbuminuria: Patients in the treatment group were more likely to regress to a lower albumin excretion category than placebo.

Adverse effects: 7.7% of patients treated with dapagliflozin had bone fractures, while none in the placebo group did.

"Improvement of glycemic measures with dapagliflozin in this population was not statistically significant because of the inadequate renal function in these patients,” the authors concluded. “The reduced glucose excretion in this population still appears sufficient to account for the weight loss and blood pressure reduction … The imbalance in fractures raises a safety question specific to patients with advanced stage (3B or greater) CKD, and calls for further study of the issue.”

In an accompanying editorial, Richard E. Gilbert, MD, Research Chair in Diabetes Complications of the Canadian Diabetes Association, pointed out the surprising similarity between reductions in A1c of 0.41-0.44% in the treatment group, and the 0.32% drop in the placebo group, which could be related to methodological issues inherent in what he terms “the perils of clinical trials.” ³

Moreover, Gilbert highlights the initial drop in eGFR in the treatment group. In the following 100 weeks, eGFR slowly fell in the placebo group, while it stabilized and even rose slightly in the treatment group. He noted that the initial fall in eGFR in the treatment group could be related to mild volume depletion, while the longer-term results could suggest possible nephroprotective effects in SGLT2 inhibitors similar to that seen with ACE inhibitors.

“Although potentially of great interest, it would be a mistake to instigate SGLT2 inhibitor therapy in the hope of long-term renoprotection,” Gilbert emphasized. “Such an eventuality would require a solid evidence base from clinical trials, designed specifically to test that hypothesis.”

“The significance of [the use of SGLT2 inhibitors] in overall CKD progression is unclear,” agreed George Bakris, who has special expertise in the treatment of diabetic nephropathy and is Professor of Medicine and Director of the Comprehensive Hypertension Center at the University of Chicago. “Reduced filtration will [also] occur with better glycemic control. The concept of nephroprotection remains to be proven and the ongoing Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial will address this issue,”

The CREDENCE trial⁴ was launched in February 2014 by Janssen Research and Development and is a randomized, double-blind, placebo-controlled, Phase 3 trial intended to assess whether canagliflozin can slow the progression of diabetic nephropathy.

“SLGT2 agents are very useful to lower glucose levels in people with diabetes.  However only one [canagliflozin] is approved for use down to eGFR of 45 ml/min,” Bakris emphasized, while also noting that the safety issue of greatest concern coming out of this trial was the increased number of fractures in the treatment group compared to controls. “I would say that [my colleagues who] have studied and used SGLT2 inhibitors are generally quite enthusiastic. Those who have not tried [this drug class] or are waiting for more data are cautiously optimistic. [Personally] I think that this class is very promising and quite useful as it manages major risk factors in addition to glucose control.” 

Though SGLT2 inhibitors may hold promise for slowing the progression of diabetic nephropathy, time will tell whether research supports this protective potential.

For the time being, then, clinicians may need to be satisfied with the benefits substantiated so far:  better glycemic control in those with normal to mild renal impairment, as well as mild weight loss and reduced blood pressure, but with the drawbacks of increased risk for genital mycotic infections and possibly increased number of fractures.

References:

• De Nicola L, Gabbai FB, Lierti ME, Sagliocca A, Giuseppe C, Minutolo R.  Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.  Am J Kidney Dis.  2014. doi:  10.1053/j.ajkd.2014.02.010
• Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control.  Kidney Int. 2014;85:962-971. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973038/pdf/ki2013356a.pdf
• Gilbert RE. The perils of clinical trials.  Kidney Int. 2014;85:745-747.
• Janssen Initiates CREDENCE Study in Patients with Type 2 Diabetes and Diabetic Nephropathy.  Accessed May 5, 2014 at:http://www.investor.jnj.com/releasedetail.cfm?ReleaseID=827412