By: Lina Le, Pharm.D. Candidate 2020 – University of North Texas System College of Pharmacy
As we know, uncontrolled diabetes mellitus can lead to nephropathy and have the risk of progressing to end-stage renal disease (ESRD).1 Approximately 40% of patients with diabetes will develop kidney disease in their lifetime.1 Sodium-glucose cotransporter (SGLT)-2 inhibitors, empagliflozin (Jardiance®) and canagliflozin (Invokana®), have gained recent attention with emerging evidence of their renoprotective benefits. In light of the new evidence from the EMPA-REG and CANVAS trials, the American Diabetes Association (ADA) now suggests the use of SGLT-2 inhibitors as an add-on agent in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).2 Additionally, the CREDENCE trial, which analyzed the effects of canagliflozin on outcomes of ESRD, doubling of the serum creatinine (SCr) level, or death from renal in patients with T2DM and albuminuric CKD, resulted this past April with additional evidence for renal benefits.3
Historically, the ADA and Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with diabetes and nephropathy for blood pressure control and kidney disease progression prevention.2,4 ACE inhibitors and ARBs cause efferent glomerular arteriole vasodilation, which in turn decreases intraglomerular pressure and albuminuria.4 Studies have supported these recommendations and have shown that ACE inhibitors and ARBs significantly reduce proteinuria, SCr, and renal-related deaths.5,6
So how does the mechanism of SGLT-2 inhibitors compare to ACE inhibitors and ARBs for use in renoprotection? In terms of glycemic control, we know that SGLT-2 inhibitors increase urine glucose excretion to regulate blood glucose by blocking SGLT receptors in the proximal renal tubules to facilitate a reduction in glucose reabsorption.7 The proposed mechanism behind SGLT-2 inhibitors and their effects on renal function is related to decreased glomerular hyperfiltration.7 Glomerular hyperfiltration is a hallmark indication of early renal damage, defined as eGFR greater or equal to 135 mL/min/1.73m2.7 Hyperfiltration occurs due to excessive blood glucose, leading to increased glucose and sodium chloride (NaCl) renal reabsorption.7 This causes decreased NaCl delivery to the macula densa of the distal tubule, causing renal vasodilatory response to increase NaCl delivery to the distal tubules and maintain hemodynamic stability.7 Renal vasodilation results in hyperfiltration, increased glomerular pressure, and kidney injury.7 SGLT-2 inhibitors decrease glucose reabsorption to restore NaCl delivery to the distal tubules and hemostasis to the kidneys.7 Decreased hyperfiltration and pressure within the glomerulus may serve to decrease albuminuria and slow the progression of kidney disease.7 With that being said, do the results from the clinical trials of empagliflozin and canagliflozin reflect this hypothesis?
The EMPA-REG trial conducted a post-hoc analysis for renal outcomes in patients with diabetes, existing cardiovascular disease (CVD), and eGFR of >30 mL/min/1.73m2.8 Wanner and colleagues found that empagliflozin significantly reduced the incidences of worsening nephropathy, progression to macroalbuminuria (> 300 mg of albumin per gram of creatinine), doubling of SCr level accompanied by eGFR < 45 mL/min/1.73m2, and initiation of renal replacement therapy (RRT) in comparison to placebo (Table 1).8 In addition, the CANVAS trial saw significant reductions in the progression to albuminuria and increased regression of albuminuria with use of canagliflozin versus placebo (Table 2).10
The CREDENCE trial observed the effects of canagliflozin on end stage renal outcomes in patients with diabetes and existing albuminuric CKD, including participants with eGFR of 30 to 89 mL/min/1.73m2.3 When compared to EMPA-REG and CANVAS, participants in CREDENCE were also required to be on standard therapy of an ACE inhibitor or ARB.3 Primary outcome measures were a composite of kidney transplantation, eGFR < 15 mL/min/1.73m2 for 30 days, dialysis for 30 days or more, doubling of SCr levels from baseline for 30 days, and death from cardiovascular or renal disease (Table 3).3 In the canagliflozin group, there was 4% absolute risk reduction for the primary composite.3
Despite recent evidence, manufacturer labeling endorses the initiation or continuation of empagliflozin and canagliflozin in patients with T2DM and an eGFR >45 mL/min/1.73m.9,11 However, the results with respect to renal outcomes have influenced the ADA to comment on the use of empagliflozin and canagliflozin to an eGFR of >30 mL/min/1.73m2, especially favored in patients with macroalbuminuria.2
SGLT-2 inhibitors have come a long way since canagliflozin first came onto the market in 2013 with indications for treatment of T2DM.11 Jardiance® and Invokana® have gained FDA approved indications for risk reduction of major cardiovascular events in patients with T2DM.9,11 So, what does the future hold for SGLT-2 inhibitors? One pending study, estimated to complete in December 2019, hypothesizes that dapagliflozin (Farxiga®) reduces proteinuria in patients without diabetes (Clinicaltrials.gov Identifier: NCT03190694). Will the use of the SGLT-2 inhibitor drug class expand beyond glycemic control of T2DM and will the FDA approve indications for use in diabetic nephropathy next?
|Empagliflozin 10 mg, 25 mg, versus placebo|
|Renal outcomes||Empagliflozin||Placebo||Hazard Ratio
|Incidence of worsening nephropathy||525/4124||388/2061||0.61 (0.53-0.70)||<0.001|
|Progression to macroalbuminuria||459/4091||330/2033||0.62 (0.54-0.72)||<0.001|
|Doubling of SCr level accompanied by eGFR <45 mL/min/1.73m2||70/4645||60/2323||0.56 (0.39-0.79)||<0.001|
|Initiation of Renal Replacement Therapy||13/4687||14/2333||0.45 (0.21-0.97)||0.04|
|Canagliflozin 100 mg versus placebo|
|Renal Outcomes||Canagliflozin (per 1000 patient-years)||Placebo (per 1000 patient-years)||Hazard Ratio
|Regression of albuminuria||293.4||187.5||1.70 (1.51-1.91)||0.4587|
|Progression of albuminuria||89.4||128.7||0.73 (0.67-0.79)||0.0184|
|Canagliflozin 100 mg versus placebo|
|Renal Outcomes||Canagliflozin||Placebo||Hazard Ratio
|Primary composite*||245/2202||340/2199||0.70 (0.59-0.82)||0.00001|
|Doubling of SCr level||118/2202||188/2199||0.60 (0.48-0.76)||<0.001|
|End-stage kidney disease||116/2202||165/2199||0.69 (0.54-0.86)||0.002|
|eGFR <15 mL/min/1.73m2||78/2202||125/2199||0.60 (0.45-0.80)||N/A|
|Initiation of dialysis or kidney transplantation||76/2202||100/2199||0.74 (0.55-1.00)||N/A|
*Primary composite outcomes: end-stage renal disease (ESRD), doubling of the serum creatinine level, or death from renal or cardiovascular causes
- de Boer IH. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011;305(24):2532.
- Microvascular complications and foot care: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2018;42(Supplement 1):S124-S138.
- Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Eng J Med. 2019;380(24):2295-2306.
- Chapter 2: Lifestyle and pharmacological treatments for lowering blood pressure in CKD ND patients. Kidney Int Suppl. 2012;2(5):347-356.
- Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Eng J Med. 2001;345(12):861-869.
- Lioudaki E, Whyte M, Androulakis E, Stylianou K, Daphnis E, Ganotakis E. Renal effects of SGLT-2 inhibitors and other anti-diabetic drugs: clinical relevance and potential risks. Clin Pharmacol Thera. 2017;102(3):470-480.
- Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme Inhibition on diabetic nephropathy. N Eng J Med. 1993;329(20):1456-1462.
- Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–597.
- Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Eng J Med. 2016;375(4):323-334.
- Jardiance (empagliflozin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; October 2018.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Eng J Med. 2017;377(7):644-657.
- Invokana (canagliflozin) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals; October 2018.
Mentored by: Megan Wesling, Pharm.D., BCPS