This article is more than 5 years old. Information may no longer be current.
Should SGLT2 inhibitors be used in the treatment of diabetic nephropathy?
Click Here to Manage Email Alerts
Click here to read the Cover Story, "New agents, novel targets show promise for diabetic kidney disease."
The available evidence for cardiovascular and kidney protection, coupled with the balance of risks, favors use of an SGLT2 inhibitor in early type 2 diabetes nephropathy in addition to renin-angiotensin-aldosterone system blockade.
The addition of an SGLT2 inhibitor is conceptually attractive to treat type 2 diabetes nephropathy via a distinct mechanism, reducing resorption of glucose and sodium in the proximal tubule, increasing distal tubule sodium delivery to the macula densa, thereby reducing glomerular pressure through tubuloglomerular feedback. Thus, SGLT2 inhibitors also reduce weight and blood pressure (4-6 mm Hg) via osmotic diuresis and natriuresis.
Heerspink and colleagues showed that canagliflozin (Invokana, Janssen) 100 mg or 300 mg daily, compared with glimepiride, added to metformin in 1,450 individuals with type 2 diabetes significantly slowed the loss of estimated glomerular filtration rate and attenuated albuminuria during a mean 2-year study period, independent of glycemic control (J Am Soc Nephrol. 2017;doi:10.1681/ASN.2016030278). Prespecified, secondary outcomes from the EMPA-REG Outcome trial of 7,020 participants with type 2 diabetes showed significant improvements in the empagliflozin (Jardiance, Boehringer Ingelheim and Eli Lilly) 10-mg or 25-mg daily groups vs. standard care, with a 39% reduction for incident or worsening nephropathy, 1.5% vs. 2.6% doubling of the serum creatinine and 0.3% vs. 0.6% renal replacement therapy. Importantly, the cohort included participants with pre-existing CVD, of whom 80.7% were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. As expected based on the mechanism, STLG2 inhibitor therapy reduced adjusted mean eGFR initially with a nadir at study week 4 before stabilizing so that there was a 4.7 mL/min/1.73 m2 higher eGFR in the empagliflozin groups vs. controls after 3.1 years. Reducing vascular risk is also a major goal of chronic kidney disease management, which is supported by the significant 14% reduction in the primary composite CV outcome associated with empagliflozin, even though the HbA1c difference between the randomized groups was marginal by design. The yet-to-be published outcomes of the canagliflozin CANVAS-R6 and dapagliflozin (Farxiga, AstraZeneca) DECLARE7 trials will help determine whether CV risk reduction for high-risk type 2 diabetes is an SGLT2 class effect or not.
Risks of the SGLT2 inhibitors include acute kidney injury and urinary and genital infections. Moreover, canagliflozin increases risk for bone fractures and decreases bone mineral density. The EMPA-REG Outcome trial did not show differences for these adverse events in the randomized groups. Because the more than 100 reported cases of acute kidney injury associated with SGLT2 inhibitors typically occurred within 4 weeks of therapy initiation, practical use of these drugs requires attention to the volume status of the patient with consideration for tapering or holding the diuretic dose at initiation and avoidance for orthostatic hypotension or a history of hemodynamic acute kidney injury.
The challenge of treating patients with type 2 diabetes with low eGFR remains unsettled by the addition of the SGLT2 inhibitors to the armamentarium, since these agents are not recommended according to the FDA package inserts (with eGFR less than 45 mL/min/1.73m2 for canagliflozin and empagliflozin; with eGFR less than 60 mL/min/1.73m2 for dapagliflozin). Thresholds may be informed by the ongoing CREDENCE and DAPA-CKD trials with broad kidney function inclusion criteria. Additionally, further analysis of the 7.7% EMPA-REG Outcome study population outside the FDA recommendations with eGFR 30 mL/min/1.73 m2 to 44 mL/min/1.73 m2 are of interest.
Joseph A. Vassalotti, MD, is associate clinical professor of medicine at the Icahn School of Medicine at Mount Sinai Hospital and chief medical officer at the National Kidney Foundation. Disclosure: Vassalotti reports no relevant financial disclosures.
SGLT2 inhibitors might be effective in patients with advanced nephropathy, although the mechanism remains unclear.
The benefit of an SGLT2 inhibitor in diabetic kidney disease is suggested by the findings of the EMPA-REG Outcome study in which subjects whose baseline eGFR was less than 45 mL/min/1.73 m2 benefitted similarly to those with a higher eGFR Indeed, the modest glucose lowering in the setting of a lower GFR and a similarly modest effect on blood pressure suggest that the reduction in kidney disease progression observed in the EMPA-REG Outcome study was mostly independent of empagliflozin’s effects on either blood glucose or BP. There are a lot of theories as to the mechanism that underlies the beneficial effects — and they are just theories. For something as important as diabetic kidney disease, we must explore the potential reasons SGLT2 inhibitors may be working, rather than just assuming that we know.
There are a couple of issues to note in using empagliflozin or other SGLT2 inhibitors in the setting of a low eGFR. For one, the glucose-lowering effect is small when the eGFR is low. However, we should not be considering SGLT2 inhibitors as glucose-lowering agents alone; we should be considering them as cardiac-protective and possibly kidney-protective drugs that also happen to lower glucose. Another potential issue is the propensity for acute kidney injury when using a drug that induces volume contraction and lowers BP. Yet, we see from the adverse event data in EMPA-REG Outcome that there were fewer cases of acute kidney injury in the patients who received empagliflozin, the caveat being that acute kidney injury was an adverse event, not an adjudicated outcome. Nevertheless, these findings are not concordant with the so-called hemodynamic explanation for kidney protection and should give us pause to keep an open mind about the mechanism of action of the SGLT2 inhibitors rather than thinking that we understand it already.
Richard Gilbert, MD, PhD, FRCPC, is head of the division of endocrinology at St. Michael’s Hospital and professor of medicine at the University of Toronto. Disclosure: Gilbert reports sharing patents with, receiving grant support from or serving on advisory boards in an ad hoc capacity for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck and Novo Nordisk.