Spotlight on SGLT-2 inhibitors and the kidneys
Two meta-analyses of sodium-glucose cotransporter-2 (SGLT-2) inhibitors suggested that the class offers benefits to patients at a wider range of kidney functions than targeted by current recommendations, and a third study offered a score for identifying patients who would benefit.
Three recent studies investigated the renal protection benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for different patient populations.
Two of the studies, both published by JAMA on Nov. 7, were companion meta-analyses of trials from the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. The first analysis looked at the effects of the drug class by estimated glomerular filtration rate (eGFR) or degree of albuminuria. Using data from 70,361 participants in 10 randomized trials, it found that SGLT-2 inhibitors reduced the risk of chronic kidney disease (CKD) progression, irrespective of whether a patient's baseline eGFR was over 60 mL/min/1.73 m2, under 30 mL/min/1.73 m2, or between those ranges, as well as whether their urinary albumin-to-creatinine ratio (UACR) was less than 30 mg/g (<3 mg/mmol), over 300 mg/g (>30 mg/mmol), or between. SGLT-2 inhibitors also reduced the risk of kidney failure.
The results support recommendations to initiate SGLT-2 inhibitors in patients with CKD and an eGFR greater than or equal to 20 mL/min/1.73 m2, regardless of diabetes status, and offer reason to strengthen recommendations for the drugs in patients with lower levels of albuminuria, according to the study authors. “Taken together, more widespread implementation of SGLT2 inhibitors in patients with lower levels of albuminuria and early-stage CKD, particularly those with concomitant diabetes, could have substantial benefits in preventing kidney function decline at a population level,” they wrote.
The second analysis used data from 58,816 trial participants (48,946 with diabetes and 9,870 without diabetes) and found that compared to placebo, SGLT-2 inhibitor use led to a lower rate of CKD progression, acute kidney injury, hospitalization, and death irrespective of diabetes status and UACR. Those with a UACR of 200 mg/g or greater (≥20 mg/mmol) had higher absolute risk and thus larger estimated absolute benefit on slowing CKD progression. “The presented evidence offers an opportunity for the guidelines to be simplified to reduce arguably unnecessary stratification of recommendations by diabetes status and by UACR and consequently maximize implementation of appropriate use of SGLT2 inhibitors,” said the study authors.
An accompanying editorial agreed that the studies highlight the value of SGLT-2 inhibitors for patients across the spectrum of CKD risk but noted that cost remains an issue with these medications, which are underused in populations for whom they are already recommended. “Clinical implementation of expanded indications must also take cost-effectiveness into consideration, warranting formal studies including assessment of generic options anticipated in the near future,” the editorial said.
The third study, published by Diabetologia on Nov. 9, used a British database to assess outcomes in patients who had type 2 diabetes, an eGFR of 60 mL/min per 1.73 m2 or greater, and a UACR less than 30 mg/mmol (<300 mg/g) and initiated an SGLT-2 inhibitor (n=53,096) versus a dipeptidyl peptidase-4 (DPP-4) inhibitor or a sulfonylurea (n=88,404). It found a significantly lower risk of CKD progression with SGLT-2 inhibitors (hazard ratio, 0.58; 95% CI, 0.48 to 0.69). The researchers also looked at whether the CKD Prognosis Consortium (CKD-PC) risk score could be used to predict a patient's benefit from SGLT-2 inhibitors and found that using the score to select patients would prevent more cases of progression than would a UACR cutoff of 3 mg/mmol (30 mg/g).
“Our model adapting the CKD-PC risk score accurately predicts the kidney protection benefit of SGLT2 inhibitors in individuals with type 2 diabetes, and no CKD or early-stage CKD (preserved eGFR and normal uACR or low-level albuminuria), who represent approximately 75% of those with type 2 diabetes. This approach leverages an internationally validated risk score and gold-standard evidence from a trial meta-analysis, providing a highly generalisable low-cost precision medicine tool,” the study authors wrote. Limitations include that patients older than age 80 years were excluded and that allocation to the medications was not random.