The SGLT2 inhibitors, or gliflozins, have been rising stars in the fields of endocrinology and cardiology for their ability to reduce cardiovascular risks in patients with type 2 diabetes.1,2 Beneficial effects on the kidneys have also been noted in patients with chronic kidney disease and diabetes.3

On April 30, 2021, the FDA announced the approval of the SGLT2 inhibitor dapagliflozin for patients with chronic kidney disease. According to the FDA, the drug can be useful in reducing the “risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure” in patients at risk for progression of their kidney disease.5 

About chronic kidney disease

Chronic kidney disease (CKD) affects about 47 million Americans. It involves abnormal kidney function or structure and can progress through five stages, potentially leading to dialysis-dependent kidney failure.7 Preventing CKD progression is important because more advanced kidney disease can cause serious and life-threatening complications, increased cardiovascular risks, and reduced quality of life.4 

Many patients with CKD have comorbidities, especially cardiovascular disease and type 2 diabetes; the latter is an important contributor to CKD risk and is the most common cause of kidney failure worldwide. Hypertension is another major risk factor.3 Current chronic kidney disease treatments that can help prevent progression to kidney failure include ACE inhibitors,4 which lower blood pressure; measures to improve diabetes control; avoidance of nephrotoxins; and diet and lifestyle changes.9 

Renal effects of SGLT2 inhibitors 

SGLT2 inhibitors reduce the amount of glucose that the proximal tubules within the kidneys reabsorb, leading to a reduction in blood glucose levels. However, the drugs also appear to have renal effects that are independent of their blood glucose-lowering effects.4

One hypothesis is that they lower intraglomerular pressure, which may lead to protective effects in patients who have kidney disease with or without diabetes.4

In 2019, the CREDENCE trial researchers reported that an SGLT2 inhibitor, canagliflozin, provided multiple benefits in patients with diabetes and albuminuric CKD, including a 32% decrease in relative risk of developing end-stage kidney disease.3 More recently, the authors of the SCORED trial reported that the SGLT2 inhibitor sotagliflozin reduced the number of cardiovascular events in patients who had both diabetes and CKD and who were at risk for cardiovascular disease.8 

SGLT2 inhibitors appear to have renal effects that are independent of their blood glucose-lowering effects.4 One hypothesis is that they lower intraglomerular pressure, which may lead to protective effects in patients who have kidney disease with or without diabetes.4

Dapagliflozin clinical trial

The FDA previously approved dapagliflozin, marketed by AstraZeneca as Farxiga, for use in type 2 diabetes and in certain patients with heart failure. 

The new approval in CKD is based on results from a trial in 4303 patients with CKD who had an estimated glomerular filtration rate (GFR) of between 25 and 75 ml/minute/1.73 m2 of the body surface area and a urinary albumin-to-creatinine ratio of between 200 and 5000 (albumin was measured in milligrams and creatinine in grams).4 The patients were randomized in a 1:1 ratio to receive dapagliflozin (oral, 10 mg daily) or placebo. 

The study was stopped early after the drug showed striking efficacy.4,10 The trial met its primary outcome, “a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.”4 In the dapagliflozin group, 9.2% of patients had a primary outcome event, compared to 14.5% in the placebo group (p<0.001). 

Participants treated with dapagliflozin also showed a statistically significant reduction in the number of events for each of the components of the primary outcome. Dapagliflozin was effective both among participants who had type 2 diabetes (67.5% of participants) and among those who did not.4

Chronic kidney disease can eventually progress to kidney failure requiring dialysis. The approval of dapagliflozin represents an important advance in protecting the renal function of those with CKD.5,10

FDA approval of dapagliflozin

The FDA’s approval of dapagliflozin as a chronic kidney disease treatment represents an important advance for patients with CKD. However, it is not approved for treating hereditary forms of polycystic kidney disease, and it is not for use in patients on dialysis or on immunosuppressants for kidney disease.

Safety concerns with dapagliflozin and other SGLT2 inhibitors include a risk of genital and urinary tract infections, Fournier’s gangrene, metabolic acidosis or ketoacidosis, dehydration, and hypoglycemia in patients on insulin.5 

References

  1. https://academic.oup.com/cardiovascres/article/117/4/e49/6095705
  2. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.040514 
  3. https://www.nejm.org/doi/10.1056/NEJMoa1811744?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed 
  4. https://www.nejm.org/doi/full/10.1056/NEJMoa2024816 
  5. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-chronic-kidney-disease 
  6. https://www.nejm.org/doi/full/10.1056/NEJMoa2024816 
  7. https://www.aafp.org/afp/2017/1215/p776.html 
  8. https://www.nejm.org/doi/full/10.1056/NEJMoa2030186?query=recirc_curatedRelated_article 
  9. https://www.diabetes.org/diabetes/slow-progression-chronic-kidney-disease 
  10. https://www.medscape.com/viewarticle/927820