July 19, 2021
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New drug therapy will change the CKD landscape

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In April, the FDA approved use of dapagliflozin (Farxiga, AstraZeneca)to reduce the risk for kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease.

This not only includes patients with diabetic kidney disease (DKD), but also other causes of CKD. Exceptions are patients with autosomal dominant or recessive polycystic kidney disease, those who require or have recently used immunosuppressive therapy to treat kidney disease or have type 1 diabetes mellitus (DM).

The exceptions were due to those patients being excluded from the trial.

Lance Sloan

However, patients with glomerulonephritis were studied, particularly those with IGA nephropathy (6.3% of study group), and they showed significant improvement for the primary outcome of prevention of sustained greater than 50% decline in eGFR, end-stage kidney disease or renal or cardiovascular death.

Data from the Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, published in The New England Journal of Medicine in October 2020, showed participants had a mean baseline eGFR of 43 mL/min/1.73 m2 and mean urine albumin-to-creatinine ratio (UACR) of approximately 950 mg/g. This meant they were at high risk for CKD progression and death.

Slowdown for CKD

The DAPA-CKD trial is a game changer in the prevention and progression of cardiorenal disease in our patients.

With this FDA approval, clinicians now have, for the first time, a proven treatment that can significantly alter the timeline to end-stage kidney disease and perhaps even prevent its occurrence.

Based on the DAPA-CKD trial data, for patients starting therapy with placebo who have an eGFR of 43 mL/min/1.73 m2, the time it would take to drop the eGFR to 10 mL/min/1.73 m2 and start renal replacement therapy (RRT) would be 9.2 years.

If the patients were treated with dapagliflozin (DAPA), that 9.2 years would be extended to 19.8 years, a difference of 10.6 years. That means a 62-year-old individual with CKD would start RRT at age 82 years, instead of 71 years.

Mechanistically, this is a conservative estimate, as the improved changes in GFR seen in this relatively short-term study are most likely due to an improvement in renal hemodynamics and do not include other metabolic effects of the drug that can take more than 5 years to become apparent. That could lead to even greater improvements in time.

Either way, this slowing in the drop of GFR could mean that the patient never ends up on RRT or does so for a significantly reduced period.

The other significant benefit is the reduction in all-cause mortality starting after 7 months of a 31% RR ratio and 2.1% average risk reduction (ARR) by the end of the study. A reduction in the composite of cardiovascular (CV) death or heart failure hospitalization was seen after about 4 to 6 weeks, with a RR ratio of 29% and ARR of 1.8% by the end of the study. This is particularly important, as patients with CKD are more likely to die than progress to RRT.

Inclusion criteria in the DAPA-CKD trial were an eGFR of 25 to 75 mL/min/1.73 m2 and a UACR greater than 200 mg/g to 5,000 mg/g. The patients had to be on stable max-tolerated doses of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers.

Average age of the participants was 62 years, and two-thirds were men. The average blood pressure (BP) reading was 137 mm Hg/77.5 mm Hg and the median BMI was 29.5. Two-thirds of the participants had type 2 DM. Approximately 37% had cardiovascular disease and 11% had congestive heart failure. Statins were used in 65% of patients and diuretics in 44%.

Dapagliflozin was well-tolerated in the trial, with an adverse event profile similar to placebo in patients with or without diabetes. There was no significant increase in serious adverse events, amputations or fractures in the DAPA arm vs. placebo.

Protect the kidneys

So how do dapagliflozin or sodium glucose co-transporter 2 (SGLT2) inhibitors provide protection for the kidneys? A full discussion is beyond the scope of this First Word column, but there are four primary mechanisms that cause DKD and are variably active in other forms of CKD:

Increased glucose transport. Increased glucose uptake in the proximal tubule (PTC) leads to an increase in advanced glycosylation end products and reactive oxygen species. This leads to an increase in transforming growth factor-beta, resulting in tubular interstitial fibrosis;

Increased sodium transport. An increase in sodium uptake in the PTC leads to hemodynamic changes from an increase in total body and intravascular volume along with reduced tubule-glomerular feedback, resulting in afferent glomerular arteriolar dilation and increased intraglomerular pressure;

Increased neurohormonal activity. There is an increase in neurohormonal activity of the kidney, resulting in both increased renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activity; and

Increased ischemia. Ischemia increases, particularly for highly metabolic organs such as the kidney and heart, due to decreased oxygen delivery from multiple mechanisms. This also contributes to increased renal fibrosis. DAPA, through SGLT2 inhibition, inhibits all these mechanisms.

What the DAPA indication also allows is initiation of the drug down to an eGFR of 25 mL/min/1.73 m2, regardless of diabetes status or presence of albuminuria. The drug also does not have to be stopped unless the patient starts dialysis. This is a major broadening of the indication for an SGLT2 inhibitor in CKD.

SGLT2 inhibitors, through the above mechanisms, also result in reduced A1c, weight and BP. The greater the baseline A1c, weight or BP of the patient, the greater the reduction.

Visceral obesity or visceral insulin resistance adiposity syndrome, also referred to as metabolic syndrome, is driving many of the metabolic diseases in the world, which include type 2 DM, hypertension, congestive heart failure and CKD. Therefore, using medications that do not lead to weight gain but instead result in weight loss is important in reducing the underlying cause of these diseases.

Advancing American Kidney Health

DAPA-CKD adds to the increasing body of data we have from multiple cardiovascular outcome trials and one primary outcome trial (CREDENCE) in the SGLT2 inhibitor class showing these drugs will have a significant impact on our mission to preserve kidney function, prevent kidney failure and reduce CV death in our patients.

The Advancing American Kidney Health goal of a 25% reduction of new cases of ESKD by 2030 may have seemed unattainable to some, but now should be doable — if we can identify patients with CKD early on and begin treatment with dapagliflozin or some member of this class.

This therapy should be considered as initial treatment for type 2 DM based on DAPA data to prevent kidney and heart failure. There is no reason to wait for disease to occur in this high-risk group.

This trial will add to our data on SGLT2 inhibitors but should not be a reason to wait in treating patients with non-albuminuric CKD, particularly when these patients are at high risk for heart failure.

Cost for this therapy is a concern, particularly due to the dreaded Medicare ‘donut hole.’ Hopefully, this compelling data will allow the government, insurance companies and drug manufacturers to come together to make these drugs available for those who need them. It is important for our professional organizations to work toward this outcome.