Reduce Kidney Disease Progression or CV Death in People with CKD

CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, FACP, F-RSSDI, Director – Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in.

Changing the way CKD interconnected conditions are being managed

Empagliflozin was originally developed to treat high blood sugar in people with diabetes.
It was a diabetologist’s favourite drug.
It later showed Cardio-reno protective. No wonder, now it is cardiologist’s and nephrologists’s favorite too.
A drug which causes blood sugar equivalent to 10 teaspoons a day to pass into the urine has now established itself indispensable in diabetic as well as non-diabetic practice.

The story of heart and kidney protection with Empagliflozin

Worth to mention that the EMPA-KIDNEY trial was stopped early for benefit on the recommendation of the independent data monitoring committee and the unblinded results.
Now it has been presented for the first time at ASN Kidney Week 2022 on 4th November.
As more evidence was needed on the effects of SGLT2-Inhibitors on renal and cardiovascular (CV) disease in patients with chronic kidney disease (CKD), in particular those without diabetes (DM), low estimated glomerular filtration rate (eGFR) or low albuminuria, EMPA-KIDNEY fills the gap significantly.
“The design of the EMPA-KIDNEY trial included a wider range of patients than ever before. Previous SGLT2 inhibitor trials focused on certain groups of people living with CKD, such as those with diabetes or high levels of protein in their urine. Today’s positive trial results across a broad CKD population reflect an opportunity to improve the treatment of this disease and prevent people from needing dialysis.” (November 4,2022) – Professor Richard Haynes, co-principal investigator.
It included patients with mean eGFR 37.5 mL/min/1.73m² (SD 14.8), including 78% with an eGFR <45 mL/min/1.73m². 48% had a uACR <300 mg/g and 54% had no history of DM.

Quick Take-Aways

EMPA-KIDNEY is the largest and broadest dedicated SGLT2 inhibitor trial in chronic kidney disease.

The results were announced today during the American Society of Nephrology (ASN)’s Kidney Week 2022.

We have now new therapies proven to delay CKD progression which can lead to the need for dialysis or transplantation.

EMPA-KIDNEY phase III clinical trial met its primary endpoint by demonstrating a significant kidney and cardiovascular benefit for adults living with chronic kidney disease (CKD).

EMPA-KIDNEY is the first SGLT2 inhibitor CKD trial to demonstrate a significant reduction in all-cause hospitalizations (14%) (HR; 0.86; 95% CI 0.78 to 0.95; p=0.0025) vs. placebo.

It provides new evidence for patients commonly seen in clinical practice – Phase III trial also demonstrated a statistically significant reduction (14%) in hospitalization for any cause, bringing potential relief for patients and reducing burden on healthcare systems.

Know how kidney disease progression and ESRD are defined?

It is defined as end-stage kidney disease (the initiation of maintenance dialysis or receipt of a kidney transplant), a sustained decline in estimated glomerular filtration rate (eGFR) to below 10 mL/min/1.73 m², kidney death or a sustained decline of at least 40% in eGFR from randomization).
End stage kidney disease: Includes initiation of maintenance dialysis or receipt of a kidney transplant.

What is EMPA-KIDNEY Trial?

It is a multinational, randomized, double-blind, placebo-controlled clinical trial.
It is designed to evaluate the effect of Empagliflozin on kidney disease progression and cardiovascular mortality risk.
The primary outcome:
- It is defined as time to a first event of either cardiovascular death or kidney disease progression, defined as end-stage kidney disease (the need for kidney replacement therapy such as dialysis or kidney transplantation), a sustained decline in eGFR to <10 mL/min/1.73 m², kidney death, or a sustained decline of ≥40 percent in eGFR from randomization.
Key secondary outcomes
- It includes cardiovascular death or hospitalization for heart failure, all-cause hospitalization and all-cause mortality.
With diabetes or no diabetes, does not matter
- EMPA-KIDNEY includes 6,609 adults randomized from eight countries with established CKD both with and without diabetes, as well as with and without albuminuria, receiving either Empagliflozin 10 mg or placebo, on top of current standard of care.

What EMPA-Kidney shows?

Total patients underwent randomization – 6609.
Median follow-up – 2 years.
Progression of kidney disease or death from cardiovascular causes:
- Empagliflozin group-432 of 3304 patients (13.1%).
- Placebo group- 558 of 3305 patients (16.9%).
- (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001).
- Reduction by 28%.
With or without diabetes– results were consistent among patients.
Results were also consistent among patients across subgroups defined according to eGFR ranges.
The rate of hospitalization from any cause:
- It was lower in the empagliflozin group than in the placebo group.
- (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003).
There were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular.
The rates of serious adverse events:
- Similar in the two groups.

Condition	Empagliflozin	Placebo
Serious Hyperkalemia	2.8%	3.3%
Serious Acute Kidney Injury:	3.2%	4.1%
Serious UTI	1.6%	1.6%
Serious Genital infection	2.8%	3.3%
Symptomatic Dehydration:	2.5%	2.3%
Severe Hypoglycemia:	2.3%	2.3%
Ketoacidosis	0.2%	0.0%

Credit: https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/full-data-chronic-kidney-disease-trial-efficacy

Golden Message from EMPA-KIDNEY

Among a wide range of patients with chronic kidney disease who were at risk for disease progression if you prescribe empagliflozin therapy, it will lead to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo.

CME INDIA Tail-Piece

Never happened such an AMAZING outcome:

Now available Oxford Population Health Renal Studies Group and the SGLT2 Meta-analysis Cardio-Renal Trialists’ Consortium (SMART-C): The largest meta analysis
This shows combined results from 13 comparable clinical trials of SGLT-2 inhibitors among 90,413 people with long-term kidney disease, heart failure, or Type 2 diabetes plus cardiovascular disease.
This suggests regardless of diabetes reduction in:
- Kidney failure
- AKI
- CV death
- All-cause death
Key findings:

SGLT-2 inhibitors reduced the risk of kidney disease progression by 37% overall (RR 0.63; 95% CI 0.58-0.69), with similar effects in those with and without diabetes.

The risk of cardiovascular death or hospitalisation for heart failure was reduced by 23% (RR 0.77; CI 0.74-0.81), with similar effects in those with and without diabetes.

The risk of acute kidney injury was reduced by 21% (RR 0.79; CI 0.72-0.86), with similar effects in those with and without diabetes.

SGLT-2 inhibitors reduced the risk of cardiovascular death by 14% (RR 0.86; CI 0.81-0.92), again with similar effects in those with and without diabetes.

Allocation to an SGLT-2 inhibitor did not significantly reduce the risk of non-cardiovascular death (RR 0.94; CI 0.88-1.02).

The absolute benefits of SGLT-2 inhibition outweighed serious hazards. The absolute risk of ketoacidosis (a serious problem that can happen in people with diabetes if their body starts to run out of insulin) was low.

Time to translate in clinical practice at EARLIEST

For every 1000 patients with CKD and type 2 diabetes treated for one year with an SGLT2 inhibitor, 11 fewer patients would develop kidney disease progression, four fewer patients would have acute kidney injury and there would be 11 fewer cardiovascular deaths or hospitalisations for heart failure; there would be one episode of ketoacidosis and one lower limb amputation.

In patients with CKD without diabetes, there would be 15 fewer patients with kidney disease progression, five fewer with acute kidney injury, and two fewer cardiovascular deaths or hospitalisations for heart failure, with no excess risk of ketoacidosis or amputation.

References:

https://investor.lilly.com/news-releases/news-release-details/landmark-empa-kidney-trial-showed-significant-benefit-jardiancer
EMPA-KIDNEY full data presentation, presented on 4 November 2022 at the American Society of Nephrology (ASN) Congress 2022 – Kidney Week.
Herrington, W.G. et al. Empagliflozin in Patients with Chronic Kidney Disease, N Engl J Med, online publication on November 4, 2022, at NEJM.org. DOI: 10.1056/NEJMoa2204233.
https://www.asn-online.org/education/kidneyweek/2022/program-abstract.aspx?controlId=3800804
https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/full-data-chronic-kidney-disease-trial-efficacy
https://www.empakidney.org/news/sglt-2-inhibitors-reduce-the-risk-of-cardiovascular-death-or-hospitalisation-for-heart-failure-in-adults-with-chronic-kidney-disease