In follow up to my recent blog post sharing the breaking news of the DAPA-CKD trial, below is a newsletter compiled by my colleagues Dr O’Meara (cardiology), Dr Tangri (nephrology), Dr Harris (diabetologist, primary care), and myself (endocrinologist), discussing the importance of these results to primary care physicians.

 

The DAPA-CKD Trial was designed to evaluate the efficacy of the SGLT2 inhibitor, dapagliflozin (DAPA) at a dose of 10mg daily, on renal and cardiovascular outcomes in adult patients with chronic kidney disease (CKD). Specifically, patients were included if they had an eGFR of 25-75 mL/min/1.73m2 and UACR 22.6-565mg/mmol (200-5000mg/g), and were on stable treatment with an ACEi/ARB for ≥4 weeks before screening. The trial enrolled a total of 4304 participants, including 1398 (32.5%) without Type 2 Diabetes Mellitus (T2DM). The mean eGFR was 43.1mL/min/1.73m2, and the median UACR was 108mg/mmol (949mg/g).

 

The primary endpoint of the trial was a composite of the time to the first occurrence of any of the following components of the composite endpoint: a sustained ≥50% decline in eGFR, end-stage kidney disease (ESKD), or renal or CV death. When compared to placebo, after a median follow up of 2.4 years, there was a statistically significant 39% relative risk reduction (RRR) in this composite endpoint for the DAPA group, with a number needed to treat (NNT) = 19 to prevent one event. This effect was consistent across subgroups, and importantly, the result was similar and statistically significant both in patients with T2DM (36% RRR) and without T2DM (RRR 50%).

 

Several secondary endpoints were also investigated:

  • Renal composite of the time to first occurrence of a sustained ≥50% decline in eGFR, ESKD or renal death: This showed a statistically significant 44% RRR in the DAPA group compared to placebo.
  • Composite of time to first occurrence of cardiovascular death or hospitalization for heart failure: This showed a statistically significant 29% RRR in the DAPA group compared to placebo.
  • All-Cause Mortality: This showed a statistically significant 31% RRR in the DAPA group compared to placebo.

 

Dapagliflozin was well tolerated and had a safety profile consistent with other DAPA trials. Slightly less patients had serious adverse events in the DAPA group than in the placebo group (29.5% vs 33.9%, for DAPA vs placebo, respectively), and the number that discontinued the drug due to adverse events was similar (5.5% vs 5.7% for DAPA vs placebo, respectively). Of specific interest, there were no major hypoglycemic or DKA events in patients without diabetes.

 

 

WHAT DOES THIS STUDY MEAN FOR PRIMARY CARE?

 

An Endocrinologist’s Perspective:

“DAPA-CKD is a landmark trial, as it is the first study of an SGLT2 inhibitor demonstrating a powerful renoprotective effect in patients with CKD without T2DM.  It also adds important knowledge to the existing data from the CREDENCE Trial of canagliflozin, with both studies showing a powerful renoprotective benefit in patients with T2DM and CKD.  The DAPA-CKD trial further adds to the shift in paradigm as to how we think about SGLT2 inhibitors: while they were originally developed as T2DM medications that were found to have cardiorenal benefits, we are now thinking of them more as cardiorenal medications that also treat T2DM.  The benefits emerge very soon after starting treatment (especially for heart failure treatment/prevention), highlighting the importance of avoiding clinical inertia and starting these treatments in appropriate patients who may benefit. Patients with heart failure with reduced ejection fraction (HFrEF) and/or CKD and/or T2DM can be complex and on a multitude of medications; often a collaborative approach between primary care, endocrinology, cardiology and/or nephrology is helpful  to determine if and how to introduce SGLT2 inhibition with appropriate adjustment of concomitant medications.”

 

Sue D. Pedersen, MD, FRCPC

Specialist in Endocrinology & Metabolism

Diplomate, American Board of Obesity Medicine

C-ENDO Diabetes & Endocrinology Clinic

Calgary, AB, Canada

 

 

A Cardiologist’s Perspective:

“CKD is strongly associated with CV disease and both are interrelated. Worsening kidney function has prognostic implications that reach far beyond ESKD, including a wide range of CV impacts. SGLT2 inhibitors are now firmly established for CV prevention in patients with T2DM and have more recently been shown to significantly improve clinical outcomes in patients with HFrEF.  Indeed, the EMPEROR-Reduced trial results, also just presented at the ESC meeting, were aligned with the DAPA-HF trial results, confirming clear outcome benefits in patients with HFrEF receiving excellent background HF therapy, with or without T2DM. The DAPA-CKD trial provided evidence that these agents have reached yet another major milestone, demonstrating clear kidney protection in patients with established CKD, again with or without T2DM, on top of currently recommended therapy.  Halting the progression of disease is key, whether it is about T2DM, CV disease, HF or CKD. SGLT2 inhibitors are now poised to change the course of disease for patients with any of these conditions.”

 

Eileen O’Meara, MD, FRCPC

Head, Outpatient Clinics

Montreal Heart Institute

Université de Montréal, Quebec

 

 

A Nephrologist’s Perspective:

“The DAPA-CKD Trial firmly establishes SGLT2 inhibitors, and in this case dapagliflozin, as standard of care for nearly all patients with CKD. Dapagliflozin reduced the risk of CKD progression by nearly 40 %, and reduced all-cause mortality by more than 30%. Only patients with polycystic kidney disease, Type 1 diabetes and active immune system disease, who represent no more than 10-15 % of all patients with CKD were excluded. As such, for more than 80% of individuals with CKD, SGLT2i should be prescribed, and continued until they reach dialysis or transplant. There has never been a drug in nephrology that prevents dialysis and death at this magnitude, and now there is a tremendous opportunity before us to bend the dialysis curve and save lives by implementing these findings.”

 

Navdeep Tangri, MD, PhD

Associate Professor- University of Manitoba

Scientific Director – Chronic Disease Innovation Center

 

 

A Primary Care Perspective:

“SGLT2 inhibitors have demonstrated clear cardiorenal benefits from several landmark outcome trials. The recent results from the DAPA-CKD study add additional important evidence to the benefit of renal protection in high risk populations with established CKD commonly found in primary care practice.  Additionally, the DAPA-CKD findings highlighted the benefits of DAPA 10mg which were independent of whether the patients had a diagnosis of T2DM or not.  It was also important to note that these findings were present on a background of renal protection therapies of ACEi/ARB treatment in 97% of subjects.

 

What do these findings mean for primary care?  The evidence is now overwhelmingly positive, demonstrating the renoprotective benefit of this class of drugs.  As CKD is highly prevalent in patients with T2DM in primary care, the findings of DAPA-CKD are highly relevant to general practitioners. It is incumbent on PCPs to consider the use of SGLT2 inhibitors early on in the therapeutic regimen of patients with T2DM, and additionally now in patients without diabetes with established CKD, because of the results from DAPA-CKD. These key findings further re-emphasize the recommendations from the Standards of Care by the ADA/EASD emphasizing the importance of early use of SGLT2 in T2DM to help reduce progression of renal decline and reduce HF. PCP’s thus have a key role and responsibility in protecting these patient populations with the early and safe use of SGLT2 inhibitors.”

 

Stewart Harris, CM, MD, MPH, FCFP, FACPM

Professor

Diabetes Canada, Chair in Diabetes Management

Ian McWhinney Chair of Family Medicine Studies

Schulich School of Medicine and Dentistry, Western University, Ontario

 

 

Disclosure: The information and opinions expressed in this newsletter are those of the authors. Creation of the newsletter was supported by honoraria provided by AstraZeneca.

 

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