AstraZeneca's Khan Discusses Dapagliflozin and Cardiovascular, Renal Outcomes in Diabetes Care

Over the past decade, results from cardiovascular outcomes trials (CVOTs) for glucose-lowering therapies have had an enormous impact on people with type 2 diabetes (T2D). The first wave of findings reported on major adverse cardiovascular events (MACE) that were the focus of the FDA’s 2008 guidance requiring the studies.¹ In November 2018, the DECLARE-TIMI trial reported results for dapagliflozin, the sodium glucose cotransporter 2 (SGLT2) inhibitor sold as Farxiga by AstraZeneca.² Those results showed that dapagliflozin significantly reduced the risk of hospitalization for heart failure and appeared to slow the loss of kidney function.

That second finding reflects a major focus in a new wave of findings for SGLT2 inhibitors. The first dedicated renal outcomes trial reported results in April,³ and more are on the way. (Upcoming dedicated trials also will examine the effects of SGLT2 inhibitors on heart failure.) Finding ways to prevent the loss of renal function, including the need for dialysis, is a priority of managed care. Doing so would not only improve quality of life for patients but also bring savings for Medicare—the annual cost of a year of dialysis is estimated at $89,000.⁴

Evidence-Based Diabetes Management™ (EBDM) asked Naeem Khan MD, vice president of US cardiovascular and metabolic diseases at AstraZeneca, to discuss lessons from the CVOTs, the new focus on renal outcomes, and what’s next for SGLT2 inhibitors.

EBDM: As a class, SGLT2 inhibitors are proving to have many benefits beyond lowering blood glucose for patients with T2D. For the past 4 years, much of t he focus at major scientific meetings has been on CVOT results—reduction in major cardiovascular events. But those results also contained evidence that the class also had the ability to play a major role in preventing the slow progression to debilitating conditions like kidney failure. Can you discuss why the renal benefits of SGLT2 inhibitors are getting more attention now?

KHAN: The primary focus of cardiovascular safety and the reduction in major cardiovascular events by SGLT2 inhibitors stems from cardiovascular outcomes trials that were mandated following the 2008 guidance from the FDA to confirm these medicines were safe from a cardiovascular perspective.¹ With this in mind, it’s easy to see why confirming the CV safety and efficacy of these medicines was established as the primary objectives of these trials and therefore were the first topics of scientific discussion.

We have always known that patients with diabetes have an increased risk of renal complications. In fact, diabetes is the leading cause of kidney disease, and approximately 1 in 4 adults with diabetes has kidney disease.⁵ Although the initial SGLT2 inhibitor CVOTs were focused on CV outcomes, secondary analyses were included to assess renal impact. These secondary analyses generated interesting hypotheses about SGLT2s and their impact on renal outcomes. As a result of these findings, AstraZeneca is prospectively evaluating these hypotheses in a large randomized clinical trial known as Dapa-CKD,⁶ a study evaluating the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (CKD).

EBDM: Can you discuss the new indication that dapagliflozin received from the FDA and why this is important?

KHAN: The FDA approved an updated label for Farxiga that expands who may benefit from the medicine—specifically, for patients with T2D and moderate renal impairment [CKD with an estimated glomerular filtration rate (eGFR) of 45-59 mL/min/1.73 m².⁷ The updated label lowers the eGFR threshold to 45 mL/min/1.73 m² from 60 mL/min/1.73 m²].

Because patients may be affected by metabolic and renal complications that are interrelated, it’s important to have information about how these medicines work in patients with both conditions included in the prescribing information for [dapagliflozin].

EBDM: When the first CVOT, EMPA-REG OUTCOME,⁸ was announced, AstraZeneca added a primary end point to its CVOT, the DECLARE-TIMI trial, which has reported results at meetings for the American Heart Association and American College of Cardiology. Can you discuss this decision and the importance of this additional primary end point?

KHAN: Every time you conduct a clinical trial, you ask a specific question and receive an answer, but each trial also generates new hypotheses and therefore questions that need to be answered by a subsequent clinical trial. The benefit of being the third CVOT is that we were able to take some of the questions generated by the results of the other CVOTs and prospectively study them in DECLARE. In DECLARE, the study design was adjusted to include coprimary end points of MACE as

well as the composite of hospitalization for heart failure or CV death, because we believed understanding the impact on hospitalizations for heart failure would be especially important—particularly because 1 out of every 3 patients with diabetes will go on to have heart failure, heart failure is the first cardiac complication for most patients, and the mortality rates for heart failure are quite high.

With more than 17,000 patients in 33 counties, DECLARE provides a broad representation of type 2 diabetes patients with cardiovascular risk factors and established cardiovascular disease, offers a rich body of scientific evidence for this patient population, and the benefit was seen in the broadest patient population to date, making it highly relevant to the real-world clinical setting.

[Note: DAPA-HF,⁹ the first trial evaluating the effect of an SGLT2 inhibitor on the incidence of worsening heart failure or cardiovascular death in patients with chronic heart failure and with and without T2D, is expected to read out this year.]

EBDM: What is the significance of the American Diabetes Association (ADA) releasing a midyear guideline update to include new evidence on dapagliflozin?¹⁰

KHAN: The addition of new data that feature the most up-to-date research on CV and renal risk reduction in patients with type 2 diabetes for the SGLT2 inhibitor class in the ADA Standards of Care [Standards of Medical Care in Diabetes] helps empower healthcare professionals to provide evidence-based care to their patients and help improve outcomes. Heart failure is the No. 1 cardiac complication in patients with type 2 diabetes.

EBDM: We just had the first of the new wave of reported results from renal outcomes trials, and Dapa-CKD will be complete in 2020. Significantly, half of these patients do not have diabetes. Is there anything you can tell us about the study so far?

KHAN: The Dapa-CKD trial is designed to evaluate the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with CKD and includes both patients with and without type 2 diabetes. It is a randomized, multicenter, event-driven, double-blind, placebo-controlled study involving 4000 patients with CKD. The

primary outcome is defined as the composite of time to first occurrence of ≥50% sustained decline in eGFR, reaching end stage renal disease (ESRD) or CV death or renal death. ESRD is defined as sustained eGFR <15 mL/min/1.73m2, chronic dialysis treatment or receiving a renal transplant.

Dapa-CKD is expected to read out in 2020.

EBDM: Given the extreme burdens for patients, high mortality rates for those who begin dialysis, the diminished quality of life, and the cost to Medicare, how do the potential renal benefits of SGLT2 inhibitors compare with the CV benefits?

KHAN: It is probably too early to make a definitive statement about this. What we know is that the risk of developing renal impairment or CKD is high among patients with diabetes, and the SGLT2 class of medicines has generated some interesting and promising hypotheses about how they may affect the kidney. As we continue to evaluate the potential benefits of SGLT2 inhibitors, we believe these treatments could become innovative options that may address cardiorenal risks for patients with diabetes.References

1. US Food and Drug Administration. Guidance for Industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Published December 2008. Accessed March 26, 2019.

2. Wiviott SD, Raz I, Bonaca MP, et al; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;390(4):347-357. doi: 10.1056/NEJMoa1812389.

3. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy [published online April 14, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1811744.

4. The Kidney Project. Statistics. University of California at San Francisco website. https://pharm.ucsf.edu/kidney/need/statistics. Accessed June 6, 2019.

5. Diabetic Kidney Disease. National Institute of Diabetes and Digestive and Kidney Diseases website. niddk.nih.gov/health-information/diabetes/overview/preventing-problems/diabetic-kidney-disease. Updated February 2017. Accessed June 6, 2019.

6. A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD). clinicaltrials.gov/ct2/show/NCT03036150. Updated April 29, 2019. Accessed June 6, 2019.

7. US FDA approves expanded Farxiga and Xigduo XR labels for use in patients with type 2 diabetes and moderate renal impairment [press release]. Wilmington, DE: AstraZeneca; February 27, 2019. businesswire. com/news/home/20190227005113/en/FDA-Approves-Expanded-FARXIGA-XIGDUO-XR-Labels. Accessed June 6, 2016.

8. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.

9. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF). clinicaltrials.gov/ct2/show/NCT03036124. Updated April 19, 2019. Accessed June 6, 2016.

10. American Diabetes Association issues critical updates to 2019 Standards of Medical Care in Diabetes [press release]. Arlington VA: American Diabetes Association; March 27, 2019. diabetes.org/newsroom/press-releases/2019/ada-issues-critical-updates-to-2019-standardsof-care.html. Accessed June 6, 2016.

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