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DAPA-CKD: Is SGLT2i the ANSWER? Will the guidelines change?

Over the past years, series of clinical trials prove the beneficial effect of glucose cotransporter 2 (SGLT2) inhibitors in reducing the risk of cardiovascular events in people with type 2 diabetes mellitus. The results from these trials were consistent, significant, and demonstrated a considerable reduction in heart failure hospitalization among patients who used SGLT2 inhibitors, whereas the benefit on atherothrombotic events such as myocardial infarction and stroke was moderate.

Similar findings from The Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation trial (CREDENCE) were obtained for patients with type 2 diabetes mellitus and chronic kidney disease who are exceptionally at higher risk for cardiovascular disease. In CREDENCE trial, Canagliflozin reduced the risk of chronic kidney disease, cardiovascular death or hospitalization, myocardial infarction, and stroke. Although diabetes is not the only cause of chronic kidney disease, and people with chronic kidney disease are still at increased risk for cardiovascular disease, regardless if they had a preexisting history of cardiovascular disease or not. Therefore, its essential to implement guidelines that recommend the use of certain therapeutics as routine treatment for primary and secondary prevention of cardiovascular disease in patients with chronic kidney disease, regardless of their diabetes status.

During #AHA20, I enjoyed attending the online session by Dr. John McMurray, where he shared scientific breakthrough results from the Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) Mega-Trial. The session reported the results of the effect of dapagliflozin on prespecified kidney and cardiovascular outcomes in patients with chronic kidney disease with and without diabetes. The DAPA-CKD trial was a randomized, double-blind, placebo-controlled, multicenter trial, where adults with or without type 2 diabetes, with estimated glomerular filtration rate (eGFR) between 25 and 75 ml/min/1.73 m2, and a urinary albumin-to-creatinine ratio (UACR) between 200 and 5000 mg/g were eligible for DAPA-CKD trial. In this trial, patients were randomized to dapagliflozin 10 mg once daily or placebo with follow up at 2 weeks, 2,4, and 8 months and at 4 months intervals thereafter. The primary composite outcome was the time to the first occurrence of any of the following: > 50% decline in eGFR, onset of end-stage renal disease, or death from kidney or cardiovascular disease. Moreover, secondary outcomes were: 1) kidney composite outcome identical to the primary endpoint with the exception of death from cardiovascular death 2)( a cardiovascular composite outcome consisting of hospitalization for heart failure or death from cardiovascular  causes; and 3) death from any cause.

 

Effects of dapagliflozin on prespecified clinical outcomes according to the baseline history of cardiovascular disease.

 The DAPA-CKD trial found that among patients with cardiovascular disease who received dapagliflozin, the primary composite outcome occurred in 11.2% participants, while the primary outcome occurred in 17.2% in participants who were in the placebo group, (HR 0.61; 95% CI, 0.47-0.79) and the corresponding numbers in people without cardiovascular disease were 7.9% and 12.9% respectively, (HR 0.61; 0.48-0.78).

The DAPA-CKD trial also found that for both the primary and secondary prevention patients, the event rates favored dapagliflozin for all components of the primary and secondary outcomes, although reduction in cardiovascular risk was not statistically significant.

DAPA-CKD Figure

Additionally, among patients with cardiovascular disease, cardiovascular death or hospitalization for heart failure occurred in 9.3% of participants in the dapagliflozin group and 12.8% of participants in the placebo group, (HR 0.7; 0.52-0.94) and the corresponding numbers for patients without cardiovascular disease were 1.8% and 2.7% respectively, (HR 0.67; 0.40-1.13). The observed reduction in cardiovascular risk for these two groups was driven by reduction in heart failure hospitalization which occurred in 4.1% of participants in the dapagliflozin group and 7.3% participants in the placebo group with cardiovascular disease and the corresponding numbers for patients without cardiovascular disease were 0.3% and 1.0% (HR, 0.31; 0.10-0.94) respectively. These results show that dapagliflozin reduced the risk of adverse kidney outcomes irrespective of baseline cardiovascular disease status. Moreover, the mortality benefit from dapagliflozin as demonstrated from the DAPA-CKD study supports the findings of the DAPA-HF trial. In summary, dapagliflozin reduced the risk of kidney failure, death from cardiac disease or hospitalization for heart failure, furthermore, it prolonged survival, in people with chronic kidney disease, irrespective of the presence of a concomitant cardiovascular disease.

 

What is next?

The data from DAPA-CKD trial for dapagliflozin effect on patients with cardiovascular disease and chronic kidney disease is clear, but we have so much work to do. Is Dapagliflozin the answer? How would this change the guideline directed medical therapy (GDMT) for the care of patients with an increased heart failure, cardiovascular or chronic kidney disease risk, regardless of their glycemic status?

 

References:

  1. Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease. John J.V. McMurray , David C. Wheeler , Bergur V. Stefánsson , Niels Jongs , Douwe Postmus , Ricardo Correa-Rotter , Glenn M. Chertow , Tom Greene , Claes Held , Fan Fan Hou , Johannes F.E. Mann , Peter Rossing , C. David Sjöström , Robert D. Toto , Anna Maria Langkilde , and Hiddo J.L. Heerspink for the DAPA-CKD Trial Committees and Investigators
  2. Presented by Dr. John J. V. McMurray at the American Heart Association Virtual Scientific Sessions, November 13, 2020.
  3. Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al., on behalf of the DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients With Chronic Kidney Disease.N Engl J Med 2020;383:1436-46.
  4. Presented by Dr. Hiddo J.L. Heerspink at the European Society of Cardiology Virtual Congress, August 30, 2020.
  5. Rationale and protocol:Heerspink HJ, Stefansson BV, Chertow GM, et al., on behalf of the DAPA-CKD Investigators. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant 2020;35:274-82.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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Any Physical Activity is Enough

When I was a nutrition intern in 2014, I would excitedly tell patients that walking 30 minutes a day, 5 days a week doesn’t have to be a daunting goal. In fact, research showed that accumulating bouts of 10 minutes conferred cardiac benefits.

Under the often cited “150 minutes/week moderate activity or 75 minutes/week vigorous activity” was the implication that if you couldn’t meet that goal, then why bother?

Did the research specifically say that? Nope. And over the years research on the so-called “Weekend Warriors” has flourished. Is it regular physical activity, or the cumulative amount, that reduces risk?

And then in 2016, the catchy phrase “Sitting is the new smoking” highlighted the birth of a newly emphasized term – physical inactivity – and the distinction between physical activity and exercise.

Earlier this month in Chicago, navigating the bustling 2018 AHA Scientific Sessions, the new Physical Activity Guidelines were revealed. Lo and behold, the news is even better – even a little bit of physical activity is worth it.

It’s not all about aerobic activity, either. We know that resistance training improves insulin sensitivity and helps maintain muscle mass as the human body ages. The result? Less frailty. “Healthy aging”. Fewer injuries from falls, and fewer falls overall.

The new Physical Activity Guidelines didn’t leave that goody out. Upper body weight training even once a week is beneficial – for your heart! Just when you thought you had to huff and puff to beef up your heart health.

With the new Hypertension Guidelines released at Scientific Sessions last year in Anaheim, a renewed effort surfaced for clinicians to encourage lifestyle behavior changes. Not enough time with the patient isn’t an excuse. Research showing that physicians who exercise are more likely to prescribe exercise hit headlines, and the simple fact that clinicians can utilize their position of authority to impart importance upon a topic.

“As a health care provider, you know it’s important to help your patients get more physical activity. But it can be challenging to motivate patients in the short time you spend together.” – Move Your Way, Physical Activity Guidelines 2nd Ed., Health Care Provider Fact Sheet

While not everyone feels comfortable taking on a counseling role with patients, there are key phrases and questions you can use to start the conversation. Check out this short Motivational Interviewing primer, which includes example wording to build rapport with your patient, empower them to make change, and establish a collaborative relationship.

  1. Help them set goals. “Are there activities you’d like to be able to do?” We’ve all heard “I want to be able to pick up my grandkids”. Knowing your patients’ motivations means you can work together to set goals that are important to them.
  2. Meet your patient where they are. Find out what they know, what they perceive as important and as barriers, and suggest small changes. Being able to walk a long driveway to get the mail is a better place to start than jumping from the couch to a 5K.
  3. Let them know what to look for. Instead of “aim for moderate intensity activity”, translate it to perceived exertion. A lazy walk is “I’m comfortable and could maintain this pace all day.” Encourage them to reach a Level 3 to 5 – “Comfortable but breathing harder – sweating a little but feel good and can carry on a conversation – just above comfortable, sweating more, and can still talk easily”. Everyone should start slow and build up to longer durations and higher intensities – take a look at the exertion table below to see what exertion level your patient should start in.

 

 

The new guidelines come with Move Your Way tools and resources to get the message out to your friends and family, your patients, and your community. Interactive tools and widgets, fact sheets and poster, and even videos, can help teach all Americans how they can move their way to move more.

Forming new habits is hard, and lifestyle change is no exception. We know the research, and we have the responsibility to translate that data into actionable information for our patients.

I had the opportunity to recap Scientific Sessions over dinner with my parents. What did I share? Just because you can’t run a marathon doesn’t mean you can’t reap the benefits of physical activity. A little bit goes a long way.