Application of the Dapagliflozin Heart Failure Indication to Clinical Practice

  • Roundtable ID: CV38639
    Citation: Published online ahead of print.
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DR BUTLER: The amputation risk was  a “doubling of the risk” but it was a doubling of a small risk and actually the benefit was even more in those high-risk patients. So, I think it behooves us, if somebody has an open wound or an ulcer or history of peripheral vascular disease, things like that, to be more careful. 

DR WASSON: The DECLARE trial showed a reduction in hospitalizations for HF. What does that finding mean for our diabetic patients in general and especially for those diabetics who have known HF?

DR BUTLER: The reason this discussion gets a little bit difficult is because unlike myocardial infarction or stroke where there’s a very defined pathophysiology that at one point you did not have a heart attack and then you had rupture and a blockage in the artery and then you have a heart attack. HF is much more insidious. You don’t have that sort of sharp demarcation. There are people who don’t have HF and then there are people who have HF, and then there’s sort of this whole grey transition zone, where depending on how closely you look and how much you evaluate, one can go this way or that way. So, this is a spectrum per se, and remember that HF is not a biochemical diagnosis. It’s not troponin, not myocardial infarction, HbA1c, and diabetes––it’s a clinical diagnosis. 

Based on that, I would say that if a patient does not have a history of HF but needs to be treated for diabetes, then by giving an SGLT-2 inhibitor you are likely preventing or delaying HF development, which is a big deal because HF hospitalization is associated with a particularly high risk, and in patients who develop HF, you’re talking about 50% five-year mortality. So, if you are preventing HF, HF hospitalization as a surrogate for new-onset HF with those people who don’t have HF at baseline, you’re doing the patient a whole lot of good. Now, using hospitalization in those pa­tients with HF, you’re seeing ≈25% to 30% mortality at 1 year, so there’s a lot of benefit in that group as well. But the nuance is that for prevention of HF, in those people who don’t have HF, absolutely use the drug and you will have a very good chance of preventing HF. If you have somebody with diabetes and HF, you’re using this drug for diabetes control… absolutely, good idea—you’re likely to have the HF benefit. The question comes up whether these are HF drugs per se, forget about diabetes—even if you don’t have diabetes—should these be given only for HF. We have seen the beneficial results in reduced EF but not preserved EF yet.

DR SHANIK: What is unique about it is the fact that they had studied a very large population, as we alluded to earlier, in a primary prevention population—patients without known CV disease, without known HF—and it demonstrated a clear benefit regardless of whether there was HF at baseline. Based on this study, dapagliflozin benefit applies to a broad population. We don’t have to single out patients with HF or try to screen patients for HF. What we should be doing is assessing patients with diabetes using dapagliflozin for glycemic control but also knowing that if they meet the criteria where they have diabetes and additional risk factors for CV disease, they will also get that benefit for hospitalization for HF. It was a primary prevention study showing a benefit in a large number of patients over the course of a number of years and also establishing safety.

DR WASSON: What do you feel is the advantage of using dapagliflozin over the other medications in the SGLT-2 class?

DR BUTLER: We have no really good reason to believe that these drugs are very different than each other. The question is what population you have studied and what outcome you have seen and there are always these differences between trials within the same class of drug. So, the bigger difference is the patient population that was studied rather than the drug itself.

DR WASSON: The dosage of dapagliflozin used in the DECLARE trial that showed improvement in outcome for HF was the 10-mg dose. Is there any benefit for the diabetic patient who has CHF or suspected CHF with the 5-mg dose? 

DR SHANIK: The study itself looked at 10 mg versus placebo. Typically, when we start dapagliflozin in patients with type 2 diabetes, we start at 5 mg and titrate to 10 mg. Do we know whether 5 mg would have a similar benefit? We really don’t know because we haven’t looked at that dose for this specific indication. If you’re comfortable using 10 mg to start to mirror the data or using 5 mg and then titrating up, I think that the higher dose doesn’t necessarily give any greater risk than 5 mg when it comes to hypoglycemia or anything else other than mycotic infections. So, I think most people should feel comfortable using either dose.

DR WASSON: Would you start at 10 mg
immediately in some patients with HF?

DR SHANIK: There is no contraindication, so no reason you couldn’t. If using dapagliflozin for glycemic control, it is recommended to start at 5 mg and titrate to 10 mg if needed. For patients who have type 2 diabetes and risk factors for CV disease, 10 mg is indicated for reduction of hospitalization for HF.  

DR WASSON: Are there any other closing comments you would like
to express before concluding our
discussion?

DR BUTLER: Traditionally, we were really worried about the atherosclerotic complications of diabetes, stroke, peripheral vascular disease, myocardial infarction—not as much HF. We have over the years realized that: (1) atherosclerotic CV disease is very common in patients with diabetes; and (2), while coronary artery disease remains a very potent risk factor for HF, there are all of these other mechanisms where, in the absence of myocardial infarction, you can still develop HF. Now we have all of these therapies that are coming up in these trials that can actually prevent HF. So, if you already have manifest HF, the more likely it is that you will see a cardiologist and you’ll get good therapy. The bigger thing is in the primary care setting and the endocrine setting and nephrology setting and other settings, where patients have not developed HF and are not under the care of a cardiologist, that we worry about HF prevention and give these therapies.

DR SHANIK: I would reiterate those points as well as add that I think we’ve come a long way when it comes to diabetes treatments. Not only have we established CV safety but we have all of these additional benefits that we wouldn’t have known without these large outcomes trials. We are no longer managing HbA1c, per se, but we’re looking at diabetes patients and managing the comorbidities and trying to improve outcomes with various agents. The DECLARE trial showed us that HF is a significant comorbidity in patients with diabetes. HF is not what we typically think of as a risk factor in patients with diabetes and CV risk. But it’s pretty clear that patients with diabetes have a high risk for HF. We have clear long-term benefits that will affect a broad population of patients with diabetes.

DR WASSON: Fantastic. Gentleman, I can’t thank you enough for your input, your expertise, and your lifelong work as physicians. I want to thank you again for helping us with this roundtable discussion. All the best to you.

 

REFERENCES

1 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;380:347–357.

2 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.

3 Neal B, Perkovic V, Mahaffey KW, et al; for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377;644–657.

4 McMurray JJ, Solomon SD, Inzucchi SE, et al; for the DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.

5 McMurray JJ, DeMets DL, Inzucchi SE, et al; for the DAPA-HF Committees and Investigators. The Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019;21:1402–1411. doi: 10.1002/ejhf.1548

6 Butler J, Handelsman Y, Bakris G, Verma S. Use of sodium-glucose co-transporter-2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure. Eur J Heart Fail. 2020;22:604–617.

7 Farxiga (dapagliflozin) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

8 Perkovic V, Jardine MJ, Neal B, et al; for the CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306. 

 

ADDITIONAL REFERENCES

1 Farxiga (dapagliflozin) [medication guide]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

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