Hailed by AstraZeneca as the first trial examining use of an SGLT2 inhibitor for heart failure in patients with and without diabetes, the results of DAPA-HF, which were presented at ESC Congress 2019 in Paris, was one of the most anticipated presentations at this year’s annual meeting.
Results of the study reveal that 10 mg dapagliflozin (Farxiga) reduced death and hospitalization by 26% in patients with heart failure and reduced ejection fraction with and without type 2 diabetes.
“The trial shows that dapagliflozin reduces death and hospitalization, and improves health-related quality of life, in patients with heart failure and reduced ejection fraction, with and without diabetes,” said lead investigator John McMurray, MD, professor at the University of Glasgow. “The clinical implications are potentially huge – few drugs achieve these results in heart failure and dapagliflozin does even when added to excellent standard therapy.”
The trial enrolled a cohort of 4744 patients from 20 countries and randomly assigned them to either dapagliflozin 10 mg once daily or a matching placebo. A total of 2373 patients received dapagliflozin while 2371 received placebo.
Study treatments were given on top of standard of care treatment. Investigators noted 94% of patients received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker or angiotensin receptor-neprilysin inhibitor. Additionally. 96% took a beta-blocker and 71% took a mineralocorticoid receptor agonist.
The primary endpoint of the study was the composite of a first episode of worsening heart failure or death from cardiovascular causes. Over the follow-up period, which had a median length of 18.2 months, the primary outcome occurred in 16.3% in the dapagliflozin group and in 21.2% in the placebo group (HR 0.74; 95% CI 0.65-0.85; P
Investigators also performed analyses assess each primary outcome component separately. Comparing the 2 groups, investigators found 9.6% of patients in the dapagliflzoin group and 11.5% of patients in the placebo group died from cardiovascular causes (HR P
=0.029). Additionally, 10% of those receiving dapagliflozin and 13.7% receiving placebo experienced a first episode of worsening heart failure (HR 0.70; 95% CI 0.59–0.83; P
In regard to side effects, 7.5% in the dapagliflozin group had an adverse event related to treatment volume depletion compared to 6.9% in the placebo group — no significant difference between groups was noted. Adverse events related to renal dysfunction were reported in 6.5% of the dapagliflozin group and 7.2% of the placebo group with no significant differences between the 2 groups.
Investigators also noted that major hypoglycemia and lower limb amputation and fracture were infrequent and occurred at similar rates in both groups.
Recently, Mikhail Kosiborod, MD, cardiologist at Saint Luke’s Mid America Heart Institute, sat down with MD Magazine
to discuss the potential use of the treatment as it nears closer to an FDA decision. Kosiborod, who led the DEFINE-HF trial, offered insight on the impact dapagliflozin could have in the lives of patients and physicians.
MD Mag: What would it mean for patients if dapagliflozin were to receive additional approvals for heart failure?
So, a couple of things. One is, what we know from the press release is that the trial met the primary endpoint, which was a composite of cardiovascular death or worsening heart failure (defined as either hospitalization for heart failure or urgent heart failure visit requiring intravenous therapy). And the trial was done in patients with and without type 2 diabetes. As of right now dapagliflozin is approved for glucose lowering in patients with type 2 diabetes.
Once the results from the trial are submitted to the US Food and Drug Administration, and if those results are compelling enough for the US Food and Drug Administration to grant a cardiovascular indication for dapagliflozin — which in this case would be an indication for heart failure — it could substantially change how dapagliflozin would be viewed as a therapeutic agent.
Right up until now, it was a medication to treat type 2 diabetes. With this development, if all of those assumptions that I just mentioned actually come true, if all of these things were to transpire, then dapagliflozin would no longer be just an agent for treating type 2 diabetes, but rather, an agent to treat heart failure.
Therefore, the potential application of this particular agent, dapagliflozin, would really evolve quite dramatically from being a glucose-lowering medication primarily, which is what it's currently approved for, to being a therapeutic agent to treat heart failure.
So, the key concept here is that you're stepping out - as far as the potential therapeutic uses of this agent - of the realm of it being a glucose lowering drug to being an agent to treat heart failure, potentially regardless of type 2 diabetes status or glycemic status of the patient. Of course, that has a number of potential implications to the whole new therapeutic area.
People with heart failure, have a very poor prognosis, as they have high risk of recurrent hospitalizations, death and progression of the disease, frequently leading to death, and also a very high symptom burden. And if in fact, once we see these results and if the FDA finds them compelling and it's indicated for patients with heart failure, this would be a very welcome development for patients with heart failure and reduced ejection fraction.
What are some of the other implications? Of course, while there are a number of different specialties that treat patients with type 2 diabetes — this may include internal medicine, family practice, primary care, endocrinology and cardiology for some patients, especially those with diabetes and established heart disease — but heart failure primarily is the domain of a cardiovascular specialist. So, that's another important facet. I think, if all of these assumptions come through, cardiologists will need to be a lot more actively engaged, potentially, in the actual clinical use of dapagliflozin than they have been so far.
MD Mag: What does it mean, for cardiologists when you see SGLT2 inhibitors beginning to receive additional CV indications from the FDA?
So, this would be a bit of a different development, right? Because to date what we've seen, if we're talking specifically about SGLT2 inhibitors — or the 2 SGLT2 inhibitors currently on the market that have cardiovascular indications — Empagliflozin has an FDA indication for reducing cardiovascular death in patients with diabetes and established atherosclerotic cardiovascular disease and canagliflozin has a MACE reduction indication in the same patient population. These are indications specifically in people with Type 2 diabetes.
If all of these things were to occur, if what we are postulating may happen actually happens, and there is a heart failure indication for dapagliflozin -- and if that indication transcends type 2 diabetes and actually applies to people with or without type 2 diabetes who have heart failure, this, of course, would be different, because it will be a completely new therapeutic indication for an agent, regardless of diabetes status, and, essentially would squarely land this particular agent — and possibly other SGLT2 inhibitors to be determined in future trials — as treatment for heart failure regardless of the type 2 diabetes. This lands it squarely in the domain of a cardiologist. I just wanted to make sure we understand that there is a difference between a cardiovascular indication specifically in people with type 2 diabetes versus a broader cardiovascular indication that applies to people with or without diabetes, which this may potentially lead to.
In terms of how this applies to manage,ent of patients with Type 2 diabetes -- as we get more data about cardiovascular effects of SGLT2 inhibitors, and, especially, data suggesting that they have substantial cardiovascular benefits, it certainly builds the case for cardiologists to become much more involved in type 2 diabetes management — and that's part of it. The main goal of management of patients with type two diabetes, as far as I'm concerned, should be to provide treatments for these patients that improve survival and the quality of life.
So, make patients live longer and feel better -- and the number one cause of morbidity and mortality in people with type 2 diabetes is cardiovascular disease, including cardiovascular complications, like heart attacks, strokes, and heart failure hospitalizations. So, anything that we can do, to try to reduce that burden is welcome and it's very important for both the cardiologists and the patients that we treat.
So, I think on a practical level, when there are specific indications by the US FDA, to reduce cardiovascular risk, for these agents — it certainly makes it easier for us to then incorporate the use of these agents into our daily practice. But again, I think what's happened so far, including indications currently in existence, have been very specific just for patients with type 2 diabetes because that's how the trials were done.
Dapa-HF is very different in this regard, because it's enrolled patients with and without diabetes. So, it's really not just about patients with diabetes anymore, it's about anybody with a disease condition — in this particular case, heart failure. So, this class has had an interesting journey, right? It started with these agents just being developed for glucose lowering, then it became 'Yes, these agents lower blood glucose and hemoglobin A1C, but they also have important cardiovascular benefits'.
Now, it’s “These agents can have benefits regadless of diabetes status and glycemia”. That's kind of the journey that we are in the middle of right now — that's what we're witnessing.
MD Mag: With a Priority Review designation for chronic kidney disease recently announced, it appears dapagliflozin may also receive indications in other areas — what sets dapagliflozin apart from other SGLT2 inhibitors?
So, dapagliflozin will be the first agent with a dedicated, heart failure trial completed in people with and without diabetes. So, at this point, that's the main distinguishing feature is that there will be outcome data for heart failure, regardless of diabetes status, with dapagliflozin in a large global trial that can truly informe clinical practice and possibly translate into a new indication. Again, we will see whether that happens.
With that acknowledged, there are other agents in the class that have ongoing heart failure trials, and that includes empagliflozin in the EMPEROR program, and sotagliflozin in the SOLOIST program, and SOLOIST is specifically in people with type 2 diabetes but the EMPEROR program includes people with without type 2 diabetes. So, there will be more data coming and that's for big outcome trials, there are also smaller trials looking at other important outcomes in patients with heart failure, both with reduced and preserved ejection fraction. Dapa-HF of course is specifically in patients with heart failure and reduced ejection fraction.
So, I think what sets dapagliflozin apart, as of right now, is that it's the first agent for which dedicated outcome trial data will be available in heart failure. But what we've seen so far in diabetes trials, is that there is quite a bit of overlap between different agents in the class in terms of cardiovascular and renal effects. They're pretty consistent.
There are a number of meta analyses that have now been published showing very consistent and robust benefits on prevention of incident heart failure primarily in patients who didn't have established heart failure at baseline – across several agents in the SGLT-2i class, as well as beneficial effects on the progression of diabetic kidney disease.
So there's quite a bit of overlap in the diabetes trials, and some of these effects appear to be be class effects. Now, whether same is going to be true in heart failure remains to be seen.
MD Mag: Is there anything else you wanted to add about dapagliflozin or SGLT2 inhibitors that we may not have touched on?
It's a very exciting time for patients with heart failure, because as I said, it's a really deadly disease and has a very high risk of progression. These patients suffer from a very substantial burden of debilitating symptoms. So, having additional agents which appear to be efficacious in reducing important adverse outcomes in this patient population is really great news for the patients and for those of us who take care of them.
*Editor's note: This interview took place before the release of full DAPA-HF results and, as such, Kosiborod declined to comment on any data points from the study.