Mikhail Kosiborod, MD: Comorbidity Care with SGLT-2 Inhibition

How do a pair of burgeoning agents influence endocrinology and renal outcomes in cardiovascular care?

Mikhail Kosiborod, MD

Just 2 weeks ago at the European Society of Cardiology (ESC) Congress 2019, investigators presented data showing a 26% reduced risk of death and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), with and without type 2 diabetes, when treated with dapagliflozin (Farxiga).

The DAPA-HF data added to the growing resume of cardiovascular risk benefit from sodium-glucose co-transporter-2 (SGLT-2) inhibitors—and perfectly preceded anticipated data from DEFINE-HF at the Heart Failure Society of America (HFSA) 2019 Scientific Sessions in Philadelphia, PA.

In an interview with MD Magazine® while at HFSA 2019, DEFINE-HF study chair Mikhail Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute, discussed where clinical understanding of SGLT-2 inhibitors—as well as GLP-1 agonists—are stationed headed into the new dapagliflozin data.

He also shared firsthand perspective on treatment dosing and initial patient reaction and outcomes associated with the 2 drug classes.

MD Mag: What are the biggest questions remaining in treating comorbidities of HF patients with SGLT-2 inhibitors?

Kosiborod: So if we start by looking at patients with type 2 diabetes—remember, DAPA-HF and DEFINE-HF are different studies because they look at patients with heart failure regardless of diabetes, right? So we're now going to say, 'How do we take this data and apply it to patients that have type 2 diabetes?'

I think what we now know is that, in these patients with very high risk for cardiovascular complications—remember that cardiovascular disease is the number 1 cause of morbidity and mortality in patients with type 2 diabetes—we now have 2 classes of agents with a highly effective and proven cardiovascular outcomes in GLP-1 agonists and SGLT-2 inhibitors. They have very different effectiveness profiles.

So with GLP-1's, we want to erase what appears to be an effective atherosclerotic vascular disease progression. So the main benefit appears to be reduction in major adverse cardiovascular events (MACE), which are myocardial infarction, stroke, and dying from cardiovascular disease. The effect emerges after several months of treatment, which goes along with atherosclerotic effect of that class.

Whereas with SGLT-2 inhibitors, while they do also modestly reduce the risk of MACE, the place where they really shine is in prevention of heart failure and progression of chronic kidney disease. So multiple trials, both cardiovascular and kidney outcome trials, now show signs of these drugs effectively preventing heart failure in people who have type 2 diabetes, and effectively prevent progression of chronic kidney disease.

And those 2 effects—prevention of heart failure and chronic kidney disease—appear to transcend where the patient is in terms of the spectrum of risk. So whether you're a really low-risk patient that has normal kidney function, or whether you're really high-risk patient with significant chronic kidney disease and albuminuria, these agents appear to be from a relatively protection standpoint as effective in preventing the progression of kidney disease, and also preventing heart failure hospitalization.

Of course, if you already have established kidney disease, your absolute risk of kidney disease progression and heart failure as well are much higher. So it's an absolute benefit that's greater, and the number needed to treat that's lower. But the relative risk reduction is exactly the same, and very consistent across the entire spectrum.

MD Mag: Something that's been discussed in HFSA sessions so far have been the significant need for understanding proper dosing. Where do we set dosing standards, and expectations of improvement and outcomes, relative to patient age and severity of disease?

Kosiborod: Dosing for SGLT-2 inhibitors, regardless of age, is pretty straightforward, actually. And in fact, if you're using these agents to reduce the risk of cardiovascular and kidney outcomes, the lowest dose available on the market for these agents should be sufficient. Those are the doses that have been tested primarily in cardiovascular and kidney outcome trials, and are being tested in the outcome trials. So in most cases, there is no reason to change the dose when you could just with the lowest dose available. And it appears, actually, this should be sufficient in terms of realizing cardiovascular and kidney benefits.

Now, there's this whole debate about whether these medications are safe in older patients. Remember, older patient are at a higher risk, right? So the absolute risk of heart failure and kidney disease progression, and MACE, all of those, that risk is higher. And so as the higher the absolute risk, the greater the absolute benefit, with the same relative risk reduction. So those are the patients that actually going to get more benefit, because they are high-risk.

Now, in terms of side effects, yes you of course need to educate patients about possible side effects. And older patients that may be at higher risk of potential hypoglycemic events, you need make sure that they are educated about that and that they stay well-hydrated. But again, if you look at the big outcome trials, there is no difference in benefit from a relative risk-reduction standpoint, whether you're older or younger.

Age is not a factor. That is an effect modifier, which means that whether you're older or younger, you benefit. So I think in older patients with diabetes, in most of them, the benefit-risk ratio is going to be very favorable for the class.

MD Mag: Speaking more directly to immediate patient response—what sort of feedback are physicians receiving early into prescription of these 2 drug classes? Are there any issues with sustained use?

Kosiborod: Well, as I mentioned before, these medications do have potential side effects like genital mycotic infections, for example. Or in patients with diabetes that may have a degree of insulin deficiency, we need to make sure that you at least think about the risk of diabetic ketoacidosis. But the absolute risk of that event is extraordinarily low. But you need to educate patients about that. And you need to certainly educate patients about genital mycotic infections and how to prevent those or what to do if they develop.

The key here, just like with any other drug class, is patient education. Make sure their expectations are correct. And then, following up with patients and make sure that they are tolerating medications, and you're giving them practical advice about what to do in case there any issues.

In general, I would say in my experience, prescribing these medications is no different than prescribing any other medications. For most medications, especially if you prescribing them for management of type 2 diabetes, or potential cardiovascular indications, most of the time you need to educate the patients about possible benefits, educate your patients about possible risks, and then make sure that somebody follows up with the patient to make sure that they're adhering to therapy and answer any of their concerns and giving practical advice, in case they're having any trouble.

If you do all of those things, the compliance and adherence to therapy is going to come in much greater.

MD Mag: Is there anything else you would want to add?

Kosiborod: I think it's a really exciting time we live in, in terms of all the available therapies we have for patients with type 2 diabetes that have really important, tangible benefits for the 2 most common complications of diabetes, which are cardiovascular and kidney complications.

So I think it's exciting times, but it also reminds us that it's our responsibility as clinicians to do what we can to reduce the risk of those morbid complications in our patients. And it's a good thing that we have multiple potential tools in our toolbox to be able to do it.