DR WASSON: What percentage of patients have type 2 diabetes and CHF? How do we physicians identify the diabetic patient who may have CHF? Finally, since empagliflozin has multiple clinical implications, the question arises, which medical specialty is best positioned to manage the complex diabetic patient? In other words, is there a specialty that is best positioned to care for the diabetic patient or does the complex diabetic patient require a team approach with coordination of care?
DR BUTLER: There are many questions embedded in that statement. The first issue is what proportion of patients have the comorbid conditions, so it depends on what universe you’re looking at. If you take HF patients, about 45% to 50% of them have diabetes, and if you take diabetes patients overall, about 20% to 25% of patients will HF,6 but part of that also depends on how aggressively you’re searching for it.
A patient with HF who has reduced EF is somebody who has shortness of breath and leg swelling, etc, and that makes it a little bit easier. You can perform an echocardiogram, and if their EF is low you have the diagnosis. HF with preserved EF is a little bit more nuanced, a little bit more difficult to diagnose. What can help you is if somebody is short of breath, not typical shortness of breath, but has fatigue or tiredness or inability to do what they were able to do, some of these symptoms are relatively more subtle, then natriuretic peptide testing in the primary care setting or anywhere else is pretty helpful. If natriuretic peptide levels are really elevated, then again you have your diagnosis. If you do an echocardiogram and you see diastolic dysfunction or left ventricular hypertrophy or left atrial enlargement or elevated coronary artery pressures, then that really helps, but natriuretic peptide by itself, if the levels are elevated, sort of gives you your diagnosis.
If a patient is really having symptoms but you’re not seeing natriuretic peptide level elevation, because natriuretic peptide levels tend to be lower in obese patients, refer to a cardiologist as there are some invasive tests that can be performed to help diagnose, but that’s obviously not for screening. So, on one hand, this is the algorithm to evaluate the patient in the primary care setting.
At some level, this is a little bit of an esoteric discussion because, remember, while we’re talking about treatment for HF, in the majority of the patients in the DECLARE trial who did not have HF, there was also a benefit. In other words, you’re preventing. So, actually the use of the drug is across the spectrum of patients with diabetes who have the characteristics of those in the DECLARE trial, ie, either at high risk for atherosclerotic CV disease or history of atherosclerotic CV disease. You don’t have to have a myocardial infarction if you have a couple of risk factors. I would say one can even simplify this discussion by saying that if somebody meets the criteria for the DECLARE trial, they could significantly benefit from the use of dapagliflozin. What the DAPA-HF trial adds on top of that is now it looks like patients with reduced EF who don’t even have diabetes will benefit as well. But as far as systolic and diastolic dysfunction in the DECLARE trial, everybody benefited.
DR SHANIK: I personally think that it is not necessarily important for the primary care doctor to actually try and find the HF patient. What is important is to find those patients with diabetes who have risk factors as described in the DECLARE trial. This showed that using dapagliflozin can actually have a significant benefit on hospitalization for HF regardless of known HF or not.
DR WASSON: Cardiologists now have many newly released medications for the management of CHF. We have agents such as sacubitril-valsartan,
ivabradine, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, spironolactone, and β-blockers. Do you foresee cardiologists reaching for dapagliflozin in the diabetic patient with CHF? In other words, would cardiologists be comfortable treating the diabetic CHF patient with dapagliflozin, even though the SGLT-2 class of medications were initially approved for the management of diabetes?
DR SHANIK: As I mentioned earlier, we have a lot of good drugs that have demonstrated efficacy for HF reduction and improving outcomes and CV mortality. Looking at the patients who were in the DECLARE study, those were patients who had diabetes without necessarily having HF and they showed a significant reduction in hospitalization for HF.
If you look at just HF patients regardless of whether they had diabetes in the DAPA-HF trial, there was a benefit on top of all those drugs that you just listed. Those patients who had been on the standard of care with all of the drugs that we know work well, they had an additional benefit. There are more data to come out as these trials are being published. I think that we will probably be more likely incorporating SGLT-2 inhibitors in the standard of care to treat patients with HF.
DR BUTLER: My perspective is that the cardiologist should definitely own the problem. They don’t necessarily need to own the drug, but definitely own the problem. If they feel comfortable using the drug in the appropriate patient they should do it, but because there is such a significant CV benefit and CV risk reduction, it is squarely within the job description of the cardiologist. If they don’t want to learn about a new medication, then at least identify that there is this opportunity to improve outcomes further in these high-risk patients and either work with endocrinology or work with primary care or what have you. As far as a patient getting the right treatment, that’s sort of what the purpose is, regardless of who starts it. Having said that, these drugs are really not that difficult to use and my feeling is, with the DECLARE trial findings, maybe the cardiologist would not necessarily jump on board as much, but now with the DAPA-HF trial, I think the cardiology community will slowly and gradually start using these drugs more and more.
DR WASSON: The DECLARE trial has shown delayed progression of renal disease. Estimated glomerular filtration rate (eGFR) showed benefit, especially protective, in those patients who had preserved renal function. The package insert for dapagliflozin suggests that there is "no dosage adjustment needed for patients with eGFR >45 mg/min per 1.73 m2. The glycemic efficacy of dapagliflozin is dependent of renal function, and dapagliflozin is therefore not recommended for use in the treatment of diabetes to improve glycemic control when eGFR is persistently <45 mg/min per 1.73 m2. There is limited experience in patients with eGFR <30 mL/min per 1.73 m2." Many diabetic patients experience chronic kidney disease of varying degrees, have complex medication regimens that compete for renal excretion, or require close monitoring of
renal function such as metformin. How would you prescribe dapagliflozin in the diabetic patient who has renal impairment?
DR SHANIK: The renal protective effect is very intriguing knowing that we now have this class that has all of these other beneficial effects. Not necessarily the glycemic effects, but the safety has been well established with renal patients. In the DECLARE trial, patients all had eGFRs >60 mL/min per 1.73 m2 at baseline. So, I think that the concern is not so much that if the eGFR drops that there is a problem per se. There is limited efficacy with glycemic control in renally impaired diabetes patients, but we’ve learned (especially from the CREDENCE trial)8 that with canagliflozin, patients can have an eGFR as low as 30 mL/min per 1.73 m2 and still have benefits when it comes to long-term renal protection, independent of glycemic control. We might not have as much of a benefit for blood sugars but we’re going to get a long-term protective effect on the kidneys. There is sometimes a short-term drop in eGFR initially. I don’t think that there’s necessarily a safety concern with the diminished eGFR but more so limited efficacy for glycemic control. You still should have a long-term renal benefit from what we’ve seen so far with the data.
DR WASSON: Do you see any other benefits of the SGLT-2 inhibitor class outside of the management of diabetes? Specifically, is there any benefit in using dapagliflozin in patients with hyperuricemia, gout, or fatty steatosis? Do you know of any anti-inflammatory effects of dapagliflozin that would benefit the diabetic patient?
DR BUTLER: I think there’s a potential for nonalcoholic steatohepatitis but those studies are ongoing and we’ll find out over time. I don’t think that we can consider it as a therapeutic option for hepatic steatosis or anything like that just yet.
DR SHANIK: I agree with that.
DR WASSON: SGLT-2 is not without side effects. What are the risks of causing ketoacidosis, genital infections, mycotic infections, or amputations when prescribing dapagliflozin in the management of type 2 diabetes? There were no amputations reported in DECLARE; however, in the CANVAS trial, with canagliflozin, there was "a greater risk of amputation, primarily at the level of the toe or metatarsal."
DR SHANIK: The standard risks are, especially in a dose-dependent fashion, mycotic infections. They are typically relatively easy to treat. The other risks, though very rare, are Fournier gangrene and ketoacidosis. The question about amputation is a very difficult one because this has not been shown in other trials. CANVAS did show a potential imbalance in amputation risk, but, in the higher-risk patients with more advanced renal disease in the CREDENCE trial, there was no imbalance. There was also no imbalance demonstrated in the DECLARE and DAPA-HF trials. So, I think that it’s still open to interpretation and comfort level. This is something to be aware of. Importantly, we should note that patients with diabetes have other potential complications such as amputations and, of course, microvascular disease. We need to be screening for that and be aware of that potential and in these patients in general.