SGLT2 Inhibitors, the next GDMT?

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Authors: Jeremy Pollock, MD and Stormi Gale, PharmD, BCCP

Questions regarding the role of sodium-glucose co-transporter-2 (SGLT2i) in heart failure with reduced ejection fraction (HFrEF) have been raised since the publications of EMPA-REG OUTCOME in 2015.¹ Despite being designed to assess cardiovascular risks in patients with diabetes, empagliflozin was associated with reductions in heart failure (HF) hospitalizations. Subsequent results from CANVAS and DECLARE-TIMI 58 suggested the benefits in HF are likely a class effect, although these studies only included a small number of patients with pre-existing heart failure.^2,3 The results of the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF), presented at the 2019 European Society of Cardiology Congress, shed light on the potential for these medications in HFrEF.

Summary of DAPA-HF
DAPA-HF evaluated the effects of dapagliflozin in 4,744 patients with symptomatic HFrEF and an elevated N-terminal pro–B-type natriuretic peptide.^4,5 Patients with eGFR < 30 ml/min/1.73 m², symptomatic hypotension or systolic blood pressure < 95 mmHg, or type 1 diabetes mellitus were excluded. A diagnosis of type II diabetes was not required; overall, less than half of the patients enrolled had diabetes. The majority of patients enrolled had class II or III HF (68% and 32%, respectively) and a mean ejection fraction of 31%. About half of patients had ischemic cardiomyopathy.. The majority of patients were on appropriate guideline-directed medical therapy, with 94%, 96%, and 71% of patients enrolled on renin-angiotensin system inhibitors (RASi), beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA), respectively.

After a mean follow-up of 18.2 months, dapagliflozin reduced the primary outcome of cardiovascular death, hospitalization for HF, or urgent HF visit compared to placebo (HR 0.74, 95% CI 0.65-0.85; p=0.00001), with a number needed to treat of 21. In addition to benefits in all three of the individual components of the composite primary endpoint, dapagliflozin also reduced the relative risk of all-cause mortality by 17% (HR 0.83, 95% CI, 0.71-0.97; p=0.022). Importantly, the benefits of dapagliflozin were consistent in patients both with and without a diagnosis of diabetes.

So what does this mean for current practice?
Many cardiologists have shied away from these agents due to unfamiliarity and perceived safety concerns (ie, genital infections, diabetic ketoacidosis). It’s worth noting that in clinical trials many of the commonly cited adverse effects were similar to placebo (although it may be reasonable to avoid canagliflozin due to the increased risk of lower limb amputations).² Furthermore, it is expected that updated guidelines will include SGLT2i as a treatment option in HF.

The optimal time to initiate SGLT2 inhibitors remains unanswered. Currently, SGLT-2 inhibitors should be considered for all patients with HFrEF (on GDMT) and adequate renal function (i.e., CrCl > 30 mL/min) who are not hypotensive. Additional studies are underway to evaluate the role for these agents in patients with advanced kidney disease, although this class has been shown to elicit renoprotective effects in other populations.³

Cardiologist Perspective – Jeremy Pollock, MD

I love landmark trials, especially in the field of HF. Practicing in the community, with a focus on HFrEF, I have seen first-hand the benefit of aggressive medical management and how many patients recover their EF and/or have a significant improvement in symptoms. Adding another medication to our armamentarium is of tremendous benefit to this population; I believe SGLT2i will become another “pillar” of GDMT along with of RASi, BB, and MRA.

As with any new therapy, we must judiciously incorporate it into our practice and play particular attention to study generalizabilty. DAPA-HF excluded SBP less than 95mmHg, symptomatic hypotension, and an eGFR <30; this is a large proportion of our outpatient, community populations. As mentioned previously, the systolic blood pressure (SBP) of 122 mmHg is well above the average SBP in my HFrEF population. I tell all my patients to expect mild orthostatic symptoms (if they aren’t running a low BP, you aren’t pushing meds hard enough!); as such, many of them are running SBPs in the 90’s and would not have qualified for this trial. Additionally, we must keep in mind the noted adverse events, and watch the registry data closely for untoward safety signals.

Next, as a cardiologist practicing in a in the community, I must figure out how to logistically add an SGLT2i to the already over-burdened, polypharmacy riddled, med-list of my patient (see picture for example of real HFrEFs patient pill box). Cost will drive low uptake in the community as most of these drugs are costing patients (even with good coverage) 30-50 dollars a month, which for many is prohibitive. I am blessed to have excellent staff that help with prior authorizations to get patients the medications they need; but for those without these resources, navigating the paperwork is and will remain a barrier.

Overall, I am optimistic. We now have multiple trials supporting the cardiovascular benefits of the SGLT2i. We cardiologists need to get on board. The first step is to re-brand SGLT2i; these are no longer solely for diabetes, but rather to decrease CV mortality and morbidity. I look forward to following the story of this class as more data emerges, and I hope that we can all start to think about adding this as the next pillar of care for our HFrEF population.

Bottom Line
Despite the impressive outcomes demonstrated in DAPA-HF, SGLT2i prescribing has historically been limited to endocrinologists and primary care, and resistance amongst cardiologists remains. An interesting analogy was presented several times at the 2019 Heart Failure Society of America Annual Meeting. Statins used to be considered “endocrinology” drugs prior to published evidence of benefit in cardiovascular disease, and now are a standard of care within cardiology.⁶ As such, we urge cardiologists to embrace this class of therapy in a similar manner. DAPA-HF is perhaps the most practice-changing study in HFrEF since the publication of PARADIGM-HF in 2014. It is expect that these agents will be added as an option in the next HF guideline update, and should be considered in all patients with HFrEF on established GDMT. Before then, however, it will be prudent for cardiologists to gain familiarity with the prescribing and monitoring of these medications, as there is a clear benefit in patients with HFrEF despite adequate background therapy.

Jeremy Pollock, MD

Dr. Pollock is a cardiologist at University of Maryland St. Joseph Medical Center in Towson, MD. He specializes in heart failure, preventative cardiology, and cardiac imaging. Follow him on Twitter @bmorecardiology.