Best Practices for Starting SGLT2 Inhibitors in HFpEF Treatment

Matthew C. Konerman, MD; Sarah K. Adie, PharmD


July 17, 2023

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This transcript has been edited for clarity.

Matthew C. Konerman, MD: Hello. I'm Dr Matthew Konerman. I'm a heart failure specialist at the University of Michigan Health. I'm here today to discuss sodium glucose cotransporter 2 (SGLT2) inhibitors in the treatment of heart failure with preserved ejection fraction (HFpEF) with my dear friend, Sarah Adie, PharmD, from the University of Michigan.

Sarah K. Adie, PharmD: Hi, Matt. It's great to be here.

Konerman: It's great to have you. Let's get started. We are here to discuss a very hot topic in cardiology: SGLT2 inhibitors in HFpEF. We have known that SGLT2 inhibitors have a role in the treatment of heart failure, particularly heart failure with reduced ejection fraction, as demonstrated in the DAPA-HF and EMPEROR-Reduced trials.

Today we are going to focus on a review of evidence supporting the use of SGLT2 inhibitors in HFpEF. We will also then transition to discussing common questions regarding the clinical use of SGLT2 inhibitors in HFpEF. We know that SGLT2 inhibitors are beneficial in HFpEF based on two large, randomized trials that were published recently.

In the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction (DELIVER) trial, over 6000 patients with heart failure and an ejection fraction greater than 40% were randomized to receive dapagliflozin vs placebo and followed for a median of 2.3 years. Less than half of the patients had type 2 diabetes.

The composite endpoint of worsening heart failure or cardiovascular death was significantly reduced to 16.4% in the dapagliflozin arm compared with 19.5% in the placebo arm. This difference was driven by differences in worsening heart failure.

The second trial was the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction, the EMPEROR-Preserved trial. This study had very similar results. In almost 6000 patients with heart failure and an ejection fraction greater than 40%, patients were randomized to empagliflozin or placebo and followed for about 2.2 years.

Again, SGLT2 inhibition with empagliflozin was associated with a significant reduction in the composite primary endpoint of cardiovascular death and heart failure hospitalization. The benefit was driven by a reduction in heart failure hospitalizations. Interestingly, there was no significant difference in total hospitalizations between the two groups, which does raise the importance of managing other comorbid conditions in HFpEF, given the rates of non-cardiovascular hospitalizations in that type of heart failure.

Given the supportive data from these two trials, the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure supports the use of SGLT2 inhibitors in HFpEF with a class 2a recommendation. Similarly, the recent 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction also gives a class 2a recommendation, supporting SGLT2 inhibitor use.

We know the evidence, now, that led SGLT2 inhibitors to be indicated in the treatment of HFpEF

Sarah, what should be considered when starting an SGLT2 inhibitor? What dose do you use? What contraindications should you consider?

Adie: Good questions, Matt. In terms of patient selection, we know that SGLT2 inhibitors can be used in the treatment of patients with HFpEF, with or without type 2 diabetes. These agents are contraindicated, however, in patients with type 1 diabetes or if they have prior diabetic ketoacidosis.

A dose of 10 mg daily for both dapagliflozin and empagliflozin has been approved for the heart failure indication. Notably, there are differences in terms of estimated glomerular filtration rates (eGFR) cutoff for both agents compared with the FDA indication for patients with type 2 diabetes, as the heart failure trials actually included patients with an eGFR down to 20 mL/min/1.73 m2 for empagliflozin and 25 mL/min/1.73 m2 for dapagliflozin.

Thinking about the impact on other guideline-directed medical therapy, SGLT2 inhibitors may affect potassium excretion. In a meta-analysis of clinical trials evaluating SGLT2 inhibitor treatment in those with heart failure, their use was shown to be associated with reduced discontinuation of mineralocorticoid receptor antagonist therapy.

This may be important, as it may allow for initiation of mineralocorticoid receptor antagonists or angiotensin receptor neprilysin inhibitors, which also have been shown to have some benefit in HFpEF. We also think of SGLT2 inhibitors having a slight impact on systolic blood pressure, perhaps by about 3-5 mm Hg. We should note to use caution in those with a systolic blood pressure < 95 mm Hg, as they were excluded from the trials.

Additionally, in terms of adverse effects, we know from the trials that there's associated risk for genitourinary yeast infections and urinary tract infections.

Any other thoughts on considerations for initiation of these agents, Matt?

Konerman: Sarah, I can't help but think about our goals when we round together on the heart failure service. We're always trying to optimize medications as best we can before discharge. Importantly, the benefit of SGLT2 inhibitors in clinical trials was seen within 30 days of initiation. Like other medications, we do try to get patients on these medications during the inpatient stay, especially given that these drugs are associated with a reduction in heart failure hospitalization.

When starting an SGLT2 inhibitor, especially in the hospital, we do have to recognize that an increase in serum creatinine does sometimes occur, with an average reduction of the eGFR of around 5%. Knowing this, it probably isn't the best thing to start an SGLT2 inhibitor in the setting of aggressive intravenous diuresis, though that doesn't mean it can't be started with stabilization prior to discharge.

Very importantly, the benefit of SGLT2 inhibitors remains despite mild reductions in eGFR, and over time, SGLT2 inhibitors are protective for renal function. Therefore, we encourage providers not to discontinue therapy simply because of a mild increase in creatinine or decrease in eGFR.

Sarah, how would we adjust medications for type 2 diabetes when starting an SGLT2 inhibitor?

Adie: That's a great question. We know that SGLT2 inhibitors reduce hemoglobin A1c only by about 0.5%-1%. However, if patients are well controlled in terms of their hemoglobin A1c or if they have frequent hypoglycemia and they're on sulfonylureas or insulin, we want to wean or stop the sulfonylurea and then reduce the total daily insulin by about 20% in those patients.

Additionally, we want to advise patients to monitor their blood glucose for 3-4 weeks, especially if we're making some of those changes. If patients are on other medications for their diabetes, the risk for hypoglycemia is very low. Generally, we don't need to adjust any of those medications or dosages.

In patients with type 2 diabetes, if there is a surgical procedure planned, especially if you're starting these agents during hospital admission, the SGLT2 inhibitor should be held for at least 3 days.

Matt, another common question that comes up quite a bit is whether diuretics should be adjusted at the time of SGLT2 inhibitor initiation.

Konerman: Sarah, that's a great question. I think we're still learning about the right answer to that question. We do know that, in clinical trials, the loop diuretics that patients were receiving were not routinely adjusted upon SGLT2 inhibitor initiation.

In fact, SGLT2 inhibitors were not associated with higher rates of volume depletion in clinical trials. Although routine adjustment of loop diuretics with SGLT2 inhibitor initiation is not recommended, we do recommend that you assess volume status as you otherwise would.

For example, there are instances in which a patient may be mildly fluid-volume depleted, and you may decide to decrease a loop diuretic at the time of SGLT2 inhibitor initiation. Conversely, there could be instances where the patient is fluid-volume overloaded, and you're certain that you don't want to reduce the loop diuretic at the time of SGLT2 inhibitor initiation.

Most importantly, we recommend obtaining a basic metabolic panel to assess renal function and electrolytes within 7 days of starting an SGLT2 inhibitor.

Adie: We hope our discussion today will promote the appropriate use of SGLT2 inhibitors in the treatment of HFpEF. Thank you for joining us.

Konerman: Thank you.

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