SGLT 2 inhibitors for heart failure

 SGLT2 Inhibitors

1. First developed for glycemic control for patients with diabetes, have become one of the four pillars of guideline-directed medical therapy for patients with HF 

2. In 2015, the EMPA-REG OUTCOME study evaluated the impact of empagliflozin on major adverse cardiac events in patients with diabetes and unexpectedly showed a 35% relative risk reduction in hospitalization for HF.  

How Do SGLT2 Inhibitors Work? 

1. SGLT2 inhibitors block the reabsorption of sodium in the proximal tubules of the kidney. 

2. Significant natriuresis as well as osmotic diuresis due to glucosuria. 

3. Have also been shown to attenuate adverse cardiac remodeling and fibrosis in animal models.

Available drugs

• Empagliflozin: SGLT 2 inhibitor, Dose 10 mg and 25 mg

• Dapagliflozin: SGLT2 inhibitor, Dose 5 mg and 10 mg

• Sotagliflozin: SGLT 1 and 2 inhibitor, Dose 200 mg and 400 mg

1. Sotagliflozin is slightly different than dapagliflozin and empagliflozin in that it is a combined SGLT1/2 inhibitor. 

2. SGLT2 inhibition leads to the excretion of glucose in the urine while inhibition of SGLT1 delays intestinal glucose absorption. 

Guidelines for use 

• 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure 

1. HF with reduced ejection fraction- Class I indication

2. HF with mildly reduced EF (41-49%)- Class 2a indication

3. HF with preserved ejection fraction (defined as an LVEF of 50% or greater)-Class 2a indication

How and when to start? 

1. Effects of SGLT2 inhibitors on HF-related outcomes appear to be similar across sex and race.

2. Can be initiated in the outpatient setting as well as in the inpatient setting 

3. First, it is important to ensure there are no contraindications to SGLT2 inhibitor therapy. 

4. These include a history of type 1 diabetes or history of diabetic ketoacidosis given the risk of euglycemic diabetic ketoacidosis that has been reported. 

5. Additionally, SGLT2 inhibitor therapy should be avoided in patients with a history of Fournier’s gangrene. 

6. These medications are not recommended during breastfeeding or pregnancy due to potential fetal risk during the second and third trimesters. 

7. While not an absolute contraindication, there have been increased genitourinary tract infections which patients should be counseled on. 

8. In the EMPULSE trial (Empagliflozin in Patients Hospitalized with Acute Heart Failure Who have Been Stabilized), patients were safely initiated on empagliflozin 10 mg daily once they were on a stable dose of diuretic. 

9. The recently presented DAPA-RESIST trial compared dapagliflozin with metolazone in patients hospitalized for HF who were diuretic resistant. 

10. Dapagliflozin provided a similar rate of decongestion with less frequent hypokalemia and hyponatremia.  

Effect on Kidneys 

1. SGLT2 inhibitors have also shown themselves to be disease-modifying therapies for patients with chronic kidney disease (CKD)

2. In that initial cardiovascular outcomes trial, EMPA-REG Outcome, patients with empagliflozin had significantly lower hazards of developing end-stage kidney disease or doubling of serum creatinine with reduction in albuminuria. 

3. This has been followed by CREDENCE, DAPA-CKD, SCORED and EMPA-KIDNEY, which have all focused on the CKD population. 

4. In a prespecified analysis of DAPA-CKD, a 27% reduction in the primary composite endpoint of 50% sustained decline in eGFR, end-stage kidney disease, or kidney or cardiovascular death was still observed even in those with Stage 4 CKD. 

5. It is important to recognize there will be an expected “dip” in eGFR after starting SGLT2 inhibitor therapy. However, in the absence of other adverse events, this should not lead to their discontinuation.