SGLT2 Inhibitors Shine as Therapy for Patients With Heart Failure

Patients with heart failure currently on other medications could benefit from the addition sodium-glucose co-transporter-2 (SGLT2) inhibitors to their treatment regimens, noted a recent review in Current Diabetes Reports.

SGLT2 inhibitors are especially useful in patients with heart failure and comorbid type 2 diabetes (T2D) because they block the reabsorption of filtered glucose, thereby reducing the risk of heart failure events. These 2 diseases are a common pairing in patients with one or the other.

“We highlight the unique properties of the sodium-glucose cotransporter-2 inhibitors which may lend favorably to their efficient integration in the background of other heart failure therapies,” the authors noted, adding that “combination use in clinical practice has remained low.”

This class of drugs, they added, presents minimal drug-drug interactions, does not require titration, and avoids adverse effects associated with hyperkalemia, or high potassium levels in the blood compared with thiazolidinediones and saxagliptin, which “may increase HF events and thus are discouraged among patients with established HF.”

Among the SGLT2 inhibitor areas the review covered:

• After worsening heart failure events
• Among older patients with heart failure
• Dosing and titration
• Diuretic activity
• Kidney function
• Combining with other heart failure therapies
• Needing to adjust other antihyperglycemic therapies
• Adverse effects of treatment

After Worsening Heart Failure Events

Empagliflozin is currently under investigation in EMPA-RESPONSE-AHF, and initial data are encouraging in that the 60-day mark saw reduced worsening heart failure, rehospitalization for heart failure, and death in patients with acute heart failure. The drug has already shown benefit in EMPEROR-Reduced among patients with heart failure with reduced ejection fraction (HFrEF) and no T2D.

Dapagliflozin, meanwhile, irrespective of T2D status, improved outcomes among patients with HFrEF, in the DAPA-HF trial compared with patients receiving placebo. Also, hospitalized patients in this trial saw a greater reduction in heart failure events vs patients enrolled but never hospitalized.

Among Older Patients With Heart Failure

Arterial stiffness is more common in older adults (>65 years), and there is evidence that SGLT2 inhibitors improve this condition by reducing oxidative stress and improving endothelial function. There is also a possible link between SGLT-2 inhibitors and a decrease in blood pressure, which can benefit patients with hypertension.

Dosing and Titration

“All SGLT2 inhibitors are once-daily medications,” the authors noted, “and have minimal drug interactions.” In fact, all cardiovascular outcomes trials (CVOTs) that involved SGLT2 inhibitors showed the class prevented heart failure events in at-risk patient populations with T2D. Additionally, results from large CVOTs do not point to a need to vary SGLT-2 inhibitor doses for greater cardiovascular (CV) benefit. Current trials of patients with heart failure are testing fixed SGLT2 doses, without titration.

Diuretic Activity

There is a possible link between SGLT2 inhibitors and reduced interstitial volume vs intravascular volume, so that the renin–angiotensin–aldosterone system is less activated. Therefore, blood pressure remains consistent and is not subject to increase.

Kidney Function

“Chronic kidney disease (CKD) is a key risk factor for the development and progression of HF,” the study authors said. In this space, trials of SGLT2 inhibitors have shown benefit by reducing the risk of serum creatinine doubling, end-stage kidney disease, or mortality from a CV or renal cause (CREDENCE).

Combining With Other Heart Failure Therapies

Especially for patients with HFrEF, the risks of hypotension and hyperkalemia when combining SGLT2 inhibitors with other medications is minimal and low, respectively, the study authors noted. However, patients on concomitant loop diuretics should be closely monitored during follow-up for congestive signs and symptoms, as well as orthostatic hypotension.

Again, the DAPA-HF trial showed a benefit, in that dapagliflozin benefited patients with heart failure irrespective of background angiotensin receptor neprilysin inhibitor use.

Needing to Adjust Other Antihyperglycemic Therapies

There is a low risk of hypoglycemia when combining dapagliflozin and an SGLT2 inhibitor in patients with HFrEF and T2D, although “a modest glycemic effect is anticipated,” the authors stated. DAPA-HF did show, however, a possibility of stopping sulfonylureas and dipeptidyl-peptidase-4 inhibitors or reducing their dosage.

Also, metformin likely does not have to be introduced in stages when used with SGLT-2 inhibitors, so that patients with HFrEF and T2D can effectively be treated for both conditions simultaneously.

Adverse Effects of Treatment

A typical adverse effect of SGLT-2 inhibitor use is genital yeast infections; however, these can be managed with antifungal remedies (ie, creams, single-dose oral therapies).

Euglycemic diabetic ketoacidosis is another possibility, especially among patients with comorbid T2D. Also among these patients who undergo surgery, some SGLT-2 inhibitors need to be stopped 3 (canagliflozin, dapagliflozin, and empagliflozin) or 4 (ertugliflozin) days beforehand. Ketoacidosis is a great concern, too, so patients need to curb their alcohol use.

SGLT2 inhibitors are currently under investigation for use in patients with heart failure with preserved ejection fraction in the DELIVER and EMPEROR-Preserved trials. EMPA-HEART is looking at their use in reversing adverse cardiac remodeling. And PRESERVED-HF and EMBRACE-HF are looking at how SGLT2 inhibitors affect cardiac biomarkers, structure, and hemodynamics.

“SGLT2 inhibitors represent the most recent class of therapies that have been shown to modify clinical course and improve life expectancy among patients with HFrEF,” the authors concluded. Fixed-dose, once daily dosing without need for titration or frequent electrolyte/kidney function monitoring all favor its safe and feasible introduction in multi-drug regimens across a broad range of HFrEF patients.”

Reference

Khan MS, Vaduganathan M. What makes sodium-glucose co-transporter-2 inhibitors stand out in heart failure? Curr Diab Rep. 2020;20(11):63. doi:10.1007/s11892-020-01347-3