In the past several years, major heart failure guidelines have undergone a significant shift: SGLT2 inhibitors are now considered foundational therapy for patients with reduced or preserved ejection fraction regardless of diabetes status, according to the 2022 heart failure guideline from the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice and the 2023 focused update from the European Society of Cardiology. 

The change reflects consistent findings from large clinical trials, which demonstrated significant reductions in heart failure hospitalizations and, in some cases, cardiovascular mortality. 

Despite this strong evidence base, real-world use remains uneven, particularly in primary care, where many clinicians still associate the medications with diabetes management and hesitate to prescribe them to nondiabetic patients. A 2023 study in the American Journal of Health-System Pharmacy found that SGLT2 inhibitors remain underutilized in patients with heart failure with or without type 2 diabetes.

Cardiologists say that there are many reasons for the slow uptake of these drugs in the primary care environment. It has less to do with the evidence and more to do with workflow, perceptions, and logistical challenges, they said. 

Joyce Oen-Hsiao, MD, a cardiologist and associate professor of medicine at Yale School of Medicine in New Haven, Connecticut, said insurance-related friction is a key impediment.

“The prescription requires a prior authorization from the insurance company, who [does] not want to pay for the higher-price medication,” she said. “In addition, the SGLT2 for heart failure with preserved [left ventricular] function is newer, so there may be a delay in PCPs [primary care physicians] knowing the new guidelines.”

The issue of medication burden can also contribute to clinician hesitation, said Renato Apolito, MD, a cardiologist with Hackensack Meridian Health in Hackensack, New Jersey.

 “These patients may be on five to seven drugs, and they’re going to be like, what the hell is this guy doing? All he does is give me a new drug every time I see him,” he said.

Then there’s the issue of the drug’s provenance, which Johanna Contreras, MD, advanced heart failure and transplant cardiologist at Mount Sinai Fuster Heart Hospital, said continues to shape its perception — stereotyping, in other words. 

“The medication started as a diabetes medicine, so a lot of people only saw it like that.” Contreras said. “People were reluctant at the beginning because I think they didn’t understand what the effect was in reality.”

Barriers to compliance exist once the prescription is in the patient’s hands as well, according to Contreras. She said that cost frequently prevents patients from filling prescriptions, as these medications are expensive and have high co-payments as well. 

She said a lack of patient education also plays a role.

“I give you the medication, you go to the pharmacy and the pharmacy is like, ‘Oh my god, you have diabetes,’ and you’re like, ‘No I don’t,’” Contreras said. “Patients don’t understand the concept, so it’s very important that we explain.”

The Why: How SGLT2 Inhibitors Work

Although developed for glycemic control, SGLT2 inhibitors offer multiple cardiovascular benefits that have nothing to do with blood sugar. Oen-Hsiao outlined mechanisms that included mild diuresis, decreased arterial pressure, improved renal hemodynamics, anti-inflammatory effects, and improved myocardial energetics.

Contreras expanded on the metabolic shifts these drugs induce.

“There have been a lot of theories about what this medication does. We know that there is a natriuretic effect — when you’re eliminating sugar in the urine, you also eliminate fluids — so we know that this medication helps to eliminate that extra water retention that people with heart failure have,” Contreras said. 

But there is also an effect in the myocytes, in the heart muscle. Some data, show that when sugar is eliminated from the body, the heart muscle favors using fatty acids, which are more potent as a fuel in the myocyte than the sugar, Contreras said. 

Contreras said that with the combination of natriuresis, the change in the metabolism of the myocytes, and an improvement in kidney function with this medication, “that’s when the whole thing called the cardiokinetic metabolic theory comes out.”

“In a lot of people with heart failure, it’s not just that the heart is not pumping normally, it’s a whole neurohormonal balance that happens in your body,” Contreras said. “We’ve known for many years that metabolism is affected.”

Regardless of the mechanism of action, Apolito said that SGLT2s’ place in the clinical landscape should be clear to clinicians.

“They’re equivalent to all the other drugs now that are out there for heart failure,” he said. “Like, hey, if you want to start Farxiga before Entresto, you’re allowed to.”

Safety Concerns: What PCPs Should Know

When considering SGLT2 therapy for nondiabetic heart failure, PCPs frequently express concerns about hypoglycemia, renal decline, and ketoacidosis.

“When they are hesitant to start a patient on SGLT2 inhibitors, PCPs most raise the question of worsening kidney function and dropping blood sugars,” Oen-Hsiao said. “There also have been cases of ketoacidosis in nondiabetic patients started on SGLT-2 inhibitors.”

Studies have shown that at least the renal concerns are unmerited. Oen-Hsaio said data has shown that by removing the sugar and sodium through the urine, the SGLT2 inhibitors lower the pressure in the glomeruli — small arteries in the kidney — that helps to improve kidney function. However, with this sugar exiting in the urine, both Contreras and Apolito highlighted the importance of counseling around urinary tract infections (UTIs). 

Contreras said that patient education is important in women, especially older women, while Apolito said that he would not use the drug in patients with a history of recurrent UTIs.

The Patients Who Benefit Most

As long as UTIs aren’t an issue, Contreras said that for her, indications for early initiation are broad — even if the patient first presents during an inpatient setting.

“Any patient with heart failure, independent of what kind — definitely the benefit is there. Absolutely start [an SGLT2 inhibitor],” she said. “We all have enough data showing that when you keep the SGLT2 inhibitor or you start in an acute setting when the person is congested, it’s actually helpful in decongesting a patient.”

SGLT2 inhibitors may have particular value in several subgroups of heart failure patients who are traditionally difficult to treat, one being those with comorbid chronic kidney disease. Contreras said that the renal effects of the drug class can be especially meaningful in this setting.

She said postmenopausal women, a group disproportionately affected by heart failure with preserved ejection fraction, are another critical group to consider. Hormonal shifts, metabolic changes, rising blood pressure, and increased adiposity all converge to increase cardiovascular risk in later midlife.

Other populations Contreras said would recognize enhanced benefits include patients with left ventricular hypertrophy, hypertrophic cardiomyopathy, or atherosclerosis.

Apolito, Contreras, and Oen-Hsiao report no disclosures.