Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a newer class of medications for individuals with type 2 diabetes. While their blood-sugar-lowering ability is only moderate, other properties set them apart: The protection they provide to individuals with heart failure and diabetic chronic kidney disease is nothing short of remarkable.
“SGLT2 inhibitors are powerhouses for risk reduction. That’s where they shine,” says Cleveland Clinic endocrinologist Keren Zhou, MD.
About the SGLT2 Inhibitors
| DRUG
Generic (Brand Name) |
FDA-APPROVED USES | ||
| CVD | CKD | T2D | |
| bexagliflozin (Brenzavvy) | X | ||
| canagliflozin (Invokana) | X | X | |
| dapagliflozin (Farxiga) | X | X | X |
| empagliflozin (Jardiance) | X | X | X |
| ertugliflozin (Steglatro) | X | ||
| sotagliflozin (Inpefa) | X | X | X |
CVD = cardiovascular disease | CKD = chronic kidney disease | T2D = type 2 diabetes
SGLT2 Inhibitors Are Essential in HFrEF
Early in clinical trials of SGLT2 inhibitors, the drugs appeared to benefit individuals with heart failure with reduced ejection fraction (HFrEF), in which the heart’s main pumping chamber (the left ventricle) cannot contract sufficiently to pump blood out into the circulation. The ejection fraction is the amount of blood pumped from the left ventricle with each heartbeat. People with HFrEF have an ejection fraction of 40% or less.
Trials of two SGLT2 inhibitors, empagliflozin (Jardiance) and dapagliflozin (Farxiga), found that the drugs lowered rates of heart-failure hospitalization and cardiovascular death in individuals with heart failure, whether they had type 2 diabetes or not.
Today, SGLT2 inhibitors are considered one of four essential medications for treating symptomatic HFrEF.
A Boon for People with HFpEF
One notable benefit of SGLT2 inhibitors is their effectiveness in treating heart failure with preserved ejection fraction (HFpEF), in which the left ventricle’s ability to contract is not affected but it does not expand well enough to refill with blood between heartbeats.
“Historically, very few drugs have been effective in HFpEF, so this discovery is a game changer,” says Cleveland Clinic preventive cardiologist Abhayjit Singh, MD.
HFpEF is increasingly recognized as a metabolic disease: About 80% of patients with HFpEF have type 2 diabetes and obesity. The effectiveness of SGLT2 inhibitors is thought to be due to its various metabolic effects.
“With SGLT2 inhibitors, we get a diuretic effect, some hemoglobin A1c control, a slight decrease in blood pressure, a slight loss in total body fat and some positive effects on the liver,” Dr. Singh says. “Individually, these effects are rather small, but in aggregate they are beneficial because they address so many risk factors.”
SGLT2 Inhibitors in Kidney Disease
The health of your heart and kidneys is so closely intertwined that whatever harms or benefits one harms or benefits the other.
Empagliflozin, dapagliflozin plus a third SGLT2 inhibitor, canagliflozin (Invokana®), slow the progression of chronic kidney disease, decrease the risk of needing dialysis and reduce deaths and hospitalizations in individuals with kidney disease with or without type 2 diabetes.
“Most individuals with chronic kidney disease die from heart attack or stroke, rather than kidney failure,” Dr. Singh says. “Even those who have a slight decrease in kidney function but no cardiovascular disease or type 2 diabetes are at increased risk for a bad outcome from cardiovascular disease. I think there is a place for early use of SGLT2 inhibitors in addition to lifestyle measures to help protect people with kidney disease.”
Who Should Take SGLT2 Inhibitors
“Most patients with a clinical diagnosis of HFpEF or HFrEF should be prescribed empagliflozin or dapagliflozin, assuming there are no contraindications,” Dr. Singh says.
The issue under discussion is how early in the course of the disease they should start. For individuals with type 2 diabetes, concurrent risk factors are taken into consideration when choosing the best anti-diabetes medication. “We try to select a medication that addresses those risk factors,” says Dr. Zhou. “We use SGLT2 inhibitors in individuals with type 2 diabetes and cardiovascular disease risk factors, particularly those with heart failure or diabetic kidney disease.”
Because the glucose-lowering effect of SGLT2 inhibitors is modest, the medication is generally used to boost the effect of a more powerful diabetes drug. “SGT2 inhibitors are a great option. We are lucky to have options in the diabetes medication arsenal that help provide organ protection,” Dr. Zhou says. “If you have type 2 diabetes, cardiovascular disease, and kidney disease, it’s worth looking into adding this medication.”
Who Should Not Take SGLT2 inhibitors
Despite the benefits of SGLT2 inhibitors, they may not be a good choice for some individuals, including those with poor kidney function characterized by a glomerular filtration rate below 20. “In this population, these drugs have limited ability to lower blood sugar levels and may have unwanted side effects,” Dr. Zhou says.
Because SGLT2 inhibitors increase the amount of glucose in the urine, women prone to recurrent genital yeast infections should avoid these drugs.
SGLT2 inhibitors also carry a slight risk of diabetic ketoacidosis, in which insufficient insulin causes glucose to build up in the bloodstream. Lacking insulin, the body transitions to using ketones, thereby causing the blood to become acidic and damage internal organs.
“I think most internists, cardiologists, and endocrinologists should feel comfortable prescribing SGLT2 inhibitors in patients with type 2 diabetes, given the clinical efficacy and safety of these drugs,” Dr. Singh says. “However, the risk of diabetic ketoacidosis increases in patients with type 1 diabetes, so I am generally more cautious with those patients and work closely with their endocrinologist to determine the appropriateness of SGLT2 inhibitor therapy.”
A Missing Benefit
With all these advantages, it seems logical that SGLT2 inhibitors would protect against heart attack, stroke, hospitalization and cardiovascular death, but so far clinical trials have not confirmed their ability to reduce these cardiovascular risks.
Dr. Singh notes, “Based on the clinical data we have so far, I don’t consider SGLT2 inhibitors to be first-line therapy for patients with coronary artery disease or other atherosclerotic cardiovascular disease unless they have another indication.”
