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A Medication Class Multitasker - "Flozins" For Heart Failure

I feel, at times, like I am stuck in a COVID-19 bubble. My attention to every detail of this pandemic has separated me from my continual medication knowledge learning mission. 

Part of each of my days is to learn something new about evidence-based medicine utilization. My goal is to discover current medications that lower mortality and increase patient outcomes. An example of my five-year knowledge research is prescribing a newer class of diabetic medications called flozins to decrease mortality in patients with heart failure (HF).

The average age of private pilots in the U.S is 55 years (Scientific REP. May 22, 2019). Being over 55 years also puts a person at increased risk of cardiovascular disease, diabetes, and sleep apnea.

A new medication therapy added to existing evidence and guideline-based treatment can significantly improve outcomes. Data from the CDC (Centers for Disease Control) in 2020 lists heart disease as the number one and diabetes as the number eight leading cause of death. The combination of heart disease and diabetes deaths in 2020 caused 799,150 deaths in the U.S.

Heart failure is present in 10-30% of all patients with diabetes type 2 (T2D). The majority of HF patients are 70 years of age and older. In addition, 30-40% of all acute or chronic HF cases have T2D (Eur J Heart Fail. 2018;20(5):853–72). Heart failure may also increase the risk of T2D (Eur Heart J. 2020;41(2):255–323). These two disease states are interrelated.

Diabetes type 1 (T1D) patients cannot produce insulin, and insulin is provided to the body regularly to control blood glucose. As a review, type 2 diabetic patients can still produce insulin from the pancreas. The amount and quality of insulin produced by the pancreas are less. The two most common medication classes prescribed for T2D are sulfonylureas and metformin. Sulfonylureas help squeeze more insulin out of the beta cells in the pancreas to control blood glucose levels. Examples of sulfonylureas are glipizide, glyburide, and glimepiride. Metformin decreases the amount of hepatic glucose produced in the liver, reduces intestinal absorption of glucose, and improves insulin sensitivity.

Heart failure diagnoses worldwide have increased dramatically over the past two years due to the COVID-19 pandemic. HF patients do not want to risk scheduling appointments to see their primary physician or cardiologist. Patients especially do not want to go to the emergency room, increasing their risk of contracting COVID and further damaging their weakened hearts. An HF patient with a good ejection fraction is heart failure with preserved ejection fraction (HFpEF). The second category is HF with reduced ejection fraction (HFrEF). The cardiologist is looking at the squeeze of the left ventricle. Better contraction ejects more blood to the brain, kidneys, and peripheral system of the body. The HF medications that decrease the mortality risk include beta-blockers, angiotensin-converting enzymes inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor-neprilysin inhibitors (ARNIs). The flozins may soon become evidence- and guideline-based therapy in addition to standard medication care.

On March 29, 2013, canagliflozin (Invokana®), was the first new class of medications for T2D to be introduced to the market. The indication for canagliflozin is glucose control in T2D in addition to diet and exercise. Canagliflozin is a sodium-glucose co-transporter inhibitor (SGLT2I). The kidneys play an essential role in regulating blood glucose. Glucose from the blood gets filtered to the kidney. The kidney reabsorbs the glucose back into the blood via the sodium-glucose co-transporter2 (SGLT2) receptors. Inhibiting the SGLT2 receptors moves the glucose to the urine for excretion. This process decreases blood glucose levels. The term used for this mechanism is the “gluc-uretic” (a combination of glucose and diuretic) effect. Two added benefits of canagliflozin are blood pressure and weight reduction in the patient. The pleiotropic effects (actions other than those for which the agent is explicitly developed) for all flozins are nephroprotection (kidney protectant), lowering blood pressure, and weight reduction.

In 2017, the CANVAS program study integrated two trials involving 10,142 participants with T2D and high cardiovascular risk. Patients treated with canagliflozin had a lower chance of cardiovascular events than patients who received a placebo. The placebo group had a greater risk of amputation primarily at the toe level (N Engl J Med 2017, 377: 644-657). A later indication for canagliflozin is a reduction of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke with T2D and cardiovascular disease. Another indication is the reduction in the risk of end-stage kidney disease. Kidney disease is a manifestation of diabetes that could eventually lead to kidney failure and hemodialysis.

Dapagliflozin (Farxiga®) is the second SGLT2I to be marketed in the U.S. in January of 2014. The indication for dapagliflozin is glucose control in T2D with diet and exercise. In November 2019, the DAPA-HF trial was published, studying 4744 patients with moderate to severe HF. DAPA-HF studied patients with moderate to severe HF, reduced ejection fraction with or without T2D. Dapagliflozin significantly reduced the risk of CV death and hospitalization due to HF (N Engl J Med 2019;381:1995-2008). This randomized controlled trial was the first study to look at patients without T2D. This trial was a game-changer as dapagliflozin provided efficacy evidence in HF. A new indication for dapagliflozin was approved in April 2021to decrease the worsening of chronic kidney disease. The outcomes of DAPA-CKD were a reduction in worsening renal function, the onset of end-stage renal disease, and cardiovascular and renal cell death (N Engl Med. 2020;383:1436-46).

Empagliflozin (Jardiance®) is the third SGLT2I to be marketed in the U.S. in August of 2014. Empagliflozin has the same indication for T2D with diet and exercise as the previous two SGLT2Is. The EMPEROR-Reduced trial studied 3740 patients with moderate to severe HF and a low ejection fraction. All study patients were on evidence-based HF therapy.The results of this trial were lower risk of cardiovascular death or hospitalization for heart failure regardless of the presence or absence of T2D (N Engl J Med 2020; 383:1413-1424). What differentiates empagliflozin from the other SGLT2I is the EMPEROR-Preserved trial. EMPEROR-Preserved studied 5988 patients with moderate to severe heart failure and an ejection fraction of more than 40% in addition to standard HF therapy.Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure patients and a preserved ejection fraction, regardless of the presence or absence of T2D (N Engl J Med 2021;385:1451-1461).

My fellow AOPA pilot community, prescribed empagliflozin, canagliflozin, or dapagliflozin for T2D are reaping the rewards of the multitasking effects. Flozins control the blood glucose levels and decrease the risk for a heart attack, cardiovascular death, stroke, kidney disease, and HF. That is a pretty great deal. All of our family, friends, and the world who are TD2 on flozins should be sleeping better knowing this evidence-based tidbit. Having another medication in our pharmacy toolbox to prevent mortality and hospitalizations can bring positive outcomes worldwide. Thank you, flozins, for your multitasking properties. Be well and safe.

Larry M. Diamond, PharmD, CFII

Larry Diamond has a Doctor of Pharmacy Degree and has been a pharmacist for 37 years. Larry’s pharmacy practice has been as a Clinical Pharmacy Specialist in Cardiology, Orthopedic Surgery Specialist and most recently Clinical Pharmacy Coordinator. He is a CFII, a pilot for 33 years and has been an AOPA member since 1984.

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