The drug empagliflozin is able to significantly reduce the size of abnormally large hearts

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Scientists at the University of Glasgow have furthered the understanding of how novel diabetes drugs can improve prognosis for patients with heart failure.

The results of the SUGAR-DM-HF trial – published in Circulation and presented to the American Heart Association – showed that the drug empagliflozin, originally a treatment for patients with type 2 diabetes, was able to significantly reduce the size of abnormally large hearts, which helps explain how they reduce the risk of hospitalization and cardiovascular death in patients with heart failure.

The trial tested the effects of empagliflozin on the structure and function of the heart in patients with heart failure, which is the most common reason for hospitalisations in over 65-year olds in the UK.

Empagliflozin – one of a class of drugs known as SGLT2 inhibitors – was tested in the UofG-led trial on 105 patients with heart failure who volunteered from 15 hospitals from Scotland.

Dr. Matthew Lee, from the University’s Institute of Cardiovascular and Medical Sciences, said: “By chance, these drugs were found to be excellent drugs for heart failure in patients with and without diabetes.

Very importantly, these findings help us explain, for the first time, why this new class of drugs have such powerful benefits to lessen chances of people with heart failure being admitted to hospital or dying.”

Mark Petrie, professor of cardiology at ICAMS, said; “In two recent SGLT2 inhibitor trials in patients with heart failure – DAPA-HF and EMPEROR-Reduced, both led by or contributed to by UofG clinical academics – SGLT2 inhibitors have become a ‘must have’ treatment in patients with heart failure.

The new discovery of how these drugs work to reduce hospitalisations, death and improve quality of life will help many cardiologists welcome these drugs into the care of their patients. Doctors love to know how novel drugs work.”

Naveed Sattar, professor of metabolic medicine, added: “The University of Glasgow has a world class reputation in heart failure research and we’re very proud to present the results of this study, which comes on the back of seminal heart failure trials led by or contributed to by Glasgow clinical academics.

This research is a wonderful example of how a team of experts spanning several disciplines – including doctors, nurses, pharmacists, cardiology, metabolic medicine, diabetes, nephrology and radiology – can work together to execute important trials.”

The study, “Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF),” is published in Circulation.


Empagliflozin is an antidiabetic agent used in adult patients with type 2 diabetes mellitus. It was FDA-approved in 2014. Empagliflozin can be used as a single agent or as a combination agent with other antidiabetic products. Combination products include empagliflozin and linagliptin, and empagliflozin in combination with metformin.

These newer agents can be more expensive for patients, thus impeding the physician’s ability to prescribe them based on patient financial considerations. However, the American Diabetes Association (ADA) is calling for agents with proven mortality reduction for use as second-line therapy after metformin. Such agents include empagliflozin and liraglutide.

The primary treatment for diabetes is lifestyle management and exercise, followed by metformin use. Per Standards of Medical Care in Diabetes, if the A1c is greater than 9%, then combination therapy with metformin is recommended. In 2016, the FDA (United States Food and Drug Administration) approved a new indication for empagliflozin, which was to reduce the risk of cardiovascular death in adult patients with type 2 diabetes and cardiovascular disease.

Empagliflozin has shown to reduce hospitalizations for heart failure and death from cardiovascular causes. Patients are at an increased risk of cardiovascular mortality with type 2 diabetes, so prescribers should be made aware of the benefits of empagliflozin. In a nutshell, empagliflozin may be effective in the following settings.[1][2][3]

In overt atherosclerotic CVD and/or heart failure patients with suboptimal glycemic control despite metformin and lifestyle modification
Nephropathy (urine albumin-to-creatinine >300 mg/g)
As a third-line agent in case of suboptimal glycemic control despite using two oral drugs, or metformin and insulin therapy
As a second-line agent in cases of suboptimal glycemic control for patients with metformin who cannot take insulin and weight gain and hypoglycemia is a significant issue.

Mechanism of Action

Empagliflozin works by inhibiting the sodium-glucose co-transporter-2 (SGLT-2) found in the proximal tubules in the kidneys. Through SGLT2 inhibition, empagliflozin reduces renal reabsorption of glucose and increases urinary excretion of glucose. The glucose-lowering effect of the drug is independent of insulin.

In type 2 diabetes patients, urinary glucose excretion increased by approximately 64 grams per day with 10 mg of empagliflozin and 78 grams per day with 25 mg. Empagliflozin reduces sodium and volume load, causing intravascular contraction through its diuretic and natriuretic properties.[4] Moreover, empagliflozin is associated with weight loss, with reductions in blood pressure without an increase in heart rate.

Administration

Recommended dose:

Empagliflozin is an oral medication dosed at either 10 mg daily or 25 mg daily. The recommended dose is 10 mg once daily in the morning taken with or without food. If tolerated initially, dosing may increase up to 25 mg. Correct volume depletion, if present, before starting the drug.

In patients with renal impairment:

No dose adjustment is necessary if eGFR is ≥ 45 mL/min/1.73 m2l but take precautions if it falls below this.

Adverse Effects

Empagliflozin has several adverse effects to be of note including hypotension, ketoacidosis, acute kidney injury, genital mycotic infections, hypoglycemia when used with insulin, dyslipidemia, Fournier gangrene, and pyelonephritis.

Empagliflozin causes osmotic diuresis and intravascular volume contraction and thus can cause symptomatic hypotension, particularly in patients on diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs), and the elderly, patients with renal impairment, and patients with low systolic blood pressure.

Empagliflozin increases serum creatinine and decreases eGFR. Renal function should thus be initially evaluated and further monitored periodically. Use of empagliflozin is not recommended if GFR is less than 45 mL/min, and when GFR is less than 30 mL/min/1.73m^2, the drug is contraindicated.

Empagliflozin is associated with ketoacidosis, particularly in patients with type 1 diabetes, which is why it is not used in that patient population. Factors predisposing to ketoacidosis are pancreatic disorders, history of pancreatitis, pancreatic surgery, alcohol abuse.

Hypoglycemia risk increases when using empagliflozin in combination with a sulfonylurea or insulin. Use caution if co-prescribing and consider lowering the sulfonylurea dose.

Empagliflozin increases the risk of genital mycotic infections and urinary tract infections. Evaluate for signs and symptoms and treat appropriately. Male genital mycotic infections include balanitis, balanoposthitis, scrotal abscess, and penile infection. Female mycotic infections include vulvitis and vulvovaginal candidiasis. In women, urinary tract infections and genital mycotic infections were more common than in males.

A rare but serious bacterial infection is necrotizing fasciitis of the perineum; Fournier gangrene. Symptoms begin as early as week one of treatment and as late as two years after starting the medication. Patients taking SGLT2 inhibitors should receive counseling about the risk of necrotizing fasciitis of the perineum. Clinicians should report confirmed infections to the FDA.

Contraindications

In instances of severe renal impairment, defined as GFR less than 30 mL/min/1.73m^2, empagliflozin is contraindicated. The use of empagliflozin is not recommended if GFR is less than 45 mL/min or during the second and third trimesters of pregnancy. Other contraindications include those with end-stage renal disease, those on dialysis, and those with a severe hypersensitivity reaction to empagliflozin. Empagliflozin may be used in cases of hepatic impairment. Empagliflozin is not for use with patients with Type 1 diabetes or those with diabetic ketoacidosis.

Monitoring

Monitoring for empagliflozin includes a hemoglobin A1c (HbA1c) reading every 3 to 6 months. Renal function, blood pressure, lipid profile, and pregnancy test need require verification before initiation. Empagliflozin should not be given during the second and third trimester of pregnancy due to potential fetal risk.

Renal function and blood pressure require routine monitoring during treatment course due to effects on intravascular contraction. Moreover, clinicians should ask patients whether they experience any urinary symptoms or issues to rule out mycotic and urinary tract infections.

Geriatric patients are more prone to suffering adverse effects related to reduced renal function and volume depletion. Patients should be carefully monitored for hypoglycemia and hypotension if they are co-prescribed insulin, sulfonylureas, or diuretics.

Toxicity

The most commonly reported side effects were urinary tract infections, genital mycotic infections, and dyslipidemia. Due to its diuretic properties related to volume depletion, there were also reports of dehydration, hypotension, hypovolemia, and syncope. The FDA issued a warning for Fournier gangrene, a type of necrotizing fasciitis of the perineum. There were twelve reported cases, and all twelve were hospitalized, requiring surgical debridement. If suspected, stop the drug and have the patient report to the ED promptly for a surgical evaluation.[5][6]

Enhancing Healthcare Team Outcomes

The landmark trial for empagliflozin is called the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes mellitus patients (EMPA REG OUTCOME) which pooled a total of 7020 patients and found significantly lower rates of death from cardiovascular causes, hospitalizations for heart failure, and death from any co-transporter in the empagliflozin group[7]. This trial was the first of its kind to show a reduction in cardiovascular mortality in patients with type 2 diabetes and cardiovascular risk.

Due to findings in the EMPA REG and LEADER trial, societies are now favoring SGLT2 inhibitors and GLP 1 agonists as second-line therapy over insulin depending on patient characteristics. According to the Efficacy and Durability of Initial Combination (EDICT) for Type 2 diabetes trial, triple dose combination therapy of metformin, SGLT 2 inhibitor, and pioglitazone in patients with newly diagnosed type 2 diabetes had a more significant reduction in HbA1c levels than patients who sequentially added on therapy with medications.[8]

The entire interprofessional healthcare team should participate in empagliflozin therapy. The family doctor or endocrinologist will make the initial prescribing decision. Nursing should understand the adverse event profile of this drug, and assist in monitoring at follow-up visits, for both side effects as well as therapeutic effectiveness.

The pharmacist should weigh in with dosing verification, suggestions on dosing titration, and performing medication reconciliation to prevent drug interactions, and can suggest other agents if additional glucose control is necessary. These various disciplines collaborating as a cohesive interprofessional unit will optimize therapy with empagliflozin while minimizing risks. [Level 5]

References

  • 1.Home P. Cardiovascular outcome trials of glucose-lowering medications: an update. Diabetologia. 2019 Mar;62(3):357-369. [PubMed]
  • 2.Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, Sambevski S, Kaspers S, Pfarr E, George JT, Zinman B. Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation. 2019 Mar 12;139(11):1384-1395. [PMC free article] [PubMed]
  • 3.Schwaiger E, Burghart L, Signorini L, Ristl R, Kopecky C, Tura A, Pacini G, Wrba T, Antlanger M, Schmaldienst S, Werzowa J, Säemann MD, Hecking M. Empagliflozin in posttransplantation diabetes mellitus: A prospective, interventional pilot study on glucose metabolism, fluid volume, and patient safety. Am J Transplant. 2019 Mar;19(3):907-919. [PMC free article] [PubMed]
  • 4.Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, Lund SS, Woerle HJ, Broedl UC. Acute Pharmacodynamic Effects of Empagliflozin With and Without Diuretic Agents in Patients With Type 2 Diabetes Mellitus. Clin Ther. 2016 Oct;38(10):2248-2264.e5. [PubMed]
  • 5.Smyth B, Perkovic V. New hypoglycemic agents and the kidney: what do the major trials tell us? F1000Res. 2018;7 [PMC free article] [PubMed]
  • 6.Cheng JWM, Colucci VJ, Kalus JS, Spinler SA. Managing Diabetes and Preventing Heart Disease: Have We Found a Safe and Effective Agent? Ann Pharmacother. 2019 May;53(5):510-522. [PubMed]
  • 7.Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE., EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. [PubMed]
  • 8.Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015 Mar;17(3):268-75. [PMC free article] [PubMed]

More information: Matthew M. Y. Lee et al. Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF), Circulation (2020). DOI: 10.1161/CIRCULATIONAHA.120.052186

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