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American Diabetes Association mini-symposium on heart failure in diabetes presented by Biykem Bozkurt, MD, Ph.D., FHFSA, FACC, FAHA, FESC.
Diabetes mellitus has an array of secondary associated complications that can arise from poor glycemic control. For example, heart failure has a higher risk of developing and leading to cardiovascular death in people with diabetes. Every 1% increase in HbA1C is associated with an 8% increase in risk for developing heart failure. Comorbidities that increase the risk and probability of heart failure include hypertension, obesity, and coronary heart disease. There are 100 million people with obesity and/or hypertension in the United States alone, 92 million with prediabetes and 26 million with diabetes. Thus, a large percentage of Americans are at higher risk of developing heart failure.
SGLT-2 inhibitors are known to have cardiovascular benefits on top of glycemic control effects. Previous trials have established a correlation between SGLT-2 inhibitors and the prevention of heart failure in people with diabetes. DECLARE-TIMI 58, published in January of 2019, assessed the safety outcomes of cardiovascular death, myocardial infarction, or ischemic stroke for patients with type two diabetes and with, or at increased risk for, cardiovascular disease. 17,160 patients were randomly assigned to the dapagliflozin or placebo group. Patients treated with dapagliflozin had a lower rate of cardiovascular death or hospitalization for heart failure. The study did not result in a higher or lower rate of myocardial infarction, or ischemic stroke in the dapagliflozin group.
December 2020, a relationship study between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure patients with and without SGLT-2 in the DECLARE-TIMI 58 trial was published. This assessed and determined that patients with type 2 diabetes and higher N-terminal-pro hormone B-type natriuretic (NT-proBNP) or high sensitivity troponin T (hsTnR) levels are at increased risk of cardiovascular death or heart failure hospitalization. Dapagliflozin reduces the risk in patients with higher baseline NT-proBNP and hsTnT biomarkers. The multiple studies of SGLT-2 outcomes and biomarker screenings have been incorporated into numerous guidelines to reduce heart failure risk in patients with type 2 diabetes.
A new universal definition and classification of heart failure were released in March of 2021 by Bozkurt et al. Due to lack of standardization; the new approach utilizes hemodynamic and physiologic characteristics to define heart failure. Stage A is for patients at risk for heart failure without current prior symptoms or signs of heart failure and a structural, biomarker, or genetic marker of heart disease. Stage B is pre-heart failure for patients without current or prior symptoms or signs of heart failure, but evidence of structural or functional cardiac abnormality or biomarkers abnormality with peptides or troponin. Stage C is heart failure for patients with current or prior symptoms of heart failure caused by a structural and functional cardiac abnormality. This stage can be further divided into heart failure in remission with guideline-directed management therapy (GDMT) and risk factor modifications or persistent heart failure. Stage D is advanced heart failure for patients with severe symptoms and signs of heart failure at rest, recurrent hospitalizations, despite GDMT refractory or intolerant to GDMT.
The EMPEROR-Reduced trial released in October of 2020 aimed to determine the effects of empagliflozin treatment on cardiovascular death or hospitalization for worsening heart failure. The study consisted of 3730 with NYHA class II, III, or IV heart failure and ejection fraction of less than or equal to 40%. The trial concluded that patients treated with empagliflozin have a lower risk of death from cardiovascular causes or hospitalizations for heart failure than those in the placebo group. In April 2021, an analysis of the EMPEROR-Reduced trial was published and evaluated the 71% of patients enrolled in the trial who were using mineralocorticoid receptor agonists (M.R.A.). They concluded that M.R.A.s did not influence the effects of empagliflozin on clinical outcomes.
The SCORED and SOLOIST trials from January 2021 evaluated the use of sotagliflozin, a sodium-glucose cotransporter 1 and 2, compared to a placebo in patients with diabetes and chronic kidney disease or recent hospitalization for heart failure. The primary endpoint was the number of deaths from cardiovascular causes and hospitalizations/urgent visits for heart failure. Among the 10,584 participants, sotagliflozin reduced the risk of cardiovascular deaths and hospitalizations/urgent visits from heart failure compared to placebo in the SCORED trial. In addition, SOLOIST concluded that patients who initiate sotagliflozin therapy before or shortly after discharge could lower their risk of cardiovascular death and hospitalizations/urgent visits from heart failure compared to placebo.
Practice Pearls:
- DECLARE-TIMI 58 concluded that patients with type 2 diabetes and with or increased risk for cardiovascular disease treated with dapagliflozin had a lower rate of cardiovascular death or hospitalization for heart failure. In addition, patients with higher NT-proBNP or hsTnR levels are at increased risk of cardiovascular death or heart failure hospitalization.
- The new universal definition of heart failure helps standardize the New York Heart Association classification of stage A thru D by utilizing biomarkers, structural abnormalities, genetic markers, and guideline-directed management therapy.
- SCORED and SOLOIST demonstrated that sotagliflozin effectively reduced cardiovascular deaths and hospitalizations/urgent visits linked to heart failure.
Mosenzon O, Wiviott SD, Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomized trial. Lancet Diabetes Endocrinol. 2019 Aug;7
Zelniker TA, Morrow DA, Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium-glucose cotransporter 2 inhibitor therapy in DECLARE-TIMI 58. Eur J Heart Fail. 2020 December 2.
Packer M, Butler J, EMPEROR-Reduced Trial Committees and Investigators. Evaluation of the effect of sodium-glucose cotransporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail. 2019 Oct;21
Bhatt DL, Szarek M, Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021 January 14;
Bozkurt B. Heart Failure in Diabetes—New Therapeutic Insights. American Diabetes Association mini-symposium. June 25, 2021. https://www.ada2021.org/sessions (ADA Symposium login required).
Jasmine Dumontier-Hiott, PharmD Candidate 2022, University of South Florida Taneja College of Pharmacy