Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes

State-of-the-art Review

Milton Packer, MD

JACC Heart Fail. 2021;9(7):535-549.

Conclusions

The totality of experimental and clinical evidence suggests that diabetes may promote the development of heart failure by effects on intracellular nutrient deprivation and surplus signaling and autophagy, by effects on sodium-hydrogen exchange in the heart and kidneys, and by effects on biological active adipose tissue depots, which—acting alone or in concert—may lead to the development of both HFrEF and HFpEF. Antagonism of these mechanisms may underlie the demonstrated ability of SGLT2 inhibitors to reduce the risk of serious heart failure events.

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Abbreviations And Acronyms
Akt = protein kinase B; AMPK = adenosine monophosphate-activated protein kinase; FGF21 = fibroblast growth factor 21; HFpEF = heart failure with a preserved ejection fraction; HFrEF = heart failure with a reduced ejection fraction; LV = left ventricular; mTOR = mammalian target of rapamycin complex 1; NHE1 = sodium-hydrogen exchanger isoform 1; NHE3 = sodium-hydrogen exchanger isoform 3; SIRT1 = sirtuin-1; PGC-1α = proliferatoractivated receptor-gamma coactivator; SGLT2 = sodium-glucose cotransporter 2

Table 1. Effect on Time to First Heart Failure Hospitalization in Large-Scale Randomized Controlled Cardiovascular Outcomes Trials With SGLT2 Inhibitors
Trial	Patient Population	Active Treatment Assignment	Effect on Time to First Hospitalization for Heart Failure HR (95% CI)
EMPA-REG OUTCOMES	7,020 patients with type 2 diabetes	Empagliflozin	0.65 (0.50–0.85)
CANVAS	10,142 patients with type 2 diabetes	Canagliflozin	0.67 (0.52–0.87)
DECLARE-TIMI58	17,160 patients with type 2 diabetes	Dapagliflozin	0.73 (0.61–0.88)
VERTIS-CV	8,246 patients with type 2 diabetes	Ertugliflozin	0.70 (0.54–0.90)
CREDENCE	4,401 patients with type 2 diabetes with chronic kidney disease	Canagliflozin	0.61 (0.47–0.80)
DAPA-CKD	4,304 patients with chronic kidney disease, 67% with diabetes	Dapagliflozin	0.51 (0.34–0.76)
SCORED	10,584 patients with type 2 diabetes with chronic kidney disease	Sotagliflozin	0.67 (0.55–0.82)
DAPA-HF	4,744 patients with chronic heart failure and reduced ejection fraction, 42% with diabetes	Dapagliflozin	0.70 (0.59–0.83)
EMPEROR-Reduced	3,730 patients with chronic heart failure with reduced ejection fraction, 50% with diabetes	Empagliflozin	0.69 (0.59–0.81)
SOLOIST	1,222 with type 2 diabetes with worsening heart failure, with reduced and preserved ejection fraction	Sotagliflozin	0.64 (0.49–0.83)

Endpoint for the SOLOIST and SCORED trials was total heart failure hospitalization and urgent care visits for worsening heart failure. See Supplemental Appendix for references.
CANVAS = CANagliflozin cardioVascular Assessment Study; CREDENCE = Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD = Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF = Dapagliflozin And Prevention of Adverse outcomes in Heart Failure; DECLARE-TIMI58 = Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOMES = BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Reduced = EMPagliflozin outcome tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction; SCORED = Effect of Sotagliflozinon Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2 = sodium-glucose cotransporter 2; SOLOIST = Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes; VERTIS-CV = Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes.

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Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes

State-of-the-art Review

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