Sodium–glucose cotransporter 2 inhibitors in heart failure: does it matter how they work?

It has been almost a decade since EMPA-REG OUTCOME was published, identifying empagliflozin and the sodium–glucose cotransporter 2 inhibitors (SGLT2i) that followed, as the first glucose-lowering therapies found to improve cardiovascular outcomes in type 2 diabetes.[1–3] Subsequent trials demonstrating striking benefits of SGLT2i in people  with heart failure and chronic kidney disease, irrespective of the presence of diabetes, have led to a paradigm shift in the contemporary management of cardiovascular, renal and metabolic disease.[4–8] Specifically in heart failure, the SGLT2i empagliflozin and dapagliflozin were shown in four landmark trials to reduce mortality and hospitalisation rates in patients with reduced or preserved ejection fraction.[4,6–8] Consequently, SGLT2i have been rapidly adopted in cardiology clinical practice. So it may come as a surprise to learn, even after randomised trial data in over 20,000 patients with heart failure, that the mechanisms by which SGLT2i exert their beneficial effects on the heart remain elusive.

As oral hypoglycaemic agents, SGLT2i prevent reabsorption of glucose in the proximal convoluted tubule promoting urinary glucose excretion and thereby lowering blood glucose levels. Secondary effects include weight loss, a modest diuretic effect and blood pressure reduction.[9] How this translates to the observed reductions in mortality and heart failure hospitalisations in clinical trials, which appear independent of glucose and blood pressure lowering effects of SGLT2i, is an area of intense research interest. Several theories have been proposed, including their diuretic effects, decreased arterial stiffness, a positive influence on endothelial function, and preferential shifts to fatty acid oxidation and ketotic metabolism that are favourable to cardiac energetics. However, imaging studies evaluating the impact of SGLT2i on cardiac structure and function have only demonstrated modest and inconsistent improvements in diastolic function and reductions in left-ventricular mass that are not sufficient to account for the observed effects on outcomes in clinical trials.[10–15]

Recognising these uncertainties surrounding cardiac effects of SGLT2i, Hundertmark and colleagues sought to determine whether empagliflozin favourably impacts cardiac energetics in heart failure, which has been loosely shown in one small (n=10), single-group intervention study in type 2 diabetes subjects without heart failure.[16] Published in April in Circulation, the elegant EMPA-VISION trial was a single-centre, double-blind, placebo-controlled, randomised trial of 12 weeks’ empagliflozin 10 mg/day in people with heart failure and preserved or reduced ejection fraction (n=62; age 68±12 years; 58% males; 13% type 2 diabetes). Participants underwent detailed cardiometabolic phenotyping pre- and post-intervention, including cardiac MRI and rest/dobutamine stress phosphorous magnetic resonance spectroscopy (MRS), and targeted metabolomics by mass spectroscopy.[17] The primary endpoint was change in cardiac phosphocreatine:adenosine triphosphate ratio (PCr:ATP) measured using 31P-MRS, a sensitive in vivo measure of the myocardial energetic state, and shown to be abnormal in heart failure with both preserved and reduced ejection fraction.[18] Shifts in cardiac substrate utilisation and energetics are leading mechanisms through which SGLT2i are hypothesised to benefit the heart, and EMPA-VISION would, at last, reveal the missing link bridging the cardiac and clinic effects of these wonder drugs. Sadly, this was not the case and empagliflozin treatment did not alter PCr:ATP in either heart failure with reduced or ejection fraction groups, nor were any changes in circulating metabolomics or ketone bodies observed. Authors of the study concluded: “It is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in heart failure”.[17]

Where do EMPA-VISION and other mechanistic studies of SGLT2i leave us? It appears we are no closer to elucidating why SGLT2i work, and this begs the question: does it really matter? Earnest researchers have expended considerable time and financial investment in this space, mostly in vain. Given the overwhelming clinical evidence base to support SGLT2i use in cardiometabolic diseases, it is reasonable to assert that further mechanistic studies are reductionist and unnecessary. The counterargument to this point is that drug target identification and mechanism of action studies serve future drug discovery or repurposing. For example, aspirin might still be regarded as a simple analgesic were it not for mechanistic studies identifying it as a nonselective cyclooxygenase inhibitor with anti-inflammatory and antiplatelet activity, paving the way for development of a wealth of new drugs spanning medicine from rheumatology to cardiology.[19] The breadth and complexity of cardiometabolic diseases across which SGLT2i are beneficial surely warrants further exploration as to their effects. This in no way prevents eligible patients from receiving these medications now, but has the very real potential to expand applications and open possibilities for other patient groups. Of EMPA-VISION it must be said that, although a negative trial, it moves us a step closer to understanding cardiac mechanisms of SGLT2i and, in this spirit, I congratulate the investigators for their work. 

A digest of the study can be read here.

References

1. Zinman B, Wanner C, Lachin JM et al; EMPA-REG OUTCOME Investigators (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117–28
2. Wiviott SD, Raz I, Bonaca MP et al; DECLARE–TIMI 58 Investigators (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380: 347–57
3. Neal B, Perkovic V, Mahaffey KW et al; CANVAS Program Collaborative Group (2017) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 377: 644–57
4. McMurray JJV, Solomon SD, Inzucchi SE et al; DAPA-HF Trial Committees and Investigators (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381: 1995–2008
5. Heerspink HJL, Stefansson BV, Correa-Rotter R et al; DAPA-CKD Trial Committees and Investigators (2020) dapagliflozin in patients with chronic kidney disease. N Engl J Med 383: 1436–46
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8. Solomon SD, McMurray JJV, Claggett B et al; DELIVER Trial Committees and Investigors (2022) Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 387: 1089–98
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13. Verma S, Garg A, Yan AT et al (2016) Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial? Diabetes Care 39: e212–213
14. Singh JSS, Mordi IR, Vickneson K et al (2020) Dapagliflozin versus placebo on left ventricular remodeling in patients with diabetes and heart failure: The REFORM trial. Diabetes Care 43: 1356–9
15. Brown AJM, Gandy S, McCrimmon R et al (2020) A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial. Eur Heart J 41: 3421–32
16. Thirunavukarasu S, Jex N, Chowdhary A et al (2021) Empagliflozin treatment is associated with improvements in cardiac energetics and function and reductions in myocardial cellular volume in patients with type 2 diabetes. Diabetes70: 2810–22
17. Hundertmark MJ, Adler A, Antoniades C et al (2023) Assessment of cardiac energy metabolism, function, and physiology in patients with heart failure taking empagliflozin: the randomized, controlled EMPA-VISION trial. Circulation 18 Apr [Epub ahead of print]
18. Watson WD, Miller JJJ, Lewis A et al (2020) Use of cardiac magnetic resonance to detect changes in metabolism in heart failure. Cardiovasc Diagn Ther 10: 583–97
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