March 22, 2018
View Full PaperAre the Effects of Drugs to Prevent and to Treat Heart Failure Always Concordant? The Statin Paradox and its Implications for Understanding the Actions of Antidiabetic Medications
Key Result
The distinction between HFrEF and HFpEF may explain why drugs like statins and antidiabetic medications have discordant effects in preventing versus treating heart failure.
Structured PICO
Why do drugs like statins and antidiabetic medications have discordant effects in preventing versus treating heart failure, particularly between HFrEF and HFpEF?
P
Population
Patients with heart failure (HFrEF and HFpEF), obesity, and diabetes
I
Intervention
Statins, GLP-1 receptor agonists, and SGLT2 inhibitors
O
Outcome
Heart failure morbidity and mortality
The pathophysiological distinctions between HFrEF and HFpEF may explain why drugs that prevent heart failure in metabolic disorders (often HFpEF) may not be effective in treating established HFrEF.
Abstract
Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.