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Sodium-Glucose Transporter 2 Inhibitors

Management of Heart Failure

Author/s: 
Belkin, M. N., Cifu, A. S., Pinney, S.

GUIDELINE TITLE 2022 American College of Cardiology
(ACC)/American Heart Association AHA)/Heart Failure
Society of America (HFSA) Guidelines for the Management
of Heart Failure
RELEASE DATE April 1, 2022
PRIOR VERSIONS 2017 ACC/AHA/HFSA Focused Update
of the 2013 ACCF/AHA Guideline for the Management of
Heart Failure and 2013 ACCF/AHA Guideline for the
Management of Heart Failure
DEVELOPER AND FUNDING SOURCE ACC/AHA Joint
Committee on Clinical Practice Guidelines
TARGET POPULATION Adult patients with a diagnosis of
or at risk for heart failure (HF)
MAJOR RECOMMENDATIONS
• Classifications for HF are separated into 4 categories based
on ejection fraction (EF) and disease history: HF with
reduced EF (EF 40%), HF with mildly reduced EF
(EF 41%-49%), HF with preserved EF (EF 50%), and HF
with improved EF (EF previously 40% with improvement
to >40%).
• In patients with chronic HF with reduced EF, angiotensin
receptor–neprilysin inhibitors (ARNIs) are preferred over
angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin II receptor blockers (ARBs). If ARNI use is not
feasible, ACEIs are preferred over ARBs, unless there is
significant cough or angioedema (class 1, level of
evidence [LOE] A).
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors should
be included across all HF categories (symptomatic HF with
reduced EF [class 1, LOE A]; HF with mildly reduced EF and
HF with preserved EF [class 2a, LOE B-R]).
• Patients with HF with improved EF should continue to
receive medical therapy originally indicated for HF with
reduced EF (class 1, LOE B-R).
• Evidence-based treatment of HF with preserved EF
includes blood pressure control (class 1, LOE C-LD),
SGLT2 inhibitors (class 2a, LOE B-R), mineralocorticoid
antagonists, ARBs, and ARNIs (class 2b, LOE B-R).

Keywords 
Stroke Volume American Heart Association Cardiology heart failure Sodium

GLP1Agonists and SGLT2 Inhibitors Table

Author/s: 
Mold, J. W.

Based upon the following two meta-analyses:
1. Alexander JT, et al. The longer-term benefits and harms of glucagon-like peptide-1 receptor agonists: A Systematic review and meta-analysis. JGIM, 2021; 7(2): 415-43.
2. Alexander JT, et al. Longer-term benefits and risks of sodium-glucose cotransporter-2 inhibitors in type 2 diabetes: A systematic review and meta-analysis. JGIM, 2021; 37(2): 439-44, plus Supplementary materials at https://doi.org/10.1007/s11606-021-07227-0.

Selection criteria for the RCTs was that the study period was at least 52 weeks in duration. I assume the average duration of the studies was at least 2 years. So, an absolute risk reduction of mortality of 0.5% would be per 2+ years.

Estimating Lifetime Benefits of Comprehensive Disease-Modifying Pharmacological Therapies in Patients With Heart Failure With Reduced Ejection Fraction: A Comparative Analysis of Three Randomised Controlled Trials

Author/s: 
Vaduganathan, M., Claggett, BL, Jhund, PS, Cunningham, JW, Ferreira, JP, Zannad, F, Packer, M, Fonarow, GC, McMurray, JJV, Solomon, S.D.

Background: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.

Methods: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).

Findings: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.

Interpretation: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.

Funding: None.

Keywords 
CHF patients heart failure pharmacologic management
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