Medical Therapy of Heart Failure with Reduced Ejection Fraction—A Call for Comparative Research

The armamentarium of therapies for patients with heart failure and reduced ejection fraction (HFREF) has increase substantially with the introduction of Angiotensin Receptor Neprilysin Inhibitor (ARNi), sodium glucose cotransport inhibitors (SGLTis), ivabradine, and Vericinguat, bringing to seven the number of potential therapies for HFREF. In the current review we highlight available data on the different classes of medications. Renin angiotensin blockers (RAASbs) and beta blockers (BBs) were shown to have very substantial effects in patients with HFREF. These medications are generic and hence relatively inexpensive. They have a 30-year track record of relatively benign short- and long-term safety profiles and should remain the cornerstone of therapy for patients with HFREF. ARNis are effective in further reducing adverse effects and should replace RAASbs in symptomatic HFREF patients, despite their relatively high prices. The addition of SGLTis (congested patients), Ivabradine (tachycardic patients), and Vericinguat (hypertensive patients) should be considered in patients who remain symptomatic despite optimal doses of RAASbs/ARNis, MRAs, and BBs. Comparative studies examining the efficacy of these medications, and strategies and prioritizing some over others should be considered as, given their similar side effects on heart rate, blood pressure, and renal function, it is highly unlikely that all can be given to the same patient.

SGLT-2 Inhibitors and GLP-1 Agonists: First-Line Therapy for Diabetes With Established Cardiovascular Disease

There is a growing body of evidence that diabetes represents a significant and largely modifiable risk factor for cardiovascular disease (CVD). It is known to markedly increase the risk of CVD—with CVD accounting for 2 of every 3 deaths in patients with diabetes. It is suggested that once patients with diabetes develop clinical coronary disease, they have a grim prognosis. In 2008, the Food and Drug Association mandated the evidence of CV safety in any new diabetic therapy, leading to a multitude of large CV outcome trials to assess CV risk from these medications. However, several of these outcome trials with novel antidiabetic therapies have demonstrated not only safety but a clear and definite CV advantage in patients with type 2 diabetes. In this review, we discuss 2 relatively newer classes of diabetic drugs, sodium glucose cotransport 2 inhibitors and glucagon-like peptide 1 agonists, evaluate their efficacy in improving CV outcomes, and discuss the future of CV prevention with these agents.

Urinary adenosine excretion in type 1 diabetes

In experimental models of diabetes, augmented sodium-glucose cotransport-2 (SGLT2) activity diminishes sodium (Na+) delivery at the macula densa. As a result, less vasoconstrictive adenosine is generated, leading to afferent arteriolar vasodilatation and hyperfiltration. The measurement and significance of urinary adenosine in humans has not been examined extensively in states of renal hemodynamic impairment like that of diabetes. Our aim was to validate a method for urine adenosine quantification in humans and perform an exploratory post hoc analysis to determine whether urinary adenosine levels change dynamically in response to natriuresis in patients with type 1 diabetes (T1D) before and after treatment with the SGLT2 inhibitor (SGLT2i) empagliflozin. We hypothesized that SGLT2i, which reduces renal hyperfiltration through increased Na+delivery to the macula densa, would increase urinary adenosine excretion. Urine adenosine corrected for creatinine was measured using our validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in 40 healthy participants and 40 patients with T1D. In the T1D cohort, measurements were performed during clamped euglycemic and hyperglycemic conditions before and following 8 wk of SGLT2i therapy. Urinary adenosine was detectable in healthy subjects (0.32 ± 0.11 µmol/mmol Cr) and patients with T1D. In response to SGLT2i, urine adenosine increased during clamped hyperglycemia (0.40 ± 0.11 vs. 0.45 ± 0.12 µmol/mmol Cr, P = 0.005). Similar trends were observed during clamped euglycemia ( P = 0.08). In conclusion, SGLT2i increases urinary adenosine excretion under clamped hyperglycemic conditions in patients with T1D. The potentially protective role of SGLT2i against glomerular hyperfiltration and its mediation by adenosine in diabetes merits further study.