751 Most patients with chronic heart failure respond favorably to certain β blockers despite the fact that these drugs can precipitate acute cardiac failure (see Chapter 10). Studies with bisoprolol, carvedilol, metoprolol, and nebivolol showed a reduction in mortality in patients with stable severe heart failure, but this effect was not observed with another β blocker, bucindolol. A full understanding of the beneficial action of β blockade is lacking, but suggested mechanisms include attenuation of the adverse effects of high concentrations of endogenous catecholamines (including apoptosis), up-regulation of β receptors, decreased heart rate, and reduced remodeling through inhibition of the mitogenic activity of catecholamines. 752 753 754 ## ANTIDIABETIC DRUGS 755 756 Drugs used in type 2 diabetes have been of concern because of the association of diabetes with cardiac events. Therefore, it is of interest that two groups of these agents benefit patients with heart failure with or without type 2 diabetes. The gliflozins, e.g. empagliflozin and dapagliflozin, are SGLT2 inhibitors that increase renal sodium excretion as well as glucose excretion (see chapter 41). They have complex effects in the heart, including inhibition of the sodium-hydrogen exchanger (NHE) and a reduction of glucose utilization for ATP production. They also slow development of chronic kidney disease. These drugs have been shown to reduce mortality and hospitalizations for heart failure in patients with or without type 2 diabetes. This appears to be a class effect. Empagliflozin is approved for use in both HFREF and HFpEF; dapagliflozin is currently approved for HFREF. Liraglutide and semaglutide, GLP-1 agonists used in diabetes (see chapter 41) and obesity (see Chapter 16), have been shown to reduce deaths from cardiovascular causes as well as the rates of myocardial infarction, nonfatal stroke, and hospitalization for heart failure. They are approved for use in HFREF. 757 758 759 ## OTHER DRUGS 760 761 Mavacamten, an inhibitor of myosin, is approved for use in obstructive hypertrophic cardiomyopathy. This condition reduces cardiac output and is 762 763 764 765 often associated with symptoms of heart failure. Mavacamten (as well as beta blockers), by slowing the contraction of the ventricles, may improve ejection and increase cardiac output. Neuroregulatory proteins appear to have cardiac as well as neural effects. The neuregulin GGF2 protein (cimaglermin) has been shown to benefit cardiac function in several animal models of heart failure. Vericiguat, a soluble guanylate cyclase stimulator, has been shown to have a small but significant benefit on death and hospitalization rates. It is approved for oral use in acute decompensated failure. 766 767 768 ## CLINICAL PHARMACOLOGY OF DRUGS USED IN HEART FAILURE 769 770 Detailed guidelines are issued by US and European expert groups (see References). The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of chronic heart failure specify four stages in the development of heart failure (Table 13–3). Patients in stage A are at high risk because of other disease but have no signs or symptoms of heart failure. Stage B patients have evidence of structural heart disease but no symptoms of heart failure. Stage C patients have structural heart disease and symptoms of failure, and symptoms are responsive to ordinary therapy. Patients in stage C must often be hospitalized for acute decompensation, and after discharge, they often decompensate again, requiring rehospitalization. Stage D patients have heart failure refractory to ordinary therapy, and special interventions (eg, resynchronization therapy, transplant) are required. 771 772 *TABLE 13-3 773 Classification and treatment of chronic heart failure.* 774 775 776

ACC/AHA Stage¹	NYHA Class²	Description	Management
A	Prefailure	No symptoms but risk factors present3	Treat obesity, hypertension, diabetes, hyperlipidemia, etc
B [... Output truncated due to length. 2647 tokens/10487 characters removed ...]