Pharmacological Management of Heart Failure

Sodium-glucose cotransporter 2 inhibitors block glucose and sodium reabsorption in the proximal tubule of the kidney. The resulting glucose and sodium loss in the urine produces a mild, sustained osmotic diuresis that reduces blood volume and ventricular filling pressures, similar in direction to the effect of a loop diuretic but considerably gentler.

The benefit of this drug class in heart failure is larger than this modest diuretic effect alone would predict, and the full explanation remains an area of active research. What is clear clinically is that the benefit applies broadly: this is the first drug class shown to improve outcomes across the full spectrum of ejection fraction, including heart failure with preserved ejection fraction, which had resisted nearly every other pharmacological treatment attempt.

Sodium-glucose cotransporter 2 inhibitors are now recommended for essentially all patients with heart failure, regardless of ejection fraction category and regardless of whether the patient has diabetes, since the cardiovascular benefit does not depend on having diabetes.

The most common adverse effect is genital fungal infection, a direct consequence of glucose appearing in the urine, which creates an environment favorable to yeast overgrowth. A rarer but more dangerous adverse effect is diabetic ketoacidosis, which can occur even when blood glucose is only mildly elevated, a presentation called euglycemic diabetic ketoacidosis that can delay diagnosis if blood glucose alone is used to screen for ketoacidosis.

Hydralazine and isosorbide dinitrate are both direct vasodilators. Hydralazine primarily relaxes arteries, reducing afterload, while isosorbide dinitrate primarily relaxes veins, reducing preload. Used together, this combination produces hemodynamic effects similar to a renin-angiotensin-aldosterone system blocker, but through a mechanism that does not involve the renin-angiotensin-aldosterone system at all.

This combination has two established clinical roles. First, it is used in patients who cannot tolerate any renin-angiotensin-aldosterone system blocker, providing vasodilator therapy through an alternative pathway. Second, it has a specific, well-established mortality benefit when added to standard therapy in self-identified Black patients with heart failure with reduced ejection fraction who remain symptomatic despite optimized treatment, a point introduced in Module 2.