Modified after: https://diabetesjournals.org/care/article/48/Supplement_1/S181/157569/9-Pharmacologic-Approaches-to-Glycemic-Treatment
ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin-to-creatinine ratio; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; DSMES, diabetes self-management education and support; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; MACE, major adverse cardiovascular events; MASH, metabolic dysfunction–associated steatohepatitis; MASLD, metabolic dysfunction–associated steatotic liver disease; MI, myocardial infarction; SDOH, social determinants of health; SGLT2i, sodium–glucose cotransporter 2 inhibitor; T2D, type 2 diabetes.
Excreting sugar via the kidney: SGLT2 inhibitors
Diabetes mellitus was already known in ancient times. The diagnosis was made by tasting the sweet urine. When blood glucose levels exceed 180 mg/dl (10 mmol/l), glucose is excreted in the urine via the kidneys.
As early as the beginning of the 19th century, a substance (phlorizin) was isolated from the bark of apple trees that caused increased urinary glucose. The elucidation of glucose metabolism in the kidney eventually led to the development of new oral antidiabetic drugs: the SGLT-2 (sodium-glucose linked transporter) inhibitors.
Glucose metabolism in the kidney is illustrated in the following figure.
The kidney contains many small renal corpuscles (glomeruli), which retain the solid components of the blood and secrete the primary urine. A glomerulus consists of a tuft of blood vessels embedded in a membrane, from which the primary urine is drained into a tubule, the so-called renal tubule. The tubule is divided into a proximal section (close to the glomerulus) and a distal section (further away from the glomerulus).
In the glomeruli, glucose is completely filtered. To prevent it from being fully excreted in the urine, it must be reabsorbed from the primary urine via active transport systems. These transport systems are located in the proximal tubule. About 90% of glucose is reabsorbed by the SGLT-2 transporter and about 10% by the SGLT-1 transporter, which is located further away from the glomerulus. Together, these two transporters ensure that glucose is fully reabsorbed, so that in healthy individuals no glucose is excreted in the urine.
If blood glucose concentration is too high, the glucose concentration in the primary urine also increases. At around 180 mg/dl (10 mmol/l) blood glucose, the transport systems in the kidney become saturated and can no longer reabsorb all of the glucose. The excess glucose is then excreted in the urine. Detection of glucose in urine indicates poor control of diabetes mellitus, as it means that blood glucose levels exceed 180 mg/dl (10 mmol/l).
How SGLT2 inhibitors lower blood glucose
Renal metabolism can also be used to improve blood glucose control. By inhibiting glucose transporters, up to 70 g of glucose per day can be excreted in the urine. This lowers blood glucose levels. With SGLT2 inhibitors, HbA1c can be reduced by about 0.7% compared to placebo.
The excreted glucose means that the patient loses about 280 kcal per day. Due to this energy loss, patients lose about 2 kg of body weight. The therapy produces a sustained weight effect, and long-term studies have shown that after four years, patients on combination therapy with metformin and an SGLT2 inhibitor weighed on average 4.4 kg less than the comparison group treated with metformin and a sulfonylurea.
SGLT2 inhibitors also cause a slight increase in urine output, and systolic blood pressure decreases by an average of 4.4 mmHg and diastolic blood pressure by about 1.6 mmHg. The SGLT2 transporter is found only in the kidney, while the SGLT1 transporter is located mainly in the intestine and mediates glucose absorption from the gut mucosa.
Heart failure
Outcome trials with dapagliflozin and empagliflozin showed a significant reduction in mortality in patients with heart failure. The benefits of SGLT2 inhibitors are not limited to patients with diabetes mellitus. Studies have demonstrated a marked improvement in survival in patients with heart failure who do not have diabetes. Therefore, SGLT2 inhibitors have become an established part of heart failure therapy, regardless of the presence of diabetes mellitus, and are increasingly prescribed by cardiologists.
Chronic kidney disease (CKD)
In patients with diabetes mellitus, blood glucose levels are elevated, and more glucose passes through the glomerulus of the kidney. These patients have an increased glomerular filtration rate, meaning more fluid and glucose are filtered in the glomerulus and appear in the proximal tubule.
In the proximal tubule, the SGLT2 transporter reabsorbs sodium (Na⁺) and glucose. The higher the glucose load in the proximal tubule, the more active the transporter becomes, reabsorbing additional glucose and sodium. This results in less sodium reaching the downstream tubular system.
The tubules connect back to the glomerulus at the macula densa. When too little sodium reaches the macula densa, hormones are released that dilate the afferent arterioles of the glomerulus. Since the efferent arterioles are not dilated, the intraglomerular pressure rises. Increased pressure damages the glomerulus and over time leads to diabetic nephropathy.
SGLT2 inhibitors block the Na⁺/glucose transporter in the proximal tubule. This increases sodium delivery to the macula densa, preventing dilation of the afferent arterioles. The pressure in the glomerulus normalizes, thereby preventing kidney damage. Through this mechanism, SGLT2 inhibitors protect the kidney, and outcome studies have shown that in patients with diabetes mellitus, treatment with SGLT2 inhibitors prevents further progression of chronic kidney disease. Therefore, in CKD, SGLT2 inhibitors are the preferred therapy.
If SGLT2 inhibitors are not tolerated, contraindicated, or if eGFR is insufficient, GLP-1 receptor agonists should be used instead.
If HbA1c remains above the individually defined treatment target, a combination of GLP-1 receptor agonists and SGLT2 inhibitors can also be used.
SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) significantly improve outcomes in heart failure (HF) — both with reduced (HFrEF) and preserved ejection fraction (HFpEF) — and independent of diabetes.
Their beneficial effects are multifactorial and extend beyond glucose control.
Key Mechanisms in Heart Failure
Relieves cardiac volume and pressure load.
Stabilizes kidney function and supports heart–kidney balance.
Enhances contractile energy use in the failing heart.
Prevents maladaptive cardiac remodeling.
Clinical Evidence
Summary Table
Level | Mechanism | Benefit |
Renal | Natriuresis, restored tubuloglomerular feedback | ↓ Volume, ↓ Pressure, Kidney protection |
Hemodynamic | ↓ Preload and afterload | Cardiac unloading |
Metabolic | Ketone utilization | Improved energy efficiency |
Cellular | ↓ Na⁺/Ca²⁺, ↓ Fibrosis, ↓ Inflammation | Anti-remodeling |
Clinical | ↓ HF hospitalizations, ↓ Mortality | Prognostic improvement |
This image was created using artificial intelligence.
Goals
Foundational (“Quadruple”) Therapy
Modern HFrEF treatment is based on four pillars of evidence-based therapy — started as early as possible, ideally within a few weeks after diagnosis.
Class | Example drugs | Mechanism / Benefit |
1. ARNI / ACEI / ARB | Sacubitril/valsartan (ARNI) preferred; if not tolerated → ACEI (enalapril, ramipril) or ARB (valsartan, candesartan) | Reduces afterload, neurohormonal activation, and mortality |
2. Beta-blocker | Bisoprolol, Carvedilol, Metoprolol succinate, Nebivolol | Reduces sympathetic drive, prevents remodeling, improves survival |
3. Mineralocorticoid receptor antagonist (MRA) | Spironolactone, Eplerenone | Blocks aldosterone → reduces fibrosis, remodeling, and mortality |
4. SGLT2 inhibitor | Dapagliflozin, Empagliflozin | Improves cardiac and renal outcomes, reduces hospitalization, independent of diabetes |
These four drugs form the “core therapy” (often started in parallel with dose titration).
Additional / Adjunctive Therapies
Class | Indication | Examples |
Loop diuretic | For volume overload or congestion (symptom control) | Furosemide, Torasemide, Bumetanide |
If sinus rhythm, HR >70 bpm despite beta-blocker | Ivabradine | |
If persistent symptoms despite optimal therapy | Hydralazine + isosorbide dinitrate (especially in Black patients) | |
If QRS >130 ms with LBBB pattern | Cardiac resynchronization therapy (CRT) | |
If EF <35% despite therapy | ICD for primary prevention of sudden cardiac death |
Non-Pharmacologic Measures
Summary of Stepwise Approach
Perfect — heart failure with preserved ejection fraction (HFpEF) is an increasingly common and important condition.
Let’s break it down clearly:
Definition:
Therapeutic Goals
Unlike HFrEF (where we reverse remodeling), HFpEF therapy focuses on:
Evidence-Based Pharmacologic Therapy
Drug Class | Example | Primary Benefit |
SGLT2 inhibitors (now first-line) | Empagliflozin, Dapagliflozin | ↓ HF hospitalization and CV death (shown in EMPEROR-Preserved, DELIVER trials) |
Diuretics | Furosemide, Torasemide | Symptomatic relief of congestion (no survival benefit) |
ACEI / ARB / ARNI | Candesartan, Sacubitril/valsartan | Modest reduction in HF hospitalizations; helpful for BP control |
Mineralocorticoid receptor antagonists (MRAs) | Spironolactone | Some benefit in selected patients (TOPCAT trial) |
Beta-blockers | Bisoprolol, Carvedilol, Nebivolol | Symptom control, HR reduction, useful with hypertension or atrial fibrillation |
Management of Comorbidities (Crucial Part!)
HFpEF is often driven by systemic comorbidities:
Comorbidity | Targeted Management |
Hypertension | Strict BP control (ACEI, ARB, CCB, or thiazides) |
Atrial fibrillation | Rate/rhythm control, anticoagulation |
Obesity | Weight reduction (GLP-1 agonists emerging) |
Diabetes mellitus | Prefer SGLT2 inhibitors |
Coronary artery disease | Antianginal therapy, revascularization if needed |
Sleep apnea | CPAP treatment |
Chronic kidney disease | Optimize renal protection (avoid volume overload) |
Non-Pharmacologic Therapy
Summary Table: HFpEF vs. HFrEF First-Line Therapy
Feature | HFrEF | HFpEF |
Main goal | Reverse remodeling, reduce mortality | Relieve congestion, reduce hospitalizations |
Key drugs | ARNI / ACEI / ARB + Beta-blocker + MRA + SGLT2i | SGLT2i (core) + Diuretics + MRA/ARB/ARNI as tolerated |
Prognostic benefit | Strong (mortality ↓) | Moderate (mainly ↓ hospitalization) |
Comorbidity management | Important | Central to therapy |
Clinical takeaway
SGLT2 inhibitors are now the only class with proven mortality and hospitalization benefit in both HFrEF and HFpEF.
Everything else in HFpEF focuses on blood pressure, rhythm control, and symptom management.