Is it safe to use empagliflozin (SGLT2 inhibitor) with Rubelsus (unknown medication) in an adult patient with type 2 diabetes?

Combining Rybelsus (Semaglutide) and Empagliflozin in Type 2 Diabetes

Yes, combining Rybelsus (oral semaglutide, a GLP-1 receptor agonist) with empagliflozin (an SGLT2 inhibitor) is safe and recommended for patients with type 2 diabetes, particularly those with established cardiovascular disease, as these drug classes have complementary mechanisms and both reduce cardiovascular morbidity and mortality. 1

Rationale for Combination Therapy

The American College of Cardiology explicitly recommends considering the addition of both SGLT2 inhibitors and GLP-1 receptor agonists with demonstrated cardiovascular outcome benefit in patients with type 2 diabetes and atherosclerotic cardiovascular disease. 1 These medications work through different, complementary mechanisms:

• Empagliflozin removes glucose through urinary excretion by blocking renal glucose reabsorption, independent of insulin 2
• Semaglutide (Rybelsus) increases insulin secretion in a glucose-dependent manner and decreases glucagon levels 2

Both drug classes significantly reduce cardiovascular morbidity and mortality when used appropriately. 1

Cardiovascular and Mortality Benefits

Empagliflozin Benefits

• Reduces cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77) 3
• Reduces all-cause mortality by 32% (HR 0.68,95% CI 0.57-0.82) 3
• Reduces hospitalization for heart failure by 35% 1
• Reduces the composite of cardiovascular death or heart failure hospitalization by 31% 1

GLP-1 RA Benefits

The American Diabetes Association notes that GLP-1 receptor agonists like semaglutide reduce major adverse cardiovascular events in patients with established cardiovascular disease. 1

Practical Implementation

Starting Empagliflozin

• Initiate at 10 mg orally once daily - this lowest dose provides full cardioprotective benefit 3
• Assess eGFR before initiation; do not start if eGFR <45 mL/min/1.73 m² 3
• Check renal function within 1-2 weeks after starting 4

Starting Rybelsus

• Initiate at 0.25 mg subcutaneously weekly (for injectable semaglutide) or follow oral Rybelsus dosing 1
• Titrate slowly to reduce nausea and vomiting 1
• No dose adjustment needed for renal or hepatic impairment 1

Critical Dose Adjustments When Combining

If the patient is on insulin or sulfonylureas:

• Reduce insulin dose by approximately 20% when initiating empagliflozin 3
• Reduce or discontinue sulfonylureas to prevent hypoglycemia 3
• The hypoglycemia risk increases when SGLT2 inhibitors are combined with insulin secretagogues 1

Safety Monitoring and Precautions

Volume Status Assessment

• Assess volume status before initiating empagliflozin 4
• Consider reducing loop diuretic dose by 50% in patients on high-dose diuretics to prevent symptomatic hypotension 3
• Empagliflozin may cause intravascular volume contraction, particularly in elderly patients, those with renal impairment, low blood pressure, or those on diuretics 1, 4

Infection Risk

• Counsel patients about increased risk of genital mycotic infections (approximately 6% vs 1% with placebo) 4
• Educate on proper genital hygiene 3
• Monitor for urinary tract infections, which are more frequent with SGLT2 inhibitors 4

Euglycemic Diabetic Ketoacidosis Risk

• Warn patients about this rare but serious risk, which can occur with normal glucose levels 1, 4
• Withhold empagliflozin at least 3 days before major surgery or procedures with prolonged fasting 4
• Temporarily discontinue during acute illness 3
• This risk is particularly elevated during insulin pump malfunctions, significant insulin dose reductions, or prolonged fasting 1

Gastrointestinal Side Effects from Rybelsus

• Nausea and vomiting are common with GLP-1 RAs 1
• Slow titration minimizes these effects 1
• Discontinue if pancreatitis is suspected and do not restart if confirmed 1

Contraindications

For Empagliflozin:

• History of serious hypersensitivity reaction 3
• Severe renal impairment, ESRD, or dialysis 1, 3
• Type 1 diabetes mellitus 3

For Rybelsus:

• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2

Monitoring Schedule

Renal Function

• Check eGFR before initiation 4
• Recheck within 1-2 weeks after starting empagliflozin 4
• Monitor every 3-6 months if eGFR 45-59 mL/min/1.73 m² 4
• Monitor annually if eGFR ≥60 mL/min/1.73 m² 4

Other Parameters

• Monitor volume status and signs of dehydration 4
• Assess for signs of genital/urinary infections 4
• Monitor for hypoglycemia if on insulin or sulfonylureas 3

Additional Benefits of Combination

Beyond glycemic control, this combination provides:

• Weight loss from both agents 1, 2
• Blood pressure reduction from empagliflozin (50-100g glucose loss equals 200-400 kcal/day energy expenditure) 5
• Renal protection - empagliflozin reduces risk of end-stage kidney disease, doubling of serum creatinine, and renal death 3
• Low hypoglycemia risk when not combined with insulin or sulfonylureas 5, 6

Common Pitfall to Avoid

The most critical error is failing to reduce insulin or sulfonylurea doses when adding empagliflozin, which significantly increases hypoglycemia risk. 3 Always proactively adjust these medications before initiating the SGLT2 inhibitor.