What is the role of Synjardy (empagliflozin and metformin) in treating type 2 diabetes?

Synjardy (Empagliflozin/Metformin) in Type 2 Diabetes Management

Primary Role and Positioning

Synjardy combines metformin (the preferred first-line agent) with empagliflozin (an SGLT2 inhibitor with proven cardiovascular and renal benefits), making it an optimal choice for patients with type 2 diabetes who have established cardiovascular disease, heart failure, chronic kidney disease, or high cardiovascular risk. 1

When to Use Synjardy

Preferred Patient Populations

• Patients with established atherosclerotic cardiovascular disease (ASCVD) should receive an SGLT2 inhibitor like empagliflozin combined with metformin as part of their glucose-lowering regimen, independent of A1C level 1

• Patients with heart failure or chronic kidney disease benefit from empagliflozin's demonstrated cardiovascular and renal protective effects beyond glucose lowering 1

• High cardiovascular risk patients (age ≥55 years with coronary, carotid, or lower-extremity artery stenosis ≥50%, or left ventricular hypertrophy) should receive this combination 1

Initial Combination Therapy

• Start dual therapy with metformin plus empagliflozin simultaneously when HbA1c is 1.5-2% above target at diagnosis, as this achieves glycemic targets more rapidly and extends durability of control 2

• Consider empagliflozin addition to metformin when A1C target is not achieved after approximately 3 months of metformin monotherapy 1

Efficacy Profile

Glycemic Control

• Empagliflozin added to metformin lowers A1C by approximately 0.7-1.0%, consistent with other second-line agents 1

• At 104 weeks, empagliflozin demonstrated superiority over glimepiride as add-on to metformin (adjusted mean difference -0.11%, p=0.0153) 3

• Glucose lowering occurs through increased urinary glucose excretion (64-78 grams per day), independent of insulin secretion or action 4, 5

Additional Benefits Beyond Glucose Control

• Weight reduction of approximately 2-3 kg occurs through caloric loss via glucosuria 3, 6, 5

• Blood pressure reduction with systolic BP decreasing due to osmotic diuresis and natriuresis 6, 7, 5

• Cardiovascular mortality reduction demonstrated in the EMPA-REG OUTCOME trial in patients with established cardiovascular disease 1

• Renal protection with slowed CKD progression shown in dedicated kidney outcomes trials 1

Safety Considerations and Contraindications

Renal Function Requirements

• Do not initiate metformin if eGFR <45 mL/min/1.73 m² 1, 2

• Reduce metformin dose when eGFR falls below 45 mL/min/1.73 m² and discontinue when eGFR <30 mL/min/1.73 m² 1, 8

• Empagliflozin can be initiated if eGFR >20 mL/min/1.73 m², though glucose-lowering efficacy declines below 45 mL/min/1.73 m² 1, 4

• Empagliflozin is not effective in severe renal impairment, ESRD, or dialysis patients 4

Hypoglycemia Risk

• Minimal hypoglycemia risk with empagliflozin/metformin combination—only 2% of patients experienced confirmed hypoglycemia at 104 weeks versus 24% with glimepiride 3

• No increased hypoglycemia versus placebo when used without insulin or sulfonylureas 5

Specific Adverse Events

• Genital mycotic infections occur more frequently (approximately 5-10% of patients) but are generally mild and treatable 3, 9, 5

• Urinary tract infections do not increase significantly versus placebo 5

• Euglycemic diabetic ketoacidosis risk exists, particularly in patients with poor oral intake or during acute illness 1

• Volume depletion may occur, especially in elderly patients or those on diuretics, with mean 24-hour urine volume increasing 341 mL on Day 1 and 135 mL on Day 5 4

Metformin-Specific Precautions

• Discontinue metformin before iodinated contrast procedures in patients with eGFR <60 mL/min/1.73 m², history of liver disease, alcoholism, acute heart failure, or receiving intra-arterial contrast 1, 2

• Withhold metformin in conditions causing tissue hypoxia or hemodynamic instability (acute kidney injury, hypoxia, shock) to prevent lactic acidosis 1, 2

• Monitor vitamin B12 levels periodically as metformin can cause deficiency and worsen neuropathy 2

Dosing and Administration

Practical Dosing

• Empagliflozin is available in 10 mg and 25 mg doses, with maximum approved daily dose of 25 mg 1, 4

• Metformin should be titrated to target dose of 2000 mg daily when tolerated 2

• Fixed-dose combination tablets reduce pill burden and improve adherence compared to separate tablets 6, 7

• Can be administered with or without food as food effects are not clinically relevant 4

Pharmacokinetic Considerations

• No drug-drug interactions between empagliflozin and metformin 7

• Bioequivalence demonstrated between fixed-dose combination and individual tablets 6, 7

• Empagliflozin half-life is 12.4 hours, allowing once-daily dosing 4

Common Pitfalls to Avoid

• Do not delay treatment intensification—reassess every 3 months and add agents promptly if not at target 1, 2

• Do not discontinue metformin when adding empagliflozin unless contraindicated; continue metformin as foundation therapy 1, 2

• Do not use empagliflozin routinely in hospitalized patients due to ketoacidosis risk, particularly with poor oral intake 1

• Do not use in unstable heart failure or hospitalized patients until clinically stable 1

• Educate patients about ketoacidosis symptoms (nausea, vomiting, abdominal pain, fatigue) and instruct them to check ketones if symptoms occur, even with normal glucose 1

Cost Considerations

• Empagliflozin median monthly cost is approximately $627 (AWP) or $501 (NADAC) for 25 mg daily dose 1

• Metformin is significantly less expensive at $2-4 monthly for immediate-release formulations 1

• Fixed-dose combinations may improve cost-effectiveness through better adherence despite higher upfront costs 6