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

Synjardy: Role in Type 2 Diabetes Management

Synjardy (empagliflozin/metformin fixed-dose combination) serves as an effective treatment option for type 2 diabetes, particularly valuable as initial combination therapy in drug-naïve patients with HbA1c >7.5%, or as add-on therapy when metformin alone is insufficient, with the empagliflozin component providing proven cardiovascular and renal benefits in high-risk patients. 1, 2

Primary Indications and Patient Selection

Initial Combination Therapy

• Synjardy can be initiated as first-line therapy in drug-naïve patients with HbA1c >7.5%, achieving HbA1c reductions of 1.9-2.1% at 24 weeks, significantly superior to either component alone 2
• This approach is particularly appropriate when rapid glycemic control is needed, as early combination therapy demonstrates slower decline of glycemic control over time compared to sequential addition 1

Add-On to Metformin Monotherapy

• When metformin monotherapy fails to achieve glycemic targets after approximately 3 months, adding empagliflozin (the SGLT2 inhibitor component) is a preferred option among six treatment choices 1
• The combination improves glucose control by approximately 0.7-1.0% HbA1c reduction when added to metformin 1

Cardiovascular and Renal Benefits

High-Risk Cardiovascular Disease Patients

• For patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease, the empagliflozin component provides mortality and morbidity benefits independent of baseline HbA1c or metformin use 1
• The EMPA-REG OUTCOME trial demonstrated that empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77) and the composite outcome of MI, stroke, and cardiovascular death by 14% in patients with established cardiovascular disease 1
• These benefits should drive prescribing decisions even when glycemic targets are already met with other medications 1

Chronic Kidney Disease Management

• Empagliflozin demonstrates clear benefits for slowing CKD progression and can be initiated when eGFR is above 20 mL/min/1.73 m² 1
• The combination is particularly valuable for patients with UACR >300 mg/g and eGFR 30-90 mL/min/1.73 m², where renal outcome benefits are most robust 1
• Note that glucose-lowering efficacy declines when eGFR falls below 45 mL/min/1.73 m², though cardiovascular and renal benefits persist 1

Efficacy Profile

Glycemic Control

• As add-on to metformin, empagliflozin 25 mg demonstrated non-inferiority to glimepiride at 104 weeks, with superior HbA1c reduction of -0.11% (95% CI -0.19 to -0.02) 3
• Initial triple combination with metformin, sitagliptin, and empagliflozin achieved glycemic target (HbA1c <7.0%) in 72.5% at 12 months and 61.7% at 24 months in drug-naïve patients with baseline HbA1c of 11.0% 4

Weight and Blood Pressure Effects

• The empagliflozin component provides weight reduction of 2.8-3.8 kg when combined with metformin, significantly greater than metformin alone (0.5-1.3 kg) 2
• Blood pressure reductions occur through the SGLT2 inhibitor mechanism, providing additional cardiovascular benefit 5, 6

Safety Considerations

Hypoglycemia Risk

• The combination carries minimal hypoglycemia risk: only 2% of patients experienced confirmed hypoglycemic events at 104 weeks versus 24% with glimepiride as add-on to metformin 3
• No hypoglycemic events requiring assistance were reported in initial combination trials 2

Metformin-Specific Precautions

• Assess renal function before initiating: metformin should not be started if eGFR <45 mL/min/1.73 m², dose should be reduced when eGFR falls to 30-44 mL/min/1.73 m², and discontinued if eGFR <30 mL/min/1.73 m² 1, 7
• Monitor vitamin B12 levels periodically, especially in patients with peripheral neuropathy or after >4 years of use 1, 7
• Temporarily discontinue before procedures using iodinated contrast or during acute illness that may compromise renal function 7

SGLT2 Inhibitor-Specific Risks

• Diabetic ketoacidosis risk exists but remains low: 2.2 events per 1,000 patient-years with canagliflozin (class effect concern) 1
• Genital mycotic infections and urinary tract infections occur more frequently with SGLT2 inhibitors 5
• Volume depletion risk requires caution in elderly patients or those on diuretics 5

Practical Implementation

Dosing Strategy

• Start metformin component at 500 mg once or twice daily with meals to minimize gastrointestinal side effects, titrating by 500 mg weekly to target dose 7
• Empagliflozin is available in 10 mg and 25 mg doses; the 25 mg dose provides maximal efficacy 1
• Fixed-dose combination tablets reduce pill burden and improve adherence compared to separate tablets, with demonstrated bioequivalence 5, 6

Cost Considerations

• Empagliflozin 25 mg has a median monthly cost of $627 (AWP) or $501 (NADAC), while metformin 1,000 mg immediate-release costs $87 (AWP) or $2 (NADAC) 1
• The fixed-dose combination may improve cost-effectiveness through better adherence despite higher upfront costs 6

Monitoring Requirements

• Reassess HbA1c every 3 months until glycemic targets are achieved, then every 3-6 months 1
• Monitor eGFR at least annually if normal, every 3-6 months if <60 mL/min/1.73 m² 1, 7
• Check vitamin B12 levels periodically, particularly after several years of metformin use 7

Common Pitfalls to Avoid

• Do not delay intensification: if glycemic targets are not met after 3 months on metformin alone, add empagliflozin rather than continuing inadequate monotherapy 1
• Do not withhold in patients at glycemic goal with cardiovascular disease: the cardiovascular and renal benefits of empagliflozin are independent of HbA1c, so consider switching from other agents even when glucose control is adequate 1
• Do not ignore renal function: while empagliflozin can be initiated with eGFR >20 mL/min/1.73 m², metformin has stricter eGFR requirements that must be respected 1, 7
• Do not use as monotherapy initially: both components should be used together as Synjardy is a combination product; metformin remains the preferred first-line agent when starting therapy 1