What is the best approach to manage a patient in their sixties with uncontrolled Type 2 Diabetes Mellitus (HbA1c of 8.4%) who is currently taking Farxiga (dapagliflozin) and Actos (pioglitazone) in addition to Lantus (insulin glargine) and glipizide, considering a switch to Synjardy (empagliflozin/metformin combination) for improved glycemic control and renal/cardiovascular benefits?

Management of Uncontrolled Type 2 Diabetes with Medication Adjustment

The proposed switch from Farxiga and Actos to Synjardy (empagliflozin/metformin) is appropriate and evidence-based, but requires critical modifications to the overall regimen to optimize glycemic control and minimize hypoglycemia risk. 1

Immediate Medication Adjustments Required

Discontinue Actos (Pioglitazone)

• Stop pioglitazone immediately due to concerns about fluid retention, weight gain, bone fracture risk, and possible bladder cancer, particularly when more effective alternatives with cardiovascular and renal benefits are available. 1
• While pioglitazone has demonstrated cardiovascular benefits in specific populations, the availability of SGLT2 inhibitors with superior cardiorenal outcomes makes this transition appropriate. 1

Initiate Synjardy (Empagliflozin/Metformin)

• Start Synjardy to provide both SGLT2 inhibitor therapy and ensure adequate metformin dosing. 1
• SGLT2 inhibitors like empagliflozin are recommended as part of the glucose-lowering regimen independent of A1C in patients with established or high-risk cardiovascular disease, chronic kidney disease, or heart failure. 1
• The combination provides complementary mechanisms: empagliflozin increases urinary glucose excretion independently of insulin, while metformin reduces hepatic glucose production and improves insulin sensitivity. 2, 3
• Empagliflozin demonstrated non-inferiority to glimepiride when added to metformin, with additional benefits of weight loss (-3.9% vs +2.0%) and blood pressure reduction (-3.6 mmHg vs +2.2 mmHg). 4

Critical Evaluation of Glipizide 10 mg BID

• Strongly consider reducing or discontinuing glipizide given the HbA1c increase from 7.7% to 8.4% despite maximum sulfonylurea dosing. 1
• This worsening control suggests either disease progression requiring more effective agents or that the sulfonylurea is no longer providing adequate benefit. 1
• Sulfonylureas are associated with weight gain, hypoglycemia risk, and lack of durable glycemic effect compared to newer agents. 1
• If glipizide is continued, reduce to 5 mg BID when initiating empagliflozin to minimize hypoglycemia risk, as SGLT2 inhibitors can increase hypoglycemic potential when combined with sulfonylureas. 1

Optimize Basal Insulin (Lantus)

• Increase Lantus from 16 units to 20 units nightly immediately, then titrate aggressively. 5
• For a patient in their sixties (estimated weight 70-80 kg), 16 units represents only 0.2-0.23 units/kg/day, which is at the lower end of recommended dosing. 5
• Titrate Lantus by 4 units every 3 days if fasting glucose remains ≥180 mg/dL, or by 2 units every 3 days if fasting glucose is 140-179 mg/dL, until fasting glucose reaches 80-130 mg/dL. 5
• Daily fasting blood glucose monitoring is essential during this titration phase. 5

Critical Threshold Monitoring

Watch for Overbasalization

• When Lantus exceeds 0.5 units/kg/day (approximately 35-40 units for a 70-80 kg patient) without achieving HbA1c goals, adding prandial insulin becomes more appropriate than continuing to escalate basal insulin alone. 5
• Clinical signals of overbasalization include: basal dose >0.5 units/kg/day, bedtime-to-morning glucose differential ≥50 mg/dL, hypoglycemia episodes, and high glucose variability. 5

Consider GLP-1 Receptor Agonist

• If HbA1c remains >7.5% after 3 months despite optimized basal insulin and Synjardy, strongly consider adding a GLP-1 receptor agonist before advancing to prandial insulin. 1
• GLP-1 receptor agonists are preferred to insulin intensification when possible, providing superior glycemic control with cardiovascular benefits, weight loss, and minimal hypoglycemia risk. 1
• The combination of basal insulin plus GLP-1 RA provides potent glucose-lowering with less weight gain and hypoglycemia than basal-bolus insulin regimens. 1, 2

Foundation Therapy: Metformin Optimization

• Ensure metformin component of Synjardy is at least 1000 mg twice daily (2000 mg total), with maximum effective dose up to 2500 mg/day. 6
• Metformin must be continued when adding or intensifying insulin therapy unless contraindicated, as it reduces total insulin requirements and provides complementary glucose-lowering effects. 1

Monitoring and Follow-Up

Immediate Monitoring (First 3 Months)

• Daily fasting blood glucose monitoring during Lantus titration. 5
• Weekly phone check-ins during first month to assess for hypoglycemia and adjust medications. 1
• Monitor for genital and urinary tract infections (more common with SGLT2 inhibitors but typically respond to standard care). 7, 8

3-Month Reassessment

• Repeat HbA1c at 3 months as planned. 1
• Assess fasting glucose patterns and determine if prandial insulin or GLP-1 RA addition is needed. 1, 5
• Evaluate for signs of overbasalization if Lantus dose has increased substantially. 5
• Monitor renal function (eGFR, albumin/creatinine ratio) given SGLT2 inhibitor initiation. 6

Common Pitfalls to Avoid

• Never delay treatment intensification in patients not meeting glycemic goals—the HbA1c increase from 7.7% to 8.4% represents therapeutic inertia that must be corrected immediately. 1
• Never continue escalating basal insulin beyond 0.5-1.0 units/kg/day without addressing postprandial hyperglycemia, as this leads to overbasalization with increased hypoglycemia risk and suboptimal control. 5
• Never discontinue metformin when intensifying therapy unless contraindicated, as this leads to higher insulin requirements and more weight gain. 1, 6
• Do not rely solely on sulfonylureas for glycemic control in progressive disease—the worsening HbA1c despite maximum glipizide dosing indicates need for more effective agents. 1

Expected Outcomes

• With appropriate implementation of Synjardy, optimized Lantus titration, and potential glipizide reduction, expect HbA1c reduction of 1.0-1.5% over 3 months. 4, 8
• Empagliflozin provides additional benefits of 2-3 kg weight loss and 3-4 mmHg systolic blood pressure reduction. 4, 8
• The combination approach addresses multiple pathophysiologic defects: insulin resistance (metformin), insulin deficiency (Lantus), and glucose reabsorption (empagliflozin). 2, 3