In a patient with type 2 diabetes, HbA1c 7.4%, fasting plasma glucose 128 mg/dL, impaired renal function (creatinine 1.6 mg/dL, eGFR ~45 mL/min) who is taking dapagliflozin 10 mg daily and gliclazide 60 mg twice daily, what additional antidiabetic medication should be added?

Add a GLP-1 Receptor Agonist to the Current Regimen

For this patient with HbA1c 7.4%, eGFR 45 mL/min, already on dapagliflozin 10 mg and gliclazide 60 mg BID, the best addition is a GLP-1 receptor agonist, while simultaneously reducing or discontinuing the gliclazide to minimize hypoglycemia risk in the setting of moderate renal impairment. 1

Rationale for GLP-1 Receptor Agonist Addition

• The 2020 ADA/EASD consensus explicitly recommends GLP-1 receptor agonists as the preferred third agent when dual therapy fails to achieve glycemic targets, particularly in patients with CKD (eGFR 30–60 mL/min). 1

• GLP-1 receptor agonists provide an additional HbA1c reduction of 0.6–0.8% when added to existing therapy, which would bring this patient's HbA1c from 7.4% to approximately 6.6–6.8%—well within target. 1, 2

• These agents offer proven cardiovascular and renal protection independent of glucose lowering, which is critical given this patient's eGFR of 45 mL/min. 1

• GLP-1 receptor agonists promote weight loss rather than weight gain and carry minimal hypoglycemia risk when sulfonylureas are reduced or stopped. 1, 2

Critical Medication Adjustments Required

Reduce or Discontinue Gliclazide

• Sulfonylureas should be reduced or stopped when adding a third glucose-lowering agent in patients ≥65 years or with renal impairment (eGFR 45 mL/min) to avoid severe hypoglycemia. 2

• At eGFR 45 mL/min, sulfonylureas carry markedly elevated hypoglycemia risk because renal clearance of the drug and its metabolites is reduced. 2

• Reduce gliclazide from 60 mg BID to 30 mg BID initially, then discontinue entirely once the GLP-1 receptor agonist is titrated to therapeutic dose. 2, 3

Continue Dapagliflozin

• Dapagliflozin provides cardiovascular and renal protection that is independent of its glucose-lowering effect and should be continued even at eGFR 45 mL/min. 1

• SGLT2 inhibitors can be safely used down to eGFR >20 mL/min/1.73 m², whereas their glucose-lowering efficacy diminishes below eGFR 45 mL/min. 2

• The CREDENCE trial demonstrated clear renal benefits of SGLT2 inhibitors in patients with eGFR 30–90 mL/min, including reduction in progression to end-stage kidney disease. 1

Practical Implementation

GLP-1 Receptor Agonist Dosing

Agent	Starting Dose	Titration Schedule	Target Dose
Semaglutide (weekly)	0.25 mg SC	Increase to 0.5 mg after 4 weeks, then 1.0 mg if needed	1.0 mg weekly
Dulaglutide (weekly)	0.75 mg SC	Increase to 1.5 mg after 4 weeks if needed	1.5 mg weekly
Liraglutide (daily)	0.6 mg SC	Increase to 1.2 mg after 1 week, then 1.8 mg if needed	1.8 mg daily

2

Monitoring Timeline

• Reassess HbA1c at 3 months after GLP-1 receptor agonist initiation to determine if glycemic target is achieved. 1, 2

• Monitor for gastrointestinal side effects (nausea, vomiting) during the first 4–8 weeks after GLP-1 receptor agonist initiation—these are the most common adverse effects. 2

• Check eGFR every 3–6 months to ensure continued safety of dapagliflozin therapy. 2

• Monitor for hypoglycemia during gliclazide dose reduction; risk should decline substantially once sulfonylurea is tapered. 2, 3

Why Not Other Options?

Why Not Add Basal Insulin?

• Insulin is not indicated at HbA1c 7.4%—it is reserved for HbA1c >9% or symptomatic hyperglycemia. 1, 2

• GLP-1 receptor agonists are recommended as the first injectable option before insulin for patients who need additional glycemic lowering beyond oral agents. 2

• Insulin causes weight gain and increases hypoglycemia risk, particularly when combined with sulfonylureas in patients with renal impairment. 1, 2

Why Not Add a DPP-4 Inhibitor?

• DPP-4 inhibitors provide only 0.5% HbA1c reduction—insufficient to bring this patient to target. 1

• GLP-1 receptor agonists are superior to DPP-4 inhibitors for both glycemic control and cardiovascular protection. 1, 2

Why Not Increase Gliclazide Dose?

• Increasing sulfonylurea dose in a patient with eGFR 45 mL/min would markedly increase hypoglycemia risk without providing adequate glycemic benefit. 2, 3

• Sulfonylureas are associated with 7-fold higher incidence of major hypoglycemic events and 2-fold increase in all-cause mortality compared with metformin. 2, 3

Common Pitfalls to Avoid

• Do not continue full-dose gliclazide when adding a GLP-1 receptor agonist—this combination markedly raises hypoglycemia risk in patients with renal impairment. 2, 3

• Do not discontinue dapagliflozin when adding a GLP-1 receptor agonist—the SGLT2 inhibitor provides critical renal and cardiovascular protection independent of glucose lowering. 1

• Do not delay treatment intensification beyond 3 months if HbA1c remains above target—prolonged exposure to hyperglycemia increases complication risk. 1, 2

• Do not add metformin at this eGFR (45 mL/min)—metformin requires dose reduction when eGFR <45 mL/min and is contraindicated when eGFR <30 mL/min. 2

Expected Outcomes

• HbA1c reduction from 7.4% to approximately 6.6–6.8% within 3 months. 1, 2

• Weight loss of 2–4 kg rather than weight gain associated with insulin or sulfonylurea therapy. 1, 2

• Reduced hypoglycemia risk once gliclazide is tapered or discontinued. 2, 3

• Continued cardiovascular and renal protection from dapagliflozin. 1