What is the recommended treatment for a patient with uncontrolled glucose levels who refuses GLP-1 (Glucagon-Like Peptide-1) receptor agonists?

Treatment Options for Uncontrolled Glucose Levels When GLP-1 Receptor Agonists Are Refused

For patients with uncontrolled glucose levels who refuse GLP-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the recommended alternative treatment, especially in patients with chronic kidney disease (CKD) with eGFR ≥20 ml/min per 1.73 m².1

First-Line Treatment Options

• Metformin remains the cornerstone of therapy for patients with type 2 diabetes and should be initiated if eGFR ≥30 ml/min per 1.73 m² and continued as long as it's tolerated and not contraindicated 1
• SGLT2 inhibitors with proven cardiovascular and kidney benefits should be added to metformin for patients with eGFR ≥20 ml/min per 1.73 m² 1
• For patients with eGFR <30 ml/min per 1.73 m², metformin should be discontinued, and SGLT2i can be used as long as eGFR remains ≥20 ml/min per 1.73 m² 1

Alternative Options When GLP-1 RAs Are Refused

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

• DPP-4 inhibitors can be considered for patients who need additional glycemic control beyond metformin and SGLT2i 1
• They have a neutral effect on weight and low risk of hypoglycemia when used without insulin or sulfonylureas 1

Thiazolidinediones (TZDs)

• TZDs can be effective, particularly in patients with insulin resistance 1
• Consider carefully in patients with or at risk for heart failure due to potential fluid retention 1

Sulfonylureas

• Can be used when cost is a major concern 1
• Monitor closely for hypoglycemia, especially in elderly patients or those with irregular eating patterns 1

Insulin Therapy

• For patients with significantly elevated glucose levels (HbA1c >10%) or symptomatic hyperglycemia, insulin therapy may be necessary 1
• Can start with basal insulin and add prandial insulin if glycemic targets are not met 1

Treatment Algorithm Based on Patient Characteristics

For Patients with Established Cardiovascular Disease

• Prioritize SGLT2i with proven cardiovascular benefits 1
• If SGLT2i is contraindicated or not tolerated, consider insulin therapy 1

For Patients with Heart Failure

• SGLT2i are strongly preferred due to their proven benefits in reducing heart failure hospitalizations 1
• Avoid TZDs due to risk of fluid retention 1

For Patients with CKD

• For eGFR ≥20 ml/min per 1.73 m², use SGLT2i 1
• For eGFR <20 ml/min per 1.73 m², consider DPP-4 inhibitors or insulin 1
• Consider adding a nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) for patients with albuminuria and eGFR ≥25 ml/min per 1.73 m² 1

For Patients Concerned About Weight Gain

• SGLT2i are preferred as they promote weight loss 1
• DPP-4 inhibitors are weight-neutral alternatives 1
• Avoid sulfonylureas and insulin if weight gain is a major concern 1

Dosing Considerations

• For metformin: Start with low dose (500-850 mg daily) and titrate gradually; reduce dose when eGFR is 30-44 ml/min per 1.73 m² 1
• For SGLT2i (e.g., empagliflozin): Start with recommended dose based on renal function; can be continued at lower eGFR levels once initiated 2

Common Pitfalls and Caveats

• Don't continue metformin when eGFR falls below 30 ml/min per 1.73 m² due to increased risk of lactic acidosis 1
• Monitor renal function regularly in patients on SGLT2i, particularly those with tenuous renal function 1
• Be aware that DPP-4 inhibitors should not be used in combination with GLP-1 RAs (if the patient later reconsiders GLP-1 RA therapy) 1
• Insulin therapy requires careful education on administration and hypoglycemia management 1
• When combining multiple agents, consider potential drug interactions and additive side effects 1

By following this treatment algorithm, clinicians can provide effective glucose management for patients who refuse GLP-1 receptor agonists while still optimizing outcomes related to mortality, morbidity, and quality of life.