What are alternative treatment options for type 2 diabetes besides GLP-1 (Glucagon-Like Peptide-1) receptor agonists?

Alternative Treatment Options for Type 2 Diabetes Besides GLP-1 Receptor Agonists

For patients requiring treatment beyond metformin who cannot use GLP-1 receptor agonists, SGLT-2 inhibitors should be the preferred second-line agent, particularly in patients with heart failure or chronic kidney disease, followed by insulin if additional glucose-lowering is needed. 1

First-Line Therapy Foundation

• Metformin remains the preferred initial pharmacological agent for type 2 diabetes if not contraindicated and if tolerated 1
• Metformin should be initiated at or soon after diagnosis unless contraindications exist (eGFR <30 mL/min/1.73 m²) 1
• Metformin can reduce insulin requirements by approximately 6.6 units/day when added to insulin therapy 1

Second-Line Options When GLP-1 RAs Are Not Used

SGLT-2 Inhibitors (Preferred Alternative)

SGLT-2 inhibitors should be prioritized as the primary alternative to GLP-1 receptor agonists, especially in specific clinical contexts 1:

• Prioritize SGLT-2 inhibitors in patients with congestive heart failure or chronic kidney disease as they decrease risk of heart failure hospitalization and slow progression of kidney disease 1
• SGLT-2 inhibitors provide cardiovascular mortality reduction, particularly through hemodynamic effects rather than anti-atherogenic mechanisms 1, 2
• These agents work via insulin-independent glucose lowering by blocking renal glucose reabsorption 1
• SGLT-2 inhibitors provide modest weight loss (typically 2-4 kg) and blood pressure reduction 1, 3
• Available agents include canagliflozin (up to 300 mg daily), dapagliflozin (up to 10 mg daily), empagliflozin (up to 25 mg daily), and ertugliflozin (up to 15 mg daily) 1

Clinical caveats for SGLT-2 inhibitors:

• Most effective when eGFR >60 mL/min/1.73 m² at initiation 3
• Avoid in patients at risk for diabetic ketoacidosis 3
• Can be used down to eGFR 20-30 mL/min/1.73 m² in ongoing trials, though current recommendations suggest caution below 30 1

Insulin Therapy

Insulin should be considered as the preferred injectable when:

• Extreme and symptomatic hyperglycemia is present 1
• A1C ≥10% (≥86 mmol/mol) or blood glucose ≥300 mg/dL (≥16.7 mmol/L) 1
• Evidence of ongoing catabolism, weight loss, or ketosis exists 1
• The distinction between type 1 and type 2 diabetes is unclear 1

Basal insulin approach:

• Start with basal insulin (NPH or long-acting analogs like glargine, detemir, or degludec) at 0.5 units/kg/day 1
• Titrate based on fasting glucose targets every 2-3 days 1
• Long-acting insulin analogs show reduced risks of hypoglycemia, particularly overnight, compared to NPH insulin 1
• Basal insulin in combination with oral medications has less hypoglycemia and weight gain than premixed insulin formulations 1

Intensifying beyond basal insulin:

• If glycemic targets not met on basal insulin with oral agents, add SGLT-2 inhibitors or prandial insulin 1
• Total daily insulin dose in type 2 diabetes may exceed 1 unit/kg/day due to insulin resistance 1

DPP-4 Inhibitors

DPP-4 inhibitors are a reasonable but less preferred option:

• Available agents include sitagliptin (100 mg daily), linagliptin (5 mg daily), saxagliptin (5 mg daily), and alogliptin (25 mg daily) 1
• These agents stimulate glucose-dependent insulin release with low hypoglycemia risk 1
• Critical limitation: Some DPP-4 inhibitors may increase risk of heart failure hospitalization (though sitagliptin showed no increased heart failure signal) 1
• Never combine DPP-4 inhibitors with GLP-1 receptor agonists as no additional HbA1c reduction occurs and this increases medication burden and cost without clinical benefit 4

Sulfonylureas

Sulfonylureas are inferior to SGLT-2 inhibitors but may have limited value for glycemic control:

• Sulfonylureas are inferior to SGLT-2 inhibitors and GLP-1 RAs in reducing all-cause mortality and morbidity 1
• Available agents include glimepiride (up to 8 mg daily), glipizide (up to 40 mg daily IR or 20 mg daily XL), and glyburide (up to 20 mg daily or 12 mg micronized) 1
• Major limitation: Increased risk of severe hypoglycemia 1
• When adding SGLT-2 inhibitors or intensifying therapy, reduce or discontinue sulfonylureas due to hypoglycemia risk 1

Thiazolidinediones (Pioglitazone)

Thiazolidinediones have significant limitations:

• Pioglitazone (up to 45 mg daily) can reduce HbA1c by 1.3-2.6% depending on prior treatment 5
• Contraindicated in patients with established heart failure as they may increase risk of heart failure events through volume expansion 1
• Associated with weight gain, which is problematic in most type 2 diabetes patients 1
• Should be avoided in patients with heart failure or at high risk for heart failure 1

Algorithmic Approach for Selecting Alternatives

Step 1: Assess cardiovascular and renal status

• If heart failure (HFrEF or HFpEF) or CKD present → SGLT-2 inhibitor 1
• If eGFR <30 mL/min/1.73 m² → Insulin (metformin and SGLT-2 inhibitors contraindicated) 1

Step 2: Assess glycemic urgency

• If A1C ≥10% or glucose ≥300 mg/dL with symptoms → Insulin 1
• If A1C 8-10% without severe symptoms → SGLT-2 inhibitor 1

Step 3: Consider combination therapy

• Metformin + SGLT-2 inhibitor is the preferred non-GLP-1 RA combination 1, 2
• If inadequate control, add basal insulin to metformin + SGLT-2 inhibitor 1
• Avoid combining DPP-4 inhibitors with any regimen if considering future GLP-1 RA use 4

Step 4: Deprescribe high-risk agents

• When adequate glycemic control achieved with SGLT-2 inhibitors or insulin, reduce or discontinue sulfonylureas 1
• HbA1c levels below 6.5% should prompt consideration of stopping medications with hypoglycemia or weight gain risk 1

Important Clinical Pitfalls

• Never use thiazolidinediones in patients with any stage of heart failure as they are contraindicated and increase heart failure events 1
• Self-monitoring of blood glucose may be unnecessary in patients on metformin combined with SGLT-2 inhibitors (both have low hypoglycemia risk) 1
• Sulfonylureas and long-acting insulins carry increased severe hypoglycemia risk and should be reduced when other agents are added 1
• The combination of SGLT-2 inhibitors with insulin may provide additive benefits for cardiovascular-renal protection through different mechanisms 2