GLP-1 Receptor Agonists for Glycemic Control in Type 2 Diabetes

Add a GLP-1 receptor agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce all-cause mortality, major adverse cardiovascular events, and stroke. 1

When to Initiate a GLP-1 Receptor Agonist

Start a GLP-1 receptor agonist when:

HbA1c remains above target (typically >7%) despite metformin and lifestyle modifications 1
The patient has established atherosclerotic cardiovascular disease (ASCVD), regardless of baseline HbA1c 1, 2
The patient has chronic kidney disease with eGFR 20–60 mL/min/1.73 m² and/or albuminuria 1
The patient has advanced CKD (eGFR <30 mL/min/1.73 m²), where GLP-1 RAs are preferred over insulin due to lower hypoglycemia risk 1, 2
Weight loss is an important treatment goal (BMI ≥27 kg/m² with comorbidities or ≥30 kg/m²) 1, 3

Prioritize GLP-1 RAs over insulin as the first injectable therapy because they provide superior cardiovascular and renal protection, promote weight loss rather than weight gain, and carry minimal intrinsic hypoglycemia risk. 1, 2, 4

Agent Selection

Choose semaglutide (Ozempic) 1 mg weekly for patients with established cardiovascular disease because it reduces major adverse cardiovascular events by 26% (HR 0.74,95% CI 0.58–0.95). 1, 3

Choose tirzepatide (Mounjaro) 15 mg weekly when maximal weight loss is the priority, as it achieves 20.9% weight loss at 72 weeks versus 14.9% with semaglutide 2.4 mg. 3

Choose dulaglutide (Trulicity) 1.5 mg weekly as an alternative if semaglutide or tirzepatide are unavailable or not tolerated, as it also reduces cardiovascular events by approximately 20–26%. 1, 5

Initial Dosing and Titration

Semaglutide (Ozempic) 6, 7

Week 1–4: 0.25 mg subcutaneously once weekly
Week 5–8: 0.5 mg once weekly
Week 9+: 1 mg once weekly (maintenance dose for diabetes)
If additional glycemic control is needed after ≥4 weeks at 1 mg, increase to 2 mg once weekly 6

Tirzepatide (Mounjaro) 3, 8

Week 1–4: 2.5 mg subcutaneously once weekly
Week 5–8: 5 mg once weekly (initial maintenance dose)
Week 9–12: 10 mg once weekly (if additional control needed)
Week 13+: 15 mg once weekly (maximum dose for maximal benefit)

Dulaglutide (Trulicity) 2

Week 1–4: 0.75 mg subcutaneously once weekly
Week 5+: 1.5 mg once weekly (if additional control needed)

Administer once weekly on the same day each week, at any time of day, with or without meals. 6, 4 Inject subcutaneously in the abdomen, thigh, or upper arm. 6

Expected Glycemic and Weight Benefits

Glycemic Control 1, 2, 7

HbA1c reduction: 0.8–1.6% on average with standard GLP-1 RAs
Tirzepatide: 1.87–2.59% HbA1c reduction (most potent agent available)
Fasting glucose: Long-acting agents (liraglutide, semaglutide, dulaglutide, tirzepatide) have more profound effects on overnight and fasting plasma glucose 4

Weight Loss 3, 2, 9

Semaglutide 1 mg: ~7% weight loss in patients with type 2 diabetes
Tirzepatide 15 mg: ~20.9% weight loss at 72 weeks
Traditional GLP-1 RAs (liraglutide, dulaglutide): ~2–3 kg weight loss
Weight loss is greater in non-diabetic patients (6.1–17.4%) compared to those with diabetes (4–6.2%) 3

Common Adverse Effects and Management

Gastrointestinal effects are the most common adverse events: 1, 3, 4

Nausea: 17–44% of patients (dose-dependent, typically mild-to-moderate)
Diarrhea: 12–32% of patients
Vomiting: 7–25% of patients
Constipation: 10–23% of patients

These effects are transient and usually resolve within 4–8 weeks. 3, 2 Slow titration (every 4 weeks) significantly reduces gastrointestinal side effects. 1, 3, 2

Management strategies: 3, 2

Start at the lowest approved dose and titrate gradually
Reduce meal size
Limit alcohol and carbonated beverages
Reassure patients that symptoms typically decrease over time

Serious but rare adverse events: 1, 3

Pancreatitis: Discontinue immediately if persistent severe abdominal pain occurs (causality not definitively established)
Gallbladder disease: Cholelithiasis and cholecystitis occur 38% more frequently than placebo with semaglutide
Acute kidney injury: Monitor renal function in patients with severe gastrointestinal reactions

Monitoring Parameters

Initial Phase (First 3–4 Months) 1, 2

Every 4 weeks: Assess gastrointestinal tolerance, weight, blood pressure, and signs of pancreatitis or gallbladder disease
Week 12–16: Re-assess HbA1c, fasting glucose, body weight, and blood pressure to determine treatment efficacy

Maintenance Phase 1, 2

Every 3–6 months: Monitor HbA1c, weight, blood pressure, and cardiovascular risk factors
Hypoglycemia surveillance: GLP-1 RAs alone carry minimal intrinsic hypoglycemia risk, but risk increases when combined with sulfonylureas or insulin 1, 2

Renal Monitoring 1, 2

No dose adjustment required for semaglutide, liraglutide, or dulaglutide across all stages of CKD, including eGFR <30 mL/min/1.73 m²
Monitor for dehydration secondary to gastrointestinal side effects, especially in patients with renal impairment 1

Concomitant Medication Adjustments

When initiating a GLP-1 RA: 1, 8, 2

Reduce basal insulin by 20% to prevent hypoglycemia (e.g., if on 60 units, reduce to 48 units)
Reduce sulfonylurea dose by 50% or discontinue entirely to avoid additive hypoglycemia risk
Discontinue DPP-4 inhibitors (e.g., sitagliptin, linagliptin) before starting a GLP-1 RA, as concurrent use offers no additional benefit 1, 2
Continue metformin unless contraindicated 1, 2

After achieving glycemic control with a GLP-1 RA, consider discontinuing sulfonylureas or long-acting insulins due to increased risk of severe hypoglycemia. 1

Absolute Contraindications

Do not prescribe GLP-1 receptor agonists in patients with: 1, 3, 6

Personal or family history of medullary thyroid carcinoma (MTC)
Multiple endocrine neoplasia syndrome type 2 (MEN 2)
History of severe hypersensitivity reaction to the specific GLP-1 RA

Screen all patients for these contraindications before initiation. 1, 6

Alternative Second-Line Options

If GLP-1 RAs are contraindicated or not tolerated:

SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) are preferred for patients with heart failure (reduced or preserved ejection fraction) or CKD, as they reduce heart failure hospitalizations and slow CKD progression. 1, 8
Basal insulin (e.g., insulin glargine, insulin degludec) if the patient has evidence of insulin deficiency (HbA1c >10%, glucose ≥300 mg/dL with symptoms). 1, 2
Pioglitazone for patients with biopsy-proven NASH or high-risk NAFLD, though it causes weight gain (~1–5 kg). 1

Do not add a DPP-4 inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control, as it does not reduce morbidity or all-cause mortality. 1

Common Pitfalls to Avoid

Do not delay GLP-1 RA initiation until multiple oral agents have failed; early use in appropriate candidates (ASCVD, CKD, obesity) yields better outcomes. 1, 2
Do not discontinue metformin when starting a GLP-1 RA unless a specific contraindication exists. 1, 2
Do not overlook the need to reduce or stop sulfonylureas, as their combination with GLP-1 RAs markedly increases hypoglycemia risk. 1, 8, 2
Do not assume renal dose adjustment is necessary; semaglutide, liraglutide, and dulaglutide require no dose adjustment across all CKD stages. 1, 2
Do not prescribe GLP-1 RAs to patients with a personal or family history of MTC or MEN 2—these are absolute contraindications. 1, 3, 6

Special Considerations

Self-monitoring of blood glucose may be unnecessary in patients receiving metformin combined with a GLP-1 RA, as the intrinsic hypoglycemia risk is minimal. 1

Collaborative care plans should include integrated efforts with dietary improvement, weight management, sleep health, physical activity, stress management, and management of comorbidities. 1

Payors should cover evidence-based obesity treatments to reduce barriers to treatment access. 3

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