What are the preferred sodium‑glucose co‑transporter‑2 (SGLT2) inhibitors and glucagon‑like peptide‑1 (GLP‑1) receptor agonists, and what initial prescription should be given to a newly diagnosed adult with type 2 diabetes mellitus?

Preferred SGLT2 Inhibitors and GLP-1 Agonists for Newly Diagnosed Type 2 Diabetes

Start metformin 500 mg twice daily immediately at diagnosis, titrate to 2000 mg daily over 3–4 weeks, then add either an SGLT2 inhibitor or GLP-1 receptor agonist at 3 months if HbA1c remains >7–8%, choosing based on dominant comorbidities: SGLT2 inhibitors for heart failure or chronic kidney disease, GLP-1 agonists for stroke risk or substantial weight-loss goals. 1, 2

Initial Prescription for Newly Diagnosed Type 2 Diabetes

First-Line Metformin Therapy

• Begin metformin 500 mg once or twice daily with meals on the day of diagnosis for all adults with eGFR ≥30 mL/min/1.73 m² who have no contraindications. 1, 2
• Increase the dose by 500 mg weekly until reaching 2000 mg daily (1000 mg twice daily), which provides maximal glucose-lowering efficacy; doses above 2000 mg add minimal benefit and increase gastrointestinal intolerance. 2
• Metformin reduces all-cause mortality by approximately 36% and cardiovascular mortality by 39% compared with conventional therapy, while carrying minimal hypoglycemia risk when used alone. 2

Renal Dosing Thresholds for Metformin

eGFR (mL/min/1.73 m²)	Metformin Dosing
≥45	Standard dosing up to 2000 mg daily
30–44	Reduce dose by 50% (≈1000 mg daily) and provide sick-day guidance
<30	Discontinue metformin

2

When to Add a Second Agent

• Reassess HbA1c exactly 3 months after starting metformin plus lifestyle modifications. 1, 2
• If HbA1c remains >7–8% after 3 months, add either an SGLT2 inhibitor or GLP-1 receptor agonist immediately—do not delay beyond this timepoint. 1, 2
• Both drug classes equally reduce all-cause mortality and major adverse cardiovascular events with high-certainty evidence. 2

Choosing Between SGLT2 Inhibitors and GLP-1 Agonists

Prefer SGLT2 Inhibitors When:

• Heart failure is present (especially reduced ejection fraction)—SGLT2 inhibitors reduce heart-failure hospitalizations more effectively than any other glucose-lowering drug. 1, 2
• Chronic kidney disease exists (eGFR 30–90 mL/min/1.73 m² or albumin-to-creatinine ratio >200 mg/g)—SGLT2 inhibitors slow CKD progression with high-certainty evidence. 1, 2
• Cardiovascular mortality reduction is the priority—SGLT2 inhibitors provide robust cardiovascular protection independent of glucose lowering. 1, 2

Prefer GLP-1 Receptor Agonists When:

• Substantial weight loss is a primary goal (>10% body weight reduction)—GLP-1 agonists achieve greater weight reduction than SGLT2 inhibitors (typically 2–5 kg with GLP-1 vs. 2–4 kg with SGLT2). 2
• Stroke risk is elevated—GLP-1 agonists specifically reduce stroke incidence beyond other cardiovascular benefits. 1, 2
• All-cause mortality reduction is the priority—GLP-1 agonists provide proven mortality benefit with high-certainty evidence. 2

Preferred SGLT2 Inhibitors (Listed by Strength of Evidence)

Empagliflozin (First Choice)

• Dosing: Start 10 mg once daily; may increase to 25 mg daily if additional glycemic control needed. 2
• Renal threshold: Can be initiated at eGFR ≥20 mL/min/1.73 m² (glycemic effect attenuated below 45 but cardiovascular/renal benefits persist). 2
• Evidence: Reduces cardiovascular death by 38% in patients with established cardiovascular disease; demonstrated benefit in EMPA-REG OUTCOME trial. 1, 2

Dapagliflozin (Second Choice)

• Dosing: Start 5 mg once daily; may increase to 10 mg daily. 2
• Renal threshold: Can be initiated at eGFR ≥25 mL/min/1.73 m² for cardio-renal protection. 2
• Evidence: Reduces end-stage renal disease risk by 32% and composite kidney endpoint by 30% in CREDENCE trial. 2

Canagliflozin (Third Choice)

• Dosing: Start 100 mg once daily before first meal; may increase to 300 mg daily. 2
• Renal threshold: For eGFR 30–60 mL/min/1.73 m², limit to 100 mg daily; do not initiate if eGFR <30. 2
• Evidence: Proven cardiovascular and renal benefits in patients with ASCVD or high cardiovascular risk. 2

Preferred GLP-1 Receptor Agonists (Listed by Strength of Evidence)

Semaglutide (First Choice—Highest Efficacy)

• Subcutaneous dosing: 0.25 mg weekly × 4 weeks → 0.5 mg weekly; may increase to 1.0 mg weekly, and up to 2.4 mg weekly for weight-management goals. 2
• Oral dosing: 3 mg daily before first food/drink × ≥30 days → 7 mg daily × ≥30 days → optionally 14 mg daily. 2
• Evidence: Provides the greatest HbA1c reduction among GLP-1 agonists (up to 1.5% at 2.0 mg dose); demonstrated cardiovascular benefit in SUSTAIN-6 trial. 2
• No renal dose adjustment required; usable down to eGFR <15 mL/min/1.73 m². 2

Liraglutide (Second Choice)

• Dosing: 0.6 mg daily × 1 week → 1.2 mg daily; may increase to 1.8 mg daily, and to 3.0 mg daily for obesity (BMI >30 kg/m²). 2
• Evidence: Achieved 22% reduction in cardiovascular death in LEADER trial; comparable HbA1c lowering to semaglutide without renal dose adjustment. 2

Dulaglutide (Third Choice)

• Dosing: 0.75 mg weekly; may increase to 1.5 mg weekly. 2
• Evidence: Demonstrated cardiovascular benefit in REWIND trial; no renal dose adjustment required. 2

Tirzepatide (Dual GIP/GLP-1 Agonist—Alternative)

• Dosing: Start 2.5 mg weekly × 4 weeks → 5 mg weekly × 4 weeks → may increase to 7.5 mg, 10 mg, 12.5 mg, or 15 mg weekly based on response. 2
• Evidence: Functions as GLP-1 receptor agonist with superior efficacy to traditional GLP-1 agonists; prioritize when patient needs substantial weight loss or has increased stroke risk. 2

Expected Weight Loss with Each Class

• Metformin alone: Modest weight loss of approximately 2–3 kg when combined with lifestyle changes. 2
• Adding SGLT2 inhibitor to metformin: Additional 2–4 kg loss (total 4–7 kg) through urinary glucose excretion (≈200–300 kcal/day). 2
• Adding GLP-1 agonist to metformin: Additional 2–5 kg loss; semaglutide and tirzepatide show very high efficacy for weight reduction. 2

Critical Safety Considerations

When Adding SGLT2 Inhibitors

• Educate patients to discontinue the SGLT2 inhibitor and seek immediate medical care if they develop nausea, vomiting, dyspnea, or unusual fatigue to prevent euglycemic diabetic ketoacidosis. 2
• Use caution when combined with loop diuretics, ACE inhibitors, or ARBs; monitor for orthostatic hypotension, especially in older adults or those on multiple antihypertensives. 2
• Genital mycotic infections occur in approximately 6–8% of patients (versus 1–2% with metformin alone); infections are usually mild and respond to standard therapy. 2

When Adding GLP-1 Agonists

• Start at the lowest dose and titrate slowly over 4–8 weeks to minimize gastrointestinal side effects (nausea occurs in ~21–22% of users, peaks during dose escalation). 2
• Avoid in patients with personal or family history of medullary thyroid carcinoma or MEN 2, history of pancreatitis, severe gastrointestinal disease, or proliferative retinopathy. 2

Hypoglycemia Risk

• Metformin plus an SGLT2 inhibitor or GLP-1 agonist does not increase hypoglycemia risk when sulfonylureas or insulin are not co-prescribed. 2
• Routine self-monitoring of blood glucose is unnecessary with this combination due to minimal hypoglycemia risk. 2

Monitoring Requirements

• Renal function: Measure eGFR at baseline, 2 weeks after starting an SGLT2 inhibitor, then every 3–6 months. 2
• Vitamin B12: Perform annual testing in patients on long-term metformin, particularly if anemia or peripheral neuropathy develops. 1, 2
• HbA1c: Reassess every 3 months until target is achieved, then every 6 months once stable. 2

Glycemic Targets

• Aim for HbA1c between 7% and 8% for most adults; this range balances microvascular protection against hypoglycemia risk and treatment burden. 1, 2
• De-intensify therapy when HbA1c falls below 6.5% to avoid hypoglycemia and overtreatment. 1, 2

What NOT to Use

• Do not add DPP-4 inhibitors to metformin—they fail to reduce morbidity or all-cause mortality despite lowering HbA1c (strong recommendation, high-certainty evidence). 2
• Avoid sulfonylureas as second-line agents in patients without cardiovascular disease—they are inferior to SGLT2 inhibitors and GLP-1 agonists for reducing mortality and morbidity. 2

Special Populations

High-Risk Patients at Diagnosis (Established CVD, Heart Failure, or CKD)

• Initiate metformin plus an SGLT2 inhibitor or GLP-1 agonist at diagnosis, regardless of baseline HbA1c, because postponing organ-protective therapy increases morbidity. 1, 2
• This dual-therapy approach at diagnosis is advised because most patients rapidly progress to needing combination therapy. 1

Severe Hyperglycemia at Diagnosis (HbA1c ≥10% or Glucose ≥300 mg/dL)

• Start metformin 500 mg twice daily plus basal insulin 10 units at bedtime (or 0.1–0.2 units/kg) immediately, because oral agents alone cannot achieve adequate control at this severity. 1, 2
• Titrate insulin by 2–4 units every 3 days until fasting glucose reaches 80–130 mg/dL without hypoglycemia. 2

Cost Considerations

• No generic SGLT2 inhibitors or GLP-1 agonists currently exist; discuss medication costs with patients when selecting specific agents within these classes. 2
• Metformin is inexpensive (pennies per day), whereas SGLT2 inhibitors and GLP-1 agonists cost several hundred dollars per month without insurance coverage. 2
• Explore manufacturer assistance programs or switch to lower-cost agents within the same class before discontinuing these organ-protective therapies. 2

Common Pitfalls to Avoid

• Do not delay addition of a second agent beyond 3 months when HbA1c is not at target; intensification after 3 months improves long-term outcomes. 2
• Do not discontinue metformin when adding an SGLT2 inhibitor or GLP-1 agonist unless contraindicated; combination therapy is supported by evidence. 2
• Do not combine GLP-1 agonists with DPP-4 inhibitors—no additional glucose-lowering benefit has been demonstrated. 2
• Do not wait for metformin "failure" before initiating SGLT2 inhibitors or GLP-1 agonists in high-risk patients; both agents should be started early. 1, 2