What are the recommended drug choices, dosing regimens, and treatment sequence for type 2 diabetes mellitus, including adjustments for renal function, atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, and HbA1c thresholds?

Type 2 Diabetes Mellitus Drug Therapy and Dosing

Start metformin 500–850 mg once or twice daily with meals at diagnosis, titrate by 500 mg weekly to a minimum of 2 g/day (or equivalent extended-release formulation), and immediately add an SGLT2 inhibitor (if eGFR ≥20 mL/min/1.73 m²) or GLP-1 receptor agonist (if established ASCVD) regardless of current HbA1c. 1, 2

First-Line Therapy: Metformin

Metformin is the foundation of type 2 diabetes treatment and must be initiated at diagnosis alongside lifestyle modifications. 1, 2

Dosing Regimen

• Begin with 500–850 mg once or twice daily with meals 2
• Increase by 500 mg weekly until reaching ≥2 g/day total (or equivalent extended-release once-daily formulation) 1, 2
• Extended-release formulations reduce gastrointestinal side effects while maintaining equivalent glycemic efficacy 1, 3
• Continue metformin indefinitely while tolerated 1, 2

Renal Function Adjustments

• eGFR ≥60 mL/min/1.73 m²: Full dose up to 2000 mg daily 1, 4
• eGFR 45–59 mL/min/1.73 m²: Reduce to 50% of dose 1, 2
• eGFR 30–44 mL/min/1.73 m²: Maximum 1000 mg daily 1, 2, 4
• eGFR <30 mL/min/1.73 m²: Discontinue metformin 1, 2, 4

Monitoring

• Screen for vitamin B12 deficiency periodically, especially in patients with anemia or peripheral neuropathy, as long-term metformin causes biochemical deficiency 2

---

Second-Line Therapy: Comorbidity-Directed Selection

The choice of second agent depends on the presence of cardiovascular disease, heart failure, or chronic kidney disease—not on HbA1c level. 1

For Chronic Kidney Disease (eGFR 20–59 mL/min/1.73 m² or albuminuria ≥30 mg/g)

Add an SGLT2 inhibitor to metformin immediately, regardless of current HbA1c. 1, 4

Specific Agents and Dosing

• Empagliflozin: 10 mg once daily, may increase to 25 mg once daily 1
• Dapagliflozin: 10 mg once daily 1
• Canagliflozin: 100 mg once daily, may increase to 300 mg once daily if eGFR ≥60 mL/min/1.73 m² 1

Key Evidence

• SGLT2 inhibitors reduce CKD progression by 24–39%, lower heart failure hospitalizations, and decrease cardiovascular death by 38% (HR 0.62,95% CI 0.49–0.77) 1, 2
• Initiate when eGFR ≥20 mL/min/1.73 m² and continue even if eGFR falls below this threshold for ongoing cardiovascular and renal protection 1, 2, 4
• Continue until dialysis or transplantation is initiated 1

For Atherosclerotic Cardiovascular Disease (Prior MI, Stroke, Revascularization, or ≥50% Arterial Stenosis)

Add a GLP-1 receptor agonist to metformin immediately, regardless of current HbA1c. 1, 2

Specific Agents and Dosing

• Semaglutide (subcutaneous): 0.25 mg once weekly for 4 weeks, then 0.5 mg once weekly; may increase to 1 mg once weekly after ≥4 weeks 1, 2
• Liraglutide: 0.6 mg once daily for 1 week, then 1.2 mg once daily; may increase to 1.8 mg once daily after ≥1 week 2
• Dulaglutide: 0.75 mg once weekly, may increase to 1.5 mg once weekly 2

Key Evidence

• Liraglutide demonstrated 22% reduction in cardiovascular death (HR 0.78,95% CI 0.66–0.93) and 15% reduction in all-cause mortality (HR 0.85,95% CI 0.74–0.97) 2
• GLP-1 receptor agonists reduce HbA1c by 0.6–1.5%, produce 2–5 kg weight loss, and lower major adverse cardiovascular events including stroke 2, 4
• Preferred over insulin as first injectable medication 1, 2

For Heart Failure (Especially Reduced Ejection Fraction)

Add an SGLT2 inhibitor to metformin immediately, regardless of current HbA1c. 1, 2, 4

• Use the same SGLT2 inhibitor agents and doses listed above for CKD 1
• SGLT2 inhibitors reduce heart failure hospitalizations by 18–25% 4

For Multiple Comorbidities (ASCVD + HF/CKD)

Use triple therapy: metformin + SGLT2 inhibitor + GLP-1 receptor agonist. 2

• Prioritize SGLT2 inhibitors when heart failure or CKD dominates; prioritize GLP-1 receptor agonists when ASCVD or weight loss is the primary goal 2

---

Third-Line Therapy: When Dual Therapy Fails to Achieve HbA1c Target

If HbA1c remains above target after 3 months on metformin + SGLT2 inhibitor, add a GLP-1 receptor agonist. 1, 2

If HbA1c remains above target after 3 months on metformin + GLP-1 receptor agonist, add an SGLT2 inhibitor. 2

Alternative Third-Line Agents (When GLP-1 Receptor Agonists Are Unsuitable)

DPP-4 Inhibitors

• Sitagliptin: 100 mg once daily (50 mg if eGFR 30–50 mL/min/1.73 m²; 25 mg if eGFR <30 mL/min/1.73 m²) 2
• Linagliptin: 5 mg once daily (no dose adjustment for renal impairment) 2
• Lower HbA1c by 0.5–0.8%, weight-neutral, minimal hypoglycemia risk 2
• Do not combine with GLP-1 receptor agonists due to overlapping mechanisms 2

Thiazolidinediones (Selective Use Only)

• Pioglitazone: 15–30 mg once daily, may increase to 45 mg once daily 2
• Risks include 2–4 kg weight gain, fluid retention, and possible heart failure exacerbation 2

Sulfonylureas (Cost-Driven Alternative)

• Gliclazide (preferred): 40–80 mg once daily, may increase to 320 mg daily in divided doses 2
• Avoid in adults ≥65 years, prior severe hypoglycemia, erratic meals, or impaired hypoglycemia awareness 2

---

Insulin Initiation Criteria

Start basal insulin immediately when HbA1c ≥10% or plasma glucose ≥300 mg/dL with symptomatic hyperglycemia (polyuria, polydipsia, weight loss) or catabolic features. 1, 5, 2

Specific Regimens

• Insulin glargine U-100: 10 units once daily or 0.1–0.2 units/kg once daily, titrate by 2 units every 3 days to fasting glucose 80–130 mg/dL 2
• Insulin degludec: 10 units once daily, titrate by 2 units every 3 days 2
• Insulin detemir: 10 units once or twice daily, titrate by 2 units every 3 days 2

Critical Safety Measures

• Continue metformin and SGLT2 inhibitor or GLP-1 receptor agonist when adding insulin to preserve cardiovascular and renal protection 2
• Reduce or discontinue sulfonylureas immediately when starting insulin to prevent severe hypoglycemia 5, 2

For Ketosis or Diabetic Ketoacidosis

• Administer immediate subcutaneous or intravenous insulin; once acidosis resolves, initiate metformin while continuing insulin 2

---

Glycemic Targets

• HbA1c 7–8% for most adults to balance efficacy with hypoglycemia risk 1, 2
• HbA1c <6.5% for younger patients with early disease, no significant comorbidities, and low hypoglycemia risk 2
• HbA1c 7.5–8.5% for older adults, limited life expectancy, advanced complications, extensive comorbidities, or prior severe hypoglycemia 2

---

Monitoring and Treatment Intensification

• Measure HbA1c every 3 months until target is reached, then continue quarterly 1, 2
• Do not delay therapeutic intensification beyond 3 months of inadequate control, as treatment inertia increases microvascular complication risk 5, 2
• Reassess medication regimen every 3–6 months for comorbidities, hypoglycemia risk, weight effects, adverse events, cost, and patient preferences 1, 2

---

Common Pitfalls and How to Avoid Them

Delaying Metformin at Diagnosis

• Metformin must be started immediately at diagnosis alongside lifestyle modifications—delays prolong hyperglycemia exposure and increase complication risk 5, 2

Failing to Add SGLT2 Inhibitors or GLP-1 Receptor Agonists Based on Comorbidities

• These agents reduce mortality and morbidity independent of HbA1c—do not wait for glycemic failure before adding them in patients with ASCVD, HF, or CKD 1

Continuing Sulfonylureas or High-Dose Insulin When Adding SGLT2 Inhibitors or GLP-1 Receptor Agonists

• Immediately reduce or discontinue sulfonylureas or long-acting insulin when adding these agents to prevent severe hypoglycemia 5, 2

Premature Discontinuation of Metformin or SGLT2 Inhibitors in CKD

• Metformin can be used with dose reduction when eGFR is 30–45 mL/min/1.73 m² 1, 2
• SGLT2 inhibitors retain cardiovascular and renal benefit down to eGFR ≥20 mL/min/1.73 m² and should be continued even if eGFR falls below the initiation threshold 1, 2

Over-Basalization with Insulin

• Watch for basal insulin dose >0.5 U/kg/day, large bedtime-to-morning glucose gap, frequent hypoglycemia, or high glycemic variability—these indicate need to add prandial insulin or switch to GLP-1 receptor agonist 2

---

Adjunctive Cardiovascular Risk Management

• Prescribe moderate-to-high intensity statin therapy for all adults aged 40–75 years with diabetes, independent of baseline LDL or calculated risk 1, 2
• Target blood pressure <130/80 mmHg using ACE inhibitors or ARBs as first-line agents in patients with diabetes and hypertension 2
• Recommend low-dose aspirin (75–162 mg daily) for secondary prevention in patients with established ASCVD, unless contraindicated 2