Starting and Adjusting Antidiabetic Drugs in Type 2 Diabetes
Initiate metformin concurrently with lifestyle modifications at the time of type 2 diabetes diagnosis, unless contraindicated or not tolerated. 1
Initial Therapy Approach
Standard Presentation (Most Patients)
Begin metformin immediately at diagnosis alongside lifestyle interventions (dietary counseling, weight management, exercise), rather than waiting to see if lifestyle changes alone are sufficient 1
Metformin is the preferred first-line agent because it effectively lowers A1C without causing hypoglycemia or weight gain, is inexpensive, and may reduce cardiovascular mortality 1, 2, 3
The 2022 American Diabetes Association guidelines emphasize that first-line therapy selection should also consider cardiovascular and renal comorbidities—in patients with established atherosclerotic cardiovascular disease or high cardiovascular risk, a GLP-1 receptor agonist may be preferred over metformin 1
Severe Hyperglycemia at Presentation
When patients present with markedly elevated glucose or symptoms of catabolism, initiate insulin therapy immediately (with or without additional agents) 1
Specific thresholds requiring immediate insulin:
- A1C ≥10-12% 1
- Fasting glucose ≥250 mg/dL (13.9 mmol/L) 1
- Random glucose ≥300-350 mg/dL (16.7-19.4 mmol/L) 1
- Presence of catabolic features: weight loss, ketonuria, symptomatic polyuria/polydipsia 1
For these severe presentations, use basal insulin plus one mealtime insulin as the preferred initial regimen 1
Adjusting and Intensifying Therapy
Timing of Treatment Intensification
Reassess medication regimen every 3-6 months and do not delay intensification if glycemic targets are not met 1
The progressive nature of type 2 diabetes means most patients will require combination therapy within a few years of diagnosis 1
Adding Second-Line Agents
When metformin monotherapy fails to achieve or maintain glycemic goals:
Select agents based on comorbidities first: For patients with established cardiovascular disease or high cardiovascular risk, add a GLP-1 receptor agonist preferentially over other agents 1
Consider early combination therapy at treatment initiation in some patients to extend time to treatment failure 1
Choose agents with different mechanisms of action for greatest synergy 1
Each new class of noninsulin agent added to initial therapy lowers A1C effectively 1
Insulin Initiation in Established Diabetes
When adding insulin to oral agents:
Start with basal insulin at 10 units or 0.1-0.2 units/kg, depending on degree of hyperglycemia 1
Continue metformin (and possibly one additional noninsulin agent) when starting basal insulin 1
Provide patients with self-titration algorithms based on self-monitoring of blood glucose, which improves glycemic control 1
Combine insulin with a GLP-1 receptor agonist when using insulin therapy for greater efficacy and treatment durability 1
Avoiding Overbasalization
Watch for clinical signals of excessive basal insulin use 1:
- Basal dose >0.5 units/kg/day
- High bedtime-to-morning glucose differential
- Hypoglycemia (aware or unaware)
- High glycemic variability
When overbasalization is identified, reevaluate and add prandial coverage or alternative agents rather than continuing to increase basal insulin 1
Key Contraindications and Precautions
Metformin contraindications: Renal impairment is the primary concern; periodic vitamin B12 testing should be considered as metformin use is associated with B12 deficiency 1
Gastrointestinal side effects are common with metformin but usually tolerated; if not tolerated, select alternative first-line therapy based on patient factors 1, 2, 3
Lactic acidosis risk with metformin is minimal when contraindications (particularly renal impairment) are respected 2, 4
Patient-Centered Treatment Selection
Beyond comorbidities, consider 1:
- Hypoglycemia risk (particularly important for patients with hazardous occupations)
- Effects on body weight
- Cost and access
- Side effect profile
- Patient preferences