Treatment of Type 2 Diabetes Mellitus
Start metformin immediately at diagnosis alongside lifestyle modifications, then add an SGLT-2 inhibitor as first-line dual therapy for most patients, particularly those with cardiovascular disease, heart failure, or chronic kidney disease. 1, 2, 3
Lifestyle Modifications (Foundation for All Patients)
Prescribe at least 150 minutes per week of moderate-intensity aerobic activity (e.g., brisk walking) combined with resistance training at least 2 days per week. 1, 2
Target 5-10% weight loss from baseline through dietary modifications focusing on a plant-based, heart-healthy pattern that is low in saturated fat and refined carbohydrates but high in whole grains, vegetables, legumes, and fruits. 1, 2, 4
Limit sodium intake to <2 g/day (equivalent to <5 g sodium chloride/day) to support blood pressure management. 1, 2
Prescribe 1.0-1.2 g protein/kg body weight/day for patients on dialysis; for non-dialysis CKD patients, protein intake should be individualized based on kidney function. 1
First-Line Pharmacotherapy
Metformin (Universal First-Line Agent)
Initiate metformin 500-850 mg once or twice daily at diagnosis, titrating gradually to ≥2 g/day (e.g., 1 g twice daily) or use extended-release formulation once daily to minimize gastrointestinal side effects. 1, 2
Continue metformin indefinitely as long as tolerated and not contraindicated, even when adding other agents including insulin. 1
Adjust metformin dosing based on eGFR: full dose (up to 2000 mg/day) if eGFR ≥60 mL/min/1.73 m²; consider dose reduction if eGFR 45-59; maximum 1000 mg/day if eGFR 30-44; discontinue if eGFR <30. 1, 3
Monitor vitamin B12 levels periodically (especially in patients with anemia or peripheral neuropathy) as long-term metformin use is associated with biochemical B12 deficiency. 1
Second-Line Agent Selection (Comorbidity-Driven Approach)
Patients with Atherosclerotic Cardiovascular Disease (ASCVD) or High ASCVD Risk
Add a GLP-1 receptor agonist (preferably semaglutide or liraglutide with proven cardiovascular benefit) to metformin, regardless of current HbA1c level. 1, 2, 5
GLP-1 receptor agonists reduce major adverse cardiovascular events by 12-26%, primarily through reduction in atherosclerotic events and stroke risk, with substantial weight loss benefits. 2, 5
Liraglutide demonstrated cardiovascular death reduction (HR 0.78,95% CI 0.66-0.93) and all-cause mortality reduction (HR 0.85,95% CI 0.74-0.97) in the LEADER trial. 5
Patients with Heart Failure or Chronic Kidney Disease
Add an SGLT-2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) to metformin, regardless of current HbA1c level. 1, 2, 3
SGLT-2 inhibitors reduce CKD progression by 24-39%, lower heart failure hospitalizations by 18-25%, and decrease cardiovascular and all-cause mortality independent of glycemic effects. 2, 3, 6, 7
Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77) in the EMPA-REG OUTCOME trial. 8
Initiate SGLT-2 inhibitors when eGFR ≥30 mL/min/1.73 m² for glycemic benefit; newer evidence supports initiation down to eGFR ≥20 mL/min/1.73 m² for cardiovascular and renal protection, continuing even if eGFR declines below initiation threshold. 1, 3, 8
Patients with Multiple Comorbidities (ASCVD + HF or CKD)
Use triple therapy with metformin + SGLT-2 inhibitor + GLP-1 receptor agonist when both cardiovascular and renal protection are needed. 1, 2, 3, 9
SGLT-2 inhibitors are preferred over GLP-1 receptor agonists when heart failure or CKD predominates; GLP-1 receptor agonists are preferred when atherosclerotic disease or weight loss is the priority. 1, 2
Third-Line and Additional Agents
When HbA1c Remains Above Target on Dual Therapy
Add a GLP-1 receptor agonist as the preferred third agent if not already prescribed, due to superior efficacy, weight loss benefits, and cardiovascular protection. 1, 2, 3
Consider DPP-4 inhibitors (sitagliptin, linagliptin) when GLP-1 receptor agonists are not tolerated or unavailable, though they provide less robust glycemic control and no cardiovascular benefit. 1, 2
Avoid sulfonylureas in older adults or those at high hypoglycemia risk; if used, select agents with lower hypoglycemia potential and use the lowest effective dose. 1, 2
Thiazolidinediones (pioglitazone) may be considered in select cases but recognize risks of weight gain, fluid retention, and potential heart failure exacerbation. 1, 2
Insulin Initiation Criteria
Start basal insulin immediately when HbA1c ≥10% (or plasma glucose ≥300 mg/dL) and the patient is symptomatic or catabolic (weight loss, ketosis) to prevent metabolic decompensation. 1, 2
Initiate long-acting insulin analogs (glargine, degludec, detemir) that induce the least weight gain and have the lowest hypoglycemia risk. 1, 4
Continue metformin and SGLT-2 inhibitor or GLP-1 receptor agonist when adding insulin to maintain cardiovascular and renal protection. 1, 2
When initiating insulin, immediately reduce or discontinue sulfonylureas to prevent severe hypoglycemia. 2
Glycemic Targets
Target HbA1c between 7% and 8% for most adults to balance efficacy and hypoglycemia risk. 2
Consider HbA1c <6.5% for selected individuals when achievable without significant hypoglycemia or treatment burden (younger patients, short disease duration, no cardiovascular disease). 2
Use less stringent targets (HbA1c 7.5-8.5%) for older adults, those with limited life expectancy, advanced complications, extensive comorbidities, or history of severe hypoglycemia. 1
Monitoring and Treatment Intensification
Measure HbA1c every 3 months until glycemic targets are achieved, then continue quarterly monitoring. 2
Do not delay therapeutic intensification beyond 3 months of inadequate control, as treatment inertia increases microvascular complication risk. 2
Reassess medication regimen every 3-6 months and adjust based on comorbidities, hypoglycemia risk, weight effects, side effects, cost, and patient preferences. 1
Monitor for overbasalization with insulin: clinical signals include basal dose >0.5 units/kg/day, high bedtime-morning glucose differential, hypoglycemia, or high glycemic variability. 1
Special Populations
Older Adults
Avoid sulfonylureas, meglitinides, and high-dose insulin due to severe hypoglycemia risk. 2
De-intensify hypoglycemia-causing medications in older adults at high risk while maintaining individualized glycemic targets. 2
Simplify complex insulin regimens to reduce hypoglycemia, polypharmacy, and treatment burden. 2
Chronic Kidney Disease
Most patients with T2DM, CKD, and eGFR ≥30 mL/min/1.73 m² benefit from dual therapy with metformin and SGLT-2 inhibitor as first-line treatment. 1, 3
Engage accredited nutrition providers and diabetes educators in multidisciplinary care, considering cultural differences, food resources, and cost. 1
Critical Safety Considerations
When adding SGLT-2 inhibitors or GLP-1 receptor agonists that achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins to prevent severe hypoglycemia. 2
Check eGFR before initiating any oral diabetes medication to guide metformin dosing and SGLT-2 inhibitor eligibility. 3
Assess cardiovascular disease status at every visit to prioritize SGLT-2 inhibitors or GLP-1 receptor agonists appropriately. 3
Adjunctive Cardiovascular Risk Management
Prescribe moderate-to-high intensity statin therapy for all patients aged 40-75 years with diabetes, regardless of baseline LDL or cardiovascular risk. 1
Target blood pressure <130/80 mmHg using renin-angiotensin system inhibitors as first-line agents. 1, 9
Prescribe aspirin 75-162 mg daily for secondary prevention in all patients with established ASCVD unless contraindicated. 1